32 results on '"Asmita Mishra"'
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2. Outpatient Treatment with Anti-Sars-Cov-2 Monoclonal Antibodies and Remdesivir for COVID19 Infections Demonstrates Encouraging Outcomes in Hematopoietic Stem Cell Transplant Recipients: A Single-Center Experience
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Filip Ionescu, Eloho Ajayi, Aamia Leach, Melissa Alsina, Nelli Bejanyan, Omar Castaneda-Puglianini, Hany Elmariah, Ciara L. Freeman, Doris K. Hansen, Michael D. Jain, Farhad Khimani, Aleksandr Lazaryan, Hien D. Liu, Frederick L. Locke, Bryan McIver, Asmita Mishra, Michael Nieder, Jose Ochoa, Lia Perez, Joseph Pidala, Aliyah Baluch, Olga Klinkova, Rod Quilitz, Taiga Nishihori, and Rawan Faramand more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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3. Phase 1/1b Safety Study of Prgn-3006 Ultracar-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes
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David A. Sallman, Hany Elmariah, Kendra Sweet, Asmita Mishra, Cheryl A Cox, Marion Chakaith, Roshanak Semnani, Sheeba Shehzad, Asha Anderson, Helen Sabzevari, Amy Lankford, Onyee Chan, Luis SanchezMolina, Chen Wang, Eric Padron, Andrew Kuykendall, Rami S. Komrokji, Jeffrey E. Lancet, Marco L. Davila, and Nelli Bejanyan more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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4. Sarcopenia Prevalence and Influence on the Development of Toxicity and Length of Stay in Patients with Relapsed and Refractory Myeloma Treated with Commercial Anti-BCMA CART Cells
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Nathan Parker, Karnav Modi, Ricardo Villanueva, Lawrence Skelson, Ashley Scotto, Margaret Booth-Jones, Gabriel De Avila, Michael D. Jain, Asmita Mishra, Rawan Faramand, Othman Salim Akhtar, Jason Brayer, Omar Castaneda-Puglianini, Ariel F. Grajales-Cruz, Rachid C. Baz, Brandon J. Blue, Kenneth H. Shain, Melissa Alsina, Hien D. Liu, Taiga Nishihori, Frederick L. Locke, Doris K. Hansen, and Ciara L. Freeman more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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5. Phase I Trial of CD8-Depleted Human Leukocyte Antigen (HLA) Mismatched Unrelated Donor Lymphocyte Infusion (DLI) to Achieve Remissions in Myelodysplastic Syndrome (MDS) and Secondary Acute Myeloid Leukemia (sAML)
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Hany Elmariah, Jongphil Kim, Kayla M. Reid, Christopher Cubitt, Andrew Kuykendall, Jeffrey E. Lancet, Rami S. Komrokji, David A. Sallman, Onyee Chan, Kendra Sweet, Albert J Ribickas, Rawan Faramand, Asmita Mishra, Farhad Khimani, Lia Perez, Debra Kessler, Stephanie Dormesy, Joseph Pidala, Claudio Anasetti, Ephraim J. Fuchs, Michael D. Jain, Frederick L. Locke, Marco L. Davila, Nelli Bejanyan, and Amy E. DeZern more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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6. Impact of Obesity and Weight-Based Chemotherapy Dosing Adjustments on Outcomes of Allogeneic Hematopoietic Cell Transplant Outcomes for Acute Myeloid Leukemia
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Omar Albanyan, Syeda Mahrukh Hussnain Naqvi, Qianxing Mo, Athena Belfon, Eric Gaskill, Taiga Nishihori, Rawan Faramand, Aleksandr Lazaryan, Doris K. Hansen, Farhad Khimani, Asmita Mishra, Michael Nieder, Lia Perez, Hien D. Liu, Joseph Pidala, Claudio Anasetti, Frederick L. Locke, Nelli Bejanyan, and Hany Elmariah more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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7. Post-Allogeneic Stem Cell Transplant Outcomes in Patients Treated with Hypomethylating Agent Plus Venetoclax Compared to CPX-351
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Akriti G Jain, Somedeb Ball, Luis E.E. Aguirre, Andrew Kuykendall, Onyee Chan, Rami S. Komrokji, Eric Padron, David A. Sallman, Jeffrey E. Lancet, Asmita Mishra, and Kendra Sweet
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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8. Sirolimus Results in Similar Outcomes to Tacrolimus for Gvhd Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide
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Hany Elmariah, Salman Otoukesh, Ambuj Kumar, Haris Ali, Shukaib Arslan, Amrita Desai, Amanda Blackmon, Hoda Pourhassan, Taiga Nishihori, Rawan Faramand, Asmita Mishra, Farhad Khimani, Hugo F Fernandez, Aleksandr Lazaryan, Michael Nieder, Lia Perez, Hien D. Liu, Ryotaro Nakamura, Joseph Pidala, Guido Marcucci, Stephen J Forman, Claudio Anasetti, Frederick L. Locke, Nelli Bejanyan, and Monzr M. Al Malki more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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9. Phase II Trial of Eprenetapopt (APR-246) in Combination with Azacitidine (AZA) As Maintenance Therapy for TP53 Mutated AML or MDS Following Allogeneic Stem Cell Transplantation (SCT)
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Asmita Mishra, H. Joachim Deeg, Mahasweta Gooptu, Roni Tamari, Amy E. DeZern, Eyal C. Attar, Phillip Gallacher, Yi-Bin Chen, Anders Wennborg, Hugo F. Fernandez, Michael Byrne, and Denice Hickman
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Azacitidine ,Cell Biology ,Hematology ,Biochemistry ,Transplantation ,Maintenance therapy ,Internal medicine ,medicine ,Stem cell ,business ,medicine.drug - Abstract
Background Mutations in the tumor suppressor gene TP53 are found in up to 20% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Allogeneic hematopoietic SCT remains the only potentially curative therapy however outcomes remain poor, with a 1-year relapse-free survival (RFS) of ~30% and median overall survival (OS) of ~8 months. Prior data on post-SCT maintenance therapies, including AZA, have failed to demonstrate improved post-SCT outcomes. Eprenetapopt, a small molecule p53 stabilizer, targets cellular redox balance resulting in tumor cell apoptosis and ferroptosis as well as immune modulation of the tumor microenvironment. Pre-clinical data demonstrates synergistic myeloid cell cytotoxicity in vitro and in vivo AML burden reduction when eprenetapopt is combined with AZA. Additionally, the known tolerability of this combination in AML/MDS patients makes it an attractive maintenance strategy. Methods This is a multi-center, open label, Phase II clinical trial to assess the safety and efficacy of eprenetapopt in combination with AZA as maintenance therapy after SCT for patients with TP53 mutant AML and MDS. Patients with MDS and AML with a known TP53 mutation were prescreened prior to SCT and protocol eligibility was confirmed post-SCT. Treatment consisted of up to 12 cycles of eprenetapopt 3.7 g/day Days 1-4 with AZA 36 mg/m 2/day IV/SC on Days 1-5 every 28 days. The primary objectives of this study are to assess RFS and the safety and tolerability of the combination. Additional endpoints include OS, time to progression (TTP), non-relapse mortality (NRM) and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). Results The study enrolled a total of 33 patients (19 MDS, 14 AML) for active therapy. Demographics across all patients included median age 65 years (range: 40-74), 64% males, and Karnofsky performance status of ≥ 80 in 79%. The majority (76%) received a reduced intensity conditioning regimen. At initial diagnosis, 97% (32) had TP53 mutations, 9% (3) had >1 TP53 mutation, 82% (27) had complex cytogenetics (>=3), 45% (15) had chromosome (chr) 17, 76% (25) had chr 5, and 45% (15) had chr 7 abnormalities. Among 25 patients with available molecular data from a pre-SCT sample, 22 (88%) patients had a residual detectable TP53 gene mutation, 8 (36%) had > 1 TP53 mutation, and 9 (36%) patients had non-TP53 gene mutations: ASXL1 (2 ), JAK2 (4), DNMT3A (3), IDH2 (2), IDH1 (2), NRAS (1) and SF3B1 (1). As of the data cutoff date of 22 June 2021, patients completed a median of 7 cycles (1,12) of study treatment with 6 patients (18.2%) remaining on study treatment. The primary reasons for study treatment discontinuation among 27 patients, were completion of 12 cycles of treatment (9) and disease relapse (9). With median duration of RFS follow up of 413 days the median RFS was 368 days [95% CI (233-not evaluable)] and the 1-year RFS was 58%. With median duration of OS follow up of 429 days the median OS was 586 days [95% CI (369-not evaluable)] and 1-year OS 79%. All-grade treatment emergent adverse events (TEAEs) occurring in ≥20% of patients included nausea (61%), platelet count decreased (49%), vomiting (46%), anemia, dizziness, and white blood cell count decreased (39% each), fatigue (36%), diarrhea and tremor (33% each), cough, neutrophil count decreased, pruritus, and pyrexia (24% each), abdominal pain, constipation, decreased appetite, headache and hypocalcemia (21% each). Grade ≥3 TEAEs in ≥10% of patients were platelet count decreased (36%), white blood cell count decreased (33%), anemia (27%), neutrophil count decreased (24%), thrombocytopenia and hypertension (12% each). SAEs in ≥2 patients were pyrexia (12%), febrile neutropenia and dyspnea (6% each). Two patients (6%) experienced TEAEs leading to discontinuation of study treatment. Acute and chronic GVHD events of any grade were reported in 12% and 30% of patients, respectively. Conclusions Post-SCT maintenance therapy with eprenetapopt in combination with AZA was safe and tolerable with favorable results in patients with TP53 mutant MDS and AML, with 9 patients completing 12 cycles of therapy at the data cutoff date and the majority of reported TEAEs comprising known complications of high-risk MDS and AML patients in the post-SCT period. In addition, the observed RFS and OS data are highly encouraging compared to the historical outcomes for this high-risk group of patients with unmet medical need. Disclosures Mishra: Novartis: Research Funding. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrne: Karyopharm: Research Funding. Chen: Gamida: Consultancy; Incyte: Consultancy. Gallacher: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wennborg: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kaylor Hickman: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Attar: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fernandez: Incyte: Honoraria. OffLabel Disclosure: The presentations includes the use of experimental agent eprenetapopt (APR-246) and the agent azacitidine in the post-transplant maintenance setting. more...
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- 2021
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10. Phase 1/1b Safety Study of Prgn-3006 Ultracar-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes
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David A. Sallman, Hany Elmariah, Kendra Sweet, Chetasi Talati, Asmita Mishra, Cheryl A Cox, Roshanak Semnani, Rutul R Shah, Helen Sabzevari, Marion Chakiath, Justin Uthuppan, Amy Lankford, Chen Wang, Eric Padron, Andrew T. Kuykendall, Rami S. Komrokji, Jeffrey E. Lancet, Marco L. Davila, and Nelli Bejanyan more...
