187 results on '"Sandhu, Karamjeet"'
Search Results
152. Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide
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Al Malki, Monzr M., Palmer, Joycelynne, Tsai, Ni-Chun, Mokhtari, Sally, Hui, Susanta, Tsai, Weimin, Aldoss, Ibrahim, Ali, Haris, Aribi, Ahmed, Cao, Thai, Mei, Mathew, Sandhu, Karamjeet S., Siddiqi, Tanya, Forman, Stephen J., Nakamura, Ryotaro, Marcucci, Guido, Stein, Anthony, Wong, Jeffrey Y.C., and Rosenthal, Joseph
- Abstract
Post-transplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GvHD) and non-relapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, due to the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allow for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end-organs. In this phase I trial (NCT02446964), 31 patients with high-risk and/or active primary refractory leukemias or MDS underwent peripheral blood stem cells (PBSC)-HaploHCT with TMLI, fludarabine and cyclophosphamide as conditioning regimen. Primary objectives were to evaluate safety and determine TMLI’s recommended phase 2 dose (RP2D). Radiation dose was escalated in increments of 200cGy (1200-2000cGy). GvHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade-2 toxicities by Bearman-scale were mucositis (n=1), hepatic (n=3), gastrointestinal (n=5), and cardiac (n=2). One patient (1800cGy) experienced grade 3 pulmonary toxicity (dose limiting toxicity). The RP2D was determined at 2000 cGy. At follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day-100 grade 2-4 and 3-4 acute GvHD were 52%, 6%, respectively. Chronic GvHD at 2 years was 35%. For patients treated at the RP2D (n=12); median follow-up duration of 12.3 months; 1-year relapse/progression, progression-free survival and overall survival rates were 17%, 74% and 83%; respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population. Promising low relapse/progression rate was achieved without increasing GvHD or transplant-related mortality.
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- 2022
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153. Flotetuzumab as a salvage immunotherapy in advanced CD123-positive hematological malignancies, a phase 1 pilot study.
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Aldoss, Ibrahim, Zhang, Jianying, Robbins, Marjorie, Song, Joo, Al Malki, Monzr M., Otoukesh, Salman, Sandhu, Karamjeet, Agrawal, Vaibhav, Herrera, Alex F., Popplewell, Leslie L., Ghoda, Lucy, Stein, Anthony, Marcucci, Guido, Forman, Stephen, and Pullarkat, Vinod
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HEMATOLOGIC malignancies , *HODGKIN'S disease , *CYTOKINE release syndrome , *IMMUNOTHERAPY , *CANCER remission - Abstract
CD123 "expression" is common in hematological malignancies, including acute lymphoblastic leukemia (ALL). Flotetuzumab is a novel, investigational CD3/CD123 DART®. We conducted a phase 1 study evaluating safety and efficacy of flotetuzumab in relapsed/refractory ALL (Cohort A) and other advanced CD123-positive hematological malignancies (excluding myeloid malignancies) (cohort B). Thirteen patients (9 in Cohort A and 4 in Cohort B) were treated at dose level 1 (500 ng/kg/day) before early closure due to discontinuation of drug development by sponsor. Two dose limiting toxicities (Grade 4 thrombocytopenia and neutropenia) occurred in one patient in Cohort B. Cytokine release syndrome occurred in most patients (85%), all being grade ≤2. Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin's lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies. [ABSTRACT FROM AUTHOR]
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- 2024
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154. Therapy‐related acute lymphoblastic leukaemia in women with antecedent breast cancer.
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Pourhassan, Hoda, Zhang, Jianying, Tinajero, Jose, Pullarkat, Vinod, Agrawal, Vaibhav, Koller, Paul, Al Malki, Monzr, Aribi, Ahmed, Salhotra, Amandeep, Sandhu, Karamjeet, Ali, Haris, Stein, Anthony, Marcucci, Guido, Forman, Stephen, and Aldoss, Ibrahim
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LYMPHOBLASTIC leukemia , *ACUTE leukemia , *BREAST cancer , *CARCINOGENS , *PHILADELPHIA chromosome - Abstract
Summary: Therapy‐related acute lymphoblastic leukaemia (tr‐ALL) is a disease entity attributed to previous exposure to chemotherapy and/or radiation for antecedent malignancy. There is observed female predominance for tr‐ALL, likely due to high prevalence and excellent curable rate for non‐metastatic breast cancer as well as the frequent use of carcinogenic agents as part of adjuvant therapy. Here, we reviewed 37 women with diagnosis of ALL following breast cancer treatment with focus on cytogenetic categorization. Philadelphia chromosome positivity (Ph+), KMT2A alterations and other cytogenetic change groups were observed in 32%, 22% and 46% of patients respectively. Median overall survival (OS) and relapse‐free survival (RFS) were 19.4 and 12.9 months, overall while both OS and RFS were superior in tr‐ALL with Ph+ disease compared to KMT2Ar and other cytogenetics respectively. Seventeen (45.9%) patients underwent consolidative allogeneic haematopoietic cell transplantation (alloHCT) in CR1 out of which 4 (24%) relapsed following transplant. Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr‐ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT. [ABSTRACT FROM AUTHOR]
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- 2024
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155. High remission rates and transition to allogeneic transplant in older patients with newly diagnosed FLT-3 mutated acute myelogenous leukemia with midostaurin plus intensive chemotherapy.
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Tinajero, Jose, Ngo, Dat, Zhang, Jianying, Tsai, Ni-Chun, Aribi, Ahmed, Aldoss, Ibrahim, Agrawal, Vaibhav, Arslan, Shukaib, Amanam, Idoroenyi, Pourhassan, Hoda, Sandhu, Karamjeet, Al-Malki, Monzr, Pullarkat, Vinod, Becker, Pamela, Nakamura, Ryotaro, Stein, Anthony, Marcucci, Guido, Artz, Andrew, Koller, Paul, and Salhotra, Amandeep
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ACUTE myeloid leukemia , *OLDER patients - Abstract
This document presents data on the outcomes and toxicities of a treatment regimen for older adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML). The study found that the treatment approach, which included induction chemotherapy with the addition of midostaurin, resulted in a high complete remission rate and a median overall survival of 9.3 months. Additionally, a significant number of patients underwent allogeneic hematopoietic stem cell transplantation (allo-HCT) with favorable outcomes. The authors conclude that this treatment approach is feasible and effective for older adults with FLT3-mutated AML. However, the study lacked long-term follow-up and data on minimal residual disease achievement and allo-HCT outcomes. [Extracted from the article]
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- 2024
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156. A Randomized Open Label Pilot Study of Clostridium ButyricumMiyairi 588 (CBM588) in Recipients of Allogeneic Hematopoietic Cell Transplantation
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Sandhu, Karamjeet S., Yang, Dongyun, Mokhtari, Sally, Dadwal, Sanjeet S, Pullarkat, Vinod A., Al Malki, Monzr M., Cao, Thai, Spielberger, Ricardo, Salhotra, Amandeep, Ali, Haris, Artz, Andrew S., Stein, Anthony S., Htut, Myo, Budde, Elizabeth, Popplewell, Leslie L., Xu, Harry, Reining, Lauren, Ghoda, Lucy Y, Aldoss, Ibrahim, Marcucci, Guido, Forman, Stephen J, Highlander, Sarah, and Nakamura, Ryotaro
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The gut microbiota plays an important role in maintaining intestinal homeostasis by regulating the maturation of the mucosal immune system, which constitutes an immune barrier for the integrity of the intestinal tract. In recent years, the role of the human GI microbiota in graft-versus-host disease (GVHD) and other outcomes after allogeneic hematopoietic cell transplantation (HCT) has been increasingly evaluated in observational studies. However, there have been limited interventional trials specifically designed to alter the microbiota of HCT recipients. CBM588 (clostridium butyricum MIYAIRI 588) is a novel Live Biotherapeutic Product (LBP) that produces short chain organic acids, mainly butyric acid, which plays a key role in the maintenance of colonic homeostasis by regulating fluid and electrolyte uptake, epithelial cell growth, and inflammatory responses. In this pilot trial (NCT03922035) we sought to determine the safety, feasibility, biologic activities, and preliminary efficacy of CBM588 in HCT recipients.
