Publications by authors named "Guillermo Garcia-Manero"

749 Publications

Single-cell Polyfunctional Proteomics of CD4 Cells from Patients with AML Predicts Responses to Anti-PD-1-based therapy.

Blood Adv 2021 Sep 23. Epub 2021 Sep 23.

MD Anderson Cancer Center, Houston, Texas, United States.

Acute myeloid leukemia (AML) remains a difficult disease to treat disease. In a phase 2 clinical trial in patients with relapsed/refractory AML, combining the hypomethylating agent, azacitidine, with the PD-1 checkpoint inhibitor, nivolumab, demonstrated encouraging response rates (33%), median event-free and overall survival, compared with a historical cohort of contemporary patients treated with azacitidine-based therapies, with an acceptable safety profile. Biomarkers of response are yet to be determined. In this study, we leveraged a multiplexed immune assay to assess the functional states of CD4+ and CD8+ cells at a single-cell level in pretherapy bone marrows in 16 patients with R/R AML treated with azacitidine/nivolumab. Effector CD4+ but not CD8+ cells had distinct polyfunctional groups and were associated with responses and better outcomes. Further evaluation of the polyfunctional strength index composition across cell types revealed that IFN-g and TNF-a were the major drivers of enhanced polyfunctionality index of pretherapy CD4+ subset, while Granzyme B, IFN-g, MIP-1b and TNF-a drove the non-significantly enhanced pretreatment PSI of CD8+ subset in the responders. Single cell polyfunctional assays were predictive of response in AML and may have a potential role as a biomarker in the wider sphere of immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004583DOI Listing
September 2021

Myelodysplastic Syndromes: A New Decade.

Clin Lymphoma Myeloma Leuk 2021 Aug 2. Epub 2021 Aug 2.

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

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders. The 2020 Surveillance, Epidemiology, and End Results data demonstrates the incidence rate of MDS increases with age especially in those greater than 70 years of age. Risk stratification that impact prognosis, survival, and rate of acute myeloid leukemia (AML) transformation in MDS is largely dependent on revised International Prognostic Scoring System along with molecular genetic testing as a supplement. Low risk MDS typically have a more indolent disease course in which treatment is only initiated to ameliorate symptoms of cytopenias. In many, anemia is the most common cytopenia requiring treatment and erythroid stimulating agents, are considered first line. In contrast, high risk MDS tend to behave more aggressively for which treatment should be initiated rapidly with Hypomethylating Agents (HMA) being in the frontline. In those with high risk MDS and eligible, evaluation for allogeneic stem cell transplant should be considered as this is the only potential curative option for MDS. With the use of molecular genetic testing, a personalized approach to therapy in MDS has ensued. As the treatment landscape in MDS continues to flourish with novel targeted agents, we ambitiously seek to improve survival rates especially among the relapsed/refractory and transplant ineligible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2021.07.031DOI Listing
August 2021

Outcomes of Acute Lymphoblastic Leukemia with KMT2A (MLL) rearrangement - The MD Anderson Experience.

Blood Adv 2021 Sep 15. Epub 2021 Sep 15.

University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States.

Acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23) - KMT2A-AFF1 is associated with a poor prognosis. The impact of KMT2A rearrangements other than t(4;11) is uncertain and the benefit of allogeneic stem cell transplant (HSCT) is unclear. We reviewed adult patients with ALL treated at our institution from 1984 to 2019 and identified 50/1102 (5%) with KMT2A rearrangement: 42 (84%) with t(4;11)/KMT2A-AFF1 and 8 (16%) with other gene partners. The median age was 45 years old (range, 18 - 78 years); median white blood cell count was 109.0 x 109/L (range, 0.5 - 1573.0). The complete remission (CR) rate was 88% and the rate of measurable residual disease negativity by flow cytometry at CR was 41% (76% overall during follow-up). At the last follow-up, 14 patients were alive. The 5-year overall survival (OS) rate was 18% (95% CI, 9 - 35%) with no difference between t(4;11) and other KMT2A rearrangements (p=0.87). In a 4-month landmark analysis, the 5-year OS rate was 32% (95% CI, 14 - 70%) in patients who underwent HSCT versus 11% (95% CI, 3 - 39) in others (p=0.10). Our study confirms the poor prognosis of ALL with any KMT2A rearrangement and the role of HSCT in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004580DOI Listing
September 2021

Treatment outcomes for patients with myelodysplastic syndrome/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis.

Leuk Lymphoma 2021 Aug 27:1-6. Epub 2021 Aug 27.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2021.1971217DOI Listing
August 2021

Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis.

Blood Adv 2021 08;5(16):3163-3173

Department of Leukemia.

Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405193PMC
August 2021

Personalized Prediction Model to Risk Stratify Patients With Myelodysplastic Syndromes.

J Clin Oncol 2021 Aug 18:JCO2002810. Epub 2021 Aug 18.

Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.

Purpose: Patients with myelodysplastic syndromes (MDS) have a survival that can range from months to decades. Prognostic systems that incorporate advanced analytics of clinical, pathologic, and molecular data have the potential to more accurately and dynamically predict survival in patients receiving various therapies.