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education ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,health care economics and organizations - Abstract
Introduction: Therapeutic options for relapsed/refractory (r/r) acute myeloid leukemia (AML) and hypomethylating agent (HMA) failure higher risk myelodysplastic syndrome (MDS) are limited with a median overall survival of < 6 months. Although chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B-cell malignancies, significant challenges exist in myeloid CAR development. PRGN-3006 UltraCAR-T are engineered using non-viral gene delivery to simultaneously express CD33 CAR, membrane bound IL-15 (mbIL15) and kill switch to be effective against AML with improved safety profile. UltraCAR-T cells are manufactured at medical center's cGMP facility using autologous T cells in < 48 hours without ex vivo expansion. Methods: A Phase 1/1b first-in-human dose escalation/dose expansion clinical trial (NCT03927261) of PRGN-3006 in adult pts with r/r AML, HMA failure higher risk MDS or chronic myelomonocytic leukemia (CMML) with ≥ 5% blasts. Pts who have relapsed post allogeneic stem cell transplant (SCT) are allowed if > 3 months out from transplant without evidence of active graft versus host disease (GvHD) and off immunosuppression for 6 weeks. Ps receive PRGN-3006 infusion without (Cohort 1) or with lymphodepletion (fludarabine 30mg/m 2 and cyclophosphamide 500mg/m 2 days -5 to -3; Cohort 2). Dose escalation of Cohorts 1 and 2 occur in parallel with initial clearance of Cohort 1 at each dose level (DL; Table 1). Results: As of July 25, 2021, data cut-off, 15 r/r AML pts have been treated in Cohort 1 (n=9) and Cohort 2 (n=6) with a median age of 60 years (33-77). Pts were heavily pre-treated with a median of 3 prior regimens (1-7), with 93% and 80% of pts being r/r to a HMA + venetoclax or intensive chemotherapy, respectively. Additionally, 40% of pts (n=6) had relapsed after SCT. 93% of pts were int/adv by ELN 2017 criteria (60% adverse). PRGN-3006 infusion at doses up to 1x10 6 cells/kg was well tolerated. There have been no deaths, DLTs, bone marrow aplasia, neurotoxicity or unexpected on-target/off-target toxicities related to PRGN-3006, and no use of the kill switch to date. One incidence of grade 2 GvHD was observed in a post-SCT patient (Cohort 2) on day 31, which resolved completely with corticosteroid therapy, and notably this patient responded to therapy. Cytokine release syndrome (CRS) occurred in 47% of pts (n=7; G1 in 5 pts) with only 1 transient grade 3 event (DL 1, Cohort 1) that resolved in < 24 hours with tocilizumab and dexamethasone. Median onset to maximum CRS was 11 days (range 4-15 days). Peak CRP and ferritin levels occurred at a median of days 8 and 9, respectively. No significant increase in plasma levels of inflammatory cytokines, including IL-6 and TNFa, was observed post treatment. The plasma levels of IL-15 did not increase with treatment confirming mbIL15 is not shed. In Cohort 1, dose escalation through DL3 has been completed. Dose-dependent expansion of PRGN-3006 was observed in all patients with mean peak copy numbers following DL1, DL2 and DL3 in peripheral blood at approximately 600, 9,700 and 28,000 copies/µg DNA, respectively, with persistence up to 7 months post-infusion in a pt with stable disease/blast reduction. No objective responses in cohort 1 have been observed to date. In Cohort 2, dose escalation through DL2 has been completed. Expansion of PRGN-3006 was higher in Cohort 2 compared to Cohort 1 with mean peak copy numbers following DL1 and DL2 in peripheral blood at approximately 11,000 and 120,000 copies/µg DNA, respectively, and persistence 3+ months post-infusion. The objective response rate (ORR) for Cohort 2 was 50% (3/6). At DL1, 1 of 3 pts obtained CRi and was bridged to SCT and remains in a measurable residual disease negative CR 6 months post-SCT. At DL2, 2 post-SCT relapse patients also obtained response: 1 CRh with complete cytogenetic remission and NGS clearance with a remission length of 2 months; and 1 PR that lasted 3 months in a patient with isolated extramedullary leukemia (Figure 1). All 3 responders remain alive at data cut-off (5-10 months). Conclusion: PRGN-3006 UltraCAR-T cells targeting CD33 have been well tolerated with low grade CRS. In the setting of mbIL15, there has been a dose-dependent robust expansion and durable persistence of PRGN-3006 with encouraging responses (50%) in patients treated following lymphodepletion. Enrollment is ongoing to DL4, and updated safety, efficacy, PK/PD and cytokine data to be presented. Figure 1 Figure 1. Disclosures Sallman: AbbVie: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magenta: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Talati: AbbVie: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Jazz: Speakers Bureau; Astellas: Speakers Bureau. Mishra: Novartis: Research Funding. Semnani: Precigen: Current Employment. Shah: Precigen: Current Employment, Current equity holder in publicly-traded company. Sabzevari: Precigen: Current Employment, Current equity holder in publicly-traded company; Compass Therapeutics: Current equity holder in publicly-traded company; Kinnate BioPharma: Membership on an entity's Board of Directors or advisory committees. Chakiath: Precigen: Current Employment. Lankford: Precigen: Current Employment, Current equity holder in publicly-traded company. Padron: Stemline: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; BMS: Research Funding; Taiho: Honoraria. Kuykendall: PharmaEssentia: Honoraria; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria. Komrokji: Geron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau. Lancet: AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Astellas: Consultancy; Agios: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy. Davila: Precigen: Research Funding. Bejanyan: Medexus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Avrobio (Spouse disclosure): Current equity holder in publicly-traded company; Magenta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen (Spouse disclosure): Consultancy, Membership on an entity's Board of Directors or advisory committees; Crispr Therapeutics (Spouse disclosure): Current equity holder in publicly-traded company; Teladoc Health (Spouse disclosure): Current equity holder in publicly-traded company; Organon (Spouse disclosure): Current equity holder in publicly-traded company; Kadmon (Spouse disclosure): Consultancy; Merck (Spouse disclosure): Current equity holder in publicly-traded company; American Well Corp (Spouse disclosure): Current equity holder in publicly-traded company; Thermo Fisher (Spouse disclosure): Current equity holder in publicly-traded company; Unitedhealth Group (Spouse disclosure): Current equity holder in publicly-traded company. more...
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- 2021
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11. Non-Relapse Mortality in TP53-Mutated MDS/AML - a Multi-Center Collaborative Study
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Michael R. Savona, Victoria Klein, Asmita Mishra, Bhavana Bhatnagar, Sanghee Hong, Dilan A Patel, Patricio Rojas, Benjamin H. Goldenson, Lohith Gowda, Roni Tamari, Salyka Sengsayadeth, Benjamin M Manning, Catherine J. Lee, Daniel Margalski, Tony Kurian, Raksha Madhavan, Andrew Kent, Kseniya Petrova-Drus, Haitham Abdelhakim, Dianna S. Howard, Saar Gill, Nicholas Tschernia, Leland Metheny, Betty K. Hamilton, Aaron C Logan, Ajoy Dias, Nathalie Byrne, Aaron M. Goodman, William A. Wood, Antonio M. Jimenez, Michael Byrne, Jonathan A. Gutman, Heidi Chen, and Muhammad Husnain more...
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,Medicine ,Nonrelapse mortality ,Center (algebra and category theory) ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background: Patients with TP53 MUT MDS/AML experience poor clinical outcomes with high rates of disease recurrence and short overall survival (OS). Characterization of these individuals' post-HCT mortality is uniquely challenging due to competing risks from disease relapse and treatment toxicity. Transplant registries contain high-level outcomes data, however, there is a lack of detailed data in molecularly defined subsets of diease. This analysis was undertaken to bridge this gap. Methods: Allogeneic HCT recipients between 1/2014 and 12/2018 were retrospectively studied. Key inclusion criteria were TP53 MUT by NGS or deletion of chromosome 17/17p by FISH/cytogenetics. The primary outcome of non-relapse mortality (NRM) was defined as death from any cause other than disease with relapse as competing risk. Secondary outcomes for this analysis were OS, cumulative incidence of relapse (CIR), and relapse free survival (RFS). Relapse was defined as relapse/progression with NRM as competing risk. Results: 384 TP53 MUT MDS/AML patients were analyzed. 55% of patients were transplanted for AML, 41% received myeloablative conditioning (MAC), 39% had secondary MDS/AML, and 26% received prior chemo and/or radiation therapy (XRT). Median time from HCT to last follow-up was 321 days (range 8-2,385 days). Mutational data was available in 264 patients and cytogenetic data was available in 368 patients; 78% of patients had a complex karyotype (CK), 82% had TP53 missense mutations, and 74% had bi-allelic targeting of the TP53 gene. The incidence of all-grade acute and chronic GVHD (cGVHD) was 52% and 31%, respectively. One and 2 year OS was 48.5% and 30.9%, respectively. Estimated CIR at 1 and 2 years was 49% and 54.9%, respectively. The 1 year NRM was 13.7% and 2 year NRM was 18.1%. In multivariate analysis (MVA), there was no association between NRM and the clinical, molecular, or genetic features of TP53 MUT MDS/AML. HCT diagnosis of MDS (HR: 0.67, 95% CI: 0.46-0.97, p: 0.036), mono-allelic TP53 MUT (HR: 0.6, 95% CI: 0.39-0.94, p: 0.023), achievement of full donor PB chimerism (HR: 0.33, 95% CI: 0.14-0.85, p: 0.022), BM chimerism (HR: 0.33, 95% CI: 0.18-0.60, p: 0.003), and cGVHD (HR: 0.35, 95% CI: 0.23-0.51, p: In subgroup analysis, history of chemo and/or XRT increased NRM in AML (HR: 4.24, 95% CI: 1.35-13.39, p: 0.014). Pre-HCT TP53 MUT persistence by NGS (HR: 3.59, 95% CI: 1.43-9, p: 0.007) predicted for post-HCT relapse whereas pre-HCT CR (HR: 2.93, 95% CI: 1.54-5.59, p: 0.001) and full donor BM chimerism (HR: 0.14, 95% CI: 0.05-0.38, p: No significant NRM associations were identified in MDS. CK (HR: 5.04, 95% CI: 1.95-13.01, p: Conclusions: From this large multi-institutional cohort of TP53 MUT myeloid neoplasms, we report a low NRM rate, likely due to high rates of post-HCT relapse/progression. These data demonstrate associations between bi-allelic TP53m/CK and post-HCT outcomes. Our work highlights the importance donor chimerism after HCT and provides new understanding of the importance of chronic GVHD in TP53 MUT MDS/AML. Figure 1 Figure 1. Disclosures Byrne: Karyopharm: Research Funding. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding. Lee: CareDx: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Fresensius Kabi: Consultancy; Jazz,: Consultancy; Incyte: Research Funding. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Jimenez: Takeda: Research Funding; AbbVie: Research Funding. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Bhatnagar: Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Kite: Honoraria; Karyopharm: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Mishra: Novartis: Research Funding. Savona: BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. more...
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- 2021
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12. Biological and Clinical Impact of JAK2/mTOR Blockade in Gvhd Prevention: Preclinical and Phase I Trial Results
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Joseph Pidala, Rawan Faramand, Kelly Walton, Nicholas J. Lawrence, Jongphil Kim, Nelli Bejanyan, Brian C. Betts, Hany Elmariah, Marco L. Davila, Harshani R. Lawrence, Lia Perez, Michael Nieder, Claudio Anasetti, Said M. Sebti, Asmita Mishra, Farhad Khimani, and Taiga Nishihori more...
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business.industry ,T cell ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,medicine.disease ,Biochemistry ,Tacrolimus ,Blockade ,Transplant rejection ,Transplantation ,Pacritinib ,medicine.anatomical_structure ,Sirolimus ,medicine ,business ,CD8 ,medicine.drug - Abstract
Background: Distinct from broadly acting graft-versus-host disease (GVHD) prophylaxis, JAK2 inhibition suppresses alloreactive T cells, while sparing regulatory T cells (Tregs) and graft-versus-leukemia (GVL). Early IL-6 activity via JAK2 and phosphorylated STAT3 in CD4+ T cells is associated with acute GVHD onset. In mice, we show combined JAK2/mTOR blockade synergistically prevents xenogeneic GVHD. In this first-in-human phase I/II GVHD prevention trial we combine pacritinib, a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL-6 activity. With phase I complete, we demonstrate that dual JAK2/mTOR inhibition is safe, suppresses pathogenic Th1 and Th17 cells, spares Tregs and key GVL effector cells, and exhibits preliminary activity in preventing GVHD. The primary aim of phase I was to identify the lowest biologically active dose of pacritinib (defined as < 35% of CD4+ pSTAT3+ T cells at day +21) that is safe when combined with sirolimus-based immune suppression. The preliminary activity of JAK2/mTOR inhibition in GVHD prevention was also investigated. Materials and Methods: This single-arm phase I/II trial (NCT02891603) tested the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation (alloHCT). A 3+3 dose escalation design was followed, including dose level 1 (PAC 100mg daily), level 2 (PAC 100mg twice daily), and level 3 (PAC 200mg twice daily). Clinical safety, pharmacodynamic assessments, and pharmacokinetic (PK) studies were followed during the study. Acute GVHD was scored through day +100. Patient characteristics are described in Table 1 (n=12). Allowed donor types were HLA-A, -B, -C, and -DRB1 matched-related or unrelated donors. Adequate vital organ function and Karnofsky performance status (KPS ≥ 80%) were required. Results: Dose level 2, PAC 100mg twice a day, was the lowest biologically active and safe dose, and thus the recommended phase II dose. Blood samples acquired at day +21 showed that PAC 100mg twice a day reduced the mean frequency and geometric MFI of CD4+ pSTAT3+ T cells (Figure 1A, B). Consistent with suppressed pSTAT3, PAC 100mg twice a day decreased pathogenic Th1 and Th17 cells (Figure 1C, D). pSTAT5 is critical for Tregs and effectors of GVL. PAC 100mg twice a day favored STAT5 phosphorylation in CD4+ T cells, preserved Tregs and increased the ratio of Tregs to pathogenic T helper cells, and supported CD3+ T cell and NK cell effectors (Figure 1E-J). Patients treated on dose level 2 of PAC exhibited a robust increase in Th2 cells at day +21 (29.5% v 4.87% level 1 or 4.5% baseline, P To test the efficacy of dual JAK2/mTOR inhibition in vivo, NSG mice were transplanted with human peripheral blood mononuclear cells (PBMCs) and treated with either vehicle, PAC, STAT3 inhibitor S3I-201, SIR, PAC/SIR, or S3I/SIR. The combination of JAK2 or downstream STAT3 inhibition plus SIR significantly reduced xenogeneic GVHD in mice (Figure 1M) and maintained donor anti-tumor activity by CD8+ T cells (data not shown). Further, dual JAK2 or STAT3 inhibition with mTOR blockade significantly increased the induction of Tregs in mice transplanted with Treg-depleted human PBMCs (62.3% PAC/SIR or 74% S3I/SIR v 29.9-38% with vehicle or inhibitors alone, P Conclusions: We demonstrate that PAC/SIR/TAC (RP2D: PAC 100mg twice a day) is safe and effectively reduces IL-6 signal transduction, pathogenic Th1 and Th17 cells, and preserves Tregs and effectors necessary for GVL and antiviral immunity. Preliminarily, adding pacritinib limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial. Disclosures Pidala: Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Lawrence:Patent Pending: Patents & Royalties: Dr. Lawrence has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Lawrence:Patent Pending: Patents & Royalties: Dr. Lawrence has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Sebti:Patent Pending: Patents & Royalties: Dr. Sebti has a patent WO2014070859A1: Stat3 dimerization inhibitors. . Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. OffLabel Disclosure: Pacritinib and its use in GVHD prevention as part of a phase I trial more...
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13. Comparison of Outcomes of Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Older Versus Younger Patients
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Joseph Pidala, Asmita Mishra, Hien D. Liu, Nelli Bejanyan, Rawan Faramand, Farhad Khimani, Taiga Nishihori, Michael Nieder, Claudio Anasetti, Giacomo Adoncecchi, Ambuj Kumar, Lia Perez, and Hany Elmariah more...