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- 2021
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157. Treatment of relapsed or refractory FLT-3 acute myelogenous leukemia with a triplet regimen of hypomethylating agent, venetoclax, and gilteritinib.
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Ngo, Dat, Tinajero, Jose, Li, Shanpeng, Palmer, Joycelynne, Pourhassan, Hoda, Aribi, Ahmed, Nakamura, Ryotaro, Stein, Anthony, Marcucci, Guido, Salhotra, Amandeep, Sandhu, Karamjeet, Pullarkat, Vinod, Ball, Brian, and Koller, Paul
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ACUTE myeloid leukemia , *VENETOCLAX , *HEMATOPOIETIC stem cells , *STEM cell transplantation , *PROTEIN-tyrosine kinases - Abstract
Relapsed or refractory (R/R) acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations remains a difficult and hard to treat entity. Gilteritinib is a potent oral FLT-3 inhibitor that improves overall survival in R/R AML, but studies are limited in combining gilteritinib with a hypomethylating agent and venetoclax treatment backbone (HMA-VEN-GILT). Here we report our experience with HMA-VEN-GILT for 22 R/R FLT3 AML patients. HMA-VEN-GILT yielded an ORR of 77.3% (17/22), CR 4.5% (1/22), CRi 13.6% (3/22), MLFS 59.1% (13/22). Median follow-up was 10.4 months with a relapse rate of 29.4% (5/17), median time to relapse of 69 days (range 35–298 days), 6-month overall survival of 84%, and median OS of 10.1 months. Additionally, 36.4% (8/22) of patients proceeded to hematopoietic stem cell transplant. In conclusion, HMA-VEN-GILT for the treatment of R/R FLT3 AML is feasible and can be used as a bridge to allogeneic transplantation. [ABSTRACT FROM AUTHOR]
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- 2024
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158. WT1-mutated acute myeloid leukemia is sensitive to fludarabine-based chemotherapy and conditioning regimens.
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Aribi, Ahmed, Salhotra, Amandeep, Afkhami, Michelle, Munteanu, Anamaria, Ali, Haris, Aldoss, Ibrahim, Otoukesh, Salman, Al Malki, Monzr M., Sandhu, Karamjeet S., Koller, Paul, Arslan, Shukaib, Stewart, Forrest, Artz, Andrew, Curtin, Peter, Ball, Brian, O'Hearn, James, Spielberger, Ricardo, Smith, Eileen, Budde, Elizabeth, and Nakamura, Ryotaro
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ACUTE myeloid leukemia , *STEM cell transplantation , *CANCER chemotherapy , *FLUDARABINE - Abstract
We conducted a retrospective analysis of WT1-mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with WT1-mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent ex vivo study, WT1-mutated AML samples exhibited greater sensitivity to fludarabine (p = 0.026) and melphalan (p = 0.0005) than non-WT1-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with WT1 mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS. [ABSTRACT FROM AUTHOR]
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- 2023
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159. Use of monoclonal antibody therapy in hematologic patients with mild-to-moderate COVID-19: A retrospective single-center experience.
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Amanam, Idoroenyi, Janny Yao, Puing, Alfredo, Ni-Chun Tsai, Samuels, Diana, Dat Ngo, Stephanie Ho, Ali, Haris, Aribi, Ahmed, Arslan, Shukaib, Artz, Andrew, Myo Htut, Koller, Paul, Salhotra, Amandeep, Sandhu, Karamjeet, Liana Nikolaenko, Pawlowska, Anna, Shouse, Geoffrey, Stein, Anthony, and Marcucci, Guido
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COVID-19 , *MONOCLONAL antibodies , *VIRAL shedding , *HEMATOLOGIC malignancies - Abstract
Introduction: In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression. Methods: We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. Results: Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n = 0/26 and 36% n = 4/11, respectively; p < 0.01). Conclusions: This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients. [ABSTRACT FROM AUTHOR]
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- 2023
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160. Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia.
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Ngo, Dat, Tinajero, Jose, Zhang, Jianying, Stein, Anthony, Marcucci, Guido, Salhotra, Amandeep, Pullarkat, Vinod, Sandhu, Karamjeet S, Ball, Brian J, Pourhassan, Hoda, and Koller, Paul
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ACUTE myeloid leukemia , *PROTEIN-tyrosine kinases , *MYCOSES , *ANTINEOPLASTIC agents , *CYTOCHROME P-450 CYP3A - Abstract
Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 mutated (FLT3m) acute myeloid leukemia (AML). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as midostaurin through the CYP3A pathway. However, there are no midostaurin related dose modifications recommended with strong CYP3A inhibitors.We retrospectively reviewed 40 patients between 2017–2022 and compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3m AML.Median age of both groups was approximately 55 years and 70% of patients harbored FLT-3 internal tandem duplication mutations. Most patients in the concurrent arm were on either posaconazole (33%) or isavuconazole (50%) for antifungal prophylaxis and micafungin (72%) for the sequential/no azole arm. Overall CR/CRi rate with concurrent versus sequential/no azole were 72% and 77%, and non-hematologic grade 3 toxicities were 22% and 40% (
p = 0.21), respectively. Rates of dose reductions (6% vs. 0%,p = 0.26) and held doses (17% vs. 14%,p = 0.79) were not different between concurrent and sequential/no azole. There were no differences in the rates of new fungal infection during induction between the two groups.Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size. [ABSTRACT FROM AUTHOR]- Published
- 2024
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161. Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplant with Fludarabine and Melphalan Conditioning and Tacrolimus/Sirolimus as Graft-versus-Host Disease Prophylaxis in Patients with Acute Lymphoblastic Leukemia.
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Mei, Matthew, Tsai, Ni-Chun, Mokhtari, Sally, Al Malki, Monzr M., Ali, Haris, Salhotra, Amandeep, Sandhu, Karamjeet, Khaled, Samer, Smith, Eileen, Snyder, David, Marcucci, Guido, Forman, Stephen J., Pullarkat, Vinod, Stein, Anthony, Aldoss, Ibrahim, and Nakamura, Ryotaro
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FLUDARABINE , *LYMPHOBLASTIC leukemia , *ALEMTUZUMAB , *ACUTE leukemia , *GRAFT versus host disease , *RAPAMYCIN , *TACROLIMUS - Abstract
• HCT outcomes in ALL patients after Flu/Mel conditioning & Tac/Siro GVHD prophylaxis. • OS and PFS at 4 years were 58% and 44%, respectively. • Cumulative incidences of relapse and NRM at 4 years were 34% and 22%, respectively. • Patients with Philadelphia chromosome–positive (Ph+) status had lower relapse. • This regimen had favorable outcomes in adult ALL patients with Ph+ status. Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome–positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P =.007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL. [ABSTRACT FROM AUTHOR]
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- 2020
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162. Outcomes of Allogeneic Hematopoietic Cell Transplantation after Salvage Therapy with Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.
