206 results on '"Katherine R. Calvo"'
Search Results
2. Spectrum of clonal hematopoiesis in VEXAS syndrome
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Fernanda Gutierrez-Rodrigues, Yael Kusne, Jenna Fernandez, Terra L Lasho, Ruba N Shalhoub, Xiaoyang Ma, Hugh Alessi, Christy M. Finke, Matthew J. Koster, Abhishek A. Mangaonkar, Kenneth J Warrington, Kebede Begna, Zhuoer Xie, Amanda K Ombrello, David S Viswanatha, Marcela A. Ferrada, Lorena Wilson, Ronald S. Go, Taxiarchis V. Kourelis, Kaaren K Reichard, Horatiu Olteanu, Ivana Darden, Dalton Hironaka, Lemlem Alemu, Sachiko Kajigaya, Rodrigo T. Calado, Emma M. Groarke, Sofia Rosenzweig, Daniel L Kastner, Katherine R Calvo, Colin O. Wu, Peter C. Grayson, Neal S Young, David B. Beck, Bhavisha A. Patel, and Mrinal M. Patnaik
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.
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- 2023
3. Supplementary Data from Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Nonmalignant Clonal Hematopoiesis
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Christopher S. Hourigan, Yuesheng Li, Patrick Burr, J. Philip McCoy, Pradeep K. Dagur, Aik Ooi, Shu Wang, Saurabh Gulati, Aaron Llanso, Robert Durruthy-Durruthy, Adam Sciambi, Catherine Lai, Christin B. DeStefano, Janet Valdez, Julie Thompson, Clifton L. Dalgard, Gauthaman Sukumar, Anthony R. Soltis, Matthew D. Wilkerson, Karolyn A. Oetjen, Katherine E. Lindblad, Katherine R. Calvo, Meghali Goswami, Gege Gui, Chidera Nosiri, Jack Ghannam, and Laura W. Dillon
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Supplementary Data
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- 2023
4. Data from Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Nonmalignant Clonal Hematopoiesis
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Christopher S. Hourigan, Yuesheng Li, Patrick Burr, J. Philip McCoy, Pradeep K. Dagur, Aik Ooi, Shu Wang, Saurabh Gulati, Aaron Llanso, Robert Durruthy-Durruthy, Adam Sciambi, Catherine Lai, Christin B. DeStefano, Janet Valdez, Julie Thompson, Clifton L. Dalgard, Gauthaman Sukumar, Anthony R. Soltis, Matthew D. Wilkerson, Karolyn A. Oetjen, Katherine E. Lindblad, Katherine R. Calvo, Meghali Goswami, Gege Gui, Chidera Nosiri, Jack Ghannam, and Laura W. Dillon
- Abstract
Genetic mutations associated with acute myeloid leukemia (AML) also occur in age-related clonal hematopoiesis, often in the same individual. This makes confident assignment of detected variants to malignancy challenging. The issue is particularly crucial for AML posttreatment measurable residual disease monitoring, where results can be discordant between genetic sequencing and flow cytometry. We show here that it is possible to distinguish AML from clonal hematopoiesis and to resolve the immunophenotypic identity of clonal architecture. To achieve this, we first design patient-specific DNA probes based on patient's whole-genome sequencing and then use them for patient-personalized single-cell DNA sequencing with simultaneous single-cell antibody–oligonucleotide sequencing. Examples illustrate AML arising from DNMT3A- and TET2-mutated clones as well as independently. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts.Significance:This study offers a proof of principle of patient-personalized customized single-cell proteogenomics in AML including whole-genome sequencing–defined structural variants, currently unmeasurable by commercial “off-the-shelf” panels. This approach allows for the definition of genetic and immunophenotype features for an individual patient that would be best suited for measurable residual disease tracking.
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- 2023
5. Supplementary Table 1 from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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Adrian Wiestner, Sarah E.M. Herman, Mohammed Z.H. Farooqui, Susan Soto, Janet Valdez, Constance Yuan, Katherine R. Calvo, Gerald E. Marti, Maryalice Stetler-Stevenson, Dalia Salem, Irina Maric, Sabrina Martyr, Yuh Shan Lee, Carsten U. Niemann, and Martin Skarzynski
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Supplementary Table 1. Characteristics of all patients studied.
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- 2023
6. Supplementary materials-Neutrophil chemotaxis videos from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Mark R. Gilbert, John I. Gallin, Douglas B. Kuhns, William D. Figg, Katherine R. Calvo, Terri S. Armstrong, Javier Gonzales, Heather Leeper, Marta Penas-Prado, Eric M. Burton, Brett J. Theeler, Orwa Aboud, Christine Cordova, Nicole Lollo, Christine Siegel, Nancy Garren, Ramya Antony, Lisa Boris, Kelly Mentges, Ewa Grajkowska, Matthew Lindsley, Christine Bryla, Salman Ahmad, Elizabeth Vera, Tito R. Mendoza, Madison K. Butler, Guangyang Yu, Ying Pang, Yu-Ting Su, Tristan M. Sissung, Cody J. Peer, Danielle Fink, Debra A. Long Priel, Ying Yuan, and Jing Wu
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Neutrophils chemotaxis video
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- 2023
7. Data from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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Adrian Wiestner, Sarah E.M. Herman, Mohammed Z.H. Farooqui, Susan Soto, Janet Valdez, Constance Yuan, Katherine R. Calvo, Gerald E. Marti, Maryalice Stetler-Stevenson, Dalia Salem, Irina Maric, Sabrina Martyr, Yuh Shan Lee, Carsten U. Niemann, and Martin Skarzynski
- Abstract
Purpose: Clinical trials of ibrutinib combined with anti-CD20 monoclonal antibodies (mAb) for chronic lymphocytic leukemia (CLL) report encouraging results. Paradoxically, in preclinical studies, in vitro ibrutinib was reported to decrease CD20 expression and inhibit cellular effector mechanisms. We therefore set out to investigate effects of in vivo ibrutinib treatment that could explain this paradox.Experimental Design: Patients received single-agent ibrutinib (420 mg daily) on an investigator-initiated phase II trial. Serial blood samples were collected pretreatment and during treatment for ex vivo functional assays to examine the effects on CLL cell susceptibility to anti-CD20 mAbs.Results: We demonstrate that CD20 expression on ibrutinib was rapidly and persistently downregulated (median reduction 74%, day 28, P < 0.001) compared with baseline. Concomitantly, CD20 mRNA was decreased concurrent with reduced NF-κB signaling. An NF-κB binding site in the promoter of MS4A1 (encoding CD20) and downregulation of CD20 by NF-κB inhibitors support a direct transcriptional effect. Ex vivo, tumor cells from patients on ibrutinib were less susceptible to anti-CD20 mAb-mediated complement-dependent cytotoxicity than pretreatment cells (median reduction 75%, P < 0.001); however, opsonization by the complement protein C3d, which targets cells for phagocytosis, was relatively maintained. Expression of decay-accelerating factor (CD55) decreased on ibrutinib, providing a likely mechanism for the preserved C3d opsonization. In addition, ibrutinib significantly inhibited trogocytosis, a major contributor to antigen loss and tumor escape during mAb therapy.Conclusions: Our data indicate that ibrutinib promotes both positive and negative interactions with anti-CD20 mAbs, suggesting that successfully harnessing maximal antitumor effects of such combinations requires further investigation. Clin Cancer Res; 22(1); 86–95. ©2015 AACR.
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- 2023
8. Supplementary Figures from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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Adrian Wiestner, Sarah E.M. Herman, Mohammed Z.H. Farooqui, Susan Soto, Janet Valdez, Constance Yuan, Katherine R. Calvo, Gerald E. Marti, Maryalice Stetler-Stevenson, Dalia Salem, Irina Maric, Sabrina Martyr, Yuh Shan Lee, Carsten U. Niemann, and Martin Skarzynski
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Supplementary Figure 1. Uniform CD20 loss from the surface of primary CLL cells after in vivo exposure to ibrutinib. Supplementary Figure 2. Loss of CD20 on ibrutinib and basal CD20 expression levels do not correlate with high risk prognostic factors. Supplementary Figure 3. Selective NF-κB inhibitor diminishes CD20 cell surface expression. Supplementary Figure 4. Complement regulatory proteins membrane cofactor protein and protectin are not consistently inhibited by ibrutinib.