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medicine.medical_specialty ,Neutrophil Engraftment ,Multivariate analysis ,Cyclophosphamide ,Platelet Engraftment ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Internal medicine ,Cohort ,Medicine ,Cumulative incidence ,Progression-free survival ,business ,Survival analysis ,medicine.drug - Abstract
Introduction: Previous studies have demonstrated that allogeneic haploidentical (haplo) peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) yields improved progression free survival (PFS) when compared to haplo bone marrow transplant (BMT) with PTCy, attributable to lower relapse without an increase in non-relapse mortality (NRM) (Bashey, et al. JCO. 2017). However, haplo PBSCT results in higher rates of graft-versus-host disease (GVHD) which may negate these benefits in older patients who are more susceptible to transplant related toxicity. Thus, evaluation of the outcomes of haplo PBSCT with PTCy in older patients is warranted. Methods: We retrospectively evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic T-cell replete PBSCT from a haplo donor followed by PTCy-based GVHD prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Myeloablative (n=70, 58%) and reduced intensity (n=51, 42%) conditioning regimens were included. Transplant related outcomes were compared between two age groups: 60 years (n=55). Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan-Meier curves and cumulative incidence function curves were also plotted. Results: The median age at the time of transplant was 42 years (range: 20-59) for the younger group and 66 years (range: 61-75) for the older group. The median follow-up was 17 months (range: 2-53) for the entire cohort. Younger patients were more likely to receive myeloablative conditioning (83% versus 27%, p Neutrophil engraftment (>500/uL) by day 30 did not differ significantly between the younger and older group (98% versus 93%, p=0.26). However, the median time to neutrophil engraftment was faster in the younger group versus the older group (16 versus 21 days, p20,000/uL) by day 90 was achieved in 92% in the younger group versus 76% in the older group (p=0.03). The time to platelet engraftment was faster in the younger group: 28 days versus 36 days (p=0.006). At day 100, the cumulative incidence (CuI) of grade II-IV acute GVHD in younger patients was 42% (95% CI 29-61%) and for older patients was 35% (95% CI 22-55%, p=0.82). The CuI for grade III-IV acute GVHD for the younger and the older groups were 8% (95% CI 4-25%) and 15% (95% CI 7-38%, p=0.23), respectively. At 2 years, the CuI of chronic GVHD was 67% (95% CI 55-82%) for younger patients versus 56% (95% CI 38-82%) for older patients (p=0.20). NRM for the younger group and the older group, respectively, was 6% (95% CI 2-16%) versus 19% (95% CI 11-34%) at 100 days and 14% (95% CI 6-30%) versus 22% (95% CI 13-37%) at 2 years (p=0.17). The CuI of relapse at 2 years was not significantly different between the two age groups, with the younger recipients having a CuI of 42% (95% CI 20-60%) and the older group 31% (95% CI 17-56%, p=0.70). The 2-year DFS was similar between the younger and older group, respectively: 51% (95% CI 36-66%) and 53% (95% CI 37-70%, p=0.72). Similarly 2-year overall survival (OS) for the younger group was 59% (95% CI 44-74%), while the older group was 66% (95% CI 52-80%, p=0.92). In multivariate analysis, NRM was superior in the younger group (HR=0.31, 95% 0.12-0.82, p=0.02). Otherwise, age was not associated with engraftment, risk of acute or chronic GVHD, relapse, DFS, or OS. Conclusion: Our results demonstrate that outcomes following allogeneic haplo PBSCT with PTCy in patients >60 years approximate outcomes in patients Disclosures Khimani: Bristol Myers Squibb-Moffitt-Alliance: Research Funding. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution. Pidala:Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. more...
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- 2020
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14. Impact of TP53 gene Mutation Clearance and Conditioning Intensity on Outcome in MDS or AML Patients Prior to Allogeneic Stem Cell Transplantation
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Hany Elmariah, David A. Sallman, Anthony M. Hunter, Rami S. Komrokji, Alan F. List, Onyee Chan, Eric Padron, Andrew T. Kuykendall, Nelli Bejanyan, Chetasi Talati, Jeffrey E. Lancet, Mohammad Hussaini, Kendra Sweet, Asmita Mishra, Hannah Asghari, and Jinming Song more...
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Oncology ,medicine.medical_specialty ,Mutation ,business.industry ,Immunology ,Complete remission ,Cell Biology ,Hematology ,medicine.disease_cause ,Biochemistry ,Intensity (physics) ,Log-rank test ,Transplantation ,Internal medicine ,Medicine ,Stem cell ,business ,TP53 Gene Mutation ,Clearance - Abstract
Background: Tumor protein 53 (TP53), located on the short arm of chromosome 17, is an important tumor suppressor gene responsible for critical regulatory functions. There is existing controversy regarding the role of allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a TP53 mutation. While most studies report increased relapse and poor survival after allo-SCT with TP53 mutated AML or MDS, (Bajar et al., JCO 2014; Lindsley et al., 2017) others found no influence of TP53 mutation on allo-SCT outcomes (Aldoss et al., 2017). Notably, previous studies have predominantly evaluated the prognostic impact of TP53 mutation at the time of diagnosis and not serially in response to treatment. In this study, we aim to clarify the prognostic impact of TP53 mutation clearance prior to allo-SCT in patients with TP53 mutated AML or MDS. Methods: Data was obtained and analyzed on MDS or AML patients who received allo-SCT at the Moffitt Cancer Center (2013-2018) and had presence of TP53 at least once after diagnosis and prior to allo-SCT. TP53 clearance was defined by last next-generation sequencing (NGS) test prior to allo-SCT demonstrating no TP53 mutation with a variant allele frequency (VAF) greater than 5%. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis with log-rank test was used to estimate relapse free survival (RFS) and median overall survival (OS) from the time of allo-SCT. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were performed as defined by the Fine and Gray model. Results: We identified 47 patients (29 males/18 females) with TP53 mutation prior to allo-SCT with primary diagnosis of AML (55.3%) or MDS (44.7%) (Table 1). The median follow-up was 25.4 months with 2-year OS of 32.8% for the entire cohort. The median age at diagnosis was similar between TP53-cleared and TP53-persistent groups with 68% of the patients >= 60 years at the time of allo-SCT. Only 26% (n=12) had clearance of their TP53 mutation prior to allo-SCT. The majority of the patients had complex cytogenetics at diagnosis (85%) with deletion 5q being the most common coexisting aberration (75% in TP53-cleared and 68.6% in TP53-persistent, p=NS). Patients with TP53 clearance received hypomethylating agent (HMA) as frontline treatment more frequently compared to those with persistent TP53 (66.7% vs. 45.7%, p=NS). They also had fewer lines of therapy (83.3% with 1 line vs. 62.9%, p=NS), and a higher rate of complete response prior to allo-SCT (83.3% vs. 57.1%, p=NS). Amongst patients receiving HMA as frontline therapy (n=24), we observed significantly better survival in TP53-cleared patients compared to those with persisted TP53 (median OS of 21.73 months vs. 6.44 months, p=0.042) (Figure 1). Myeloablative conditioning (MAC) regimen was used in 33.3% of TP53-cleared in comparison to 42.9% in TP53-persistent cohort (p=NS). Median OS was 21.7 months for patients with clearance of TP53 vs. 8.1 months for those with persistent TP53 at allo-SCT; although it did not meet statistical significance (p=0.106). MAC compared to reduced intensity conditioning (RIC) regimen resulted in significantly worse RFS (HR 2.06, 95% CI 1.04-4.12, p=0.040) and OS (HR 2.70, 95% CI 1.30-5.60, p=0.008). Conditioning intensity was the only factor that significantly influenced RFS and OS outcomes (Table 2). When repeating these analyses separately on the TP53-cleared and TP53-persistent groups, only the latter remained significant for conditioning (MAC, univariate OS: HR 2.6, 95% CI 1.14-5.92, p=0.023). Conclusions: TP53 clearance at the time of allo-SCT is predictive of better outcomes in patients who had frontline HMA therapy. For patients with persistent TP53 at the time of allo-SCT, those received MAC experienced worse outcomes compared to RIC in this cohort. The OS at 2-year for TP53-persistent patients is over 30% suggesting even these patients can potentially benefit from transplantation. Disclosures Talati: Celgene: Honoraria; Agios: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Bejanyan:Kiadis Pharma: Other: advisory board. Kuykendall:Celgene: Honoraria; Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria. Padron:Incyte: Research Funding. Komrokji:Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; celgene: Consultancy; DSI: Consultancy; pfizer: Consultancy. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy. Sweet:Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Stemline: Consultancy; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. more...
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15. Outcomes Following Intolerance to Tacrolimus/Sirolimus for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant
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Michelle R. Kidd, Farhad Khimani, Taiga Nishihori, Nelli Bejanyan, Ambuj Kumar, Ankita Tandon, Shu Cao, Sayeef Mirza, Dakota Jenneman, Asmita Mishra, Michael Nieder, Joseph Pidala, Hien D. Liu, Lia Perez, and Hany Elmariah more...
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medicine.medical_specialty ,Thrombotic microangiopathy ,business.industry ,Immunology ,Acute kidney injury ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Tacrolimus ,Discontinuation ,Regimen ,Graft-versus-host disease ,Sirolimus ,Internal medicine ,medicine ,Liver function ,business ,medicine.drug - Abstract
INTRODUCTION: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplant (HCT) resulting in significant morbidity and mortality. The combination of tacrolimus and sirolimus (TAC/SIR) has emerged as a GVHD prophylaxis platform preferred by many institutions given its association with rapid engraftment and acceptable transplant-related toxicity. However, overlapping toxicities between the two drugs can lead to intolerance and premature discontinuation in some patients. There is limited literature describing outcomes and subsequent management of such patients. The goal of this study is to investigate the clinical outcomes of patients becoming intolerant to the combination of TAC/SIR prophylaxis. METHODS: We retrospectively evaluated consecutive adult patients (n=100) at the Moffitt Cancer Center who received allogeneic HCT with TAC/SIR for GVHD prophylaxis in 2018. TAC/SIR intolerance was defined as discontinuation due to the toxicity of either TAC or SIR before post-transplant day 100. Survival analyses were estimated from the time of transplant with the Kaplan-Meier method and compared using the log-rank test. Patients intolerant of this prophylaxis regimen were compared to patients who completed >100 days of therapy, using Mann-Whitney U test for continuous variables and Pearson Chi-square tests for categorical variables. All statistical analyses were performed using SPSS v25 and NCSS v11. RESULTS: Demographics and clinical characteristics of all patients are summarized in Table 1A. TAC/SIR intolerance occurred in 25% (24 discontinued TAC, 1 discontinued SIR) of patients at a median duration of therapy of 19 days (range 4-92). The most common TAC/SIR toxicity (Table 1B) was acute kidney injury (AKI, n=11, 44%), followed by thrombotic microangiopathy (TMA, n=3, 12%). Baseline metabolic and clinical variables including creatinine, liver function, and conditioning intensity were not predictive of TAC-SIR intolerance. At a median follow-up of 10 months, the median overall survival (OS) for patients intolerant of TAC/SIR was 10 months versus was not reached for the patients without intolerance (HR 5.42; 95% CI 1.71-17.14; p CONCLUSIONS: Outcomes for patients completing over 100 days of TAC/SIR for GVHD prophylaxis following allogeneic HCT are favorable. However, early intolerance of TAC/SIR GVHD prophylaxis occurred in 25% of allogeneic HCT in 2018 alone and predicted a poor prognosis with increased NRM and overall mortality, largely from drug-related toxicities. Notably, premature discontinuation of TAC/SIR did not contribute to higher subsequent risks of GVHD. Strategies to mitigate the risks of TAC/SIR toxicity are warranted. Future studies are also needed to identify the optimal GVHD prophylactic regimen for patients after TAC/SIR intolerance. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board. more...
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16. Clearance of Somatic Gene Mutations in Patients with Acute Myeloid Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) Predicts Outcome
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Eric Padron, Joseph Pidala, Jinming Song, Mohammad Hussaini, Hannah Asghari, Lia Perez, Alan F. List, Michael Nieder, Junmin Zhou, Jeffrey E. Lancet, Nelli Bejanyan, Rami S. Komrokji, Asmita Mishra, Hany Elmariah, Kendra Sweet, Chetasi Talati, Andrew T. Kuykendall, Onyee Chan, David A. Sallman, Jongphil Kim, Farhad Khimani, and Taiga Nishihori more...
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Univariate analysis ,Mutation ,business.industry ,Somatic cell ,medicine.medical_treatment ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Gene mutation ,medicine.disease_cause ,Biochemistry ,Transplantation ,hemic and lymphatic diseases ,Cancer research ,Medicine ,business ,Complement membrane attack complex - Abstract
Background: In recent years, genomic studies have uncovered a number of driver gene mutations in acute myeloid leukemia (AML). There is great interest in leveraging residual disease detection methods including next-generation sequencing (NGS) to predict outcomes, especially in the setting of allogeneic hematopoietic cell transplantation (HCT). One study showed measurable minimal residual disease (MRD) at the time of HCT increases the risk of relapse in patients who received a reduced-intensity conditioning (RIC) regimen (Hourigan et al. 2019). In this study, we evaluate the prognostic impact of somatic mutation clearance using NGS prior to HCT in patients with AML. Methods: We identified a total of 139 patients with AML who underwent HCT at the Moffitt Cancer Center (2013-2018). Using European LeukemiaNet (ELN) criteria, patients were included if at the time of HCT they were adverse risk in complete remission (CR)1, intermediate risk in CR1, favorable risk in CR1 if indication for transplant present, or favorable risk in CR2 with at least one time point when NGS was performed before and after HCT. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Molecular testing via NGS included 54-gene TruSight Myeloid panel tested on Illumina sequencers with a lower limit of detection of 5%. Positive persistent detectable disease (PDD) was defined as presence of detectable mutations on NGS at HCT. Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis was used to estimate overall survival (OS) and relapse free survival (RFS) from the time of diagnosis. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated by the Fine and Gray model. Results: Of the 139 patients (74 males/65 females), 59% were PDD positive at HCT and 41% PDD negative at HCT. Median age at HCT was 59 years. More patients were in ELN-defined adverse risk (46.8%) in comparison to intermediate risk (35.3%) or favorable risk (18%). In both cohorts, majority of the patients had 1 line of therapy prior to HCT. Overall, 57.6% of patients received myeloablative conditioning regimen (MAC) with the remaining receiving RIC. More patients received MAC in both PDD positive at HCT and PPD negative at HCT groups (Table 1). There were 35 patients (25.2%) who relapsed after HCT, and 17 had NGS available at diagnosis, at the time of HCT, and at relapse. The mutation frequencies and changes over time are shown in Figure 1. Univariate analysis showed inferior OS in patients who are PDD positive at HCT compared to PDD negative at HCT (HR 1.98, 95% CI 1.06-3.72, p=0.032). After adjusting for ELN risk and PDD status, the patients who received more than 1 line of therapy prior to HCT had significantly worse OS (p=0.005). Patients with negative PDD at HCT had a significantly better OS at 2-year compared to PDD positive at HCT patients, 78.7% vs. 62.4% (p=0.029) with a median follow up of 29.9 months (Figure 2A). The RFS at 2-year were 72.6% for PDD negative at HCT patients and 51.8% for PDD positive at HCT patients (p=0.090). There was no difference in NRM or CIR between these two groups (p=0.605 and p=0.136, respectively). Further subgroup analysis did not find a significant difference between PDD status and different types of conditioning regimen (Figure 2B). Conclusions: In this study, we report that clearance of somatic gene mutations in AML patients prior to HCT confers better outcomes compared to those with measurable PDD at HCT. There is a survival advantage in patients who received fewer lines of treatment prior to HCT. Larger cohort and greater depth of NGS coverage is needed to better clarify the impact of conditioning regimen in this population. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. Bejanyan:Kiadis Pharma: Other: advisory board. Komrokji:JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Kuykendall:Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Abbvie: Honoraria; Celgene: Honoraria. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Pfizer: Consultancy; Incyte: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Jazz: Speakers Bureau. more...
