Publications by authors named "David Sallman"

82 Publications

What is the optimal time to initiate hypomethylating agents (HMAs) in higher risk myelodysplastic syndromes (MDSs)?

Leuk Lymphoma 2021 Jun 11:1-6. Epub 2021 Jun 11.

Malignant Hematology Department, H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Hypomethylating agents (HMAs) are the standard of care for higher risk MDS (HR-MDS) patients. The current dogma is to begin HMA therapy in all HR-MDS patients at the time of initial diagnosis. We investigated the impact of the timing of HMA initiation among HR-MDS patients presenting with adequate blood counts to discern the possible benefit of early treatment based solely on disease risk. We identified 320 HR-MDS patients with adequate hematopoiesis who were treated with HMA. The complete response rates were 21%, 26%, 23%, and 7% respectively for patients treated within 30, 31-60, 61-90, and more than 90 days from time of diagnosis (=.046). The median OS from the date of diagnosis was 641, 550, 979, and 806 days, respectively (=.2). A delay in initiating HMA therapy in HR-MDS patients with adequate blood counts is not associated with worsened outcomes.
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http://dx.doi.org/10.1080/10428194.2021.1938028DOI Listing
June 2021

Impact of obesity on survival of patients with myelodysplastic syndromes.

Hematology 2021 Dec;26(1):393-397

Hematology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Obesity has been associated with increased incidence of myelodysplastic syndromes (MDS). Recently intriguing data in mouse models suggested that obesity increases survival in animals with MDS. This was a retrospective analysis using the Moffitt MDS database. Obesity was defined by using body mass index (BMI), whereby a BMI ≥ 30 was regarded as obese. Among 3089 MDS patients with known BMI, 963 patients (31%) were categorized as obese. There were no differences in baseline characteristics between patients with BMI ≥ 30 and those with <30. The median OS for patients with BMI ≥ 30 was 34 months compared to 37 months for those with BMI < 30 ( 0.04). For patients with lower-risk MDS median OS was 52 months versus 57 months, respectively, ( 0.08) while for higher-risk patients median OS was 17 months for both groups. The rate of AML transformation was 36% for patients with BMI ≥ 30 compared to 32% for those with BMI < 30 ( 0.009). There was no difference in response to azacitidine. In multivariable analysis, BMI was associated with inferior OS. For patients < 45 years old, the median OS was 25 months for patients with BMI ≥ 30 compared to 116 months for those with BMI < 30 ( 0.034). Obesity is associated with inferior overall survival (OS) in MDS patients in less than 65 years old and lower MDS risk. Impact of obesity on the outcome of MDS is being explored in both mice and human. Here we reported the impact of obesity on OS in MDS patients. Obesity is associated with inferior OS in MDS patients particularly younger age groups and lower MDS risk.
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http://dx.doi.org/10.1080/16078454.2021.1929692DOI Listing
December 2021

ELN 2017 Genetic Risk Stratification Predicts Survival of Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 Mar 2;27(3):256.e1-256.e7. Epub 2021 Feb 2.

Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address:

European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. We included 500 adult (≥18 years) AML patients in first (n = 370) or second (n = 130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and nonrelapse mortality were analyzed by the Fine-Gray regression model. OS at 2 years was 72% in the favorable versus 60% in the intermediate versus 45% in the adverse risk groups (P < .001). In multivariable analyses, the 2017 ELN classifier was an independent predictor of OS after alloHCT with significantly higher overall mortality in the intermediate (hazard ratio [HR] = 1.68, 95% confidence interval [CI], 1.06-2.68; P = .03) and adverse (HR = 2.50, 95% CI, 1.54-4.06; P < .001) risk groups compared to the favorable risk group. Similarly, LFS was worse in the intermediate (HR = 1.63, 95%, CI 1.06-2.53; P = .03) and adverse (HR 2.23, 95% CI, 1.41-3.54; P < .001) risk groups while relapse was higher in the adverse risk group (HR = 2.36, 95% CI, 1.28-4.35; P = .006) as compared to the favorable risk group. These data highlight the prognostic impact of the 2017 ELN genetic risk stratification on the survival of AML patients after alloHCT. Patients in the adverse risk group had the highest risk of relapse and worst survival. Thus the 2017 ELN prognostic system can help identify AML patients who may benefit from clinical trials offering relapse mitigation strategies to improve transplant outcomes.
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http://dx.doi.org/10.1016/j.jtct.2020.12.021DOI Listing
March 2021

Eprenetapopt Plus Azacitidine in -Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM).