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- 2023
9. Supplementary materials-Clinical trial protocol from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Mark R. Gilbert, John I. Gallin, Douglas B. Kuhns, William D. Figg, Katherine R. Calvo, Terri S. Armstrong, Javier Gonzales, Heather Leeper, Marta Penas-Prado, Eric M. Burton, Brett J. Theeler, Orwa Aboud, Christine Cordova, Nicole Lollo, Christine Siegel, Nancy Garren, Ramya Antony, Lisa Boris, Kelly Mentges, Ewa Grajkowska, Matthew Lindsley, Christine Bryla, Salman Ahmad, Elizabeth Vera, Tito R. Mendoza, Madison K. Butler, Guangyang Yu, Ying Pang, Yu-Ting Su, Tristan M. Sissung, Cody J. Peer, Danielle Fink, Debra A. Long Priel, Ying Yuan, and Jing Wu
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Clinical trial protocol
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- 2023
10. Supplementary figures S1-S5 from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
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Adrian Wiestner, Mohammed Z.H. Farooqui, Gerald E. Marti, Clare Sun, Jade Jones, Deanna H. Wong, Yuh Shan Lee, Janet Valdez, Raul C. Braylan, Katherine R. Calvo, Constance M. Yuan, Maryalice Stetler-Stevenson, Sabrina Martyr, Betty Y. Chang, Angelique Biancotto, Julio Gomez-Rodriguez, Irina Maric, Sarah E.M. Herman, and Carsten U. Niemann
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Supplementary Figure S1. Ibrutinib alters the absolute expression of inflammatory cytokines and chemokines in serum from patients with CLL. Supplementary Figure S2. Ibrutinib treatment reduces tumor burden. Supplementary Figure S3. Both CD4+ and CD8+ T cell subsets are decreased on ibrutinib. Supplementary Figure S4. Grading of macrophage interaction with CLL cells in bone marrow specimens. Supplementary Figure S5. Ibrutinib alters the absolute expression of chemokines in bone marrow supernatant from patients with CLL.
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- 2023
11. Data from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
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Adrian Wiestner, Mohammed Z.H. Farooqui, Gerald E. Marti, Clare Sun, Jade Jones, Deanna H. Wong, Yuh Shan Lee, Janet Valdez, Raul C. Braylan, Katherine R. Calvo, Constance M. Yuan, Maryalice Stetler-Stevenson, Sabrina Martyr, Betty Y. Chang, Angelique Biancotto, Julio Gomez-Rodriguez, Irina Maric, Sarah E.M. Herman, and Carsten U. Niemann
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Purpose: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B-cell receptor (BCR) signaling. Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment.Experimental Design: Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed.Results: Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, ibrutinib treatment decreased circulating tumor cells and overall T-cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4+ T cells was observed concurrent with reduced expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4+ T cells in vitro. Finally, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13, and decreased the chemoattraction of CLL cells.Conclusions: In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. Clin Cancer Res; 22(7); 1572–82. ©2015 AACR.See related commentary by Bachireddy and Wu, p. 1547
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- 2023
12. Supplementary tables and figure legends from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
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Adrian Wiestner, Mohammed Z.H. Farooqui, Gerald E. Marti, Clare Sun, Jade Jones, Deanna H. Wong, Yuh Shan Lee, Janet Valdez, Raul C. Braylan, Katherine R. Calvo, Constance M. Yuan, Maryalice Stetler-Stevenson, Sabrina Martyr, Betty Y. Chang, Angelique Biancotto, Julio Gomez-Rodriguez, Irina Maric, Sarah E.M. Herman, and Carsten U. Niemann
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Supplementary Table S1: Evaluation of serum cytokine levels on ibrutinib Supplementary Table S2: Evaluation of chemoattractant levels in bone marrow supernatant on ibrutinib supplementary figure legends for supplementary figures S1-S5
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- 2023
13. Supplementary Table S1 from Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer
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Zhong Chen, Carter Van Waes, Katherine R. Calvo, John C. Morris, Xiaojiang Xu, Gerhard S. Mundinger, Kunal Saigal, Bhavana Dabir, Jay Friedman, Bin Yan, Mary E. Winters, Clint T. Allen, and Francisco G. Pernas
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Supplementary Table S1 from Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer
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- 2023
14. Conflict of Interest Form from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
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Adrian Wiestner, Mohammed Z.H. Farooqui, Gerald E. Marti, Clare Sun, Jade Jones, Deanna H. Wong, Yuh Shan Lee, Janet Valdez, Raul C. Braylan, Katherine R. Calvo, Constance M. Yuan, Maryalice Stetler-Stevenson, Sabrina Martyr, Betty Y. Chang, Angelique Biancotto, Julio Gomez-Rodriguez, Irina Maric, Sarah E.M. Herman, and Carsten U. Niemann
- Abstract
Conflict of Interest Form from Disruption of in vivo Chronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study
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- 2023
15. Data from Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer
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Zhong Chen, Carter Van Waes, Katherine R. Calvo, John C. Morris, Xiaojiang Xu, Gerhard S. Mundinger, Kunal Saigal, Bhavana Dabir, Jay Friedman, Bin Yan, Mary E. Winters, Clint T. Allen, and Francisco G. Pernas
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Purpose: Gefitinib targeting of the epidermal growth factor receptor (EGFR) has shown limited activity in clinical trials of head and neck squamous cell carcinoma (HNSCC). To investigate the underlying molecular mechanism, the proteomic signatures and responses of EGFR and downstream signals have been studied in a panel of HNSCC cell lines and tumor specimens pre- and post-gefitinib treatment.Experimental Design: The IC50 of gefitinib for HNSCC cell lines were determined using 3-(4,5-dmethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay. The effects of gefitinib on activation of EGFR and downstream signaling molecules were determined by Western blot, ELISA, and reverse-phase protein microarray (RPMA). The biomarkers involved in the signaling pathways were examined in HNSCC tumor specimens from patients in a phase I gefitinib trial.Results:In vitro, gefitinib inhibited cell proliferation with differing IC50, and suppressed activation of EGFR and downstream signaling molecules protein kinase B (AKT), extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor κB. The drug sensitivity was statistically correlated with activation of phosphorylated AKT (p-AKT) and phosphorylated STAT3 (p-STAT3) detected by ELISA, and consistent with results measured by RPMA. In patient samples, a broad suppression of activation of EGFR and downstream signaling molecules was observed in a molecular responder patient, in contrast to a lack of inhibition or increased activation of biomarkers in different pathways in nonresponder patients.Conclusions: Gefitinib sensitivity is correlated with p-AKT and p-STAT3 activation in HNSCC cell lines and tumor specimens. p-AKT and p-STAT3 could serve as potentially useful biomarkers and drug targets for further development of novel therapeutic agents for HNSCC.
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- 2023
16. Supplementary Figures Legends from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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Adrian Wiestner, Sarah E.M. Herman, Mohammed Z.H. Farooqui, Susan Soto, Janet Valdez, Constance Yuan, Katherine R. Calvo, Gerald E. Marti, Maryalice Stetler-Stevenson, Dalia Salem, Irina Maric, Sabrina Martyr, Yuh Shan Lee, Carsten U. Niemann, and Martin Skarzynski
- Abstract
Supplementary Figures Legends from Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy
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- 2023
17. Supplementary Data from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Mark R. Gilbert, John I. Gallin, Douglas B. Kuhns, William D. Figg, Katherine R. Calvo, Terri S. Armstrong, Javier Gonzales, Heather Leeper, Marta Penas-Prado, Eric M. Burton, Brett J. Theeler, Orwa Aboud, Christine Cordova, Nicole Lollo, Christine Siegel, Nancy Garren, Ramya Antony, Lisa Boris, Kelly Mentges, Ewa Grajkowska, Matthew Lindsley, Christine Bryla, Salman Ahmad, Elizabeth Vera, Tito R. Mendoza, Madison K. Butler, Guangyang Yu, Ying Pang, Yu-Ting Su, Tristan M. Sissung, Cody J. Peer, Danielle Fink, Debra A. Long Priel, Ying Yuan, and Jing Wu
- Abstract
Supplementary Figures and Tables
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- 2023
18. Data from Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Mark R. Gilbert, John I. Gallin, Douglas B. Kuhns, William D. Figg, Katherine R. Calvo, Terri S. Armstrong, Javier Gonzales, Heather Leeper, Marta Penas-Prado, Eric M. Burton, Brett J. Theeler, Orwa Aboud, Christine Cordova, Nicole Lollo, Christine Siegel, Nancy Garren, Ramya Antony, Lisa Boris, Kelly Mentges, Ewa Grajkowska, Matthew Lindsley, Christine Bryla, Salman Ahmad, Elizabeth Vera, Tito R. Mendoza, Madison K. Butler, Guangyang Yu, Ying Pang, Yu-Ting Su, Tristan M. Sissung, Cody J. Peer, Danielle Fink, Debra A. Long Priel, Ying Yuan, and Jing Wu
- Abstract
Purpose:To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.Patients and Methods:This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.Results:Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value.Conclusions:Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.