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17. CD34+ Cell Dose Influences Survival after Allogeneic Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide
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Joseph Pidala, Farhad Khimani, Taiga Nishihori, Jongphil Kim, Hany Elmariah, Michael Nieder, Lia Perez, Nelli Bejanyan, Hien D. Liu, Syeda Mahrukh Hussnain Naqvi, and Asmita Mishra
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Oncology ,medicine.medical_specialty ,Cyclophosphamide ,Surrogate endpoint ,business.industry ,Post transplant cyclophosphamide ,Cd34 cells ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Graft-versus-host disease ,Internal medicine ,Peripheral Blood Stem Cell Transplantation ,medicine ,Platelet ,business ,medicine.drug - Abstract
Introduction: Higher infused total nucleated cell dose (TNC) in allogeneic bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy) resulted in improved overall survival (OS) in a recent report (McCurdy, et al. BBMT. 2018). As many centers prefer peripheral blood stem cell grafts (PBSCT) with PTCy, the optimal cell dose with this platform requires elucidation. Methods: We retrospectively evaluated 144 consecutive adult patients with hematologic malignancies treated at the Moffitt Cancer Center between 2012-2018 with allogeneic T-cell replete PBSCT followed by PTCy-based graft-versus-host disease (GVHD) prophylaxis. Data were extracted from the Moffitt BMT Research & Analysis Information Network (BRAIN) database. Both myeloablative (n=87) and reduced intensity (n=57) conditioning regimens were included. For analyses, CD34+ cell dose was stratified into low (10x106/kg). TNC was stratified as higher or lower than the median. CD3+ T cell dose was evaluated as a continuous, linear variable. Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan Meier curves and cumulative incidence function curves were also plotted. RESULTS: The median follow-up for the entire cohort was 24 months. The median age at PBSCT was 58 (range: 21-76) years. Donors were haploidentical (n=72, 50%), matched unrelated (n=39, 27%), matched related (n=18, 13%), and mismatched unrelated (n=15, 10%). Median CD34+ cell dose was 8.12 x 106/kg (range: 2.27 - 22.4 x 106/kg). Stratified CD34+ dose was low for 16 patients (11.1%), intermediate for 93 patients (64.6%), and high for 35 patients (24.3%). Median CD3+ dose was 2.89 x 108 (range: 2.33 x 105 - 6.54 x 108/kg). Median TNC was 9.66 x 108/kg (range: 3.82 x 108 - 1.04 x 109/kg). Overall, successful neutrophil engraftment by day 30 was achieved in 94% (95% CI 91-98%) and platelet engraftment (>20,000/mL) by day 100 in 87% (95% CI 81-93%) of all patients. The likelihood of neutrophil recovery was similar in the high and low CD34+ cell groups, while it was higher for the intermediate CD34+ cell group (HR=1.52, 95% CI 1.0-2.2; p=0.03). Platelet recovery was similar in the intermediate and high CD34+ cell groups, but significantly lower in low CD34+ cell group (HR=0.38, 95% CI 0.2-0.8; p=0.01). CuI of grade II-IV acute GVHD at day 100 was 39% (95% CI 32-48%) and of grade III-IV acute GVHD was 10% (95% CI 6-17%). CuI of chronic GVHD at 2 years was 50% (95% CI 41-59%). The CD34+ cell dose had no significant impact on either acute or chronic GVHD. Nonrelapse mortality (NRM) at 1 year was 19% (95% CI 13-27%). By CD34+ cell dose, the rates of NRM for low, intermediate, and high dose were 46% (95% CI 25-85%), 15% (95% CI 10-25%), and 15% (95% CI 7-34%), respectively (p=0.002). Relapse rate was 30% at 2 years with no differences across dose levels. Progression free survival (PFS) probability at 2 years was 47% (95% CI 39-57%) for the entire group, 0% (95% CI 0%) for the CD34+ low group, 53% (95% CI 42-65%) for the intermediate group and 51% (95% CI 35-73%) for the high dose group (p=0.0003). Two-year OS for the entire group was 57% (95% CI 49-67%), and was inferior in the low group (0%, 95% CI 0%) with no difference between the intermediate (61%, 95% CI 50-73%) and high (67%, 95% CI 52-87%) CD34+ cell dose groups (p=0.0002). In multivariable modeling, the low CD34+ cell dose group was associated with worse NRM (HR=4.1, 95% CI 1.2-14.5, p=0.03), PFS (HR=2.9, 95% CI 1.3-6.5, p=0.01), and OS (HR=3.2, 95% CI 1.4-7.6, p=0.01) compared with the high group, while there were no differences between the high and intermediate groups. Increasing CD3+ dose was also associated with improved NRM (HR=0.8, 95% CI 0.69-0.97, p=0.02), PFS (HR=0.7, 95% CI 0.5-0.9, p=0.02), and OS (HR=0.7, 95% CI 0.5-0.9, p=0.004). TNC had no impact on survival outcomes. CONCLUSION: In patients receiving allogeneic PBSCT with PTCy, CD34+ cell doses below 5 x 106 cells/kg yielded inferior OS and PFS, attributable to higher NRM. Doses of 5-10 x 106 cells/kg and >10 x 106 cells/kg resulted in comparable outcomes. Higher CD3+ dose/kg was also associated with improved survival outcomes. Overall, this study supports targeting a CD34+ dose of >5 x 106 cells/kg for allogeneic PBSCT with PTCy. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board. more...
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- 2019
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18. Prediction of CAR T-Related Toxicities in R/R DLBCL Patients Treated with Axicabtagene Ciloleucel Using Point of Care Cytokine Measurements
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Bin Yu, Dylan Morrissey, Julio C. Chavez, Marco L. Davila, Michael D. Jain, Asmita Mishra, Jae H. Park, Hiroshi Kotani, Renier J. Brentjens, Sarah Yoo, Xuefeng Wang, Frederick L. Locke, Christina A Bachmeier, and Rawan Faramand more...
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0301 basic medicine ,medicine.medical_specialty ,Immunology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Tocilizumab ,Aldesleukin ,Acute lymphocytic leukemia ,Internal medicine ,medicine ,Adverse effect ,biology ,business.industry ,C-reactive protein ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Clinical trial ,Cytokine release syndrome ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,business - Abstract
Introduction: One of the main complications of adoptive T cell therapy (ACT) is the en-masse activation of tumor-reactive T cells inducing a large release of cytokines followed by activation of other immune cells leading to adverse events. These are classified as a cytokine release syndrome (CRS) or neurotoxicity described as a CAR T Related Encephalopathy Syndrome (CRES). Several biomarkers have been associated with CRS and/or neurotoxicity such as LDH, ferritin and CRP. Cytokines have also been associated with CRS and and/or CRES, but present approaches rely on retrospective study of collected biomarkers. Here, we report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with relapsed/refractory (R/R)DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods: Patients with R/R DLBCL treated with commercial axi-cel were included in this study. Baseline serum samples were collected prior to lymphodepleting chemotherapy and then daily during hospitalization. To select which cytokines to monitor, we retrospectively analyzed 38 serum cytokines in a cohort of 53 patients with R/R B cell acute lymphoblastic leukemia (B-ALL) who were treated with 19-28z CAR T cells. The patients were divided into those requiring treatment with tocilizumab and/or steroids versus those who did not require treatment. We observed several cytokines, including IL-2, IL-6, IL-15 and IFNg, which were significantly elevated in patients with CRS and/or CRES requiring treatment (Figure 1a). Based on this analysis and results of published studies, eight serum proteins were selected in our study including IL-1b, IL-2, IL-6, IL-15, IFNg, TNFa, and angiopoietin-1 &2. We monitored these proteins using a POC device that allows for rapid daily monitoring with a turnaround time of two hours. We established that the results from the POC device strongly correlate with a current gold standard device(Luminex), which has a typical two day turn around time. CRS and CRES were prospectively graded using revised Lee criteria (Lee et al Blood 2014) and the CARTOX group (Neelapu et al. NRCO 2017) respectively by an experienced clinical team and confirmed by chart review retrospectively. Results: A total of 20 patients with R/R DLBCL treated with commercial axi-cel were identified. Median age 64 years ( range 43-73) with 80% male.In our cohort, grades 1-3 CRS were observed in 45%, 40% and 5% respectively. There were no observed grade 0 or grade 4 CRS. There were two patients (10%) who died in the setting of severe toxicity. Patients with grade 5 CRS had higher levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one, which correlated with severity of toxicity r=0.52 (p= 0.039) , and r=0.53 (p=0.033) respectively (Fig. 1b). Furthermore, patients with high grades CRS had elevated levels of IL-15 at day seven (r=0.83, p=0.006). The majority of patients (55%) had grade 1-2 CRES.There were no significant correlations between serum cytokine levels and CRES or between those who required tocilizumab/steroids vs. those who did not, likely due to the small sample size. In select cases, daily monitoring of cytokines using the POC device provided clinical insight that wasn't evident from standard biomarkers. For example, one patient who developed delayed CRS had high serum levels of IL-6 but did not have elevated levels of CRP(Fig.1c). Discussion: In this analysis of 20 patients, we observed a correlation between severe CRS and elevated serum cytokine levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with ACT. While this study is limited by small sample size, our observations correlate with previously published biomarkers data in patients enrolled in clinical trials. To our knowledge this is the first reported cytokine data using commercial axi-cel. Monitoring of cytokines using a POC device is feasible and will be useful clinically. High risk patients may be identified early and help guide intervention in real time, for example day one elevated IL-6 levels might inform earlier use of tocilizumab. We continue to enroll patients to validate cytokines as predictive biomarkers with the goal of informing the development of preventative strategies to mitigate CAR T cell therapy immune related adverse events. Disclosures Locke: Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor; Novartis Pharmaceuticals: Other: Scientific Advisor. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Shire: Consultancy. Davila:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. more...
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- 2018
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19. Fludarabine and Melphalan Results in Fewer Relapses Compared to Fludarabine and Targeted Busulfan in Patients Receiving Reduced Intensity Conditioning for AML and MDS
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Joseph Pidala, Ernesto Ayala, Zhenjun Ma, Rebecca Tombleson, Brian C. Betts, Taiga Nishihori, Frederick L. Locke, Ryan J. Caddell, Braydon Schaible, Claudio Anasetti, Elizabeth DiMaggio, Hugo F. Fernandez, Asmita Mishra, and Mohamed A. Kharfan-Dabaja more...