J Clin Oncol 2021 May 18;39(14):1575-1583. Epub 2021 Feb 18.

GFM.

Purpose: -mutated () myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions.

Patients And Methods: This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R MDS and AML patients.

Results: Fifty-two patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( < .01) and higher age ( = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively.

Conclusion: In this very high-risk population of MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.
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http://dx.doi.org/10.1200/JCO.20.02342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099409PMC
May 2021

Baseline and serial molecular profiling predicts outcomes with hypomethylating agents in myelodysplastic syndromes.

Blood Adv 2021 02;5(4):1017-1028

Malignant Hematology Department and.

Hypomethylating agents (HMAs) are widely used in the treatment of myelodysplastic syndromes (MDSs), yet identifying those patients unlikely to benefit remains challenging. We assessed response and overall survival (OS) in 247 patients molecularly profiled by next-generation sequencing (NGS) before first-line HMA therapy, and a subset of 108 patients were sequenced serially during treatment. The most common mutations included TP53 (33.1%), ASXL1 (19%), TET2 (16.5%), DNMT3A (14.1%), and SRSF2 (12.1%). The overall response rate was 42.1%, with the composite TET2-mutant/ASXL1 wild-type genotype representing the strongest predictor of response (overall response rate, 62.1%; complete remission rate, 34.5%). The median OS for the cohort was 15 months, and the number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02), as well as mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were identified as independent covariates associated with inferior OS in multivariable analysis. Serial molecular profiling revealed that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic hematopoietic cell transplantation. These data support baseline molecular profiling by NGS in MDS patients treated with HMAs and provide novel observations of sequential profiling during therapy that provide particular value in TP53-mutated disease.
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http://dx.doi.org/10.1182/bloodadvances.2020003508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903224PMC
February 2021

Genomic characteristics and prognostic significance of co-mutated ASXL1/SRSF2 acute myeloid leukemia.

Am J Hematol 2021 04 15;96(4):462-470. Epub 2021 Feb 15.

Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

The ASXL1 and SRSF2 mutations in AML are frequently found in patients with preexisting myeloid malignancies and are individually associated with poor outcomes. In this multi-institutional retrospective analysis, we assessed the genetic features and clinical outcomes of 43 patients with ASXL1 SRSF2 AML and compared outcomes to patients with either ASXL1 (n = 57) or SRSF2 (n = 70) mutations. Twenty-six (60%) had secondary-AML (s-AML). Variant allele fractions suggested that SRSF2 mutations preceded ASXL1 mutational events. Median overall survival (OS) was 7.0 months (95% CI:3.8,15.3) and was significantly longer in patients with de novo vs s-AML (15.3 vs 6.4 months, respectively; P = .04 on adjusted analysis). Compared to ASXL1 SRSF2 and ASXL1 SRSF2 , co-mutated patients had a 1.4 and 1.6 times increase in the probability of death, respectively (P = .049), with a trend towards inferior OS (median OS = 7.0 vs 11.5 vs 10.9 months, respectively; P = .10). Multivariable analysis suggests this difference in OS is attributable to the high proportion of s-AML patients in the co-mutated cohort (60% vs 32% and 23%, respectively). Although this study is limited by the retrospective data collection and the relatively small sample size, these data suggest that ASXL1 SRSF2 AML is a distinct subgroup of AML frequently associated with s-AML and differs from ASXL1 SRSF2 /ASXL1 SRSF2 with respect to etiology and leukemogenesis.
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http://dx.doi.org/10.1002/ajh.26110DOI Listing
April 2021

Eprenetapopt (APR-246) and Azacitidine in -Mutant Myelodysplastic Syndromes.