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- 2023
19. Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
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Adriana A. de Jesus, Guibin Chen, Dan Yang, Tomas Brdicka, Natasha M. Ruth, David Bennin, Dita Cebecauerova, Hana Malcova, Helen Freeman, Neil Martin, Karel Svojgr, Murray H. Passo, Farzana Bhuyan, Sara Alehashemi, Andre T. Rastegar, Katsiaryna Uss, Lela Kardava, Bernadette Marrero, Iris Duric, Ebun Omoyinmi, Petra Peldova, Chyi-Chia Richard Lee, David E. Kleiner, Colleen M. Hadigan, Stephen M. Hewitt, Stefania Pittaluga, Carmelo Carmona-Rivera, Katherine R. Calvo, Nirali Shah, Miroslava Balascakova, Danielle L. Fink, Radana Kotalova, Zuzana Parackova, Lucie Peterkova, Daniela Kuzilkova, Vit Campr, Lucie Sramkova, Angelique Biancotto, Stephen R. Brooks, Cameron Manes, Eric Meffre, Rebecca L. Harper, Hyesun Kuehn, Mariana J. Kaplan, Paul Brogan, Sergio D. Rosenzweig, Melinda Merchant, Zuoming Deng, Anna Huttenlocher, Susan L. Moir, Douglas B. Kuhns, Manfred Boehm, Karolina Skvarova Kramarzova, and Raphaela Goldbach-Mansky
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
SummaryNeutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. We identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies reveal increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. These findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.
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- 2023
20. ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome
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Robert R. West, Dennis D. Hickstein, Desiree Tillo, Amy P. Hsu, Weixin Wang, Thomas R. Bauer, Katherine R. Calvo, Stephenie Droll, Justin B. Lack, Laura M. Tuschong, Lisa J. Embree, and Steven M. Holland
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Myeloid ,GATA2 Deficiency ,Cell Cycle Proteins ,Disease ,medicine.disease_cause ,Trisomy 8 ,Germline mutation ,Neoplasms ,medicine ,Humans ,Chromosome 7 (human) ,Mutation ,Myeloproliferative Disorders ,business.industry ,Hematology ,medicine.disease ,GATA2 Transcription Factor ,Repressor Proteins ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,Immunology ,Disease Progression ,Female ,Bone marrow ,business - Abstract
Patients with GATA2 deficiencyharbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic syndrome (MDS) was the most common diagnosis (∼44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID; ∼37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (∼43%), notably trisomy 8 (∼23%) and monosomy 7 (∼12%), but the changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ∼25% of patients, although the mutations were rarely concomitant. Mutations in DNMT3A were found in ∼10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 deficiency.
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- 2022
21. The Spectrum of GATA2 Deficiency Syndrome
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Katherine R. Calvo and Dennis D. Hickstein
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Inherited or de novo germ line heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency. This results in a constellation of clinical features including nontuberculous mycobacterial, bacterial, fungal, and human papillomavirus infections, lymphedema, pulmonary alveolar proteinosis, and myelodysplasia. The onset, or even the presence, of disease is highly variable, even in kindreds with the identical mutation in GATA2. The clinical manifestations result from the loss of a multilineage progenitor that gives rise to B lymphocytes, monocytes, natural killer cells, and dendritic cells, leading to cytopenias of these lineages and subsequent infections. The bone marrow failure is typically characterized by hypocellularity. Dysplasia may either be absent or subtle but typically evolves into multilineage dysplasia with prominent dysmegakaryopoiesis, followed in some instances by progression to myeloid malignancies, specifically myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelomonocytic leukemia. The latter 3 malignancies often occur in the setting of monosomy 7, trisomy 8, and acquired mutations in ASXL1 or in STAG2. Importantly, myeloid malignancy may represent the primary presentation of disease without recognition of other syndromic features. Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency, including the following: (1) Why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2? (2) What are the genetic changes that lead to myeloid progression? (3) What causes the apparent genetic anticipation? (4) What is the role of preemptive HSCT?
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- 2022
22. A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies
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Byung-Chul Lee, Yifan Zhou, Erica Bresciani, Neval Ozkaya, Alina Dulau-Florea, Blake Carrington, Tae-Hoon Shin, Valentina Baena, Zulfeqhar A. Syed, So Gun Hong, Tao Zhen, Katherine R. Calvo, Paul Liu, and Cynthia E. Dunbar
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Germ line loss-of-function heterozygous mutations in the RUNX1 gene cause familial platelet disorder with associated myeloid malignancies (FPDMM) characterized by thrombocytopenia and a life-long risk of hematological malignancies. Although gene therapies are being considered as promising therapeutic options, current preclinical models do not recapitulate the human phenotype and are unable to elucidate the relative fitness of mutation-corrected and RUNX1-heterozygous mutant hematopoietic stem and progenitor cells (HSPCs) in vivo long term. We generated a rhesus macaque with an FPDMM competitive repopulation model using CRISPR/Cas9 nonhomologous end joining editing in the RUNX1 gene and the AAVS1 safe-harbor control locus. We transplanted mixed populations of edited autologous HSPCs and tracked mutated allele frequencies in blood cells. In both animals, RUNX1-edited cells expanded over time compared with AAVS1-edited cells. Platelet counts remained below the normal range in the long term. Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization. In conclusion, the lack of a competitive advantage for wildtype or control-edited HSPCs over RUNX1 heterozygous–mutated HSPCs long term in our preclinical model suggests that gene correction approaches for FPDMM will be challenging, particularly to reverse myelodysplastic syndrome/ acute myeloid leukemia predisposition and thrombopoietic defects.
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- 2022
23. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS
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Wanxia L. Tsai, Robert A. Colbert, Marcus Y Chen, Arlene Sirajuddin, Ryan S. Laird, Peter C. Grayson, Patrycja Hoffmann, Sinisa Savic, Marcela A. Ferrada, Emma M. Groarke, Kristina V. Wells, Massimo Gadina, Bhavisha A Patel, Mariana J. Kaplan, Keith A. Sikora, Emily Rose, Lorena Wilson, Daniel L. Kastner, Gustaf Wigerblad, Zuoming Deng, Amanda K. Ombrello, Oskar Schnappauf, Emily Rominger, Kaitlin A. Quinn, Daniela Ospina Cardona, Jeff Kim, Ivona Aksentijevich, Neal S. Young, David B. Beck, Wendy Goodspeed, Clint T. Allen, Mimi T. Le, Katherine R. Calvo, Yiming Luo, and Anne Jones
- Subjects
030203 arthritis & rheumatology ,0301 basic medicine ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Costochondritis ,Mortality rate ,Immunology ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,Internal medicine ,medicine ,Immunology and Allergy ,Chondritis ,Macrocytic anemia ,business ,Exome ,Mean corpuscular volume ,Relapsing polychondritis ,Multiple myeloma - Abstract
Objective Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. Methods Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. Results Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count
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- 2021
24. Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1
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Fernanda Gutierrez-Rodrigues, Daniel L. Kastner, David B. Beck, Patrycja Hoffmann, Marcela A. Ferrada, Bhavisha A Patel, Nisha Patel, Megan Trick, Neal S. Young, Peter C. Grayson, Zhijie Wu, Ifeyinwa Emmanuela Obiorah, Daniela Ospina Cardona, Alina Dulau-Florea, Lorena Wilson, Emma M. Groarke, Weixin Wang, Katherine R. Calvo, Jennifer Lotter, and Amanda K. Ombrello
- Subjects
Male ,medicine.medical_specialty ,Myeloid ,Neutropenia ,Monoclonal Gammopathy of Undetermined Significance ,Gastroenterology ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Multiple myeloma ,Myeloid Neoplasia ,business.industry ,Myelodysplastic syndromes ,Hematology ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Hematologic disease ,Myelodysplastic Syndromes ,Mutation ,Macrocytic anemia ,Multiple Myeloma ,business ,Monoclonal gammopathy of undetermined significance - Abstract
Somatic mutations in UBA1 involving hematopoietic stem and myeloid cells have been reported in patients with the newly defined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Here, we report clinical hematologic manifestations and unique bone marrow (BM) features in 16 patients with VEXAS. All patients were male and had a history of severe autoinflammatory and rheumatologic manifestations and a somatic UBA1 mutation (p.Met41). Ten patients had hematologic disorders: myelodysplastic syndrome (MDS; 6 of 16), multiple myeloma (2 of 16), monoclonal gammopathy of undetermined significance (2 of 16), and monoclonal B-cell lymphocytosis (2 of 16), and a few of those patients had 2 co-existing clonal processes. Although macrocytic anemia (100%) and lymphopenia (80%) were prevalent in all patients with VEXAS, thrombocytopenia and neutropenia were more common in patients with progression to MDS. All BMs in VEXAS patients had prominent cytoplasmic vacuoles in myeloid and erythroid precursors. In addition, most BMs were hypercellular with myeloid hyperplasia, erythroid hypoplasia, and varying degrees of dysplasia. All patients diagnosed with MDS were lower risk (low blast count, very good to intermediate cytogenetics) according to standard prognostic scoring with no known progression to leukemia. In addition, 10 of 16 patients had thrombotic events, including venous thromboembolism and arterial stroke. Although VEXAS presents symptomatically as a rheumatologic disease, morbidity and mortality are associated with progression to hematologic disease. Given the increased risk of developing MDS and multiple myeloma, surveillance for disease progression is important.