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Gastroenterology ,Fludarabine ,Surgery ,Transplantation ,03 medical and health sciences ,Regimen ,0302 clinical medicine ,International Prognostic Scoring System ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Cumulative incidence ,Progression-free survival ,business ,Busulfan ,030215 immunology ,medicine.drug - Abstract
Introduction: Fludarabine (Flu)-based conditioning regimens, combined with either melphalan (Mel) or intravenous busulfan (Bu), are often utilized in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). While recent data supports that a myeloablative conditioning (MAC) strategy improves survival in patients who are able to tolerate this approach, the optimal regimen for patients elderly or unfit for MAC remains unclear. A single-center retrospective analysis was performed to evaluate outcomes in patients with AML or MDS deemed eligible only for reduced intensity regimens. Methods: Patients with AML and MDS who underwent peripheral blood mobilized allogeneic HCT at a single institution between January 2008 and December 2014 were identified. Of those, patients who received conditioning with either once-daily Bu (75-95 mg/m2) targeted to an area under the curve of 3500 µM*L/min and Flu 160 mg/m2 (Flu/Bu 3500) or Mel 140 mg/m2 plus Flu 120-160 mg/m2 (Flu/Mel) were evaluated and compared. All disease statuses (complete remission (CR), second CR, or with active disease) at time of HCT were included. Regimen toxicities, cumulative incidences of acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), cumulative incidence of relapse (CIR), progression free survival (PFS), and overall survival (OS) were evaluated. Results: We identified 150 consecutive patients who received Flu/Bu 3500 (n=81) or Flu/Mel (n=69). Regimens were selected at physicians' discretion. The median ages for Flu/Bu 3500 and Flu/Mel were similar (66.9 (range, 48.2-75.9) and 65.8 (40.9-75.2) (p=0.14)). No differences were detected between the two groups with regard to recipient and donor gender, primary disease, donor type, recipient and donor cytomegalovirus (CMV) status, and Karnofsky performance status. Additionally, there were no differences between either groups in disease specific prognostic variables such as Disease Risk Index (Armand et al.), blast percentage at time of HCT, International Prognostic Scoring System (IPSS) and revised IPSS scoring in MDS patients, or AML cytogenetics at time of HCT. Patients receiving Flu/Mel had higher HCT-specific comorbidity index (HCT-CI, >3) when compared to Flu/Bu 3500 prior to transplantation (66.7% versus 46.9%, p=0.02). OS was similar between both arms (p=0.1) as was NRM (Hazard ratio (HR) 0.61 (CI, 0.34 - 1.1, p=0.1)) and PFS, HR 1.26 (CI, 0.83 - 1.94, p=0.2). However, CIR at 2 years post-allograft was significantly higher in the Flu/Bu 3500 arm, HR 2.54 (CI, 1.4 - 4.6, p=0.002) in comparison to Flu/Mel regimen (Figure 1). There was no difference detected in the cumulative incidences of either grades 2-4 acute GVHD, HR 1.00 (CI, 0.66 - 1.55, p=1.0), or grades 3-4 acute GVHD, HR 0.66 (CI, 0.27 - 1.57, p=0.3) between either conditioning regimen. The cumulative incidence of chronic GVHD was also similar, HR 1.27 (CI, 0.84 - 1.92, p=0.2). With regard to toxicity, diarrhea occurred more frequently in the Flu/Mel arm (p=0.0003) in the first 20 days following transplant. However, in the same period, mucositis occurred more frequently in the Flu/Bu 3500 arm (p=0.005). No differences were noted between the arms when assessing incidence of sinusoidal obstructive syndrome, diffuse alveolar hemorrhage, or thrombotic microangiopathy up to 90 days. Amongst patients receiving Flu/Mel, the most common cause of death was pneumonia or pulmonary failure (n=7) whereas the most common cause of death in the Flu/Bu 3500 arm was disease related (n=31). Conclusion: Flu/Mel resulted in a lower CIR at 2 years post-HCT compared to patients receiving Flu/Bu 3500 conditioning. Regarding toxicity, Flu/Mel produced more diarrhea but significantly less mucositis in comparison to Flu/Bu 3500; otherwise toxicity was comparable. Though there were no differences in OS and NRM between the two conditioning regimens, we speculate that the impact of the higher HCT-CI in the Flu/Mel arm may have contributed negatively to the lack of benefit in NRM and OS. Disclosures Locke: Kite: Membership on an entity's Board of Directors or advisory committees. Nishihori:Signal Genetics: Research Funding; Novartis: Research Funding. Fernandez:Chimerix: Honoraria; Otsuka: Honoraria; Sanofi: Speakers Bureau. more...
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- 2016
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20. Body Composition Predicts Survival in Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Recipients
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Joseph Pidala, Martine Extermann, Asmita Mishra, Claudio Anasetti, Heather S.L. Jim, Binglin Yue, Jongphil Kim, and Vickie E. Baracos
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Prognostic variable ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Surgery ,Log-rank test ,Transplantation ,Quartile ,Quality of life ,Interquartile range ,Internal medicine ,Cohort ,medicine ,business - Abstract
Background: Innovative means to risk-stratify HSCT patients are needed. Previous studies in cancer patients suggest association between body composition and survival. However, this has not been previously described is allogeneic HSCT recipients. Furthermore, the correlation of body composition with pre- and post-HSCT physical activity in cancer patients remains undefined. We postulated that body composition prior to HSCT is associated with post-HSCT outcomes. Methods: Patients who had completed pre-HSCT physical function assessment as part of ongoing prospective clinical trial were identified. Analysis of self-reported and measured physical activity and their association with outcomes after transplantation is currently ongoing. Regional CT at the 4th thoracic vertebra (T4) was obtained for post-hoc analysis of body composition within this cohort. Using Slice-O-Matic software V4.3 (Tomovision, Magog, Quebec, Canada), both adipose and muscle tissue were quantified to obtain the respective cross sectional area (cm2). Fat and skeletal muscle were identified and quantified within the following CT Hounsfield unit thresholds: -29 to +150 for skeletal muscle and -190 to -30 for adipose tissue. Tissue boundaries were manually corrected as necessary. Cross sectional areas were subsequently normalized for stature (height2) to obtain a tissue index for both fat and muscle (cm2/m2). For this analysis, fat index (FI) and muscle index (MI) were divided into quartiles (group 0: ≤25%, group 1: 26-50%, group 2: 51=75%, group 3: ≥75%). Statistical significance was defined as p < 0.05 and all analyses were done on SAS 9.3. Results: All patients (n=50) enrolled on the pre-HSCT functionality trial between 02/2014 and 02/2015 were identified for this analysis. 3 patients were excluded for analysis: 2 subjects ultimately did not proceed to HSCT and 1 subject had a CT scan that was not evaluable. Thus, 47 subjects had evaluable data; baseline characteristics are summarized (Table 1). Median follow-up for survivors is 298 days (interquartile range (IQR): 272-368 days). Overall survival (OS) significantly differs between FI strata (log rank p value =0.0013) (Figure 1). MI is not associated with OS (p=NS). FI is inversely correlated with distance walked during 6-minute walk test pre-HSCT (r = -0.33, p = 0.027). FI and MI are not significantly associated with self-reported physical activity using the International Physical Activity Questionnaire (IPAQ) post-HSCT (day 1, 30, 90), or patient-reported quality of life (QOL). Conclusions: These data provide the first evidence supporting an association between CT-defined cross sectional adipose tissue index and survival following HSCT. This non-invasive, routinely employed imaging modality may provide a new avenue for enhanced risk-assessment for HSCT patients. Subsequent studies will examine this effect in larger populations, with specific attention to other established prognostic variables. Table 1. Baseline Characteristics Variables N (%) Age, yrs (median, range) 60 (24-75) Gender, male 30 (63.8%) KPS ≥90 42 (89.3%) HCT-CI≥3 29 (61.7) Diagnosis § AML § ALL § CLL § CML § MDS § HD § MM § MPS § NHL 12 (25.5%) 5 (10.6%) 3 (6.4%) 2 (4.3%) 9 (19.1%) 2 (4.3%) 3 (6.4%) 2 (4.3%) 9 (19.1%) Conditioning Intensity, Myeloablative 24 (51.1%) Armand Disease Risk at HSCT § Low § Intermediate § High/Very High 2 (4.3%) 26 (55.3%) 19 (40.4%) Donor Type § Matched Related Donor § Matched Unrelated Donor § Mismatched Unrelated Donor § Double Umbilical Cord Blood 13 (27.7%) 27 (57.4%) 6 (12.8%) 1 (2.1%) Disclosures No relevant conflicts of interest to declare. more...
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- 2015
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21. TP53 and IDH2 Somatic Mutations Are Associated with Poor Outcomes Following Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome
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Lynn C. Moscinski, Asmita Mishra, Taiga Nishihori, Alan F. List, Ling Zhang, Janelle Perkins, Karma Salem, Teresa Field, Mohamed A. Kharfan-Dabaja, Rami S. Komrokji, Hugo F. Fernandez, Najla Al Ali, Eric Padron, Qing Zhang, David A. Sallman, Claudio Anasetti, and Jeffrey E. Lancet more...
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Oncology ,medicine.medical_specialty ,business.industry ,Proportional hazards model ,medicine.medical_treatment ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Bioinformatics ,medicine.disease_cause ,medicine.disease ,Biochemistry ,IDH2 ,Transplantation ,Internal medicine ,Medicine ,Missense mutation ,KRAS ,business ,medicine.drug - Abstract
Background: Despite growing understanding of clinical and genetic basis of myelodysplastic syndromes (MDS) and increased use of allo-HCT, the disease remains incurable in approx. half of cases. Availability of next generation gene sequencing is an important tool that helps further prognosticate outcomes. Pts, materials and methods: We performed targeted amplicon-based next generation sequencing (NGS) of the 26 most frequently mutated genes in MDS. DNA was extracted from paraffin embedded bone marrow (FFPE) samples obtained during pre-transplant work-up at a median of 30 (9-53) days prior to allo-HCT. Sequencing was performed on the Illumina platform with an average read depth of 1500x. The Qiagen GeneRead software suite was used for alignment and variant calling. Frameshift, nonsense, and missense variants that were not present in germline databases at >1% frequency and those that were predicted to be functionally significant by SIFT and Polyphen were deemed true mutations. Cutoff for variant allele frequency was set at 20%. Kaplan-Meier estimates were used for overall survival (OS) and Cox regression for multivariable analysis. Results: We identified 139 pts who received an allo-HCT between 01/2005 and 06/2012 for MDS (89%), AML (4%) or CMML (7%). However, 38 samples were excluded for inability to isolate DNA due to poor sample quality. Patient, disease, and transplant characteristics are summarized (Table 1). Median age of pts was 58 (22-74) yrs and the majority (77%) had received prior azacitidine. Somatic mutations (≥1) at time of allo-HCT were identified in 39% of cases. The most common mutations in decreasing frequency were: ASXL1 (11%), DNMT3A (6%), IDH2 (5%), KRAS (4%), RUNX1 (4%), TP53 (4%), TET2 (3%), SRSF2 (3%), SF3B1 (2%), EZH2 (1%), BCL (1%), MLL (1%), and WT1 (1%). FLU-BU was the most common preparative regimen (92%). Median F/U for all surviving pts was 36 months. Median OS for all pts was 29 (95% CI=10-48) mos. There was no difference in OS between pts harboring ≥1 mutation vs. those with none (34 (95%CI=10-57) mos vs. 29 (95%CI=16-42) mos, p=0.7), or in the presence of >5% vs. ≤ 5% BM myeloblasts at time of allo-HCT (20 (95%CI=10-31) mos vs. 34 (95%CI=13-55) mos, p=0.5), or if pts were ≥ 60 yrs of age vs. Conclusion: Our study confirms the adverse prognostic significance of TP53 mutation in MDS pts undergoing allo-HCT and identifies mutated IDH2 as an independent predictor of inferior OS in allo-HCT. Identifying these extremely high-risk populations (TP53 and IDH 2 mutations) is useful as standard allo-HCT seems ineffective (OS< 12 mos); and there is an unmet need to improve outcomes by integrating novel agents as post-transplant consolidation or maintenance. The lower frequency of somatic mutations in our study sample compared to previously reported might be explained by our more stringent criteria to screen out FFPE artifacts, among others. Given the relatively small sample size, our findings merit validation in a larger data set.Table 1.VariablesN=101Recipient median age (range), yrs58 (22-74)Recipient sexM=54%WHO at DxRA=2% RARS=3% RCMD=16% RAEB-I=31% RAEB-II=26% CMML=8% MDS-unclas=5% MDS/MPN=1% MDS-RS=5% AML=4%Azacitidine before allo-HCTNo=22% Yes=77% Unk=1%Best response to Azacitidine pre-HCTCR=8% CR marrow=4% PR=12% HI=5% SD=43% PD=7% Missing=22%Donor sourceMRD=35% MUD=46% MMUD=17% Cord=3%Cell sourcePBSC=96% BM=1% Cord=3%Preparative regimenFLU-BU=92% FLU-MEL=3% Other=5%GVHD prophylaxisMTX=66% SIR=19% MMF=15%R-IPSS at allo-HCTVery low=15% Low=24% Int=18% High=20% Very high=20% Missing=4%Cytogenetic scoring2=56% 3=16% 4=22% 5= 2% Missing= 4%Mutation presentNo=61% Yes=39% Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Pharmacylics: Speakers Bureau; Incyte: Consultancy. Field:PDL Biopharma: Research Funding. Perkins:PDL Biopharma: Research Funding. Lancet:Seattle Genetics: Consultancy; Pfizer: Research Funding; Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. List:Celgene Corporation: Honoraria, Research Funding. more...
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- 2015
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22. Hypo-Albuminemia at Day+90 after Allogeneic Hematopoietic Cell Transplantation for Lymphoid Malignancies Independently Predicts for Inferior Overall Survival and Higher Non-Relapse Mortality
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Julio C. Chavez, Binglin Yue, Jongphil Kim, Marcie L. Riches, Josephine Emole, Asmita Mishra, Taiga Nishihori, Ernesto Ayala, Claudio Anasetti, Mohamed A. Kharfan-Dabaja, and Frederick L. Locke
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medicine.medical_specialty ,Univariate analysis ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Fludarabine ,Surgery ,Transplantation ,Blood product ,hemic and lymphatic diseases ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,Hypoalbuminemia ,business ,Busulfan ,medicine.drug - Abstract
Introduction Pretransplant patient and donor characteristics can predict outcomes after allogeneic hematopoietic cell transplantation (HCT), but the utility of post-transplant characteristics to predict outcomes after HCT remains unknown. Our group previously noted that hypoalbuminemia ( Methods We identified pts with lymphoid malignancies who underwent allo-HCT at Moffitt Cancer Center from 2/1/2005 to 3/22/2013. Patient, donor and transplant characteristics from before and day+90 after HCT were retrospectively reviewed. OS was calculated by Kaplan-Meier estimates. NRM was determined by competing risk analysis. Multivariable models were developed for both endpoints. Patient's age, Center for International Blood and Marrow Transplantation Research (CIBMTR) risk category and acute graft versus host disease (aGVHD) grade were forced into the multivariate model along with significant covariates. Results 271 pts met the inclusion criteria (65% male, 35% female) with median age of 50 years. HCT indications were chronic lymphocytic leukemia (14%), Hodgkin's lymphoma (7%), non-Hodgkin's lymphoma (44%) and acute lymphoblastic leukemia (35%). CIBMTR disease risk categories were low (30%), intermediate (55%), or high (15%). Stem cell source was mainly peripheral blood (92%). Most common conditioning regimens were fludarabine + busulfan (69%) and pentostatin + busulfan (12%). 25 pts (9.2%) died prior to day+ 90 and were excluded from outcomes analyses. For the 249 evaluable pts, median OS was 78.4 months (95% CI: 32.1, NR). The 2-year and 5-year OS were 59% and 54% respectively. The 2-year and 5-year cumulative incidence of NRM were 19% and 21% respectively. On univariate analysis, transfusion of any blood product prior to day +90 (HR 1.82, CI 1.23-2.70, p=0.0028), prednisone dose of ≥20mg/day at day +90 (HR 2.18, CI 1.43-3.33, p=0.0003), and serum albumin(SA) of Similarly, univariate analysis showed that transfusion of any blood product prior to day+90 (HR 1.82, CI 1.04-3.18, p=0.03), SA of 3-3.5g/dl (HR 2.04, CI 1.14-3.65, p= 0.02) and prednisone dose of ≥20mg/day (HR 3.07, CI 1.76-5.37, p A prior or current diagnosis of aGVHD did not predict for NRM or OS in the multivariable models consistent with results on the myeloid malignancy study. Patient age, disease risk, comorbidity index, CD34 cell dose and GVHD prophylaxis type did not significantly predict for OS or NRM (Table 1). Conclusion Our study supports the adverse prognostic value of day +90 hypoalbuminemia (< 3g/dl) in regards to NRM and OS in pts who undergo allo-HCT for lymphoid malignancies. We propose inclusion of serum albumin at day +90 in algorithms to predict HCT outcomes. Disclosures No relevant conflicts of interest to declare. more...