J Clin Oncol 2021 May 15;39(14):1584-1594. Epub 2021 Jan 15.

Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Purpose: Approximately 20% of patients with -mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in -mutant cells.

Methods: This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with -mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043).

Results: Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only mutations by next-generation sequencing had higher rates of CR (69% 25%; = .006). Responding patients had significant reductions in variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 7.5 months; = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).

Conclusion: Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with -mutant MDS and oligoblastic AML.
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http://dx.doi.org/10.1200/JCO.20.02341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099410PMC
May 2021

Validation of International Working Group response criteria in higher-risk myelodysplastic syndromes: A report on behalf of the MDS Clinical Research Consortium.

Cancer Med 2021 01 22;10(2):447-453. Epub 2020 Dec 22.

Leukemia Program, Cleveland Clinic, Cleveland, OH, USA.

The utility of the International Working Group (IWG) 2006 response criteria for myelodysplastic syndromes (MDS) as a surrogate endpoint for outcomes is unclear. We assessed the validity of the IWG 2006 response criteria in a large cohort of higher-risk MDS patients (pts) treated at centers from the MDS Clinical Research Consortium. The best overall response rate (ORR) by IWG 2006 criteria to first-line therapy among 597 evaluable pts was 38% and include complete response (CR) 16%, marrow CR (mCR) 2%, partial response (PR) 10%, hematological improvement (HI) 10%, stable disease (SD) 33%, and progressive disease (PD) 24%. CR was associated with a better overall survival (OS) compared to all other response groups (P < 0.001). Among 470 pts treated with hypomethylating agent (HMA) as first-line therapy, the overall Response Rate, defined as HI or better was 39%. The median OS from time of best response was 21 mo, 8 mo, 14 mo, 12 mo, 13 mo, and 8 mo for CR, mCR, PR, HI, SD, and PD, respectively (P < 0.001). We validated those results in a separate cohort of 539 higher-risk MDS pts treated at Moffitt Cancer Center who received first-line HMA therapy, particularly addressing the value of mCR and mCR+HI. mCR alone without HI, SD, and PD outcomes were inferior to CR, PR, mCR+HI, and HI. In conclusion, CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher-risk MDS pts. Any response associated with restoration of effective hematopoiesis is associated with better outcome.
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http://dx.doi.org/10.1002/cam4.3608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877342PMC
January 2021

The promise of macrophage directed checkpoint inhibitors in myeloid malignancies.

Best Pract Res Clin Haematol 2020 12 6;33(4):101221. Epub 2020 Nov 6.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

To date, many of the most successful checkpoint inhibitor-based therapies in cancer have targeted T-cells and adaptive immunity. However, there is an ongoing search for novel checkpoints with targeting innate immunity via activation of macrophage phagocytosis representing an exciting therapeutic strategy. CD47 is the dominant negative macrophage immune checkpoint expressed on cancer cells which acts as a "don't eat me signal", preventing phagocytosis via its interaction with SIRP-α on macrophages. CD47 has been shown to be upregulated in many cancer types including myeloid malignancies with increased expression associated with inferior OS. Magrolimab, an anti-CD47 antibody, has shown proof-of-principle of efficacy in this therapeutic class with promising early results in both higher risk myelodysplastic syndromes (MDS) and TP53 mutant acute myeloid leukemia (AML). The toxicity profile to date has been shown safe and manageable with on-target anemia related to CD47 being present on aged red blood cells and without evidence of immune related toxicities. Investigation of novel agents targeting this pathway and novel combinations are ongoing. New strategies targeting macrophage checkpoints are encouraging and likely will lead a paradigm shift in the current treatment of myeloid malignancies.
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http://dx.doi.org/10.1016/j.beha.2020.101221DOI Listing
December 2020

Fluorescence in Situ Hybridization (FISH) Utility for Risk Score Assessment in Patients With MDS With Normal Metaphase Karyotype.