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- 2021
25. miR-181c regulates MCL1 and cell survival in GATA2 deficient cells
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Stephenie Droll, Rui Chen, Dennis D. Hickstein, Meghan Corrigan-Cummins, Zhen Zhao, Layla M. Saleh, Emily Barber, Amy P. Hsu, Weixin Wang, Katherine R. Calvo, Donald C. Vinh, Nga Voong Hawk, Steven M. Holland, Vollter Anastas, and Megan Trick
- Subjects
Myeloid ,Cell Survival ,GATA2 Deficiency ,Immunology ,Cell ,GATA2 ,Myeloid leukemia ,Cell Biology ,Transfection ,Biology ,medicine.disease ,Molecular biology ,GATA2 Transcription Factor ,MicroRNAs ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,medicine ,Humans ,Myeloid Cell Leukemia Sequence 1 Protein ,Immunology and Allergy ,B cell - Abstract
GATA2 is a transcription factor critical for hematopoiesis. Germline mutations in GATA binding protein 2 (GATA2) led to haploinsufficiency, severe cytopenias of multiple cell lineages, susceptibility to infections and strong propensity to develop myelodysplastic syndrome, and acute myeloid leukemia. Mechanisms of progressive cytopenias remain unclear. MicroRNA (miRNA) represents a unique mechanism of post-transcriptional gene regulation. In this study, miRNA profiles were evaluated and eight miRNAs were found to be differentially expressed (≥2-fold, P ≤ 0.05) in patient-derived cell lines (N = 13) in comparison to controls (N = 10). miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582 showed increased expression, whereas miR-223 and miR-424-3p showed decreased expression. Cell death assays indicated that miR-181c potently induces cell death in lymphoid (Ly-8 and SP-53) and myeloid (HL-60) cell lines. miR-181c was predicted to target myeloid cell leukemia (MCL)1, which was confirmed by transfection assays, resulting in significantly reduced MCL1 mRNA and decreased live cell numbers. Bone marrow analysis of 34 GATA2 patients showed significantly decreased cellularity, CD34-positive cells, monocytes, dendritic cells, NK cells, B cells, and B cell precursors in comparison to healthy controls (N = 29; P
- Published
- 2021
26. The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia
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Martina, Rudelius, Olga K, Weinberg, Charlotte M, Niemeyer, Akiko, Shimamura, and Katherine R, Calvo
- Abstract
Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200-1228, 2022).
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- 2022
27. Classification of rare pediatric myeloid neoplasia-Quo vadis?
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Charlotte M, Niemeyer, Martina, Rudelius, Akiko, Shimamura, Christian, Flotho, Henrik, Hasle, Elliot, Stieglitz, Brigitte, Strahm, Lucy A, Godley, Olga K, Weinberg, Attilio, Orazi, and Katherine R, Calvo
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Myeloproliferative Disorders ,Neoplasms ,Humans ,Syndrome ,Child - Published
- 2022
28. Skin in the game: the emergence of myelodysplasia cutis
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Katherine R, Calvo
- Subjects
Myelodysplastic Syndromes ,Immunology ,Humans ,Cell Biology ,Hematology ,Biochemistry ,Skin - Published
- 2022
29. Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Nonmalignant Clonal Hematopoiesis
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Shu Wang, Robert Durruthy-Durruthy, Karolyn A. Oetjen, Jack Ghannam, Catherine Lai, Julie Thompson, Katherine E. Lindblad, Katherine R. Calvo, Adam Sciambi, Aaron Llanso, Gege Gui, Chidera Nosiri, Yuesheng Li, Aik Ooi, Janet Valdez, Meghali Goswami, Pradeep K. Dagur, Matthew D. Wilkerson, Anthony R. Soltis, Patrick Burr, Gauthaman Sukumar, Christopher S. Hourigan, Clifton L. Dalgard, Christin B. DeStefano, Laura W. Dillon, Saurabh Gulati, and J. Philip McCoy
- Subjects
Neoplasm, Residual ,medicine.diagnostic_test ,business.industry ,Hybridization probe ,Myeloid leukemia ,General Medicine ,Computational biology ,Biology ,Precision medicine ,Malignancy ,medicine.disease ,Proteogenomics ,Article ,DNA sequencing ,Clone Cells ,Flow cytometry ,Leukemia, Myeloid, Acute ,hemic and lymphatic diseases ,medicine ,Humans ,Personalized medicine ,Clonal Hematopoiesis ,business - Abstract
Genetic mutations associated with acute myeloid leukemia (AML) also occur in age-related clonal hematopoiesis, often in the same individual. This makes confident assignment of detected variants to malignancy challenging. The issue is particularly crucial for AML posttreatment measurable residual disease monitoring, where results can be discordant between genetic sequencing and flow cytometry. We show here that it is possible to distinguish AML from clonal hematopoiesis and to resolve the immunophenotypic identity of clonal architecture. To achieve this, we first design patient-specific DNA probes based on patient's whole-genome sequencing and then use them for patient-personalized single-cell DNA sequencing with simultaneous single-cell antibody–oligonucleotide sequencing. Examples illustrate AML arising from DNMT3A- and TET2-mutated clones as well as independently. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts. Significance: This study offers a proof of principle of patient-personalized customized single-cell proteogenomics in AML including whole-genome sequencing–defined structural variants, currently unmeasurable by commercial “off-the-shelf” panels. This approach allows for the definition of genetic and immunophenotype features for an individual patient that would be best suited for measurable residual disease tracking.