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Salhotra, Amandeep, Yang, Dongyun, Mokhtari, Sally, Malki, Monzr M. Al, Ali, Haris, Sandhu, Karamjeet S., Aribi, Ahmed, Khaled, Samer, Mei, Matthew, Budde, Elizabeth, Snyder, David, Cao, Thai, Spielberger, Ricardo, Marcucci, Guido, Pullarkat, Vinod, Forman, Stephen J., Nakamura, Ryotaro, Stein, Anthony, and Aldoss, Ibrahim
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CELL transplantation , *LYMPHOBLASTIC leukemia , *SALVAGE therapy , *ACUTE leukemia , *BISPECIFIC antibodies , *ALEMTUZUMAB , *RITUXIMAB - Abstract
• HCT outcomes were analyzed in r/r ALL patients, after salvage with blinatumomab. • Pre-HCT blinatumomab was given for morphologic (n = 24) or MRD-positive disease (n = 11). • No unusual toxicities or delayed engraftment was observed post-HCT. • Subgroup analysis (MRD/cytogenetics) showed no significant difference in survival. • Blinatumomab may be considered as a safe and effective salvage therapy pre-HCT. Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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163. Long-Term Outcomes of Patients with Acute Myelogenous Leukemia Treated with Myeloablative Fractionated Total Body Irradiation TBI-Based Conditioning with a Tacrolimus- and Sirolimus-Based Graft-versus-Host Disease Prophylaxis Regimen: 6-Year Follow-Up from a Single Center
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Salhotra, Amandeep, Hui, Susanta, Yang, Dongyun, Mokhtari, Sally, Mei, Matthew, Al Malki, Monzr M., Aldoss, Ibrahim, Ali, Haris, Sandhu, Karamjeet S., Aribi, Ahmed, Khaled, Samer, Dandapani, Savita, Peng, Kelly, Teh, Jennifer Berano, Murata-Collins, Joyce, Budde, Elizabeth, Dadwal, Sanjeet, Pullarkat, Vinod, Snyder, David, and Spielberger, Ricardo
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BUSULFAN , *ACUTE myeloid leukemia , *TOTAL body irradiation , *GRAFT versus host disease , *MEDICAL registries , *HEPATIC veno-occlusive disease , *ALEMTUZUMAB , *CELL transplantation - Abstract
• Fractionated total body irradiation-based myeloablative conditioning is well tolerated in young adults with acute myelogenous leukemia. • Tacrolimus/sirolimus graft-versus-host disease (GVHD) prophylaxis was associated with high rates of chronic GVHD (71%). • GVHD-free, relapse free survival at 2 years was low (39%), indicating the dynamic nature of chronic GVHD. • This regimen was associated with a low risk of long-term toxicities. Cyclophosphamide (Cy)/etoposide combined with fractionated total body irradiation (FTBI) or i.v. busulfan (Bu) has been the main conditioning regimens for allogeneic hematopoietic cell transplantation (alloHCT) for young patients with acute myelogenous leukemia (AML) eligible for a myeloablative conditioning (MAC) regimen. Recent data has suggested that i.v. Bu could be the preferred myeloablative regimen in patients with myeloid malignancies. However, Bu-based regimens are associated with higher rates of sinusoidal obstruction syndrome. Here we report long-term survival outcomes of patients with AML receiving FTBI combined with Cy or etoposide before undergoing alloHCT at City of Hope (COH). We obtained a retrospective review of a prospectively maintained institutional registry of clinical outcomes in 167 patients (median age, 41 years; range, 18 to 57 years) with AML in first or second complete remission who underwent alloHCT at COH between 2005 and 2015. Eligible patients received a MAC regimen with FTBI (1320 cGy) and Cy (120 mg/kg) for unrelated donor transplantation or etoposide (60 mg/kg) for related donor transplantation. Graft-versus-host disease (GVHD) prophylaxis was provided with tacrolimus and sirolimus. In this retrospective study, 6-year overall survival was 60% and nonrelapse mortality was 15%. The GRFS rate was 45% at 1 year and 39% at 2 years. We also describe late metabolic effects and report the cumulative incidence of secondary malignancies (9.5%). Overall, in this young adult patient population, our results compare favorably to chemotherapy-based (i.v. Bu) conditioning regimens without significant long-term toxicity arising from TBI-based regimens. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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164. Melphalan-Based Reduced-Intensity Conditioning is Associated with Favorable Disease Control and Acceptable Toxicities in Patients Older Than 70 with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.
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Al Malki, Monzr M., Nathwani, Nitya, Yang, Dongyun, Armenian, Saro, Dadwal, Sanjeet, Salman, Jaroslava, Mokhtari, Sally, Cao, Thai, Sandhu, Karamjeet, Rouse, Michelle, Mei, Matthew, Ali, Haris, Parker, Pablo, Alvarnas, Joseph, Smith, Eileen, Donnell, Margaret O., Marcucci, Guido, Snyder, David, Nademanee, Auayporn, and Forman, Stephen J.
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HEMATOPOIETIC stem cell transplantation , *MELPHALAN , *HEMATOLOGIC malignancies , *GRAFT versus host disease , *NEUTROPHILS , *ACUTE myeloid leukemia , *OLDER patients , *PROGRESSION-free survival , *PATIENTS - Abstract
Highlights • Semiablative melphalan-based conditioning regimen is safe for eligible elderly patients. • Rapid hematopoietic reconstitution after this regimen led to favorable survival outcomes. • Morbidity indicators (infection, etc.) were similar to younger patients undergoing same regimen. • This regimen is effective with promising relapse rate and minimal toxicities for patients > 70. Abstract Allogeneic hematopoietic stem cell transplantation (alloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent alloHCT with melphalan-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with the "semiablative" nature of this regimen. With a median follow-up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative incidence of relapse at 1 and 2 years was 17.0% and 19.3%, respectively. One hundred–day cumulative incidence of grades II to IV acute graft-versus-host disease was 37.7% (grades III to IV, 18.9%), and 2-year cumulative incidence of chronic graft-versus-host disease was 61.9% (extensive, 45.9%). The only significant predictor for poor OS was high/very high disease risk index. Transplant-related complications and morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion, alloHCT with a melphalan-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse, and favorable OS and PFS in patients aged 70 years or older. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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165. Allogeneic Hematopoietic Cell Transplantation for Adult T Cell Acute Lymphoblastic Leukemia.
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Hamilton, Betty Ky, Rybicki, Lisa, Abounader, Donna, Adekola, Kehinde, Advani, Anjali, Aldoss, Ibrahim, Bachanova, Veronika, Bashey, Asad, Brown, Stacey, DeLima, Marcos, Devine, Steven, Flowers, Christopher R., Ganguly, Siddharth, Jagasia, Madan, Kennedy, Vanessa E., Kim, Dennis Dong Hwan, McGuirk, Joseph, Pullarkat, Vinod, Romee, Rizwan, and Sandhu, Karamjeet
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HEMATOPOIETIC stem cell transplantation , *LYMPHOBLASTIC leukemia , *T cells , *TOTAL body irradiation , *CORD blood , *PHYSIOLOGY - Abstract
Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P = .021), age >35 years (HR, 1.55; P = .025), and disease status at HCT (HR, 1.98; P = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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166. Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.
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Othman T, Koller P, Tsai NC, Yang D, Pourhassan H, Agrawal V, Ngo D, Chen J, Farol L, Spielberger R, Sahebi F, Al Malki MM, Cai JL, Sandhu KS, Mansour J, Salhotra A, Ali H, Aribi A, Arslan S, Marcucci G, Forman SJ, Stein AS, Nakamura R, Pullarkat V, Aldoss I, and Mei M
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Retrospective Studies, Aged, Maintenance Chemotherapy, Philadelphia Chromosome, Pyridazines therapeutic use, Pyridazines adverse effects, Pyridazines administration & dosage, Imatinib Mesylate therapeutic use, Imatinib Mesylate adverse effects, Imatinib Mesylate administration & dosage, Imidazoles adverse effects, Imidazoles administration & dosage, Imidazoles therapeutic use, Young Adult, Transplantation, Homologous, Adolescent, Tyrosine Kinase Inhibitors, Hematopoietic Stem Cell Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors administration & dosage
- Abstract
Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common., (© 2024 Wiley Periodicals LLC.)