Clin Lymphoma Myeloma Leuk 2021 01 18;21(1):e52-e56. Epub 2020 Aug 18.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL. Electronic address:

Background: Cytogenetic profile is an essential parameter in myelodysplastic syndromes (MDS) risk stratification by both International Prognostic Symptom Score (IPSS) and Revised (R)-IPSS. Almost one-half of patients with MDS have normal cytogenetics by metaphase karyotype. Here we report the yield of MDS fluorescence in situ hybridization (FISH) panel detecting cytogenetic abnormalities in these patients and its impact on risk stratification.

Patients And Methods: Among patients with normal metaphase karyotype, we assessed those patients who had cytogenetic abnormalities detected by an MDS FISH panel, which included probes for del (5), del (7), del (20), trisomy 8, and del (17p). Risk stratification was calculated by both IPSS and R-IPSS.

Results: Of 1600 patients with MDS with normal metaphase karyotype, 53 (3%) patients had cytogenetic abnormality detected by MDS FISH panel. Integrating the MDS FISH panel cytogenetics (IPSS + FISH restaging) resulted in upstaging the score, where 53% of low-risk IPSS were upstaged to intermediate (int)-1, 56% of int-1 were upstaged to int-2, and 78% of int-2 were upstaged to high risk. Based on the R-IPSS, 61% of very low-risk patients, all low-risk patients, 92% of intermediate-risk patients, and 50% of high-risk patients with FISH abnormalities were upstaged, respectively.

Conclusion: The yield of MDS FISH panel detecting cytogenetic abnormalities in patients with normal karyotype by G-banding is low and may not warrant ordering the panel in all patients. Among the 3% of patients with normal karyotype who had cytogenetic abnormality detected by FISH, the risk score assignment by IPSS and R-IPSS was upstaged.
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http://dx.doi.org/10.1016/j.clml.2020.08.012DOI Listing
January 2021

The Problem of TP53-Mutant MDS/AML.

Authors:
David A Sallman

Clin Lymphoma Myeloma Leuk 2020 09;20 Suppl 1:S65-S66

Malignant Hematology Department, H. Lee Moffitt Cancer Center, Tampa, Florida, United States. Electronic address:

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http://dx.doi.org/10.1016/S2152-2650(20)30465-1DOI Listing
September 2020

Retrospective Analysis of the Clinical Use and Benefit of Lenalidomide and Thalidomide in Myelofibrosis.

Clin Lymphoma Myeloma Leuk 2020 12 16;20(12):e956-e960. Epub 2020 Jul 16.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL. Electronic address:

Introduction: Anemia in myelofibrosis (MF) occurs frequently, is poorly addressed by US Food and Drug Administration-approved JAK inhibitors, and negatively impacts quality of life. Immunomodulatory imide agents (IMiDs) such as thalidomide and lenalidomide are among the limited treatment options that have demonstrated anemia benefit in single-arm studies.

Patients And Methods: To better understand the comparative impact of lenalidomide and thalidomide in MF patients, we analyzed 176 consecutive MF patients who received lenalidomide or thalidomide for at least 4 weeks. We sought to understand the variability in patient populations receiving lenalidomide versus thalidomide, to assess the efficacy of these agents, and to investigate clinical or genomic features that predict response.

Results: Clinical benefit (CB) was assessable in 83 lenalidomide- and 67 thalidomide-treated patients. Thalidomide-treated patients were more likely to have thrombocytopenia (P < .001) and high-risk disease (P = .02). Forty-one (49%) lenalidomide-treated patients were deemed to have CB, predominantly due to anemia benefit. Similarly, 28 (42%) of thalidomide-treated patients had CB attributable to anemia benefit. Overall survival was similar for lenalidomide- and thalidomide-treated patients (P = .51). Lenalidomide-treated patients with CB had longer overall survival than those who did not (P = .01). High-risk mutations were found in 12 (41%) of 29 and 20 (57%) of 35 patients treated with lenalidomide and thalidomide, respectively (P = .32). Splicing mutations were common in both cohorts, though thalidomide-treated patients were more likely to have a high-risk SRSF2 or U2AF1 Q157 mutation (P = .01).