- Published
- 2021
30. Clonal Hematopoiesis in Vexas Syndrome
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Bhavisha A. Patel, Fernanda Gutierrez-Rodrigues, Yael Kusne, Jenna A. Fernandez, Terra Lasho, Ruba Shalhoub, Xiaoyang Ma, Hugh Alessi, Christy Finke, Matthew Koster, Abhishek A. Mangaonkar, Kenneth Warrington, Kebede H. Begna, Zhuoer Xie, Amanda Ombrello, David S. Viswanatha, Marcela Ferrada, Lorena Wilson, Ronald Go, Taxiarchis Kourelis, Kaaren K. Reichard, Horatiu Olteanu, Emma M. Groarke, Ivana Darden, Dalton Hironaka, Sofia Rosenzweig, Daniel L. Kastner, Katherine R. Calvo, Colin O. Wu, Peter C. Grayson, David B. Beck, Mrinal M.M. Patnaik, and Neal S. Young
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
31. Abnormal Cytotoxic T-Cell Expansion in the Bone Marrow of Patients with SASH3 Deficiency and Cytopenias
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Saber Tadros, Shamik Majumdar, Ottavia Delmonte, Jenna Bergerson, Irene Cortese, David H. McDermott, Jaspal Khillan, Kyoungin Cho, Luigi D. Notarangelo, Philip M. Murphy, and Katherine R. Calvo
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
32. Thrombotic Manifestations in Patients with Vexas Syndrome
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Pedro E. Alcedo Andrade, Ruba Shalhoub, Alina Dulau-Florea, Khanh Nghiem, Marcela Ferrada, Lorena Wilson, Ivana Darden, Wendy Goodspeed, Katherine R. Calvo, David B. Beck, Daniel L. Kastner, Peter C. Grayson, Neal S. Young, Colin O. Wu, Yogendra Kanthi, Bhavisha A. Patel, and Emma M. Groarke
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
33. Spatial-Temporal Multiomic Analysis of Tumor-Immune Interactions in Patients with AML Receiving Pembrolizumab and Decitabine
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Gege Gui, Abigail Wong-Rolle, Laura W. Dillon, Meghali Goswami, Eddie Martin, Prajan Divakar, Jason Reeves, Katherine R. Calvo, Kasper D. Hansen, Christopher S. Hourigan, and Chen Zhao
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
34. Eosinophilia in Vexas Syndrome: Expanding Hematologic Phenotype
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Ashvind Anand Prabahran, Fernanda Gutierrez-Rodrigues, Serene Ahmad, Edward W Cowen, Ivana Darden, Emma M. Groarke, Marcela Ferrada, Peter C. Grayson, Amy D Klion, Katherine R. Calvo, Irina Maric, Neal S. Young, and Bhavisha A. Patel
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
35. A macaque clonal hematopoiesis model demonstrates expansion of TET2-disrupted clones and utility for testing interventions
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Tae-Hoon Shin, Yifan Zhou, Shirley Chen, Stefan Cordes, Max Z. Grice, Xing Fan, Byung-Chul Lee, Aisha A. Aljanahi, So Gun Hong, Kelli L. Vaughan, Julie A. Mattison, Steven G. Kohama, Margarete A. Fabre, Naoya Uchida, Selami Demirci, Marcus A.F. Corat, Jean-Yves Métais, Katherine R. Calvo, Manuel Buscarlet, Hannah Natanson, Kathy L. McGraw, Alan F. List, Lambert Busque, John F. Tisdale, George S. Vassiliou, Kyung-Rok Yu, and Cynthia E. Dunbar
- Subjects
Inflammasomes ,Interleukin-6 ,Immunology ,Interleukin-1beta ,Cell Biology ,Hematology ,Biochemistry ,Macaca mulatta ,Hematopoiesis ,Clone Cells ,Dioxygenases ,DNA-Binding Proteins ,Young Adult ,CRISPR-Associated Protein 9 ,NLR Family, Pyrin Domain-Containing 3 Protein ,Humans ,Animals ,Clonal Hematopoiesis ,Aged - Abstract
Individuals with age-related clonal hematopoiesis (CH) are at greater risk for hematologic malignancies and cardiovascular diseases. However, predictive preclinical animal models to recapitulate the spectrum of human CH are lacking. Through error-corrected sequencing of 56 human CH/myeloid malignancy genes, we identified natural CH driver mutations in aged rhesus macaques matching genes somatically mutated in human CH, with DNMT3A mutations being the most frequent. A CH model in young adult macaques was generated via autologous transplantation of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9–mediated gene-edited hematopoietic stem and progenitor cells (HSPCs), targeting the top human CH genes with loss-of-function (LOF) mutations. Long-term follow-up revealed reproducible and significant expansion of multiple HSPC clones with heterozygous TET2 LOF mutations, compared with minimal expansion of clones bearing other mutations. Although the blood counts of these CH macaques were normal, their bone marrows were hypercellular and myeloid-predominant. TET2-disrupted myeloid colony-forming units isolated from these animals showed a distinct hyperinflammatory gene expression profile compared with wild type. In addition, mature macrophages purified from the CH macaques showed elevated NLRP3 inflammasome activity and increased interleukin-1β (IL-1β) and IL-6 production. The model was used to test the impact of IL-6 blockage by tocilizumab, documenting a slowing of TET2-mutated expansion, suggesting that interruption of the IL-6 axis may remove the selective advantage of mutant HSPCs. These findings provide a model for examining the pathophysiology of CH and give insights into potential therapeutic interventions.
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- 2022
36. Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas
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Ying Yuan, Brett Theeler, Eric M. Burton, Cody J. Peer, Douglas B. Kuhns, Salman Ahmad, Marta Penas-Prado, Nicole Lollo, Jing Wu, Matthew Lindsley, Christine Cordova, William D. Figg, John I. Gallin, Ramya Antony, Danielle Fink, Mark R. Gilbert, Javier Gonzales, Lisa Boris, Madison Butler, Tito R. Mendoza, Elizabeth Vera, Debra A. Long Priel, Ewa Grajkowska, Tristan M. Sissung, Ying Pang, Christine Bryla, Heather E. Leeper, Orwa Aboud, Katherine R. Calvo, Guangyang Yu, Terri S. Armstrong, Yu Ting Su, Kelly Mentges, Christine Siegel, and Nancy Garren
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Astrocytoma ,Neutropenia ,Article ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Pharmacokinetics ,Clinical Research ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Temozolomide ,medicine ,Humans ,Oncology & Carcinogenesis ,Dosing ,Survival rate ,Cancer ,Brain Neoplasms ,business.industry ,Evaluation of treatments and therapeutic interventions ,Bayes Theorem ,medicine.disease ,Discontinuation ,Dacarbazine ,030104 developmental biology ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Absolute neutrophil count ,Patient Safety ,Digestive Diseases ,business ,medicine.drug - Abstract
Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.
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- 2021
37. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease
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Sarthak Gupta, Amanda K. Ombrello, Emily Rominger, Megan Trick, Karyl S. Barron, Ryan S. Laird, Sinisa Savic, Shuichiro Nakabo, Daniela Ospina Cardona, Ivona Aksentijevich, Carmelo Carmona-Rivera, Gustaf Wigerblad, Mariana J. Kaplan, Emma M. Groarke, Laura W. Dillon, Chyi-Chia Richard Lee, Kalpana Manthiram, Kristina V. Wells, Nicholas Balanda, Zhijie Wu, Helen J. Lachmann, Daniel L. Kastner, Fernanda Gutierrez-Rodrigues, Achim Werner, Michele Nehrebecky, Lisha Xu, Alina Dulau-Florea, Wanxia L. Tsai, Bhavisha A Patel, Stefania Dell'Orso, Weixin Wang, Anthony J. Asmar, Danica Novacic, Katherine R. Calvo, David B. Beck, Robert A. Colbert, Massimo Gadina, William A. Gahl, Wendy Goodspeed, Natalie Deuitch, Dorota Rowczenio, Peter C. Grayson, Daron L. Ross, Sofia Rosenzweig, Anne Jones, Christopher S. Hourigan, James C. Mullikin, Stephen R. Brooks, Jason C. Collins, Wuhong Pei, May Christine V. Malicdan, Neal S. Young, Shawn M. Burgess, Keith A. Sikora, Mones Abu-Asab, Kyle Retterer, Patrycja Hoffmann, Hirotsugu Oda, Marcela A. Ferrada, Zuoming Deng, Benjamin D. Solomon, and Jae Jin Chae
- Subjects
Genetics ,Mutation ,Somatic cell ,business.industry ,Sequence analysis ,General Medicine ,UBA1 ,030204 cardiovascular system & hematology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,Medicine ,Missense mutation ,030212 general & internal medicine ,Age of onset ,business ,Gene - Abstract
Background Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may...
- Published
- 2020
38. Treating Rosai–Dorfman disease and RAS‐associated autoimmune leucoproliferative disorder with malignant transformation
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Kenneth L. McClain, Luis Fayad, Carl E. Allen, Tapan M. Kadia, Naly Champa, Koneti V. Rao, Katherine R. Calvo, Wei Wang, Naveen Pemmaraju, Hong Fang, Sanam Loghavi, Guilin Tang, U. Popat, Nathaniel R Wilson, Rodney O. Haltom, and Caitlin R. Rausch
- Subjects
medicine.medical_specialty ,business.industry ,Medicine ,Hematology ,business ,medicine.disease ,Dermatology ,Rosai–Dorfman disease ,Malignant transformation - Published
- 2020
39. Eltrombopag for patients with moderate aplastic anemia or uni-lineage cytopenias
- Author
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Ruba Shalhoub, Neal S. Young, Fernanda Gutierrez-Rodrigues, Katherine R. Calvo, Ma Evette Barranta, Xing Fan, Ronan Desmond, Stephanie Sellers, Bogdan Dumitriu, Thomas Winkler, Colin O. Wu, Danielle M. Townsley, Janet Valdez, David J. Young, Maher Albitar, Jennifer Lotter, and Cynthia E. Dunbar
- Subjects
medicine.medical_specialty ,Hematopoiesis and Stem Cells ,Anemia ,Eltrombopag ,Phases of clinical research ,Benzoates ,Gastroenterology ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Aplastic anemia ,Diamond–Blackfan anemia ,Prospective cohort study ,Cytopenia ,business.industry ,Anemia, Aplastic ,Hematology ,medicine.disease ,Hydrazines ,medicine.anatomical_structure ,chemistry ,Pyrazoles ,Bone marrow ,business - Abstract
There is no standard or widely effective treatment of patients with moderate aplastic anemia (MAA) or hypo-productive uni-lineage cytopenias (UC). Eltrombopag (EPAG), a small molecule thrombopoietin mimetic, has previously been shown to result in durable multi-lineage hematologic responses with low toxicity in patients with refractory severe aplastic anemia (SAA). Its safety and efficacy in MAA are unknown. This prospective phase 2 study enrolled previously untreated and treated MAA and UC patients with clinically relevant cytopenias. EPAG was administered at doses escalating from 50 to 300 mg/d. Hematologic responses were assessed at 16 to 20 weeks. Responding patients were continued on EPAG until reaching defined robust or stable blood counts. EPAG was reinstituted for relapse. Thirty-four patients were enrolled between 2012 and 2017, including 31 with MAA and 3 with UC. Seventeen patients responded in at least 1 eligible lineage by the primary end point. A striking improvement in anemia was observed in a patient with Diamond-Blackfan anemia. EPAG was well tolerated, and it was discontinued for robust or stable blood counts in 12 of 17 patients after a median of 8 months. A majority required re-initiation of EPAG for declining counts, and all regained response. Two of 34 patients developed non–chromosome 7 bone marrow cytogenetic abnormalities while taking EPAG, without dysplasia or increased blasts. Somatic mutation allele frequencies in cancer genes did not increase overall on EPAG. EPAG is a well-tolerated oral treatment of cytopenias in patients with MAA/UC. This trial was registered at www.clinicaltrials.gov as #NCT01328587.
