Publications by authors named "Martin S Tallman"

451 Publications

Measurable residual disease negativity in acute myeloid leukemia: the destination may matter more than the journey.

Leuk Lymphoma 2021 Sep 14:1-2. Epub 2021 Sep 14.

Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1080/10428194.2021.1929967DOI Listing
September 2021

Venetoclax-based combinations in AML and high-risk MDS prior to and following allogeneic hematopoietic cell transplant.

Leuk Lymphoma 2021 Sep 3:1-8. Epub 2021 Sep 3.

Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

The role of allogeneic hematopoietic cell transplant (allo-HCT) as consolidation after initial venetoclax therapy and the efficacy of venetoclax salvage therapy for relapse after allo-HCT in patients with acute myeloid leukemia (AML) are unclear. We conducted a retrospective study of patients with AML or myelodysplastic syndrome (MDS) who received venetoclax either before or after allo-HCT at Memorial Sloan Kettering Cancer Center and Yale University from 11 August 2016 to 16 November 2020. Among 39 heavily pretreated patients who received venetoclax before allo-HCT, median OS from allo-HCT was not reached after a median follow up of 12.5 months resulting in a 12-month OS estimate of 79.0%. In 37 patients who had received venetoclax-based combinations as salvage therapy after allo-HCT, the overall response rate was 32% with a median OS of 4.7 months (12-month OS estimate: 43.4%). Four patients underwent a second allo-HCT following venetoclax-based salvage therapy suggesting it as a potential salvage treatment option.
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http://dx.doi.org/10.1080/10428194.2021.1966788DOI Listing
September 2021

Measurable Residual Disease Does Not Preclude Prolonged Progression-free Survival in CLL Treated with Ibrutinib.

Blood 2021 Aug 18. Epub 2021 Aug 18.

Mayo Clinic, Rochester, Minnesota, United States.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus six cycles of rituximab (IR) to six cycles of fludarabine, cyclophosphamide and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (< 1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4% and 8.6% at 3, 12, 24 and 36 months for FCR, and significantly lower at 7.9%, 4.2% and 3.7% at 12, 24 and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24 and 36 months was associated with longer progression-free survival (PFS) for the FCR arm with hazard ratios (MRD detectable / MRD undetectable) of 4.29 (95% CI 1.89 - 9.71), 3.91 (95% CI 1.39 - 11.03), 14.12 (95% CI 1.78 - 111.73), and not estimable (no events among those with undetectable MRD), respectively. For the IR arm, patients with detectable MRD did not have significantly worse PFS compared to those in whom MRD was undetectable; however, PFS was longer for those with MRD levels of less than 10-1 compared to those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate endpoint for PFS in patients receiving FCR. For patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, while those with MRD less than 10-1 tend to have longer PFS, although continuation of ibrutinib is very likely required to maintain treatment efficacy.
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http://dx.doi.org/10.1182/blood.2020010146DOI Listing
August 2021

Maintenance therapies in acute myeloid leukemia: the renaissance of an old therapeutic concept.

Curr Opin Oncol 2021 Aug 2. Epub 2021 Aug 2.

Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, Connecticut Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA Department of Medical Oncology, Adult Leukemia Program, Dana-Farber Cancer Institute, Boston, MA.

Purpose Of Review: Disease relapse remains the major cause of death in patients with acute myeloid leukemia (AML) and is driven by the persistence of leukemic cells following induction chemotherapy or allogeneic hematopoietic cell transplant (allo-HCT). Maintenance therapies to extend the duration of remission and to improve survival have been proposed for several years with mixed results but have experienced a renaissance recently.

Recent Findings: The oral hypomethylating agent CC-486 has been the first agent to show an overall survival (OS) benefit compared with observation in AML patients in remission following intensive chemotherapy who are not proceeding to allo-HCT. In the realm of postallo-HCT maintenance therapy, the FLT3 inhibitor sorafenib has yielded superior results in terms of OS and relapse-free survival in randomized trials compared with observation. Several open questions remain regarding patient selection, timing, duration and safety of maintenance therapies. Various targeted agents are currently tested in clinical trials and could potentially enable an even more individualized therapeutic approach.