Conclusion: Overall, in this retrospective analysis, lenalidomide and thalidomide showed similar rates of CB in a cohort of MF patients that frequently harbored splicing mutations.
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http://dx.doi.org/10.1016/j.clml.2020.07.006DOI Listing
December 2020

TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype.

Blood 2020 12;136(24):2812-2823

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.
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http://dx.doi.org/10.1182/blood.2020006158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731792PMC
December 2020

Prognostic significance of serial molecular annotation in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML).

Leukemia 2021 04 29;35(4):1145-1155. Epub 2020 Jul 29.

Malignant Hematology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

The implementation of next-generation sequencing (NGS) has influenced diagnostic, prognostic, and therapeutic decisions in myeloid malignancies. However, the clinical relevance of serial molecular annotation in patients with myelodysplastic syndrome (MDS) undergoing active treatment is unknown. MDS or secondary acute myeloid leukemia (sAML) patients who had at least two NGS assessments were identified. Outcomes according to mutation clearance (NGS-) on serial assessment were investigated. Univariate and multivariate Cox regression models were used to evaluate the prognostic impact of NGS trajectory on overall survival (OS). A total of 157 patients (MDS [n = 95]; sAML [n = 52]; CMML [n = 10]) were identified, with 93% of patients receiving treatment between NGS assessments. Magnitude of VAF delta from baseline was significantly associated with quality of response to treatment. Patients achieving NGS- had significantly improved OS compared to patients with mutation persistence (median OS not reached vs. 18.5 months; P = 0.002), which was confirmed in multivariate analysis (HR,0.14; 95%CI = 0.03-0.56; P = 0.0064). Serial TP53 VAF evaluation predicts outcomes with TP53 clearance representing an independent covariate for superior OS (HR,0.22; 95%CI = 0.05-0.99; P = 0.048). Collectively, our study highlights the clinical value of serial NGS during treatment and warrants prospective validation of NGS negativity as a biomarker for treatment outcome.
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http://dx.doi.org/10.1038/s41375-020-0997-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854836PMC
April 2021

Characterization of myelodysplastic syndromes (MDS) with T-cell large granular lymphocyte proliferations (LGL).

Leukemia 2020 11 21;34(11):3097-3099. Epub 2020 Jun 21.

Formerly Department of Malignant Hematology, H. Lee Moffitt Cancer center, Tampa, FL, USA.

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http://dx.doi.org/10.1038/s41375-020-0928-4DOI Listing
November 2020

Comparison of induction strategies and responses for acute myeloid leukemia patients after resistance to hypomethylating agents for antecedent myeloid malignancy.

Leuk Res 2020 06 1;93:106367. Epub 2020 May 1.

Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, United States.

Outcomes in patients with secondary acute myeloid leukemia (sAML) (including therapy related myeloid neoplasms and AML with myelodysplasia related changes (MRC)) are poor. Patients treated with hypomethylating agents (HMAs) for antecedent hematological malignancy (AHM) have suboptimal responses to induction chemotherapy upon transformation to AML. We investigated outcomes after various induction strategies in patients with sAML who had prior HMA exposure. We identified 242 patients with sAML who had prior HMA treatment for AHM and later received induction chemotherapy upon AML transformation and divided into 3 cohorts based on induction regimen: (A) CLAG/M (B) 7 + 3 and (C) CPX-351. The CR/CRi rate was 53% in cohort A, 32% in cohort B and 41.2% in cohort C (p = 0.005 between cohort A and B) (p = 0.329 between cohorts A and C) (p = 0.402 between cohorts B and C). The early death rates were not significantly different among the three cohorts (p = 0.200). In patients who received ≤4 cycles of HMAs prior to AML transformation, response rates to CPX-351 were higher (64.3%) with a trend toward better overall survival (OS) (19.9 vs. 5.5 months) compared to >4 cycles (p = 0.092). There was no significant difference in median OS among the 3 groups: cohort A (7.27 months), cohort B (7.63 months) and cohort C (7.07 months) (p = 0.887). We demonstrate that CLAG/M and CPX-351 yield higher CR/CRi rates compared to 7 + 3 in patients with sAML after HMA failure. Median OS remains poor and did not differ among the 3 groups, illustrating the unmet need for more efficacious therapy for sAML patients following HMA failure.
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http://dx.doi.org/10.1016/j.leukres.2020.106367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771257PMC
June 2020

SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS.