- Published
- 2020
40. Serum microRNA profiles among dioxin exposed veterans with monoclonal gammopathy of undetermined significance
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Emily Barber, Joel E. Michalek, Gerald E. Marti, Layla M. Saleh, Weixin Wang, Katherine R. Calvo, Norma S. Ketchum, Rene Costello, Ola Landgren, Byeong Yeob Choi, Youn K. Shim, Chen Pin Wang, and Robert F. Vogt
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Polychlorinated Dibenzodioxins ,Materials science ,Health, Toxicology and Mutagenesis ,Population ,Cellular homeostasis ,Toxicology ,Monoclonal Gammopathy of Undetermined Significance ,Article ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,microRNA ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,education ,Multiple myeloma ,Aged ,Veterans ,Aged, 80 and over ,education.field_of_study ,Herbicides ,Middle Aged ,medicine.disease ,United States ,MicroRNAs ,Circulating MicroRNA ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,Monoclonal gammopathy of undetermined significance - Abstract
We previously reported an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) has been demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, we sought to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous study, using serum specimens and exposure data archived by the Air Force Health Study (AFHS). We measured 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) in serum stored during the 2002 AFHS follow-up and evaluated their relationship to lipid-adjusted serum TCDD levels in 1987 determined by the AFHS. miR-34a showed the strongest association with TCDD (coefficient 2.184, p-value 0.02); after age-adjustment, this positive association was more pronounced (coefficient 2.294, p-value 0.008). In contrast, the other 12 miRNAs had absolute values of age-adjusted coefficient estimates below 1.16 and p-values greater than 0.18. The observed strong positive relationship between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM.
- Published
- 2020
41. Donor source and post-transplantation cyclophosphamide influence outcome in allogeneic stem cell transplantation for GATA2 deficiency
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Diana X. Nichols-Vinueza, Jennifer Cuellar-Rodriguez, Katherine R. Calvo, Seth M. Steinberg, Steven M. Holland, Thomas R. Bauer, Dennis D. Hickstein, Robert R. West, Nirali N. Shah, Mark Parta, Luigi D. Notarangelo, and Amy P. Hsu
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,Adolescent ,GATA2 Deficiency ,Neutrophils ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Comorbidity ,Leukocyte Count ,Young Adult ,Immune Reconstitution ,immune system diseases ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Postoperative Care ,Transplantation Chimera ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Combined Modality Therapy ,Tacrolimus ,Tissue Donors ,Transplantation ,Regimen ,surgical procedures, operative ,Treatment Outcome ,Hematologic disease ,Methotrexate ,Female ,business ,Busulfan ,medicine.drug - Abstract
GATA2 deficiency was described in 2011, and shortly thereafter allogeneic hematopoietic stem cell transplantation (HSCT) was shown to reverse the hematologic disease phenotype. However, there remain major unanswered questions regarding the type of conditioning regimen, type of donors, and graft-versus-host disease (GVHD) prophylaxis. We report 59 patients with GATA2 mutations undergoing HSCT at National Institutes of Health between 2013 and 2020. Primary endpoints were engraftment, reverse of the clinical phenotype, secondary endpoints were overall survival (OS), event-free survival (EFS), and the incidence of acute and chronic GVHD. The OS and EFS at 4 years were 85·1% and 82·1% respectively. Ninety-six percent of surviving patients had reversal of the hematologic disease phenotype by one-year post-transplant. Incidence of grade III-IV aGVHD in matched related donor (MRD) and matched unrelated donor recipients (URD) patients receiving Tacrolimus/Methotrexate for GVHD prophylaxis was 32%. In contrast, in the MRD and URD who received post-transplant cyclophosphamide (PT/Cy), no patient developed grade III-IV aGVHD. Six percent of haploidentical related donor (HRD) recipients developed grade III-IV aGVHD. In summary, a busulfan-based HSCT regimen in GATA2 deficiency reverses the hematologic disease phenotype, and the use of PT/Cy reduced the risk of both aGVHD and cGVHD.
- Published
- 2021
42. Characteristic bone marrow findings in patients with UBA1 somatic mutations and VEXAS syndrome
- Author
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Katherine R. Calvo, Alina Dulau-Florea, and Nisha Patel
- Subjects
Cytopenia ,Pathology ,medicine.medical_specialty ,Hemophagocytic lymphohistiocytosis ,Myeloid ,medicine.diagnostic_test ,business.industry ,Hematology ,Ubiquitin-Activating Enzymes ,medicine.disease ,Bone marrow examination ,medicine.anatomical_structure ,Hematologic disease ,Bone Marrow ,Macrophage activation syndrome ,Myelodysplastic Syndromes ,Mutation ,medicine ,Humans ,Bone marrow ,Macrocytic anemia ,business ,Multiple Myeloma - Abstract
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a newly characterized syndrome with underlying somatic UBA1 mutations in myeloid cells linking hematologic disease with autoinflammatory rheumatologic disorders. Hematologic abnormalities, particularly peripheral blood cytopenia(s) may prompt bone marrow evaluation in patients with known or unrecognized VEXAS syndrome. This review highlights key findings and diagnostic considerations encountered during bone marrow examination in patients with this disorder. Frequently reported hematologic changes include macrocytic anemia, cytoplasmic vacuoles in myeloid and erythroid precursors, marrow hypercellularity, and varying degrees of dysplasia. Myelodysplastic syndrome and plasma cell neoplasms have been diagnosed in patients with VEXAS syndrome. Macrophage activation syndrome and/or hemophagocytic lymphohistiocytosis and monoclonal B-cell lymphocytosis have also been reported. The bone marrow is a target organ in VEXAS syndrome. Heightened awareness of the bone marrow features and hematologic complications may aid in identifying individuals with VEXAS who may benefit from increased disease surveillance or alternative therapeutic strategies.