Summary: Maintenance therapies following intensive chemotherapy or allo-HCT offer a new therapeutic paradigm for an increasing number of AML patients and have been shown to result in an OS benefit in selected patients.
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http://dx.doi.org/10.1097/CCO.0000000000000778DOI Listing
August 2021

Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results.

Leukemia 2021 Jul 28. Epub 2021 Jul 28.

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.
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http://dx.doi.org/10.1038/s41375-021-01323-0DOI Listing
July 2021

TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors.

Cancer Res 2021 Jul 2. Epub 2021 Jul 2.

Cambridge Stem Cell Institute/Haematology, University of Cambridge.

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK -mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2 - Wilms tumor 1 (WT1) binding ability were responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3761DOI Listing
July 2021

Neutropenia in adult acute myeloid leukemia patients represents a powerful risk factor for COVID-19 related mortality.

Leuk Lymphoma 2021 08 28;62(8):1940-1948. Epub 2021 Jun 28.

Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Patients with hematological malignancies are at risk for poor outcomes when diagnosed with coronavirus disease 2019 (COVID-19). It remains unclear whether cytopenias and specific leukemia subtypes play a role in the clinical course of COVID-19 infection. Here, we report outcomes and their clinical/laboratory predictors for 65 patients with acute and chronic leukemias diagnosed with COVID-19 between 8 March 2020 and 19 May 2020 at Memorial Sloan Kettering Cancer Center in New York City. Most patients had CLL (38%) or AML (26%). A total of 14 (22%) patients required high flow nasal cannula or were intubated for mechanical ventilation and 11 patients (17%) died. A diagnosis of AML (OR 4.7, =.028), active treatment within the last 3 months (OR 5.22, =.047), neutropenia within seven days prior and up to 28 days after SARS-CoV-2 diagnosis (11.75, =.001) and ≥3 comorbidities (OR 6.55, =.019) were associated with increased odds of death.
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http://dx.doi.org/10.1080/10428194.2021.1885664DOI Listing
August 2021

Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia.

J Clin Oncol 2021 Jun 22:JCO2001739. Epub 2021 Jun 22.

Cellerant Therapeutics, San Carlos, CA.

Purpose: Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy.

Patients And Methods: One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital.

Results: Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 3.90; = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% 47.5%; = .09), reaching a statistically significant difference from d15 to d28 (6.8% 27.9%; = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% 63.9%; = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% 63.9%; = .02) and d15-d28 (42.4% 62.3%; = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 28.7; = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed.

Conclusion: Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.
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http://dx.doi.org/10.1200/JCO.20.01739DOI Listing
June 2021

Prognostic effect of gender on outcome of treatment for adults with acute myeloid leukaemia.

Br J Haematol 2021 Jul 17;194(2):309-318. Epub 2021 Jun 17.

Mayo Clinic, Rochester, MN, USA.

There are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi-institutional treatment studies from March 1984 to November 2008. Kaplan-Meier estimates were used to estimate event-time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two-sided tests. Non-APL female patients had a significantly better overall (OS) but not disease-free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.
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http://dx.doi.org/10.1111/bjh.17523DOI Listing
July 2021

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis-A Systematic Review and Meta-Analysis.

Transplant Cell Ther 2021 May 28. Epub 2021 May 28.