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- 2024
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167. Comparing transplant outcomes in ALL patients after myeloablative conditioning in mismatch-related or unrelated donor settings.
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Otoukesh S, Yang D, Mokhtari S, Pourhassan H, Agrawal V, Arslan S, Amanam I, Ball B, Koller P, Salhotra A, Sandhu K, Aribi A, Artz A, Aldoss I, Pullarkat V, Ali H, Blackmon A, Becker P, Curtin P, Stewart F, Smith E, Stein A, Marcucci G, Forman SJ, Nakamura R, and Al Malki MM
- Abstract
The optimal myeloablative conditioning regimen for ALL patients undergoing hematopoietic cell transplant (HCT) with an alternative donor is unknown. We analyzed HCT outcomes ALL patients (n = 269) who underwent HCT at our center from 2010 to 2020 in complete remission (CR) after FTBI-etoposide and CNI-based GvHD prophylaxis for matched donor HCT (ETOP-package; n = 196) or FTBI-Fludarabine and post-transplant cyclophosphamide (PTCy)-based prophylaxis for HLA- mismatched (related or unrelated) donors (FLU-package; n = 64). Patients in FLU-package showed a significant delay in engraftment (p < 0.001) and lower cumulative incidence (CI) of any and extensive chronic GVHD (p = 0.009 and 0.001, respectively). At the median follow up of 4.6 years (range 1-12 years); non-relapse mortality, overall or leukemia-free survival and GVHD-free/relapse-free survival were not significantly impacted by the choice of conditioning. However, in patients at CR2 or with measurable residual disease (MRD+), there was a trend towards higher relapse after FLU-package (p = 0.08 and p = 0.07, respectively), while patients at CR1 regardless of MRD status had similar outcomes despite the package/donor type (p = 0.9 and 0.7, respectively). Our data suggests that FLU-package for alternative donors offers comparable outcomes to ETOP-package for matched donor HCT to treat ALL. Disease status and depth of remission at HCT were independent predictors for better outcomes., (© 2024. The Author(s).)
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- 2024
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168. Consolidation with First and Second Allogeneic Transplants in Adults with Relapsed/Refractory B-ALL Following Response to CD19CAR T Cell Therapy.
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Aldoss I, Shan H, Yang D, Clark MC, Al Malki M, Aribi A, Agrawal V, Sandhu K, Salhotra A, Pourhassan H, Koller P, Ali H, Artz A, Karras N, Pawlowska AB, Murphy L, Palmer J, Stein A, Marcucci G, Pullarkat V, Nakamura R, and Forman SJ
- Subjects
- Humans, Adult, Female, Male, Middle Aged, Retrospective Studies, Young Adult, Transplantation, Homologous methods, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Recurrence, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Receptors, Chimeric Antigen therapeutic use, Adolescent, Aged, Hematopoietic Stem Cell Transplantation, Antigens, CD19 immunology, Immunotherapy, Adoptive methods
- Abstract
CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR-T therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). Considering the limited published data for the utility of post CAR-T therapy consolidative alloHCT in r/r B-ALL, especially data related to patients receiving a second alloHCT, we sought to describe outcomes of patients with r/r B-ALL at our institution who received their first or second alloHCT following response to CAR-T therapy. We performed a retrospective analysis of adult patients with r/r B-ALL who responded to either investigational or standard of care (SOC) CD19-targeted CAR-T therapy and underwent consolidation with alloHCT while in CR without interim therapy. We identified 45 patients, of whom 26 (58%) and 19 (42%) received their first and second alloHCT as consolidation post CAR-T therapy, respectively. The median age was 31 years (range: 19-67) and 31 (69%) patients were Hispanic. Ph-like was the most common genetic subtype and comprised over half of cases (53%; n = 24). The median number of prior therapies pre-transplant was 5 (range: 2-7), and disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 7 (16%), 22 (49%) and 16 (35%) patients, respectively. The median time from CAR-T therapy until alloHCT was 93 (range: 42-262) days. The conditioning regimen was radiation-based myeloablative (MAC) in 22 (49%) patients. With a median follow-up of 2.47 years (range: 0.13-6.93), 2-year overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 57.3% (95% CI: 0.432-0.760), 56.2% (95% CI: 0.562-0.745), 23.3% (95% CI: 0.13-0.42), and 20.4% (95% CI: 0.109-0.384), respectively. Two-year OS (52% vs. 68%, P = .641), RFS (54% vs. 59%, P = .820), CIR (33.5% vs. 8.5%, P = .104), and NRM (12.5% vs. 32.2%, P = .120) were not significantly different between patients who underwent their first vs. second transplant, respectively. In univariate analysis, only Ph-like genotype was associated with inferior RFS (P = .03). AlloHCT post CAR-T response is associated with a relatively low early mortality rate and encouraging survival results in high-risk adults with r/r B-ALL, extending to the second alloHCT for fit and eligible patients., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2024
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169. Outcomes following allogeneic hematopoietic cell transplantation relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia.
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Othman T, Li S, Zhang J, Pourhassan H, Agrawal V, Ngo D, Chen J, Farol L, Sahebi F, Sandhu K, Spielberger R, Marcucci G, Forman SJ, Stein AS, Nakamura R, Pullarkat V, Mei M, Aldoss I, and Koller P
- Subjects
- Humans, Male, Female, Adult, Middle Aged, Allografts, Treatment Outcome, Aged, Hematopoietic Stem Cell Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Recurrence, Philadelphia Chromosome, Transplantation, Homologous
- Abstract
Improved first progression-free survival following allogeneic hematopoietic cell transplantation relapse with the use of immunotherapy., (© 2024 Wiley Periodicals LLC.)
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- 2024
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170. Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.
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Wang ES, Goldberg AD, Tallman M, Walter RB, Karanes C, Sandhu K, Vigil CE, Collins R, Jain V, and Stone RM
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- Humans, Middle Aged, Adult, Female, Male, Aged, Young Adult, Piperidines administration & dosage, Piperidines adverse effects, Piperidines therapeutic use, Benzimidazoles administration & dosage, Benzimidazoles adverse effects, Benzimidazoles therapeutic use, Induction Chemotherapy, Cytarabine administration & dosage, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Mutation
- Abstract
Purpose: Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD - and TKD -mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3 -mutant AML., Methods: Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m
2 ) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m2 or idarubicin 12 mg/m2 , once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m2 twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant., Results: Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD , and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3 -mutant clones were detected at relapse in patients completing consolidation., Conclusion: Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3 -mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.- Published
- 2024
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171. A review of low dose interleukin-2 therapy in management of chronic graft-versus-host-disease.
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Salhotra A, Falk L, Park G, Sandhu K, Ali H, Modi B, Hui S, and Nakamura R
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- Humans, Interleukin-2 therapeutic use, T-Lymphocytes, Regulatory, Immunotherapy, Chronic Disease, Bronchiolitis Obliterans Syndrome, Graft vs Host Disease drug therapy
- Abstract
Introduction: Patients with chronic graft versus host disease (cGVHD) have low circulating regulatory T cells (Tregs). Interleukin-2(IL-2) is a growth factor for Tregs, and clinical trials have explored its use in cGVHD patients., Areas Covered: Here we will discuss the biology of IL-2, its rationale for use and results of clinical trials in cGVHD. We also describe its mechanisms of action and alteration in gene expression in T-cell subsets after treatment with low dose IL-2 and photopheresis., Expert Opinion: Clinical trials using Low dose IL-2 have been done at single centers in small patient series. The majority of the clinical responses seen with IL-2 in cGVHD are classified as partial responses and efficacy as a single agent is limited. Compared to currently approved oral therapies, it has to be administered subcutaneously and requires specialized processing for compounding and storage limiting its widespread use. Its use is associated with constitutional symptoms and local injection site reactions. Local reactions can be easily managed by supportive care practices like rotation of injection sites and premeditations, constitutional symptoms resolve with, dose reduction (25-50%) allowing for continued therapy. Additional studies are needed to define optimal combination strategies with approved agents. Longer acting formulations of IL-2 that require less frequent dosing may also improve patient compliance.