- Published
- 2021
43. Treatment of High Risk (HR) Smoldering Multiple Myeloma (SMM) with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Followed By Lenalidomide Maintenance (-R): A Phase 2 Clinical and Correlative Study
- Author
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Irina Maric, Nisha Patel, Manisha Bhutani, Hao-Wei Wang, Mark Roschewski, Michael Emanuel, Constance M. Yuan, Esther Mena, Monica Epstein, Raul C. Braylan, Katherine R. Calvo, Dickran Kazandjian, Maryalice Stetler-Stevenson, Crystal Lu, Liza Lindenberg, Elizabeth M. Hill, Seth M. Steinberg, Candis Morrison, Alina Dulau-Florea, Elisabet E. Manasanch, Nishant Tageja, Peter L. Choyke, Mary L Kwok, Neha Korde, Ola Landgren, William D. Figg, Alexander Dew, Sham Mailankody, Yong Zhang, and Ashley Carpenter
- Subjects
medicine.medical_specialty ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Carfilzomib ,law.invention ,Clinical trial ,chemistry.chemical_compound ,Randomized controlled trial ,Maintenance therapy ,chemistry ,law ,Internal medicine ,medicine ,Progression-free survival ,Febrile neutropenia ,Lenalidomide ,medicine.drug - Abstract
Background: HR-SMM is a plasma cell disorder with a 5-year risk of progression to symptomatic multiple myeloma (MM) of ~75% without therapy. Early treatment with novel therapies, may decrease the risk of progression and prolong survival as evidenced by studies (Quiredex and ECOG E3A06) comparing lenalidomide ± dexamethasone to observation. Randomized studies in MM have demonstrated that triplet are superior to doublet regimens and whole exome sequencing in HR-SMM suggests a more treatment-sensitive biology. Together, these support our initial pilot study (Korde et al, JAMA Onc 2015) in using effective therapy with KRd-R as early intervention. Given the favorable initial results of our pilot in terms of minimal residual disease (MRD) negativity rates, we designed a single-arm, phase 2 study with the primary objective of determining the rate of MRD negative complete remissions. Herein, we show that rates of MRD negativity are high and they are sustained with the use of KRd-R. Methods: Patients with HR-SMM (Mayo Clinic or PETHEMA models) received eight 28-day cycles of carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after 4 cycles of KRd and then resumed treatment without an intent for early high-dose melphalan with stem cell support (HDM-ASCT). After 8 cycles of KRd, patients transitioned to receive maintenance therapy with lenalidomide 10 mg PO days 1-21 for 24 additional cycles. Prophylactic antiviral and anticoagulation was mandated for all. MM laboratory evaluations were performed at the start of every cycle during KRd and every 3 cycles during -R and every 3 months during indefinite follow up. Bone marrow biopsies and PET/CTs were performed by the end of cycle 8 induction and then annually indefinitely. The primary objective was to determine the rate of MRD negative remissions by validated multi-color flow cytometry (≤10-5 sensitivity). Key secondary objectives included progression free survival (PFS) to symptomatic myeloma and biochemical progression per IMWG, duration of MRD negativity, overall response rate (ORR), and duration of response. Results: As of 7/15/2020, 52 patients meeting eligibility criteria were enrolled and their demographics and disease characteristics are shown in Table 1. With a median potential follow up of 27.3 months, the primary objective of MRD negative CR rate was 70.2% and the MRD negative ≥VGPR rate was 80.9%, Table 2. The median duration of MRD negativity was 5.5 years with 2 and 5 -year rates of 78% and 55%, respectively. The median time to progression to MM and time to biochemical progression was not reached with 90-month rates of 90% and 78%, respectively - 2 patients progressed to symptomatic MM and 4 patients biochemically. The ORR was 100% and 78% achieved a best response of stringent CR. No deaths occurred. All grade and Grade 3-4 treatment-related adverse events occurred in 90% and 33% of patients, respectively. Grade 3-4 toxicities occurring in >1 patient included neutropenia (19%), lymphopenia (13%), thromboembolism (12%), anemia (8%), rash (8%), leukopenia (6%), lung infection (6%), ALT increase (4%), diarrhea (4%), hyperglycemia (4%), hypophosphatemia (4%), and thrombocytopenia (4%). Other Grade 3-4 adverse events of interest occurring in ≤1 patient included atrial fibrillation, creatinine increase, dyspnea, febrile neutropenia, heart failure, hypertension, and neoplasm. Treatment discontinuation occurred in 4 patients; 3 due to toxicity and 1 due to patient withdrawal. Conclusions: Treatment of HR-SMM with KRd-R to prevent symptomatic MM resulted in an MRD negative CR rate of 70% with a median duration of 5.5 years. At the 5-year landmark, only 10% of patients developed MM which is favorable compared to historical rates with no treatment of ~75%. Alternative approaches using monotherapy lenalidomide (Lonial et al, JCO 2019) resulted in no CRs and a 5-year progression rate of 22% with a treatment discontinuation rate of 51% compared to 7% in our study. More aggressive approaches include GEM-CESAR (Mateos et al, ASH 2019) incorporating HDM-ASCT with KRd-R. Importantly, the rate of MRD negativity reported in GEM-CESAR was 56% compared to 70% in this study. Overall, the benefit compared to risk with KRd in SMM is very favorable. Future randomized trials will be needed to lock in this conclusion. Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Manasanch:Quest Diagnostics: Research Funding; Sanofi: Research Funding; JW Pharma: Research Funding; Merck: Research Funding; Takeda: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Research Funding. Bhutani:BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute; Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Landgren:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Seattle Genetics: Research Funding. OffLabel Disclosure: carfilzomib, lenalidomide, and dexamethasone are not approved for smoldering myeloma.
- Published
- 2020
44. Distinguishing constitutional from acquired bone marrow failure in the hematology clinic
- Author
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Katherine R. Calvo, Emma M. Groarke, and Neal S. Young
- Subjects
Oncology ,medicine.medical_specialty ,Clinical Biochemistry ,Hematology clinic ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Bone Marrow ,Internal medicine ,medicine ,Humans ,Genetic Testing ,Aplastic anemia ,Bone Marrow Diseases ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Bone marrow failure ,Cancer ,Anemia, Aplastic ,Hematology ,biochemical phenomena, metabolism, and nutrition ,Bone Marrow Failure Disorders ,medicine.disease ,Diagnosis of exclusion ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Bone marrow ,business ,030215 immunology - Abstract
Distinguishing constitutional from immune bone marrow failure (BMF) has important clinical implications. However, the diagnosis is not always straightforward, and immune aplastic anemia, the commonest BMF, is a diagnosis of exclusion. In this review, we discuss a general approach to the evaluation of BMF, focusing on clinical presentations particular to immune and various constitutional disorders as well as the interpretation of bone marrow histology, flow cytometry, and karyotyping. Additionally, we examine the role of specialized testing in both immune and inherited BMF, and discuss genetic testing, both its role in patient evaluation and interpretation of results.
- Published
- 2021
45. Long term follow-up of a phase II study of cladribine with concurrent rituximab with hairy cell leukemia variant
- Author
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Hong Zhou, Julie Feurtado, Hao-Wei Wang, Seth M. Steinberg, Chin-Hsien Tai, Mark Raffeld, Constance M. Yuan, Lacey James-Echenique, Evgeny Arons, Raul C. Braylan, Dai Chihara, Liqiang Xi, Alina Dulau-Florea, Katherine R. Calvo, Robert J. Kreitman, Keyur P. Patel, Maryalice Stetler-Stevenson, and Irina Maric
- Subjects
medicine.medical_specialty ,Leukemia, Hairy Cell ,business.industry ,Remission Induction ,Phases of clinical research ,Purine analogue ,Hematology ,Minimal residual disease ,Gastroenterology ,Confidence interval ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Cladribine ,Humans ,Rituximab ,Bone marrow ,business ,Hairy Cell Leukemia Variant ,medicine.drug ,Follow-Up Studies - Abstract
Hairy cell leukemia variant (HCLv) responds poorly to purine analogue monotherapy. Rituximab concurrent with cladribine (CDAR) improves response rates, but long-term outcomes are unknown. We report final results of a phase 2 study of CDAR for patients with HCLv. Twenty patients with 0 to 1 prior courses of cladribine and/or rituximab, including 8 who were previously untreated, received cladribine 0.15 mg/kg on days 1 to 5 with 8 weekly rituximab doses of 375 mg/m2 beginning day 1. Patients received a second rituximab course ≥6 months after cladribine, if and when minimal residual disease (MRD) was detected in blood. The complete remission (CR) rate from CDAR was 95% (95% confidence interval, 75-100). Sixteen (80%) of 20 patients (95% confidence interval, 56-94) became MRD negative according to bone marrow at 6 months. The median duration of MRD-negative CR was 70.1 months, and 7 of 16 are still MRD negative up to 120 months. With a median follow-up of 69.7 months, 11 patients received delayed rituximab, and the 5-year progression-free survival (PFS) and overall survival (OS) were 63.3% and 73.9%, respectively. Five patients with TP53 mutations had shorter PFS (median, 36.4 months vs unreached; P = .0024) and OS (median, 52.4 months vs unreached; P = .032). MRD-negative CR at 6 months was significantly associated with longer PFS (unreached vs 17.4 months; P < .0001) and OS (unreached vs 38.2 months; P < .0001). Lack of MRD in blood at 6 months was also predictive of longer PFS and OS (P < .0001). After progression following CDAR, median OS was 29.7 months. CDAR is effective in HCLv, with better outcomes in patients who achieve MRD-negative CR. This trial is registered at www.clinicaltrials.gov as #NCT00923013.
- Published
- 2021
46. Persistence of skewed X-chromosome inactivation in pre-B acute lymphoblastic leukemia of a female ATRX mutation carrier
- Author
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Christian Bradley, Cai Chen, Minoo Battiwalla, Sara Hauffe, Sawa Ito, Cheng Yan, Matthew C. Foster, Katherine R. Calvo, Reema Panjwani, A. John Barrett, Nathan D. Montgomery, Constance M. Yuan, Prapti A. Patel, Karolyn A. Oetjen, and Richard J. Gibbons
- Subjects
Adult ,0301 basic medicine ,Heterozygote ,X-linked Nuclear Protein ,030105 genetics & heredity ,Pre-B Acute Lymphoblastic Leukemia ,Biology ,X-inactivation ,03 medical and health sciences ,Germline mutation ,Mutation Carrier ,hemic and lymphatic diseases ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,medicine ,Humans ,Gene Silencing ,Skewed X-inactivation ,Germ-Line Mutation ,X chromosome ,ATRX ,Chromosomes, Human, X ,Hematology ,medicine.disease ,Leukemia ,030104 developmental biology ,Cancer research ,Exceptional Case Report ,Female - Abstract
Key Points Leukemic blasts of a female carrier of an ATRX germline mutation have persistently skewed inactivation of the X chromosome. Germline mutation in leukemia needs to be interpreted with caution because it is not always pathologic.