Department of Medical Oncology, Adult Leukemia Program, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address:

Allogeneic hematopoietic cell transplant (allo-HCT) remains the only potentially curative therapeutic modality for patients with primary or secondary myelofibrosis (MF). However, many patients are considered ineligible for allo-HCT, and transplant-related mortality can be substantial. Data on the efficacy and safety of allo-HCT are mixed and largely derived from retrospective studies. We aimed to synthesize the available evidence on the safety and efficacy of allo-HCT in MF and to identify patient, disease, and transplant characteristics with prognostic impact on outcomes of patients with MF undergoing allo-HCT. For this systematic review and meta-analysis, Cochrane Library, Google Scholar, Ovid Medline, Ovid Embase, PubMed, Scopus, and Web of Science Core Collection were searched from inception to October 11, 2020, for studies on allo-HCT in MF. Random-effects models were used to pool response rates for the co-primary outcomes of 1-year, 2-year, and 5-year overall survival (OS). Rates of non-relapse mortality and acute and chronic graft-versus-host-disease (GVHD) were studied as secondary endpoints. Subgroup analyses on the effect of conditioning regimen intensity, baseline dynamic international prognostic scoring system (DIPSS) score, and patient age were performed. The study protocol has been registered on PROSPERO (CRD42020188706). Forty-three studies with 8739 patients were identified and included in this meta-analysis. Rates of 1-year, 2-year, and 5-year OS were 66.7% (95% confidence interval [CI], 63.5%-69.8%), 64.4% (95% CI, 57.6%-70.6%), and 55.0% (95% CI, 51.8%-58.3%), respectively. Rates of 1-year, 2-year, and 5-year nonrelapse mortality were 25.9% (95% CI, 23.3%-28.7%), 29.7% (95% CI, 24.5%-35.4%), and 30.5% (95% CI, 25.9%-35.5%), respectively. The combined rate of graft failure was 10.6% (95% CI, 8.9%-12.5%) with primary and secondary graft failure occurring in 7.3% (95% CI, 5.7%-9.4%) and 5.9% (95% CI, 4.3%-8.0%) of patients, respectively. Rates of acute and chronic graft-versus-host disease were 44.0% (95% CI, 39.6%-48.4%; grade III/IV: 15.2%) and 46.5% (95% CI, 42.2%-50.8%; extensive or moderate/severe: 26.1%), respectively. Subgroup analyses did not show any significant difference between conditioning regimen intensity (myeloablative versus reduced-intensity), median patient age, and proportion of DIPSS-intermediate-2/high patients. The quality of the evidence is limited by the absence of randomized clinical trials in the field and the heterogeneity of patient and transplant characteristics across included studies. Given the poor prognosis of patients not receiving transplants and in the absence of curative nontransplantation therapies, our results support consideration of allo-HCT for eligible patients with MF.
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http://dx.doi.org/10.1016/j.jtct.2021.05.016DOI Listing
May 2021

Optimizing Risk Stratification in Acute Myeloid Leukemia: Dynamic Models for a Dynamic Therapeutic Landscape.

J Clin Oncol 2021 Aug 27;39(23):2535-2538. Epub 2021 May 27.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.

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http://dx.doi.org/10.1200/JCO.21.00067DOI Listing
August 2021

Relapse after Allogeneic Stem Cell Transplantation of Acute Myelogenous Leukemia and Myelodysplastic Syndrome and the Importance of Second Cellular Therapy.