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- 2015
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23. Does HLA-C Matching Predict the Engrafting Unit in Double Umbilical Cord Blood Transplants?: A Single Institution Retrospective Analysis
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Ryan Hillgruber, Taiga Nishihori, Mohamed A. Kharfan-Dabaja, Hugo F. Fernandez, Teresa Field, Lia Perez, Asmita Mishra, Joseph Pidala, Ernesto Ayala, Brian C. Betts, Michael T. Tees, Marcie L. Riches, Frederick L. Locke, Claudio Anasetti, and Jose L. Ochoa-Bayona more...
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education.field_of_study ,medicine.medical_specialty ,Thymoglobulin ,business.industry ,Immunology ,Population ,Cell Biology ,Hematology ,Total body irradiation ,Single Center ,Biochemistry ,Gastroenterology ,Umbilical cord ,Confidence interval ,Transplantation ,medicine.anatomical_structure ,Internal medicine ,Medicine ,business ,education ,Survival analysis - Abstract
Background: Lower total CD34+ cell dose and increased HLA-mismatch are known predictors of engraftment failure and higher transplant related mortality (TRM) in cord blood (CB) recipients. To compensate for cell dose, double unit grafts (DUCBT) are commonly used in adult. However, in the majority of patients (pts), only one of the two CB units engrafts. Identification of the factors that predict which unit will engraft remains elusive, although increased recipient-donor HLA-matching and larger CD3+ cell dose have been associated with the predominating unit in a single center retrospective analysis (Ramirez et al, 2012). Historically, CB units are selected by maximizing matching at the HLA-A and -B antigen and -DRB1 allelic level. Evidence supports that matching at HLA-C appears to decrease TRM, and many clinicians incorporate HLA-C antigen matching into unit selection. It is unclear, however, if HLA-C matching predicts the engrafting unit in DUCBT. This study retrospective study evaluates whether HLA-C matching is associated with the winning CB unit. Design: Clinical data was reviewed from all pts with a hematologic malignancy receiving a DUCBT at Moffitt Cancer Center between November 13, 2009 and August 29, 2013. Chimerism studies identified the predominating unit (> 65% single unit) between day 21 and day 28. Subsequent chimerism analyses performed at a median of day 100 confirmed unit predominance. Unit selection required intermediate resolution antigen match at HLA-A, -B, -C, and high resolution allele match at -DRB1. Units were a minimum of 4/8 matched to the patient and each other with a minimum cell dose of 1.5 x 107 total nucleated cell dose (TNC) /kg. Serology for donor specific antibodies against both units was negative. Results: Excluding 6 pts who were missing HLA-C typing on one or both CB units, 54 pts with hematologic malignancies (ALL=6, MDS/AML=29, Other=19) received chemotherapy and total body irradiation as part of a myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) with or without thymoglobulin (ATG) followed by a DUCBT (MAC=14, RIC=23, RIC+ATG=17). Median age was 52 (range 22-69) years. Seven pts demonstrated persistent mixed chimerism in the myeloid and/or lymphoid cell lines beyond day 100. A total of 20 pts with available chimerism data received at least one CB unit matched to the recipient at HLA-C, with one patient excluded due to persistent mixed chimerism. Six pts received both CB units matched at HLA-C, but of the 13 pts receiving one matched and one mismatched unit, the HLA-C matched unit was the engrafting unit 69% (9/13) of the time. Comparing similar HLA mispairings, a matched unit engrafted over a mis-matched unit at HLA-A 50% (5/10) of the time, at HLA-B 38% (5/13) of the time, and at HLA-DRB1 50% (3/6) of the time. TNC dose (larger vs smaller with a required difference of at least 0.03 x 107 TNC/kg), order of infusion (first vs second unit), and overall CB unit HLA matching (4/8-8/8), were assessed as potential predictors for engraftment. Of evaluable patients, the CB unit with the larger TNC engrafted 44% (16/36) of the time, and the first unit infused was the engrafting unit 54% (21/39) of the time. In patients with an unequal overall match grade between the CB units, the better HLA-matched CB unit engrafted 64% (14/22) of the time. Survival analysis of all pts revealed that those who received at least one CB unit antigen matched at HLA-C (n=20) had a 100 day and 1 year overall survival (OS) of 85% (95% Confidence Interval(CI): 67–97%) and 55% (95% CI: 33–75), respectively, whereas pts receiving two HLA-C mismatched CB units (n=34), 100 day OS was 62% (95% CI: 45–77) with 1 year OS 44% (95% CI: 28–61) (Fig 1). Conclusion: HLA-C antigen matching appears to help predict the winning unit in settings of HLA-match disparity and DUCBT. Confirmation in a larger population of DUCBT recipients is necessary. To date, the effects of HLA matching and other variables influencing engraftment have been predominately evaluated in recipients of single unit transplants and studies in DUCBT have been limited. Further investigation assessing HLA matching as well as donor-donor interactions is best served through a multicenter data resource. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. more...
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- 2014
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24. Beclomethasone and Budesonide Are Partially Effective As Sole Therapy for Isolated Gastro-Intestinal Gvhd
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Brian C. Betts, Asmita Mishra, Claudio Anasetti, Jongphil Kim, Lia Perez, Joseph Pidala, Jamie Shapiro, Marcie L. Riches, Taiga Nishihori, Chiara Frairia, Teresa Field, Mohamed A. Kharfan-Dabaja, Ernesto Ayala, Hugo F. Fernandez, Frederick L. Locke, and Jose L. Ochoa-Bayona more...
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Budesonide ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Gastroenterology ,Transplantation ,Oral administration ,Prednisone ,Internal medicine ,Toxicity ,Medicine ,business ,Glucocorticoid ,medicine.drug - Abstract
Introduction: Gastro-intestinal GVHD (GI GVHD) is a common and severe complication of allogeneic hematopoietic cell transplantation (HCT). Systemic glucocorticoids remain the standard of care for GI GVHD, despite their incomplete efficacy and toxicity. Steroid-sparing activity and improved survival were reported with oral administration of poorly absorbed beclomethasone dipropionate (BDP) in combination with systemic glucocorticoids for upper GI GVHD, and promising results were described with the adjunct of budesonide (BUD) for lower GI GVHD. No data have been reported on BDP or BUD without systemic glucocorticoids. Our team has adopted the practice of administering BDP/BUD without systemic glucocorticoids as fist-line therapy. Here we assess safety and efficacy of our practice in the treatment of isolated GI GVHD. Methods: We analyzed retrospective data from 297 consecutive patients (pts) with isolated GI GVHD after hematopoietic peripheral blood stem cell transplantation performed at the Moffitt Cancer Center between July 2004 and June 2013. At discretion of the treating physician, patients with upper with or without lower GI GVHD were treated with BDP (5 mg BID or TID orally), BDP plus prednisone (PRED 0.5-2 mg/kg or equivalent glucocorticoid dose), BDP+BUD (3 mg BID or TID orally) or BDP+BUD+PRED. The primary study endpoint was response of GI GVHD after 28 days, defined as complete resolution of all GI symptoms without addition of other immune suppressive (IS) agent(s) or partial reduction of GI symptoms, without resolution and without addition of other IS agent(s). Secondary endpoints were response to treatment after 200 days, chronic GVHD (CGVHD), CMV infection, relapse free survival (RFS), and overall survival (OS). All endpoints were analyzed according to treatment arm (Figure 1). A multivariable model was used to test the association between response after 28 days and treatment arm, after adjusting for primary diagnosis, conditioning regimen, disease status at HCT, pts/donor characteristics, GI GVHD overall grade, GI GVHD site, and albumin level. Results: BDP vs. BDP+PRED. Baseline characteristics were well balanced among the BDP (n=90) and BDP+PRED (n=24) groups, including treatment for isolated upper GI GVHD (84% vs. 67%, p=0.08), with the remainder affected by both upper and lower GI GVHD. BDP+PRED showed a significantly higher response of GI GVHD after 28 days compared to BDP (88% vs. 56%, multivariate OR 23, 95% CI 3-161, p=0.002); however there was no significant difference in response after 200 days (50% vs. 33%, univariate p=0.5). There were no significant differences in terms of treatment duration, requirement of additional IS agents, CMV reactivation, CGVHD development, RFS and OS between the two treatment cohorts. BDP+BUD vs. BDP+BUD+PRED. BDP+BUD+PRED pts (n=53) had more rapid onset of GI GVHD (median 20 vs. 26 days after HCT, p=0.001), higher incidence of lower GI involvement (61% vs. 38%, p=0.008) and higher incidence lower GI stage II-III GVHD (p=0.0004) compared to BDP+BUD pts (n=130). Despite adjusting for these higher risk features by multivariable analyses, BDP+BUD+PRED was associated with a significantly higher response after 28 (90% vs. 75%, multivariate OR 15, 95% CI 3-62, p=0.0003) and 200 days (70% vs. 45%, univariate p=0.0003). There were no significant differences in treatment duration, CMV reactivation, CGVHD development, RFS and OS between the two treatment cohorts. Conclusions: This retrospective analysis suggests that the addition of systemic PRED to topical BDP/BUD therapy for isolated GI GVHD was associated with a better response after 28 days of treatment. Despite the inferiority in GI GVHD response, there were no differences in secondary endpoints including treatment duration, CMV reactivation, RFS and OS. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. more...
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- 2014
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25. Prolonged Sirolimus Administration after Matched Related and Unrelated Allogeneic Hematopoietic Cell Transplantation Is Associated with Decreased Risk for Moderate-Severe Chronic Graft Vs. Host Disease
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Lia Perez, Marcie L. Riches, Brian C. Betts, Mohamed A. Kharfan-Dabaja, Taiga Nishihori, Melissa Alsina, Joseph Pidala, Jongphil Kim, Frederick L. Locke, Ernesto Ayala, Asmita Mishra, Teresa Field, Jose L. Ochoa-Bayona, Claudio Anasetti, and Hugo F. Fernandez more...
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medicine.medical_specialty ,business.industry ,Immunology ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,Tacrolimus ,Surgery ,Fludarabine ,Discontinuation ,Transplantation ,stomatognathic diseases ,Median follow-up ,Prednisone ,Internal medicine ,medicine ,Cumulative incidence ,business ,Busulfan ,medicine.drug - Abstract
Current pharmacologic strategies employed in allogeneic hematopoietic cell transplantation (HCT) largely fail to prevent chronic graft vs. host disease and do not effectively induce donor-recipient immune tolerance. We report a long-term follow-up (LTFU) analysis of a randomized phase II trial comparing sirolimus/tacrolimus (SIR/TAC, n=37) vs. methotrexate/tacrolimus (MTX/TAC, n=37). The primary endpoint of the trial was grade II-IV acute GVHD within 100 days. Per protocol, SIR/TAC patients were treated with at least 1 year of SIR post-HCT. In the present LTFU analysis, we studied the following: Compliance with SIR; incidence, severity, classification, and organ manifestations of chronic and late acute GVHD; glucocorticoid exposure; discontinuation of immune suppression (IS); and current estimation of relapse, non-relapse mortality (NRM) and overall survival. A subset analysis examined chronic GVHD therapeutic outcomes. The study groups had no significant differences in recipient/donor age or gender, diagnosis and remission status, CIBMTR risk category, donor type, or conditioning regimen (p=NS). The cumulative incidence of grade II-IV acute GVHD through day 100 post-HCT differed (SIR/TAC: 43% vs. MTX/TAC: 89%, p < 0.001). Median follow up time for surviving patients was 41 months (range 27-60) for SIR/TAC and 49 months (range 29 – 63) for MTX/TAC. One patient discontinued SIR at 161 days post-HCT due to TMA (grade 1). Otherwise, SIR was not discontinued for toxicity, and the median duration of SIR therapy among patients (n=27) surviving ≥ 1 year was 33 months (range 5.29 – 60 months). NIH Consensus moderate-severe chronic GVHD was significantly lower in SIR/TAC vs. MTX/TAC (34% vs. 65%, p=0.004). NIH global (0-3) severity score was significantly lower in SIR/TAC vs. MTX/TAC (p=0.003). While not significantly different, lung, liver, and GI involvement and severity were decreased in the SIR/TAC group, and fewer cases had overlap subtype of chronic GVHD (7 vs. 14, p=0.15). Late acute GVHD was also significantly lower among SIR/TAC vs. MTX/TAC (20% vs. 43%, p=0.04). While SIR/TAC patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to TAC discontinuation SIR/TAC 368 days vs. MTX/TAC 821 days, p=0.002), there was no difference in complete IS discontinuation (at 60 months post-HCT: SIR/TAC 43% vs. MTX/TAC 31%, p=0.78). Malignancy relapse was lower among SIR/TAC vs. MTX/TAC (19% vs. 39%, p=0.06), and overall survival was not different. Co-administration of escalated dose IV busulfan (7500µM/L*min/day) together with fludarabine resulted in excess NRM among SIR/TAC (NRM: 3/5) patients, but not MTX/TAC (NRM: 1/11). When restricted to standard dose conditioning, no difference in NRM was observed (at 48 months: SIR/TAC 10% vs. MTX/TAC 16%, p=0.98). Subgroup analysis of those with chronic GVHD did not demonstrate differences (second-line systemic IS therapy, treatment success, or failure-free survival) to suggest that ongoing SIR treatment modified the natural history and therapeutic responsiveness of chronic GVHD. In summary, prolonged sirolimus administration is associated with reduced moderate-severe chronic and late acute GHVD, decreased total prednisone exposure, and earlier TAC discontinuation post-HCT. Investigation of determinants of immune suppression discontinuation and development of tools to assess immune tolerance are needed to advance the field. Figure: Cumulative incidence of NIH Consensus moderate-severe chronic GVHD Figure:. Cumulative incidence of NIH Consensus moderate-severe chronic GVHD Disclosures No relevant conflicts of interest to declare. more...