Blood 2020 07;136(2):157-170

Amsterdam University Medical Center, Amsterdam, The Netherlands.

The 2016 revision of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues is characterized by a closer integration of morphology and molecular genetics. Notwithstanding, the myelodysplastic syndrome (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a genetic abnormality. Approximately half of MDS patients carry somatic mutations in spliceosome genes, with SF3B1 being the most commonly mutated one. SF3B1 mutation identifies a condition characterized by ring sideroblasts (RS), ineffective erythropoiesis, and indolent clinical course. A large body of evidence supports recognition of SF3B1-mutant MDS as a distinct nosologic entity. To further validate this notion, we interrogated the data set of the International Working Group for the Prognosis of MDS (IWG-PM). Based on the findings of our analyses, we propose the following diagnostic criteria for SF3B1-mutant MDS: (1) cytopenia as defined by standard hematologic values, (2) somatic SF3B1 mutation, (3) morphologic dysplasia (with or without RS), and (4) bone marrow blasts <5% and peripheral blood blasts <1%. Selected concomitant genetic lesions represent exclusion criteria for the proposed entity. In patients with clonal cytopenia of undetermined significance, SF3B1 mutation is almost invariably associated with subsequent development of overt MDS with RS, suggesting that this genetic lesion might provide presumptive evidence of MDS in the setting of persistent unexplained cytopenia. Diagnosis of SF3B1-mutant MDS has considerable clinical implications in terms of risk stratification and therapeutic decision making. In fact, this condition has a relatively good prognosis and may respond to luspatercept with abolishment of the transfusion requirement.
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http://dx.doi.org/10.1182/blood.2020004850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362582PMC
July 2020

A sequential two-stage dose escalation study of eltrombopag in patients with myelodysplastic syndrome and thrombocytopenia after hypomethylating agent failure.

Leuk Lymphoma 2020 08 19;61(8):1901-1907. Epub 2020 Apr 19.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Thrombocytopenia occurs frequently in patients with myelodysplastic syndromes (MDS), and the survival of patients after failure of hypomethylating agents (HMAs) is poor. We conducted a trial of eltrombopag in patients with MDS, MDS/myeloproliferative neoplasm (MPN) or acute myeloid leukemia (AML) with 20-30% myeloblasts after HMA failure and mean baseline platelet count ≤ 50 × 10/L. Eltrombopag was escalated from 50 mg daily up to 200 mg daily. The primary objective was to determine the maximally tolerated dose (MTD). 37 patients were enrolled, and MTD was not reached. Responses were observed in 9 patients (24%), 2 achieving marrow CR with hematologic improvement (HI), 1 marrow CR without HI, and 6 HI. Median overall survival was 7.5 months. Eltrombopag was well-tolerated and yielded modest responses in heavily treated, predominantly higher-risk MDS patients after HMA failure. Future studies should focus on determining characteristics that predict response.
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http://dx.doi.org/10.1080/10428194.2020.1751841DOI Listing
August 2020

Hypomethylating Agent Therapy in Myelodysplastic Syndromes With Chromosome 3 Abnormalities.

Clin Lymphoma Myeloma Leuk 2020 09 20;20(9):e597-e605. Epub 2020 Mar 20.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Electronic address:

Background: Abnormalities of chromosome 3 in myelodysplastic syndromes (MDS), that is, inversion 3 (inv[3]), translocation 3q (t[3q]), or deletion 3q (del[3q]), are defined as poor-risk karyotypes in the Revised International Prognostic Scoring System (IPSS-R). The objective of this study was to further define the outcomes of patients with MDS with chromosome 3 abnormalities and address the impact of hypomethylating agent (HMA) therapy on this patient subset.