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- 2024
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172. Incidence, clinical presentation, risk factors, outcomes, and biomarkers in de novo late acute GVHD.
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Akahoshi Y, Spyrou N, Hogan WJ, Ayuk F, DeFilipp Z, Weber D, Choe HK, Hexner EO, Rösler W, Etra AM, Sandhu K, Yanik GA, Chanswangphuwana C, Kitko CL, Reshef R, Kraus S, Wölfl M, Eder M, Bertrand H, Qayed M, Merli P, Grupp SA, Aguayo-Hiraldo P, Schechter T, Ullrich E, Baez J, Beheshti R, Gleich S, Kowalyk S, Morales G, Young R, Kwon D, Nakamura R, Levine JE, Ferrara JLM, and Chen YB
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- Adult, Humans, Male, Female, Incidence, Acute Disease, Biomarkers, Risk Factors, Graft vs Host Disease diagnosis, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology
- Abstract
Late acute graft-versus-host disease (GVHD) is defined as de novo acute GVHD presenting beyond 100 days after allogeneic hematopoietic cell transplantation (HCT) without manifestations of chronic GVHD. Data are limited regarding its characteristics, clinical course, and risk factors because of underrecognition and changes in classification. We evaluated 3542 consecutive adult recipients of first HCTs at 24 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 2014 and August 2021 to better describe the clinical evolution and outcomes of late acute GVHD. The cumulative incidence of classic acute GVHD that required systemic treatment was 35.2%, and an additional 5.7% of patients required treatment for late acute GVHD. At the onset of symptoms, late acute GVHD was more severe than classic acute GVHD based on both clinical and MAGIC algorithm probability biomarker parameters and showed a lower overall response rate on day 28. Both clinical and biomarker grading at the time of treatment stratified the risk of nonrelapse mortality (NRM) in patients with classic and late acute GVHD, respectively, but long-term NRM and overall survival did not differ between patients with classic and late acute GVHD. Advanced age, female-to-male sex mismatch, and the use of reduced intensity conditioning were associated with the development of late acute GVHD, whereas the use of posttransplant cyclophosphamide-based GVHD prevention was protective mainly because of shifts in GVHD timing. Because overall outcomes were comparable, our findings, although not definitive, suggest that similar treatment strategies, including eligibility for clinical trials, based solely on clinical presentation at onset are appropriate., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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173. Health-Related Quality of Life in Double Umbilical Cord Blood versus Haploidentical Marrow Transplantation: A Quality of Life Analysis Report of BMT CTN 1101.
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El Jurdi N, Martens MJ, Brunstein CG, O'Donnell P, Lee SJ, D'Souza A, Logan B, Hong S, Singh AK, Sandhu K, Shapiro RM, Horowitz MM, and Hamilton BK
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- Humans, Bone Marrow, Fetal Blood, Quality of Life, Neoplasm Recurrence, Local, Chronic Disease, Bone Marrow Transplantation methods, Graft vs Host Disease epidemiology
- Abstract
The Blood and Marrow Transplant Clinical Trials Network study 1101 (BMT CTN 1101; ClinicaTrials.gov identifier NCT01597778) was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QoL) of patients with hematologic malignancies undergoing double umbilical cord blood transplantation (dUCBT) or HLA-haploidentical bone marrow transplantation (haplo-BMT) after reduced-intensity conditioning. At a 5-year follow-up, there were no significant differences in progression- free survival (PFS) or overall survival (OS) between the 2 cohorts. The impact of alternative donor source on QoL is unknown, however. English- and Spanish-speaking patients completed the Functional Assessment of Cancer Therapy-General (FACT-G), Short Form 36 (SF-36), EuroQoL-5 Dimensions EQ-5D, and Global QoL patient-reported outcome (PRO) assessments pretransplantation and at 12 and 24 months post-transplantation. We compared longitudinal QoL measures between the dUCBT and haplo-BMT cohorts and investigated the association of QoL and clinical outcomes using an inverse probability weighted-independent estimating equations method, accounting for missingness and baseline variables. We found no significant differences between the 2 cohorts in any of the QoL scores pretransplantation and at 12 and 24 months post-transplantation. Pretransplantation scores were the only significant predictors of post-transplantation QoL scores. Relapse and grade III-IV acute graft-versus-host disease (GVHD) were associated with significant declines in mean FACT-BMT and SF-36 Physical Component scores, and chronic GVHD was associated with a decline in mean EQ-5D utility scores. There were no significant associations between pretransplantation QoL scores and OS or PFS. Donor type did not impact post-transplantation QoL. Pretransplantation QoL scores and clinical events of GVHD and relapse were the only predictors of post-transplantation QoL. QoL was not associated with survival in either treatment arm. PROs may be valuable tools in pretransplantation risk assessment strategies to improve QoL outcomes., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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174. High response rates and transition to transplant after novel targeted and cellular therapies in adults with relapsed/refractory acute lymphoblastic leukemia with Philadelphia-like fusions.
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Aldoss I, Afkhami M, Yang D, Gu Z, Mokhtari S, Shahani S, Pourhassan H, Agrawal V, Koller P, Arslan S, Tomasian V, Al Malki MM, Artz A, Salhotra A, Ali H, Aribi A, Sandhu KS, Ball B, Otoukesh S, Amanam I, Becker PS, Stewart FM, Curtin P, Smith E, Telatar M, Stein AS, Marcucci G, Forman SJ, Nakamura R, and Pullarkat V
- Subjects
- Adult, Humans, Retrospective Studies, Inotuzumab Ozogamicin therapeutic use, Remission Induction, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Hematopoietic Stem Cell Transplantation, Antibodies, Bispecific therapeutic use
- Abstract
Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is associated with a poor response to standard chemotherapy. However, outcomes with novel antibody and cellular therapies in relapsed/refractory (r/r) Ph-like ALL are largely unknown. We conducted a single-center retrospective analysis of adult patients (n = 96) with r/r B-ALL and fusions associated with Ph-like who received novel salvage therapies. Patients were treated with 149 individual novel regimens (blinatumomab = 83, inotuzumab ozogamicin [InO] = 36, and CD19CAR T cells = 30). The median age at first novel salvage therapy was 36 years (range; 18-71). Ph-like fusions were IGH::CRLF2 (n = 48), P2RY8::CRLF2 (n = 26), JAK2 (n = 9), ABL-class (n = 8), EPOR::IGH (n = 4) and ETV6::NTRK2 (n = 1). CD19CAR T cells were administered later in the course of therapy compared to blinatumomab and InO (p < .001) and more frequently in recipients who relapsed after allogeneic hematopoietic cell transplantation (alloHCT) (p = .002). Blinatumomab was administered at an older age compared to InO and CAR T-cells (p = .004). The complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates were 63%, 72%, and 90% following blinatumomab, InO and CD19CAR, respectively, among which 50%, 50%, and 44% of responders underwent consolidation with alloHCT, respectively. In multivariable analysis, the type of novel therapy (p = .044) and pretreatment marrow blasts (p = .006) predicted the CR/CRi rate, while the Ph-like fusion subtype (p = .016), pretreatment marrow blasts (p = .022) and post-response consolidation with alloHCT (p < .001) influenced event-free survival. In conclusion, novel therapies are effective in inducing high remission rates in patients with r/r Ph-like ALL and successfully transitioning the responders to alloHCT., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
- Published
- 2023
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175. Post-Transplantation Sinusoidal Obstruction Syndrome in Adult Patients with B Cell Acute Lymphoblastic Leukemia Treated with Pretransplantation Inotuzumab.