Transplant Cell Ther 2021 Sep 24;27(9):771.e1-771.e10. Epub 2021 May 24.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York; Cellular Therapeutics Center, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) generally have poor overall survival (OS). Interventions that result in improved OS after relapse are not well established. The efficacy of second cellular therapy and specific indications are matters of debate. This study was conducted to evaluate factors associated with postrelapse survival and the efficacy of a second course of cellular therapy. We retrospectively analyzed consecutive patients with AML and MDS who underwent a first allo-HCT between 2010 and 2017 at our center but subsequently relapsed. One hundred and four patients with AML and 44 patients with MDS were included (total n = 148). Bone marrow (BM) and peripheral blood stem cell grafts were either unmodified or T cell-depleted (TCD) by CD34 selection ex vivo. Forty-five patients (30.4%) received a second cellular therapy after relapse, either a second allo-HCT (n = 28; 18.9%) or donor leukocyte infusion (DLI) (n = 17; 11.5%). The median age at transplantation was 60 years (range, 24 to 78 years). The median time to relapse (TTR) after transplantation was 6.5 months (range, 1 to 60.9 months), and the ensuing median OS was 6 months (95% confidence interval [CI], 4.8 to 8.9 months). In univariable analysis, longer TTR, relapse type (measurable residual disease versus morphologic), relapse occurring in the most recent years, and receipt of cellular therapy after relapse were associated with better outcomes, whereas adverse cytogenetics and/or abnormality of TP53, as well as NPM1 mutation in patients with AML, were associated with adverse outcomes. Relapse type, year of relapse, and a variable resulting from the combination of TTR and receipt of second cellular therapy remained significantly associated with postrelapse survival in multivariable analysis. In a separate multivariable model, adjusted only for TTR, relapse type, and receipt of second cellular therapy, an adverse effect of NPM1 mutation on survival was confirmed. We could not show an effect of post-transplantation maintenance on survival after relapse. In both univariable and multivariable analysis, we found a positive association for second cellular therapy with survival after relapse in patients who relapsed early (<6 months) after allo-HCT and a similar trend in patients who relapsed late (>12 months) after transplantation. Two-year OS after a second cellular therapy was 44.9% (95% CI, 28.5% to 61.4%), and it was significantly better in patients with <5% BM blasts before cell infusion. We could not show different effects on survival after second cellular therapy for DLI versus second allo-HCT in univariable analysis. Survival after relapse is improving over time, but this remains a challenging event, especially for patients who relapse early after transplantation. We found that a second cellular therapy could offer a benefit even in these cases. Nonetheless, more research is needed to clarify the most appropriate treatment choices after relapse. These are probably driven by underlying genetic and immunologic conditions, which should be the focus of future studies.
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http://dx.doi.org/10.1016/j.jtct.2021.05.011DOI Listing
September 2021

Hairy cell leukemia and COVID-19 adaptation of treatment guidelines.

Leukemia 2021 07 4;35(7):1864-1872. Epub 2021 May 4.

Haematology Department, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.
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http://dx.doi.org/10.1038/s41375-021-01257-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093591PMC
July 2021

Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.

Blood 2021 Sep;138(11):948-958

Leukaemia Research Cytogenetics Group, Newcastle University Translational and Clinical Research Institute, Newcastle-upon-Tyne, United Kingdom.

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.
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http://dx.doi.org/10.1182/blood.2020010144DOI Listing
September 2021

Arsenic trioxide therapy predisposes to herpes zoster reactivation despite minimally myelosuppressive therapy.

Leuk Res 2021 07 31;106:106569. Epub 2021 Mar 31.

Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, United States. Electronic address:

Acute Promyelocytic Leukemia (APL) is a unique subtype of acute myeloid leukemia that is highly responsive to minimally myelosuppressive therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). We and others have observed a higher than expected incidence of herpes zoster reactivation in APL patients treated with ATO. Memorial Sloan Kettering Cancer Center (MSKCC) has been using ATO since 1997 in all relapsed APL patients, and more recently has included it in our front-line APL regimens. Here we present a retrospective analysis of the factors contributing to herpes zoster reactivation among APL patients.
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http://dx.doi.org/10.1016/j.leukres.2021.106569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187313PMC
July 2021

Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia.

Nat Cancer 2020 Nov 19;1(11):1113-1127. Epub 2020 Oct 19.

Institute for Cancer Genetics, Columbia University, New York, NY, USA.

Multi-agent combination chemotherapy can be curative in acute lymphoblastic leukemia (ALL). Still, patients with primary refractory disease or with relapsed leukemia have a very poor prognosis. Here we integrate an in-depth dissection of the mutational landscape across diagnostic and relapsed pediatric and adult ALL samples with genome-wide CRISPR screen analysis of gene-drug interactions across seven ALL chemotherapy drugs. By combining these analyses, we uncover diagnostic and relapse-specific mutational mechanisms as well as genetic drivers of chemoresistance. Functionally, our data identifies common and drug-specific pathways modulating chemotherapy response and underscores the effect of drug combinations in restricting the selection of resistance-driving genetic lesions. In addition, by identifying actionable targets for the reversal of chemotherapy resistance, these analyses open novel therapeutic opportunities for the treatment of relapse and refractory disease.
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http://dx.doi.org/10.1038/s43018-020-00124-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011577PMC
November 2020

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML.