Patients And Methods: Through the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts).

Results: Specific chromosome 3 aberrations and cytogenetic complexity were predictive of survival; patients with t(3q) and isolated chromosome 3 had improved overall survival (OS), albeit still poor, whereas patients with complex cytogenetics, including those with 3p abnormalities, had inferior OS. Overall response rates to HMAs among this patient population were similar to those of patients with nonchromosome 3-MDS (52%, with a 25% complete remission rate), although with higher response rates in decitabine-treated patients (69% vs. 45%, P = .008). HMA therapy improved the OS of patients with higher-risk MDS compared with intensive chemotherapy (median OS of 15.5 vs. 8.2 months; P  =  .017). This improvement remained significant in multivariate analyses (hazard ratio, 0.60; P  =  .018); however, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs.

Conclusion: Patients with MDS with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.
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http://dx.doi.org/10.1016/j.clml.2020.03.005DOI Listing
September 2020

Defining Acute Myeloid Leukemia Ontogeny in Older Patients.

Clin Lymphoma Myeloma Leuk 2020 05 9;20(5):312-315. Epub 2019 Nov 9.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Electronic address:

Background: Acute myeloid leukemia (AML) in elderly patients is associated with poor outcomes and often arises from antecedent hematologic disorders (AHD), classified as secondary AML (sAML).

Patients And Methods: To validate the use of somatic mutations to determine AML ontogeny in the elderly population, we identified 178 elderly (> 70 years) patients with AML with NexGen Sequencing data. Patients were divided clinically into primary AML (pAML) or sAML based on prior history of AHD. Patients were then reclassified into 4 groups based on somatic mutations and cytogenetics as suggested by Lindsley et al: group 1 (pAML) with CBF rearrangements, 11q23/MLL, and NPM1 mutation (MT); group 2 (sAML) with SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 MT; group 3 with TP53 MT; and group 4 as not otherwise specified (NOS).

Results: Based on clinical criteria, 95 patients were classified as pAML and 82 patients as sAML. Based on the AML ontogeny proposed, 8 patients were classified as pAML, 72 patients as sAML, 28 patients had TP53 MT, and 70 patients were classified as NOS. The median overall survival was 22.4,14, 2.8, and 11.2 months, respectively. Clinical versus molecular classification was discordant where 25% (n = 2) of patients classified as pAML by molecular signature had a history of AHD, whereas 44% (n = 32) of patients classified molecularly as sAML had no prior AHD. In the TP53 MT and NOS categories, 37% (n = 28) and 43% (n = 70) of patients had AHD, respectively.

Conclusion: Our data shows that molecular annotation of elderly patients with AML reclassifies a significant proportion of patients as sAML, which may have therapeutic implications.
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http://dx.doi.org/10.1016/j.clml.2019.11.007DOI Listing
May 2020

Comparison of mutational profiles and clinical outcomes in patients with acute myeloid leukemia with mutated versus acute myeloid leukemia with myelodysplasia-related changes with mutated .

Leuk Lymphoma 2020 06 24;61(6):1395-1405. Epub 2020 Feb 24.

Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Studies comparing the prognostic role of mutations () in acute myeloid leukemia (AML) and acute myeloid leukemia-with myelodysplasia-related changes (AML-MRC) are limited. Our study examines the genetic profile of 118 AML patients including 57 AML with and 61 AML-MRC with and 100 AML, NOS patients with wild type (). Results revealed that AML-MRC patients with had shorter median overall survival (OS) (11 ± 3.3 months) when compared to AML with (19 ± 7.1 months) and AML, NOS with (not reached) ( = .001). The most common concurrent mutations observed in AML-MRC with patients were , , , and while in AML with patients were , , , , and . and mutations appeared to adversely affect OS in AML-MRC, but not in AML with . Concurrent mutations, in contrast had negative impact on OS in AML with , but not in AML-MRC with .
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http://dx.doi.org/10.1080/10428194.2020.1723016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269833PMC
June 2020