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Agrawal V, Pourhassan H, Tsai NC, Ngo D, Koller P, Malki MMA, Salhotra A, Ali H, Aribi A, Sandhu KS, Arslan S, Ball B, Otoukesh S, Amanam I, Artz A, Singh D, Becker PS, Stewart FM, Smith EP, Curtin P, Stein AS, Marcucci G, Forman SJ, Nakamura R, Pullarkat V, and Aldoss I
- Subjects
- Humans, Adult, Inotuzumab Ozogamicin adverse effects, Sirolimus, Hepatic Veno-Occlusive Disease drug therapy, Hepatic Veno-Occlusive Disease etiology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma chemically induced, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma complications, Burkitt Lymphoma chemically induced, Burkitt Lymphoma complications, Graft vs Host Disease prevention & control
- Abstract
Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication that can be observed after allogeneic hematopoietic cell transplantation (HCT). Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody-drug conjugate that has demonstrated high efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) but is associated with an increased risk of SOS in HCT recipients. Here we aimed to examine the incidence and outcomes of SOS in 47 adult patients with R/R ALL who received inotuzumab therapy and subsequently underwent HCT at our institution. All patients received prophylactic therapy with ursodiol, and continuous low-dose heparin also was administered to patients receiving myeloablative conditioning (MAC). SOS occurred in 12 patients (26%) post-HCT, at a median onset of 11 days (range, 3 to 41 days). SOS was graded as very severe in 50% (n = 6), severe in 25% (n = 3), and mild in 25% (n = 3). All patients diagnosed with SOS received treatment with defibrotide for a median of 21 days (range, 3 to 34 days), with resolution of SOS occurring in 8 patients (67%). Mortality from SOS was 33% (n = 4) and occurred at a median of 10 days from diagnosis (range, 3 to 31 days) in patients graded as very severe (n = 3) or severe (n = 1). There were no significant differences between patients who developed SOS and those who did not develop SOS in the median time from the last dose of inotuzumab to transplantation (46 days versus 53 days; P = .37), use of an MAC regimen (42% versus 49%; P = .75), number of lines of therapy prior to inotuzumab (P = .79), median number of administered cycles of inotuzumab (2 versus 2; P = .14), or receipt of inotuzumab as the last therapy prior to HCT (67% versus 66%; P = 1.0). Sirolimus-based graft-versus-host disease (GVHD) prophylaxis was used more frequently in the SOS group (75% versus 29%; P < .01), but there was no between-group difference in the peak sirolimus level (P = .81) or the median time to peak sirolimus level (7 days versus 3.5 days; P = .39). In univariable analysis, only the use of sirolimus-based GVHD prophylaxis was significantly associated with an increased risk of SOS (hazard ratio [HR], 7.50; 95% confidence interval [CI], 1.7 to 33.6; P < .01). In the SOS group, the 100-day mortality rate was 33% (n = 4), and median overall survival (OS) post-HCT was 4.3 months (range, 0.2 to 57.2 months). In the group without SOS, the 100-day mortality rate was 14% (n = 5) and the median OS post-HCT was 10.7 months (range, .52 to 39.6 months). In this study cohort, SOS was prevalent in HCT recipients who had been treated with inotuzumab prior to transplantation, and sirolimus-based GVHD prophylaxis was a risk factor for SOS in inotuzumab recipients., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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176. A phase 2 study of interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract.
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Ponce DM, Alousi AM, Nakamura R, Slingerland J, Calafiore M, Sandhu KS, Barker JN, Devlin S, Shia J, Giralt S, Perales MA, Moore G, Fatmi S, Soto C, Gomes A, Giardina P, Marcello L, Yan X, Tang T, Dreyer K, Chen J, Daley WL, Peled JU, van den Brink MRM, and Hanash AM
- Subjects
- Humans, Lower Gastrointestinal Tract, Adrenal Cortex Hormones therapeutic use, Interleukin-22, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease drug therapy, Graft vs Host Disease etiology
- Abstract
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This trial was registered at www.clinicaltrials.gov as NCT02406651., (© 2023 by The American Society of Hematology.)
- Published
- 2023
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177. Association of pre-transplant vancomycin resistant enterococcus colonization status on long-term outcomes of allogeneic-hematopoietic cell transplantation.
- Author
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Salhotra A, Sandhu KS, Yang D, Mokhtari S, O'Hearn J, Tegtmeier B, Al Malki MM, Abella J, Meguro A, Dickter J, Khambapati S, Spielberger R, Artz A, Forman SJ, Smith E, Nakamura R, and Dadwal SS
- Subjects
- Humans, Vancomycin, Anti-Bacterial Agents therapeutic use, Retrospective Studies, Vancomycin-Resistant Enterococci, Hematopoietic Stem Cell Transplantation, Gram-Positive Bacterial Infections drug therapy
- Published
- 2023
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178. Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL.
- Author
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Aldoss I, Khaled SK, Wang X, Palmer J, Wang Y, Wagner JR, Clark MC, Simpson J, Paul J, Vyas V, Chien SH, Stein A, Pullarkat V, Salhotra A, Al Malki MM, Aribi A, Sandhu K, Thomas SH, Budde LE, Marcucci G, Brown CE, and Forman SJ
- Subjects
- Humans, Adult, Young Adult, Middle Aged, Aged, Immunotherapy, Adoptive adverse effects, T-Lymphocytes immunology, Antigens, CD19 immunology, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen therapeutic use, Lymphoma, B-Cell drug therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Purpose: A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL)., Patients and Methods: In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II., Results: The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22-72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05-0.48; P = 0.001)., Conclusions: Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD. See related commentary by El Marabti and Abdel-Wahab, p. 694., (©2022 American Association for Cancer Research.)
- Published
- 2023
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179. Outcomes of allogeneic hematopoietic cell transplantation in adults with fusions associated with Ph-like ALL.
- Author
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Aldoss I, Yang D, Tomasian V, Mokhtari S, Jackson R, Gu Z, Telatar M, Yew H, Al Malki MM, Salhotra A, Khaled S, Ali H, Aribi A, Sandhu KS, Mei M, Arslan S, Koller P, Artz A, Aoun P, Gu D, Snyder D, Stewart FM, Curtin P, Stein AS, Pillai R, Marcucci G, Forman SJ, Pullarkat V, Nakamura R, and Afkhami M
- Subjects
- Acute Disease, Adult, Humans, In Situ Hybridization, Fluorescence, Philadelphia, Recurrence, Retrospective Studies, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for acute lymphoblastic leukemia (ALL), yet large amounts of data describing alloHCT outcomes in Philadelphia (Ph)-like ALL are lacking. We retrospectively analyzed archived DNA samples from consecutive adults with B-cell Ph-negative ALL who underwent alloHCT in complete remission (CR) (n = 127) at our center between 2006 and 2020. Identification of fusions associated with Ph-like ALL was performed using cumulative results from RNA-seq, conventional cytogenetics, fluorescence in situ hybridization, and whole genome array studies. Fusions associated with Ph-like ALL were detected in 56 (44%) patients, of whom 38 were carrying CRLF2r. Compared with other non-Ph-like ALL (n = 71), patients with fusions associated with Ph-like ALL were more frequently Hispanic (P = .008), were less likely to carry high-risk cytogenetics (P < .001), and were more likely to receive blinatumomab prior to HCT (P = .019). With the median followup of 3.5 years, patients with Ph-like ALL fusions had comparable posttransplant outcomes compared with other B-cell ALL: 3-year relapse-free survival (RFS) (41% vs 44%; P = .36), overall survival (OS) (51% vs 50%; P = .59), and relapse (37% vs 31%; P = .47). In multivariable analysis, age (P = .023), disease status at the time of transplant (P < .001), and donor type (P = .015) influenced OS. RFS (primary endpoint) was significantly influenced by disease status (P < .001) and conditioning regimen intensity (P = .014). In conclusion, our data suggest that alloHCT consolidation results in similarly favorable survival outcomes in adult patients with Ph-like fusions and other high-risk B-cell ALL., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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180. Tacrolimus initial steady state level in post-transplant cyclophosphamide-based GvHD prophylaxis regimens.