- Published
- 2019
47. Germline Predisposition to Hematolymphoid Neoplasia
- Author
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Olga K. Weinberg, Frank Kuo, and Katherine R. Calvo
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Myeloid ,Adolescent ,medicine.disease_cause ,Malignancy ,Germline ,DEAD-box RNA Helicases ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Internal medicine ,CEBPA ,medicine ,Humans ,Genetic Predisposition to Disease ,Child ,Review Articles ,Germ-Line Mutation ,Mutation ,business.industry ,Myeloid leukemia ,General Medicine ,Middle Aged ,medicine.disease ,GATA2 Transcription Factor ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Child, Preschool ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Core Binding Factor Alpha 2 Subunit ,CCAAT-Enhancer-Binding Proteins ,Female ,Tumor Suppressor Protein p53 ,business ,Hematopathology ,030215 immunology - Abstract
ObjectivesThe 2017 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review clinical cases with germline predisposition to hematolymphoid neoplasms.MethodsThe Workshop Panel reviewed 51 cases with germline mutations and rendered consensus diagnoses. Of these, six cases were presented at the meeting by the submitting pathologists.ResultsThe cases submitted to the session covering germline predisposition included 16 cases with germline GATA2 mutations, 10 cases with germline RUNX1 mutations, two cases with germline CEBPA mutations, two germline TP53 mutations, and one case of germline DDX41 mutation. The most common diagnoses were acute myeloid leukemia (15 cases) and myelodysplastic syndrome (MDS, 14 cases).ConclusionsThe majority of the submitted neoplasms occurring in patients with germline predisposition were myeloid neoplasms with germline mutations in GATA2 and RUNX1. The presence of a germline predisposition mutation is not sufficient for a diagnosis of a neoplasm until the appearance of standard diagnostic features of a hematolymphoid malignancy manifest: in general, the diagnostic criteria for neoplasms associated with germline predisposition disorders are the same as those for sporadic cases.
- Published
- 2019
48. Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque
- Author
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Katherine R. Calvo, Idalia M. Yabe, Kristin J Hope, Chuanfeng Wu, Xing Fan, Xiaolin Wu, Rong Lu, Aylin C. Bonifacino, Lauren L. Truitt, Stefan Cordes, Di Yang, Robert E. Donahue, Diego A. Espinoza, Cynthia E. Dunbar, So Gun Hong, Suk See DeRavin, Allen E. Krouse, Mark E. Metzger, John F. Tisdale, Harry L. Malech, Selami Demirci, and Naoya Uchida
- Subjects
Myeloid ,Genetic enhancement ,Genetic Vectors ,Green Fluorescent Proteins ,Clone (cell biology) ,Antigens, CD34 ,Stem cell factor ,Biology ,Transplantation, Autologous ,Viral vector ,03 medical and health sciences ,Transduction (genetics) ,0302 clinical medicine ,Transduction, Genetic ,Drug Discovery ,Genetics ,medicine ,Animals ,Protein Splicing ,Progenitor cell ,Promoter Regions, Genetic ,Molecular Biology ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Luminescent Agents ,Lentivirus ,Hematopoietic Stem Cell Transplantation ,Terminal Repeat Sequences ,Genetic Therapy ,Hematopoietic Stem Cells ,Macaca mulatta ,Clone Cells ,Hematopoiesis ,Cell biology ,Mutagenesis, Insertional ,Haematopoiesis ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Commentary ,Molecular Medicine - Abstract
Lentiviral vectors (LVs) are used for delivery of genes into hematopoietic stem and progenitor cells (HSPCs) in clinical trials worldwide. LVs, in contrast to retroviral vectors, are not associated with insertion site-associated malignant clonal expansions and, thus, are considered safer. Here, however, we present a case of markedly abnormal dysplastic clonal hematopoiesis affecting the erythroid, myeloid, and megakaryocytic lineages in a rhesus macaque transplanted with HSPCs that were transduced with a LV containing a strong retroviral murine stem cell virus (MSCV) constitutive promoter-enhancer in the LTR. Nine insertions were mapped in the abnormal clone, resulting in overexpression and aberrant splicing of several genes of interest, including the cytokine stem cell factor and the transcription factor PLAG1. This case represents the first clear link between lentiviral insertion-induced clonal expansion and a clinically abnormal transformed phenotype following transduction of normal primate or human HSPCs, which is concerning, and suggests that strong constitutive promoters should not be included in LVs.
- Published
- 2019
49. Detection of paroxysmal nocturnal hemoglobinuria (PNH) in bone marrow aspirates☆
- Author
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Irina Maric, Katherine R. Calvo, Alina Dulau-Florea, and Raul C. Braylan
- Subjects
biology ,medicine.diagnostic_test ,Chemistry ,Cell ,Hemoglobinuria, Paroxysmal ,Aerolysin ,Hematology ,CD59 ,Flow Cytometry ,medicine.disease ,Molecular biology ,Flow cytometry ,Haematopoiesis ,medicine.anatomical_structure ,Bone Marrow ,hemic and lymphatic diseases ,Paroxysmal nocturnal hemoglobinuria ,medicine ,biology.protein ,Humans ,Bone marrow ,Antibody - Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired condition in which, due to a mutation of the phosphatidylinositol glycan class A gene, hematopoietic cells lack proteins that are normally anchored to the cell surface by glycosylphosphatidylinositol (GPI). Thus, PNH cells show poor expression of surface proteins, such as CD55 and CD59, and dim or absent binding of fluorescently labeled modified aerolysin (FLAER). In clinical diagnostic laboratories, the detection and quantitation of PNH is currently performed by flow cytometry (FC) analysis of peripheral blood (PB) samples. Although PB remains the preferred source of cells for PNH detection, we and other authors have shown that a careful FC analysis of bone marrow (BM) aspirates can provide results for PNH detection and quantitation equivalent to those obtained with PB. Here, we review studies delineating the expression of GPI-anchored proteins and FLAER binding in normal BM cells, and summarize published findings demonstrating the feasibility of identifying and quantitating PNH cells in BM using FLAER as well as antibodies against GPI-anchored proteins. Detection of PNH cells in BM should be useful in patients with unsuspected PNH or with severe cytopenia in whom PB FC analysis may be challenging.
- Published
- 2019
50. Acquired and germline predisposition to bone marrow failure: Diagnostic features and clinical implications
- Author
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Alina Dulau-Florea, Weixin Wang, Katherine R. Calvo, and Michael E. Kallen
- Subjects
business.industry ,medicine.medical_treatment ,Bone marrow failure ,Anemia, Aplastic ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Bioinformatics ,Germ Cells ,medicine.anatomical_structure ,Bone Marrow ,Fanconi anemia ,hemic and lymphatic diseases ,medicine ,Humans ,Congenital amegakaryocytic thrombocytopenia ,Bone marrow ,Aplastic anemia ,Congenital Neutropenia ,business ,Germ-Line Mutation ,Dyskeratosis congenita - Abstract
Bone marrow failure and related syndromes are rare disorders characterized by ineffective bone marrow hematopoiesis and peripheral cytopenias. Although many are associated with characteristic clinical features, recent advances have shown a more complicated picture with a spectrum of broad and overlapping phenotypes and imperfect genotype-phenotype correlations. Distinguishing acquired from inherited forms of marrow failure can be challenging, but is of crucial importance given differences in the risk of disease progression to myelodysplastic syndrome, acute myeloid leukemia, and other malignancies, as well as the potential to genetically screen relatives and select the appropriate donor if hematopoietic stem cell transplantation becomes necessary. Flow cytometry patterns in combination with morphology, cytogenetics, and history can help differentiate several diagnostic marrow failure and/or insufficiency entities and guide genetic testing. Herein we review several overlapping acquired marrow failure entities including aplastic anemia, hypoplastic myelodysplasia, and large granular lymphocyte disorders; and several bone marrow disorders with germline predisposition, including GATA2 deficiency, CTLA4 haploinsufficiency, dyskeratosis congenita and/or telomeropathies, Fanconi anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, severe congenital neutropenia, and Diamond-Blackfan anemia with a focus on advances related to pathophysiology, diagnosis, and management.
- Published
- 2019
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