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- 2014
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26. Evaluation Of Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes Of One Hundred Thirty-Two Patients With Myelodysplastic Syndrome (MDS) Or Chronic Myelomonocytic Leukemia (CMML) Up To Age Seventy-Five and The Effect Of Pre-Transplant 5-Azacitidine
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Joseph Pidala, Asmita Mishra, Janelle Perkins, Ernesto Ayala, Teresa Field, Melissa Alsina, Claudio Anasetti, Rami S. Komrokji, Marcie Tomblyn, Eric Padron, Alan F. List, Jeffrey E. Lancet, Mohamed A. Kharfan-Dabaja, Brian C. Betts, Taiga Nishihori, Ryan Hillgruber, Hugo F. Fernandez, and Frederick L. Locke more...
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Chronic myelomonocytic leukemia ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Debulking ,Biochemistry ,Fludarabine ,Surgery ,Transplantation ,Graft-versus-host disease ,hemic and lymphatic diseases ,Internal medicine ,Statistical significance ,medicine ,Cumulative incidence ,business ,medicine.drug - Abstract
HCT is the only known curative treatment for MDS. Treatment with the DNA methyltransferase inhibitor 5-azacitidine (aza) can slow leukemic progression and has been utilized prior to HCT for both tumor debulking and to provide stabilization of the disease during the pre-allograft period. To discern the impact of pretransplant aza treatment on HCT outcomes, we retrospectively analyzed 132 patients (pts) according to pretransplant aza exposure. Patients included those who had a diagnosis of MDS or CMML at any time point in the course of their disease who subsequently received a HCT from a HLA-compatible donor. Eligible patients proceeded to transplant if they had adverse disease features such as elevated IPSS risk, treatment related MDS, progression of disease or refractory disease. Consecutive patients referred for HCT between July 2004 and July 2009 were evaluated. Seventy percent of pts with an identified donor proceeded to HCT. All received a myeloablative HCT using fludarabine and IV-busulfan [targeted to a specific AUC of 3500, 5300, 6000 or 7500]. Graft versus host disease prophylaxis was with tacrolimus plus methotrexate or sirolimus or mycophenolate mofetil. Only those with mismatched donors received antithymocyte globulin. The median age of the 64 allograft pts not receiving preHCT aza (No AZA group) was 56.8 (24.8 –73.5) years (yrs). Thirty-seven (58%) pts were older than 55 yrs. At diagnosis, IPSS risk was Low (n=4), Int-1 (n=23), Int-2 (n=13), High (n=5), not evaluable (n=4) (NE), AML (n=16) and CMML (n=9). Seventeen had treatment related MDS (tMDS) and 18 had AML at one time. Donors included 24 sibling donors (MRD), 29 matched unrelated donors (MUD) and 11 mismatched unrelated donors (mMUD). Median follow-up is 66.2 months (29.7 – 105.7 months). Sixty-eight pts received a median of four (1-12) cycles of aza prior to HCT (YES AZA group). The median age was 57.3 (25.6 – 73.8) yrs. Thirty-nine pts (57%) were older than 55 yrs. At diagnosis, IPSS risk was Low (n=3), Int-1 (n=21), Int-2 (n=21), High (n=12), NE (n=2), AML (n=2) and CMML (n=7). Eighteen had tMDS and 10 had AML at one point. Donors included MRD (n=32), MUD (n=31) and mMUD (n=5). Median follow-up is 53.8 months (24.1 – 103.2 months). Prior to transplant the number of marrow blasts in the No-AZA vs Yes-AZA was: 20% (n=2 vs 3) and CMML (n=4 vs 6). All patients engrafted with no difference in engraftment rates or toxicities between the two groups. Additionally, cumulative incidence of non-relapse mortality and relapse rates at 1 yr/ 3 yrs were similar [NRM: No AZA 20.5/ 37.4% vs Yes AZA 20.7/ 23.9 %; REL: 34.2/ 37.5% vs 26.4/ 32.4%]. At 3 years, the RFS and OS suggest improvement with pretransplant AZA but do not reach statistical significance [RFS: No AZA 26% vs Yes AZA 44.1%; p = 0.14; OS: 30.9% vs 51.4%; p=0.15]. Utilization of pre-HCT 5-azaciticidine is a feasible strategy and doesn’t appear to have any negative impact on HCT outcomes. Given the disease control facilitated by aza it should be offered to patients with high risk MDS coming to transplant. Disclosures: Field: Celgene: Research Funding. Alsina:Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Lancet:Celgene: Research Funding. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. more...
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- 2013
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27. Utility Of Revised International Prognostic Scoring System (R-IPSS) To Predict Outcome Of Myelodysplastic Syndromes (MDS) Patients After Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT)
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Maria Gabriela Corrales-Yepez, Teresa Field, Alan List, Claudio Anasetti, Janelle Perkins, Najla H Al Ali, Asmita Mishra, Eric Padron, Jeffrey E Lancet, Mohamed A. Kharfan-Dabaja, and Rami S Komrokji
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Oncology ,Univariate analysis ,medicine.medical_specialty ,Cytopenia ,business.industry ,Myelodysplastic syndromes ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Log-rank test ,International Prognostic Scoring System ,Internal medicine ,Cohort ,Medicine ,business - Abstract
Introduction The R-IPSS at time of diagnosis was recently proposed and validated as a superior prognostic tool refining the original IPSS. The new model recognized further cytogenetic heterogeneity of the disease, and importance of the depth of cytopenia. The value of R-IPSS at time of AHSCT to predict post-transplant outcomes is not known. We examined the utility of R-IPSS prior to AHSCT in our cohort of MDS patients. Methods This was a retrospective study. We identified MDS patients who underwent AHSCT in our MDS database. Individual patient charts were reviewed. R-IPSS was calculated at time of transplant using data obtained from tests performed within 30 days of transplant. The R-IPSS karyotype was based on the new proposed 5 groups. The study main objective was to compare overall survival (OS) from time of AHSCT among R-IPSS groups and R-IPSS karyotype groups. Kaplan Meier estimates were used to calculate OS; log rank test was used to compare groups. Results Out of 1259 MDS patients in our database, 175 received AHSCT, and we excluded 65 patients who had AHSCT at any point after AML transformation. The median duration of follow up was 46 months (mo) (95% CI 39-53). Table-1 summarizes baseline characteristics of the cohort (n=110). All patients received a reduced intensity AHSCT using fludarabine and IV-busulfan. The rate of acute graft versus host disease (GVHD) II-IV was 68% and 72% for chronic GVHD. The median OS for the whole cohort was 22 mo (95% 10-33 mo.). The IPSS at time of AHSCT did not predict OS. Based on R-IPSS, 24 pts (22%) were very low, 26 (24%), low, 16 (15%) intermediate, 21 (19%) high, and 23 (21%) were very high. The R-IPSS at time of AHSCT did not predict OS. The median OS was not reached, 14, 52, 20 and 23 mo for very low, low, int, high and very high respectively. (p= 0.1). The R-IPSS karyotype groups did predict OS. The median OS was 29 mo, 26 mo, 19 mo, and 9 mo for good, intermediate, poor and very poor karyotype risk groups respectively (p=0.047) No other factors prior to AHSCT including age, myeloblasts percentage, Hemoglobin, platelets, treatment before AHSCT had impact on OS in univariate analysis. Conclusions IPSS and R-IPSS prior to AHSCT did not predict OS in our cohort of MDS patients. The R-IPSS karyotype group was the only statistically significant prognostic factor prior to AHSCT. Disclosures: List: Celgene: Membership on an entity’s Board of Directors or advisory committees. more...
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- 2013
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28. Outcome Of Patients (pts) With Low and Intermediate-1 Risk Myelodysplastic Syndrome (MDS) After Hypomethylating Agent (HMA) Failure
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Elias Jabbour, Guillermo Garcia-Manero, Lianchun Xiao, Al Ali Najla, Asmita Mishra, Eric Padron, Jeffrey E Lancet, Jeffery Bryan, Hillary Prescott, David P. Steensma, Mikkael A. Sekeres, Gail J. Roboz, Alan List, Hagop M Kantarjian, and Rami S Komrokji more...
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medicine.medical_specialty ,education.field_of_study ,business.industry ,Immunology ,Population ,Decitabine ,Cell Biology ,Hematology ,Lower risk ,Biochemistry ,Chemotherapy regimen ,Hypomethylating agent ,International Prognostic Scoring System ,Internal medicine ,Cohort ,medicine ,Clinical endpoint ,business ,education ,medicine.drug - Abstract
Background HMA are standard of care in pts with high-risk MDS and commonly used in pts with lower risk. Pts with high-risk disease post HMA failure have a poor prognosis with a median survival of 4-6 months. The prognosis of pts with low and intermediate-1 risk MDS by the International Prognostic Scoring System (IPSS) after HMA failure is not known. Aims To assess outcome of pts with low and intermediate-1 risk disease post HMA failure that might benefit from specific strategies or investigational agents. Methods Data from 423 pts with low (n= 141, 33%) and intermediate-1 risk disease (n=282, 67%) by IPSS score treated with HMA at MD Anderson Cancer Center (MDACC; n=144) and Moffitt Cancer Center (MCC; n=279) between 2000 and 2011 were analyzed. Results Median age was 69 years. 294 (69%) pts had a diploid cytogenetic analysis. 63 (15%) pts had therapy-related MDS. 282 (67%) pts received azacitidine, 87 (21%) decitabine, and 54 (12%) both. Median number of cycles of HMA administered was 6 (range, 1-64) for a median duration of therapy of 7 months (range, 1- 74). Best response to HMA was complete response (CR) in 39 (9%) pts, partial response (PR) in 13 (3%), a bone marrow CR in 6 (1%), and hematologic improvement (HI) in 90 (21%) pts. Pts had discontinued HMA because of primary resistance in 198 (47%) pts, loss of response in 141 pts (33%), intolerance in 13 pts (3%) and other reasons in 71 pts (17%). At the time of HMA failure, 81 (19%) pts transformed into acute myeloid leukemia (AML). Of the 302 remaining pts evaluable by IPSS, 67 (22%) pts were of low-risk, 158 (53%) of intermediate-1 risk, 48 (16%) of intermediate-2 risk, and 29 (9%) of high-risk disease. By the revised IPSS (R-IPSS), the percentage of pts with low, very low, intermediate, high, and very high risk disease were 11%, 29%, 30%, 20%, and 10%, respectively. By the MDACC global prognostic scoring system (MDGPSS) 18%, 35%, 29%, and 18%, of the pts were of low-risk, intermediate-1, intermediate-2, and high-risk disease, respectively. After a median follow-up of 16 months from HMA failure, 117 (28%) pts remained alive. The median overall survival (OS) was 15 months (95% CI: 12-18) with estimated 1- and 3-year OS rates of 55% and 27%, respectively. Both, the R-IPSS and the MDGPSS were predictive of survival post HMA failure (Table 1 ). Conclusion In the largest cohort of lower risk MDS pts treated with HMA, the outcome after HMA failure is poor. Treatment of those patients remains an unmet medical need. OS is a reasonable primary endpoint for clinical studies targeting this population. Disclosures: Lancet: Celgene: Research Funding. Sekeres:Celgene: Consultancy; Amgen: Consultancy. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. more...