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Yao JM, Yang D, Clark MC, Otoukesh S, Cao T, Ali H, Arslan S, Aldoss I, Artz A, Amanam I, Salhotra A, Pullarkat V, Sandhu K, Stein A, Marcucci G, Forman SJ, Nakamura R, and Al Malki MM
- Subjects
- Cyclophosphamide therapeutic use, Humans, Neoplasm Recurrence, Local drug therapy, Retrospective Studies, Tacrolimus therapeutic use, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Post-transplant cyclophosphamide (PTCy) combined with tacrolimus (TAC) as graft-versus-host disease (GvHD) prophylaxis post-hematopoietic cell transplantation (HCT) is safe and effective. Optimal serum levels of TAC in this combination remain undetermined. We hypothesized that TAC at initial steady state (TISS) of <10 ng/mL could promote optimal transplant outcomes and prevent TAC-associated toxicities. We retrospectively analyzed a consecutive case series of 210 patients who received PTCy/TAC-based prophylaxis post-HCT from 1/2013-6/2018. Patients received HCT from haploidentical (n = 172) or mismatched donors (n = 38), and flat dose (FD) or weight-based dose (WBD) TAC. Twenty-four-month overall survival (OS), disease free survival (DFS), and relapse rate (RR) were 61%, 56%, and 22%, respectively, in TISS < 10 ng/mL cohort (n = 176), and 50%, 43%, and 35%, respectively, in TISS ≥ 10 ng/mL cohort (n = 34) (OS, P = 0.71; DFS, P = 0.097; RR, P = 0.031). OS, DFS, RR, non-relapse mortality, acute GvHD grade II-IV, grade III-IV or chronic GvHD by TISS were similar in multivariable analysis. TISS ≥ 10 ng/mL conferred increased risk of viral infection (P = 0.003). More patients receiving FD vs. WBD had TISS < 10 ng/mL (P = 0.001). Overall, TISS < 10 ng/mL early post HCT conferred similar survival outcomes and lowered risk of viral infection and toxicities compared to TISS ≥ 10 ng/mL., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2022
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181. Use of high-dose mesna and hyperhydration leads to lower incidence of hemorrhagic cystitis after posttransplant cyclophosphamide-based allogeneic transplantation.
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Mac S, Ngo D, Yang D, Chen J, Ali H, Arslan S, Dadwal S, Salhotra A, Cao T, Karras N, Aldoss I, Koller P, Artz A, Aribi A, Sandhu K, Pullarkat V, Stein A, Marcucci G, Forman SJ, Nakamura R, and Al Malki MM
- Subjects
- Cyclophosphamide adverse effects, Humans, Incidence, Mesna adverse effects, Middle Aged, Retrospective Studies, Transplantation, Homologous, Cystitis epidemiology, Cystitis etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Currently, there is no consensus on best practices to prevent hemorrhagic cystitis (HC) in patients receiving posttransplant cyclophosphamide (PTCy). We retrospectively reviewed 194 patients undergoing their first hematopoietic cell transplant (HCT) who received PTCy from 2014 to 2018 to describe the incidence and severity of HC, identify potential risk factors, and impact of HC on HCT outcomes. Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was 31.4% at day +100 of HCT. Median onset of HC was 12 days with 11.5% grade 3 HC and no Grade 4 HC. Patients with chemical HC experienced earlier onset (7 days vs. 34 days, p < 0.001) with a shorter median resolution time (5 days vs. 14 days, p = 0.001) when compared to BK-associated HC. In multivariate analysis, age above 60 years (HR 4.16, p = 0.006) and myeloablative conditioning (HR 2.44, p = 0.054) were associated with higher risk for HC, but overall, HC did not affect nonrelapse mortality or overall survival. In conclusion, hyperhydration with forced diuresis combined with aggressive mesna dosing is an effective strategy in preventing severe PTCy-associated HC, subsequently preventing any negative impact on transplant outcome., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2021
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182. Allogeneic Hematopoietic Cell Transplantation for Relapsed and Refractory Philadelphia Negative B Cell ALL in the Era of Novel Salvage Therapies.
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Aldoss I, Yang D, Malki MMA, Mei M, Mokhtari S, Artz A, Cao T, Salhotra A, Ali H, Aribi A, Khaled S, Arslan S, Sandhu K, Koller P, Mansour J, Spielberger R, Stein A, Snyder D, Marcucci G, Forman SJ, Nakamura R, and Pullarkat V
- Subjects
- Adult, B-Lymphocytes, Humans, Retrospective Studies, Salvage Therapy, Hematopoietic Stem Cell Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Introduction of novel salvage therapies and expansion of the donor pool within the past decade have allowed more patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) to receive allogeneic hematopoietic cell transplantation (alloHCT). The impact of each salvage therapy on transplant outcomes have not been compared. Our primary objective was to determine post-HCT relapse-free survival (RFS) in adult patients with r/r Philadelphia-chromosome negative (Ph
neg ) B-ALL. We retrospectively studied alloHCT outcomes in 108 adult patients with r/r Phneg B-ALL transplanted in morphological remission achieved by salvage therapy. Salvage therapies were chemotherapy-based combination (n = 45, 42%), blinatumomab (n=43, 40%), inotuzumab (n = 14, 13%), or CAR T cells (n = 6, 6%). The 2-year RFS and overall survival (OS) were 44% and 50%, respectively. In multivariable analysis, conditioning with reduced-intensity or non-myeloablative regimens (hazard ratio [HR] = 2.23, 95% confidence interval [CI], 1.31-3.80; P = .003), having received ≥3 lines of therapies prior to transplant (HR = 2.66, 95% CI, 1.56-4.54; P < .001), and inotuzumab (HR = 2.42, 95% CI, 1.14-5.12; Wald P value = .021) were independently associated with lower RFS. Blinatumomab (HR = 1.10, 95% CI, 0.62-1.96) had comparable RFS to chemotherapy. Incidence of hepatic sinusoidal syndrome was highest with inotuzumab (P < .001); however, 30-day mortality and intensive care unit admissions were not different per salvage therapy. The alloHCT in r/r Phneg B-ALL after remission induction with blinatumomab or chemotherapy led to encouraging outcomes if morphologic CR was achieved. In contrast, pretransplantation inotuzumab therapy was associated with inferior RFS. Larger studies are warranted to confirm our observations. Early transplantation after relapse and the utilization of myeloablative conditioning, when feasible, were key factors associated with improved outcomes after alloHCT in these patients., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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183. Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin.
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Gergoudis SC, DeFilipp Z, Özbek U, Sandhu KS, Etra AM, Choe HK, Kitko CL, Ayuk F, Aziz M, Baez J, Ben-David K, Bunworasate U, Gandhi I, Hexner EO, Hogan WJ, Holler E, Kasikis S, Kowalyk SM, Lin JY, Merli P, Morales G, Nakamura R, Reshef R, Rösler W, Srinagesh H, Young R, Chen YB, Ferrara JLM, and Levine JE
- Subjects
- Biomarkers, Humans, Steroids, Graft vs Host Disease drug therapy, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept "preemptive" treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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184. Pulmonary hypertension is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation for myelofibrosis.