Blood Adv 2021 03;5(5):1552-1564

Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
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http://dx.doi.org/10.1182/bloodadvances.2020003734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948282PMC
March 2021

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.

Leukemia 2021 09 2;35(9):2539-2551. Epub 2021 Mar 2.

Novartis Pharma AG, Basel, Switzerland.

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.
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http://dx.doi.org/10.1038/s41375-021-01179-4DOI Listing
September 2021

Incorporation of Novel therapies for the treatment of acute myeloid leukemia: a perspective.

Leuk Lymphoma 2021 04 4;62(4):779-790. Epub 2021 Feb 4.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases that poses an array of therapeutic challenges. For decades two chemotherapeutic agents, cytarabine and daunorubicin, remained the backbone of AML therapy protocols. However, since 2017 nine novel therapies have been approved for the management of AML. With the rapid expansion of therapeutic options, hematologists must adapt their practice to optimize the benefits of these novel therapy options and minimize treatment toxicity. Here, we discuss the novel therapies that have changed the standard of care in management of patients with AML. We summarize the pivotal clinical trials that lead to the approval of these agents, and ongoing trials evaluating additional potential indications. We discuss several promising therapy candidates and their corresponding clinical trials. We discuss therapeutic strategies to incorporate these therapies into practice and pose unanswered questions that have arisen along with the expansion of treatment options.
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http://dx.doi.org/10.1080/10428194.2020.1842403DOI Listing
April 2021

Liposomal cytarabine and daunorubicin (CPX-351/Vyxeos)-associated distinct purpuric subtype of toxic erythema of chemotherapy: A retrospective review of 54 patients.

J Am Acad Dermatol 2021 Feb 2. Epub 2021 Feb 2.

Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, Department of Dermatology, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.01.096DOI Listing
February 2021

Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia.

Blood Adv 2021 01;5(2):504-512

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children's Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged <18 years completed treatment, only 57% of patients aged ≥18 years completed treatment. This scenario suggests that issues associated with age and treating physician may be a factor. Due to its improved survival rates compared with historical controls, the CALGB 10403 regimen is now a standard of care. The hope is that the rate of protocol completion will increase as more familiarity is gained with this regimen. These trials were registered at www.clinicaltrials.gov as #NCT00558519 (CALGB 10403) and #NCT00075725 (COG AALL0232).
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http://dx.doi.org/10.1182/bloodadvances.2020002439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839367PMC
January 2021

Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin.

J Clin Oncol 2021 03 13;39(9):1001-1009. Epub 2021 Jan 13.

Leukemia Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.

Purpose: Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin.

Methods: In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment.

Results: A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) ( = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively ( = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone.

Conclusion: LEN restores sensitivity to recombinant erythropoietin in growth factor-insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).
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http://dx.doi.org/10.1200/JCO.20.01691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274743PMC
March 2021

NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021.

J Natl Compr Canc Netw 2021 01 6;19(1):16-27. Epub 2021 Jan 6.

O'Neal Comprehensive Cancer Center at UAB.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.
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http://dx.doi.org/10.6004/jnccn.2021.0002DOI Listing
January 2021

Outcomes of patients with hematologic malignancies and COVID-19: a report from the ASH Research Collaborative Data Hub.

Blood Adv 2020 12;4(23):5966-5975

Division of Hematology/Oncology, Department of Medicine, St. Michael's Hospital, Toronto, ON, Canada.