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- 2013
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29. Outcome of Patients with Lower-Risk Myelodysplastic Syndrome (MDS) After Azacitidine (AZA) Treatment Failure
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Javier Pinilla-Ibarz, Alan F. List, Jeffrey E. Lancet, Rami S. Komrokji, Asmita Mishra, Bryan J Little, Viet Q. Ho, Eric Padron, and Najla Al Ali
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medicine.medical_specialty ,Pediatrics ,business.industry ,Anemia ,Immunology ,Azacitidine ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Lower risk ,Biochemistry ,International Prognostic Scoring System ,Internal medicine ,Cohort ,medicine ,business ,Refractory cytopenia with multilineage dysplasia ,Progressive disease ,medicine.drug - Abstract
2815 [][1] Background: Azacitidine has emerged as the standard of care for treatment of higher risk MDS based upon results of the AZA-001 study. Several groups reported poor outcomes after AZA failure in patients with int-2 or high risk International Prognostic Scoring System (IPSS) risk groups with a median overall survival (OS) ranging from 4–8 months (mo). In the USA, AZA is approved for all FAB types and risk groups and is as first or second line therapy for anemia after erythroid stimulating agents in low /int-1 risk non-deletion 5q MDS and is the treatment of choice for thrombocytopenia. The outcome of patients with lower risk myelodysplastic syndrome (MDS) after AZA failure has not been characterized. We report our experience in a large cohort of low/int-1 (lower risk) MDS patients after AZA failure. Methods: Patients were identified through the Moffitt Cancer Center (MCC) MDS database. Individual charts were reviewed and relevant clinical data was extracted. Patients with low or intermediate-1 (int-1) risk disease as defined by IPSS who had received AZA treatment were identified. These patients were also risk stratified based on Global MD Anderson Score (MDAS). The primary objective was to estimate OS in these patients after AZA failure. AZA failure was defined as failure to respond after 4 or more treatment courses, loss of response, or disease progression while on therapy. All responses were defined according to the International Working Group (IWG) 2006 criteria. The Kaplan–Meier method was used to estimate median overall survival. Results: Two hundred eighty MDS patients with low/int-1 IPSS risk who had received AZA treatment were identified. Most patients (81%) were greater than 60 years of age (median, 69 years), and 90% of AZA treated patients were RBC transfusion dependent. Refractory cytopenia with multilineage dysplasia (RCMD) was the most common WHO subtype (44%), and 81% of patients had good risk cytogenetics (Table-1). The median time from MDS diagnosis to AZA treatment was 12.3 months; median number of AZA cycles received was six. At the time of AZA treatment, 241 patients (86 %) were risk stratified as int-1 versus 39 patients (14 %) who were stratified as low risk IPSS. The IWG 2006 responses to AZA treatment included 4% CR (n=10 ), 1% marrow CR (n=2), 4% PR (n=10), 27% Hematological improvement (HI) (n=75), whereas 52% (n=146) had stable disease with no HI (n=146) and 10% had progressive disease (n=10); 6 patients (2%) died on therapy, and responses were missing in 2 patients (60 | 227 (81%) | | Gender | Male | 74 (64%) | | WHO subtype | RA | 26 (9%) | | | RARS | 33 (12%) | | | RCMD | 123 (43%) | | | Del5 q | 9 (3%) | | | RAEB-1 | 55 (20%) | | | RAEB-2 | 6 (2%) | | | MDS-U | 7 (3%) | | | CMML | 8 (3%) | | | MDS/MPN-U | 13 (5%) | | IPSS | | Diagnosis Prior AZA | | | Low | 61 (22%) 39 (14%) | | | Int-1 | 219 (78%) 241 (86%) | | MDAS | Low | 47 (17%) | | | Int-1 | 159 (57%) | | | Int-2 | 61 (22%) | | | High | 13 (5%) | | Cytogenetics | Good | 227 (81%) | | | Intermediate | 43 (15%) | | | Poor | 8 (3%) | Table 1 Baseline characteristics ![Figure-1][3] Figure-1 (A) KM estimates of OS (B) KM of OS in low versus int-1 risk IPSS Disclosures: List: Celgene: Consultancy. Komrokji: Celgene: Speakers Bureau. [1]: #fn-2 [2]: #F1 [3]: pending:yes more...
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- 2012
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30. The Utility of New Prognostic Models in Lower Risk MDS to Identify Patients Who Drive Survival Advantage From Disease Altering Treatment Modalities
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Rami S. Komrokji, Bryan J Little, Pearlie K. Epling-Burnette, Asmita Mishra, Maria Corrales-Yepez, Javier Pinilla-Ibarz, Najla Al Ali, Eric Padron, Alan F. List, Jeffrey E. Lancet, and Ling Zhang
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Disease ,Lower risk ,Biochemistry ,Gastroenterology ,Transplantation ,Log-rank test ,Treatment modality ,Internal medicine ,medicine ,Clinical endpoint ,Survival advantage ,business ,Prognostic models - Abstract
Abstract 3852 Background: Azanucleosides (AZN) and allogeneic stem cell transplantation (ASCT) are the only disease altering treatment modalities for patients with myelodysplastic syndrome (MDS). Azacitidine (AZA) demonstrated an overall survival (OS) advantage in higher risk MDS. The goal of treatment in patients with lower risk MDS is alleviation of symptomatic cytopenias. A key question remains the ability to identify the subset of lower risk MDS patients with poor risk features who may experience an OS benefit from AZN treatment. We hypothesized that recently proposed prognostic models such as the Global MD Anderson risk model (MDAS), revised International Prognostic Score (R-IPSS), and the Lower risk MD Anderson model (LR-MDAS), may identify patient subsets originally classified as lower risk by IPSS who have higher disease risk features and will benefit from AZA treatment. Methods: Patients classified as lower risk MDS by IPSS were identified retrospectively from the Moffitt Cancer Center (MCC) MDS database. The primary objective was to examine the utility of risk models identifying patients who benefit from AZA. The primary end point was OS. Patients were treated with AZA based on clinical judgment and primarily for management of cytopenias. The MDAS, R-IPSS, and LR-MDAS scores were recorded and calculated as previously described. The Kaplan–Meier method was used to estimate median OS. Log rank test was used to compare Kaplan–Meier survival estimates between the groups. Results: The MCC MDS database captured 608 MDS patients classified as low/int-1 risk by IPSS. The median age was 69 years, 2/3 were males, RCMD was the most common WHO subtype (38%), and 3 % had a poor risk karyotype. Among the 608 patients, 252 were treated with AZA. Based on IPSS, 162 patients were low risk and 56 received AZA, with a median OS of 86 mo (95%CI 64–107) vs. 94 mo (95%CI 66–121, p=0.9) for those 106 patients who did not. Among the 444 patients classified as int-1 risk, 192 were treated with AZA with a median OS of 45 mo (95%CI 37–53) vs. 33 mo (95%CI 32–54) for AZA-untreated (p=0.6). Based on MDAS, only 478 patients were lower risk, among whom 177 received AZA treatment with a median OS of 59 mo (95% CI 48–70), vs. 72 mo (95%CI 55–88) (p=0.24) in the 301 patients who did not receive AZA. The MDAS upstaged 162 patients (27%) into int-2/high risk categories, 71 of whom received AZA with a median OS of 27 mo (95%CI 21–34) compared to 17 mo (95% CI 14–21) (p=0.003) in the 55 patients did not receive AZA treatment. Characterization of LR-MDAS was available for 322 patients, 38 of whom stratified as category 1. Twelve of these patients were treated with AZA and 26 patients were not with a median OS that was not reached for both groups (p=0.25). Category 2 included 134 patients, 41 of whom received AZA with a median OS of 69 mo (95%CI 53–85) compared to 77 mo (95% CI 48–106) (p=0.22) in the 93 patients who did not receive AZA treatment. Finally, 150 patients were characterized as category 3, 87 of whom received AZA with a median OS of 46 mo (95% CI 39–53) vs. 34 mo (95%CI 8–61) (p=.85) for the 63 who did not. By R-IPSS, 539 patients were included in the very low/low/intermediate risk prognostic categories, including 212 patients treated with AZA and 327 who were not with corresponding median OS of 53 mo (95%CI 46–60) and 58 mo (95%CI 45–71) (p=0.16), respectively. The R-IPSS upstaged 67 patients (11%) to high or very high risk among whom 36 received AZA with a median OS of 56 mo (95%CI 18–93) vs. 23 mo (95% CI 17–29) (p=0.16) in the 31 patients who did not. Conclusion: The new proposed risk models identify a subset of patients with higher risk features originally stratified as lower risk by IPSS. AZA treatment yielded an OS advantage in patients upstaged to int-2 or high risk by MDAS, suggesting that disease modifying treatments effectively extend OS in such patients. A larger sample size is needed to determine the utility of LR-MDAS or R-IPSS. Disclosures: Komrokji: Celgene: Speakers Bureau. List:Celgene: Consultancy. more...
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- 2012
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31. Validation of the Revised International Prognostic Scoring System (R-IPSS) for Patients with Myelodysplastic Syndromes: Therapeutic Implications
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Mohamed A. Kharfan-Dabaja, Najla Al Ali, Alan F. List, Ling Zhang, Asmita Mishra, Jeffrey E. Lancet, Maria Corrales-Yepez, Rami S. Komrokji, Eric Padron, Bryan J Little, Pearlie K. Epling-Burnette, and Javier Pinilla-Ibarz more...
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medicine.medical_specialty ,Framingham Risk Score ,business.industry ,Myelodysplastic syndromes ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Log-rank test ,Hypomethylating agent ,International Prognostic Scoring System ,Internal medicine ,Cohort ,medicine ,Single institution ,business ,Prognostic models - Abstract
Abstract 2816 Background: The International Prognostic Scoring System (IPSS) was recently revised under the auspices of MDS foundation as a collaborative international effort. The proposed R-IPSS is suggested to refine the prognostic value of the IPSS. Instead of the 4 original IPSS categories, 5 categories are proposed by R-IPSS. To validate this prognostic model and examine its utility for therapy decisions, we tested the new risk model in a large external single institution patient cohort. Methods: Data were collected retrospectively from the Moffitt Cancer Center (MCC) MDS database and chart review. The primary objective was to validate the new risk model. The R-IPSS score was calculated as reported. Patients were divided into 5 prognostic categories (very low, low, intermediate, high and very high risk). The Kaplan–Meier method was used to estimate median overall survival. Log rank test was used to compare Kaplan–Meier survival estimates between the groups. Results: The MCC MDS database captured 1157 patients. Complete data was available for 1029 patients to calculate the R-IPSS score. Median age was 68 years, and the most common WHO subtype was RCMD (29%). Two thirds of patients were low/int-1 IPSS risk, and 44% were int-2 or high risk MDAS. (Table-1). Among those, 729 patients (77%) were RBC transfusion dependent (TD), and 264 (26%) had serum ferritin >1000 ng/l. Six hundred eighteen patients (60%) received hypomethylating agent (HMA). The median duration of follow up was 68 months (mo). Median OS according to IPSS risk score was 90 mo (95%CI 75–105), 44 mo (95%CI 39–46), 18 mo (95%CI 15–21), and 14 mo (95%CI 11–17), for low, int-1, int-2, and high risk categories, respectively (p < 0.005). According to MD Anderson risk Score, the median OS was 108 mo (95%CI 91–126), 55 mo (95%CI 50–60), 25 mo (95%CI 22–28), and 14 mo (95%CI 12–16), for low, int-1, int-2, and high risk respectively (p < 0.005). Using the R-IPSS, 106 (10%), 311 (30%), 247 (24%), 201 (20%), and 164 (16%) were classified as very low, low, int, high, and very high risk. The median OS was 82 mo (95% CI 64–100), 57 mo (95% CI 46–68), 41 mo (95% CI 33–49), 24 mo (95% CI 20–28), and 14 mo (95% CI12–16) for each of the corresponding R-IPSS groups (p Among those patients who received HMA, the median OS from time of diagnosis was 76 mo, 55 mo, 42 mo, 25 mo, and 16 mo for very low, low, int, high, and very high risk respectively (p < 0.005). A survival benefit for HMA therapy was only statistically significant in patients with very high risk R-IPSS, with a corresponding median OS of 16 mo with HMA versus 7 mo with no HMA (p< 0.005). OS in patients with very high or high R-IPSS who underwent Allogeneic Stem cell transplant (ASCT) was improved compared to corresponding patients who received non-ASCT management. Patients who had very low, low, and int risk R-IPSS had no apparent OS benefit with ASCT. (Table-3). Conclusion: Our data validates the prognostic value of the proposed R-IPSS, but refines prognostic discrimination only for intermediate risk group of IPSS. Both the R-IPSS and IPSS were valid prognostic models for patients treated with HMA. The benefit of ASCT was restricted to patients with high and very high R-IPSS groups. The utility of the R-IPSS as a tool for therapeutic decisions should be further examined before wide adaptation. Disclosures: No relevant conflicts of interest to declare. more...
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- 2012
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32. Obesity Is Poor Prognostic Factor in Lower Risk Myelodysplastic Syndrome
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Rami S. Komrokji, Dana E. Rollison, Najla Al Ali, Pearlie K. Epling-Burnette, Alan F. List, Jeffrey E. Lancet, Maria Corrales-Yepez, and Asmita Mishra
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Lower risk ,medicine.disease ,Biochemistry ,Obesity ,Surgery ,Hypomethylating agent ,International Prognostic Scoring System ,Refractory anemia with ring sideroblasts ,Internal medicine ,Epidemiology ,medicine ,Refractory cytopenia with multilineage dysplasia ,business ,Body mass index - Abstract
Abstract 5018 Background: Obesity was associated with a more than 2-fold greater risk of myelodysplastic syndrome (MDS) in a recent epidemiological study (Ma et al, Am J Epidemiol. 2009 June 15; 169(12): 1492–1499). The impact of obesity on outcome of disease in patients with an established diagnosis of MDS has not been studied. We examined the prognostic value of obesity in a large cohort of lower risk MDS patients treated at the Moffitt Cancer Center (MCC). Methods: Data were collected retrospectively from the Moffitt Cancer Center (MCC) MDS database and individual charts reviewed. The primary objective was to evaluate the impact of obesity on overall survival (OS) in lower risk patients with MDS. Patients with low or intermediate-1 (int-1) risk disease by International Prognostic Scoring System (IPSS) were included. Obesity was defined as a body mass index (BMI) ≥ 30 (Standard definition) measured at time of referral to MDS program at MCC. Patients were divided into two groups according to BMI ≥ 30 or BMI < 30. All analyses were conducted using SPSS version 19.0. Chi square and independent t-test were used to compare baseline characteristics between the 2 groups for categorical and continuous variables, respectively. The Kaplan–Meier method was used to estimate median overall survival. Log rank test was used to compare Kaplan–Meier survival estimates between two groups. Cox regression was used for multivariable analysis. Results: Between January 2001 and December 2009, 479 low/int-1 IPSS risk MDS patients were included. Among those, 132 (27.6%) had BMI ≥ 30 and 325 (67.8%) had BMI The median OS was 59 mo (95%CI 48–70) in patients with BMI Conclusion: Our data suggest that obesity is an independent adverse prognostic factor for OS in patients with lower risk MDS. Obesity may be associated with other comorbidities and metabolic dearrangements that contribute to the pathogenesis of the underlying disease. Disclosures: No relevant conflicts of interest to declare. more...
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- 2011
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