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Gupta R, Jamal F, Yang D, Chendri C, Aldoss I, Malki MA, Mei M, Salhotra A, Dobrin S, Tran M, Venkataraman K, Palmer J, Stein AS, Sandhu K, Khaled S, Aribi A, Marcucci G, Forman SJ, Snyder D, Nakamura R, Ali H, and Pullarkat V
- Subjects
- Humans, Retrospective Studies, Risk Factors, Hematopoietic Stem Cell Transplantation adverse effects, Hypertension, Pulmonary etiology, Primary Myelofibrosis therapy
- Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is the only curative therapy for primary myelofibrosis (MF) as well as myelofibrosis secondary to other myeloproliferative neoplasms (MPN). Pulmonary hypertension (PH) is a known complication of MF and may occur in up to 50% of such patients. PH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest) can eventually lead to right heart failure and may be associated with complications after alloHCT. We examined the association of PH with alloHCT outcome in patients with MF associated with MPN. Pre- and post-HCT echocardiograms were reviewed to estimate the peak pulmonary artery systolic pressure (PASP). Median PASP was 37.0 mmHg (range: 16.0-57.9) prior to HCT with 37 of 65 patients (57%) studied. With median follow-up of 35.0 months (range: 3.3-119.4) PH was significantly associated with inferior OS (58.9% vs. 88.8%, P = 0.025), primarily due to increased NRM (21.6% vs. 7.1%, P = 0.007). The majority of the deaths (8 of 14) in patients with PH occurred within 100 days after HCT. In patients with an available post-HCT echocardiogram (n = 33), the median PASP was 30 mmHg (range: 5.0-56.2); eight patients (24%) had persistent PH. Compared with pre-HCT values, PASP was significantly reduced after HCT (p < 0.001). We conclude that PH is associated with inferior survival due to the increased NRM in patients with MF undergoing alloHCT. PH appears at least partially reversible after successful alloHCT. PH should be considered a risk factor for early mortality after alloHCT and surveillance of pulmonary artery pressure in MF patients being considered for alloHCT may be useful.
- Published
- 2020
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185. The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease.
- Author
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Srinagesh HK, Özbek U, Kapoor U, Ayuk F, Aziz M, Ben-David K, Choe HK, DeFilipp Z, Etra A, Grupp SA, Hartwell MJ, Hexner EO, Hogan WJ, Karol AB, Kasikis S, Kitko CL, Kowalyk S, Lin JY, Major-Monfried H, Mielke S, Merli P, Morales G, Ordemann R, Pulsipher MA, Qayed M, Reddy P, Reshef R, Rösler W, Sandhu KS, Schechter T, Shah J, Sigel K, Weber D, Wölfl M, Wudhikarn K, Young R, Levine JE, and Ferrara JLM
- Subjects
- Acute Disease, Algorithms, Humans, Probability, Biomarkers blood, Graft vs Host Disease epidemiology, Graft vs Host Disease therapy
- Abstract
The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP), derived from 2 serum biomarkers, measures damage to crypts in the gastrointestinal tract during graft-versus-host disease (GVHD). We hypothesized that changes in MAP after treatment could validate it as a response biomarker. We prospectively collected serum samples and clinical stages of acute GVHD from 615 patients receiving hematopoietic cell transplantation in 20 centers at initiation of first-line systemic treatment and 4 weeks later. We computed MAPs and clinical responses and compared their abilities to predict 6-month nonrelapse mortality (NRM) in the validation cohort (n = 367). After 4 weeks of treatment, MAPs predicted NRM better than the change in clinical symptoms in all patients and identified 2 groups with significantly different NRM in both clinical responders (40% vs 12%, P < .0001) and nonresponders (65% vs 25%, P < .0001). MAPs successfully reclassified patients for NRM risk within every clinical grade of acute GVHD after 4 weeks of treatment. At the beginning of treatment, patients with a low MAP that rose above the threshold of 0.290 after 4 weeks of treatment had a significant increase in NRM, whereas patients with a high MAP at onset that fell below that threshold after treatment had a striking decrease in NRM that translated into clear differences in overall survival. We conclude that a MAP measured before and after treatment of acute GVHD is a response biomarker that predicts long-term outcomes more accurately than change in clinical symptoms. MAPs have the potential to guide therapy for acute GVHD and may function as a useful end point in clinical trials., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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186. Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents.
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Aldoss I, Dadwal S, Zhang J, Tegtmeier B, Mei M, Arslan S, Al Malki MM, Salhotra A, Ali H, Aribi A, Sandhu K, Khaled S, Snyder D, Nakamura R, Stein AS, Forman SJ, Marcucci G, and Pullarkat V
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Female, Humans, Invasive Fungal Infections etiology, Male, Middle Aged, Retrospective Studies, Sulfonamides pharmacology, Young Adult, Antineoplastic Agents therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Invasive Fungal Infections drug therapy, Leukemia, Myeloid, Acute complications, Sulfonamides therapeutic use
- Abstract
The combination of venetoclax with hypomethylating agents (VEN-HMAs) showed promising activity in newly diagnosed and relapsed/refractory (r/r) acute myeloid leukemia (AML). Treatment with VEN-HMAs results in prolonged cytopenia, thereby exposing patients to invasive fungal infections (IFIs). Here, we retrospectively studied a cohort of 119 AML patients treated with VEN-HMAs and analyzed the occurrence of IFIs, as well as our practice of antifungal prophylaxis, with the aim to identify the nature and risk factors for IFIs and their association with the type of antifungal prophylaxis used. The intended antifungal prophylaxis was micafungin in 38% of patients, azoles in 41% of patients, and none in 21% of patients. Older age was associated with no antifungal prophylaxis or micafungin use and lesser use of azoles (P = .043). We recorded 15 (12.6%) patients who developed probable or proven IFIs, with a median onset of 72 days (range, 35-281) after starting therapy. IFIs were more common among nonresponders compared with responders to VEN-HMA therapy (22% vs 6%, P = .0132) and in r/r compared with newly diagnosed AML (19% vs 5%, P = .0498); however, the antifungal prophylaxis used, patient age, hypomethylating agent schedule, history of prior allogeneic transplant, and initial neutropenia duration did not influence the development of IFIs during therapy. We conclude that the overall risk of IFIs during VEN-HMA therapy is low. The risk of IFIs is higher in nonresponders and in those who were treated in the r/r setting; these patients need reevaluation of their antifungal prophylaxis to minimize the risk of IFIs during therapy., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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187. Allogeneic Hematopoietic Cell Transplantation Outcomes in Patients Carrying Isocitrate Dehydrogenase Mutations.
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Salhotra A, Afkhami M, Yang D, Mokhtari S, Telatar M, Gu D, Pillai RK, Weisenburger DD, Murata-Collins J, Weigel D, Aoun P, Aldoss I, Al Malki MM, Khaled S, Mei M, Ali H, Aribi A, Budde E, Sandhu K, O'Donnell M, Snyder D, Pullarkat V, Forman SJ, Marcucci G, Nakamura R, and Stein A
- Subjects
- Adult, Aged, Disease Management, Female, Genetic Predisposition to Disease, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Prognosis, Transplantation, Homologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation methods, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Mutation
- Abstract
Background: Mutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown., Patients and Methods: We report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control)., Results: No statistical significance was detected in patient's overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model., Conclusion: Our results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations., (Copyright © 2019. Published by Elsevier Inc.)
- Published
- 2019
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