Coronavirus disease 2019 (COVID-19) is an illness resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019. Patients with cancer, and especially those with hematologic malignancies, may be at especially high risk of adverse outcomes, including mortality resulting from COVID-19 infection. The ASH Research Collaborative COVID-19 Registry for Hematology was developed to study features and outcomes of COVID-19 infection in patients with underlying blood disorders, such as hematologic malignancies. At the time of this report, data from 250 patients with blood cancers from 74 sites around the world had been entered into the registry. The most commonly represented malignancies were acute leukemia (33%), non-Hodgkin lymphoma (27%), and myeloma or amyloidosis (16%). Patients presented with a myriad of symptoms, most frequently fever (73%), cough (67%), dyspnea (50%), and fatigue (40%). Use of COVID-19-directed therapies, such as hydroxychloroquine (n = 76) or azithromycin (n = 59), was common. Overall mortality was 28%. Patients with a physician-estimated prognosis from the underlying hematologic malignancy of <12 months at the time of COVID-19 diagnosis and those with relapsed/refractory disease experienced a higher proportion of moderate/severe COVID-19 disease and death. In some instances, death occurred after a decision was made to forgo intensive care unit admission in favor of a palliative approach. Taken together, these data support the emerging consensus that patients with hematologic malignancies experience significant morbidity and mortality resulting from COVID-19 infection. Batch submissions from sites with high incidence of COVID-19 infection are planned to support future analyses.
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http://dx.doi.org/10.1182/bloodadvances.2020003170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724912PMC
December 2020

BL-8040 CXCR4 antagonist is safe and demonstrates antileukemic activity in combination with cytarabine for the treatment of relapsed/refractory acute myelogenous leukemia: An open-label safety and efficacy phase 2a study.

Cancer 2021 Apr 3;127(8):1246-1259. Epub 2020 Dec 3.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML.

Methods: Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23).

Results: BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts.

Conclusions: The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia.
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http://dx.doi.org/10.1002/cncr.33338DOI Listing
April 2021

Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia.

Cancers (Basel) 2020 Oct 27;12(11). Epub 2020 Oct 27.

Department of Experimental Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with transcript levels were associated with cell cycle arrest, while APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high expression was correlated with reduced leukocyte count ( = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; < 0.001). Functionally, -knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count ( = 0.001) and decreased overall survival ( = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.
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http://dx.doi.org/10.3390/cancers12113134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693375PMC
October 2020

Targeted detection and quantitation of histone modifications from 1,000 cells.

PLoS One 2020 26;15(10):e0240829. Epub 2020 Oct 26.

Departments of Chemistry, Molecular Biosciences, and the Proteomics Center of Excellence, Northwestern University, Evanston, IL, United States of America.

Histone post-translational modifications (PTMs) create a powerful regulatory mechanism for maintaining chromosomal integrity in cells. Histone acetylation and methylation, the most widely studied histone PTMs, act in concert with chromatin-associated proteins to control access to genetic information during transcription. Alterations in cellular histone PTMs have been linked to disease states and have crucial biomarker and therapeutic potential. Traditional bottom-up mass spectrometry of histones requires large numbers of cells, typically one million or more. However, for some cell subtype-specific studies, it is difficult or impossible to obtain such large numbers of cells and quantification of rare histone PTMs is often unachievable. An established targeted LC-MS/MS method was used to quantify the abundance of histone PTMs from cell lines and primary human specimens. Sample preparation was modified by omitting nuclear isolation and reducing the rounds of histone derivatization to improve detection of histone peptides down to 1,000 cells. In the current study, we developed and validated a quantitative LC-MS/MS approach tailored for a targeted histone assay of 75 histone peptides with as few as 10,000 cells. Furthermore, we were able to detect and quantify 61 histone peptides from just 1,000 primary human stem cells. Detection of 37 histone peptides was possible from 1,000 acute myeloid leukemia patient cells. We anticipate that this revised method can be used in many applications where achieving large cell numbers is challenging, including rare human cell populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588077PMC
December 2020
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