Methods: A total of 1,471 MDS patients with comprehensively annotated clinical and molecular data were included in a training cohort and analyzed using machine learning techniques. A random survival algorithm was used to build a prognostic model, which was then validated in external cohorts. The accuracy of the proposed model, compared with other established models, was assessed using a concordance (c)index.

Results: The median age for the training cohort was 71 years. Commonly mutated genes included , , and . The algorithm identified chromosomal karyotype, platelet, hemoglobin levels, bone marrow blast percentage, age, other clinical variables, seven discrete gene mutations, and mutation number as having prognostic impact on overall and leukemia-free survivals. The model was validated in an independent external cohort of 465 patients, a cohort of patients with MDS treated in a prospective clinical trial, a cohort of patients with paired samples at different time points during the disease course, and a cohort of patients who underwent hematopoietic stem-cell transplantation.

Conclusion: A personalized prediction model on the basis of clinical and genomic data outperformed established prognostic models in MDS. The new model was dynamic, predicting survival and leukemia transformation probabilities at different time points that are unique for a given patient, and can upstage and downstage patients into more appropriate risk categories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02810DOI Listing
August 2021

Clinical and molecular characterization of myeloid sarcoma without medullary leukemia.

Leuk Lymphoma 2021 Aug 12:1-9. Epub 2021 Aug 12.

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

Myeloid sarcoma (MS) in the setting of concomitant medullary AML is relatively well described, while much less is known about patients presenting with MS with <20% bone marrow blasts. We conducted a retrospective analysis of 56 patients with MS with <20% marrow blasts seen at MD Anderson between 2005 and 2020. The prevalence of MS without medullary AML was 1.4% among all newly diagnosed AML patients. The majority (75%) of patients had a single known anatomic site involved, with the skin (34%) being the most frequent. The most common histologic subtype was monocytic, and 11% of patients had a known history of an antecedent hematologic disorder. The majority of patients (70%) received frontline intensive chemotherapy induction, with 75% of those evaluable attaining complete or partial responses. The median overall survival (OS) and event-free survival (EFS) were 3.41 and 3.07 years, respectively. Patients with bone marrow blasts of ≥5% or medullary relapse had inferior outcomes, while age (>60 years) was not associated with outcomes. There was a suggestion that patients with isolated leukemia cutis may have had better outcomes compared to patients with other organ involvement, but this did not reach statistical significance. Most patients who had cytogenetic analysis had a diploid karyotype within their MS and bone marrow pathway mutations were enriched in MS at diagnosis, and at time of medullary relapse. Our study provides a large dataset summarizing the clinical and molecular analysis of patients with MS with <20% BM blasts and suggests that monitoring for medullary leukemia is important for early detection of relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2021.1961235DOI Listing
August 2021

Phase II study of single-agent nivolumab in patients with myelofibrosis.

Ann Hematol 2021 Aug 5. Epub 2021 Aug 5.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0428, Houston, TX, 77030, USA.

Dysregulated JAK-STAT signaling in myelofibrosis induces pro-inflammatory cytokines, which suppresses T cell proliferation and differentiation, likely responsible for disease progression. The PD-1 pathway, found to be overexpressed in myeloid malignancies, has gained great interest as a therapeutic target, where a significant unmet need exists for novel therapeutic strategies. Preclinical models showed JAK2 mutant cells had higher expression of PD-L1; furthermore, JAK2 mutant xenografts treated with PD-1 inhibition had prolonged survival and reduction in JAK2 allele burden. We evaluated the efficacy and safety of single-agent nivolumab in 8 adult patients with myelofibrosis. Nivolumab was given at 3 mg/kg every 2 weeks for 8 doses, then every 12 weeks for up to 4 years, or until disease progression or toxicity. The median number of nivolumab doses received was 6 [range, 5-16 doses]. Five patients had stable disease including spleen size, total symptom score, and blood requirements for a median of 3.3 months [range, 2.3-15.2 months]. After a median follow-up of 57 months, two patients were still alive. The median overall survival was 6.1 months [range, 3.2-57.4 months]. Due to failure to meet the predetermined efficacy endpoint, the study was terminated early. Trial registration: Clinical trials.gov NCT: 02,421,354.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04618-5DOI Listing
August 2021

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome.

Br J Haematol 2021 Aug 2. Epub 2021 Aug 2.

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

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34) bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17689DOI Listing
August 2021

Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial.

Lancet Haematol 2021 Aug;8(8):e552-e561

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

Background: Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia.

Methods: This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial. Here we report on the independent cohort investigating the safety and activity of venetoclax added to intensive chemotherapy (the CLIA regimen [cladribine, high-dose cytarabine, idarubicin]). Eligible patients were aged 18-65 years with a new diagnosis of acute myeloid leukaemia, mixed phenotype acute leukaemia, or high-risk myelodysplastic syndrome (≥10% blasts or International Prognostic Scoring System ≥2 [intermediate]), who received no previous potentially curative therapy for leukaemia. Patients received cladribine (5 mg/m) and cytarabine (1·5 g/m for patients aged <60 years, 1 g/m for patients aged ≥60 years) intravenously on days 1-5 and idarubicin (10 mg/m) intravenously on days 1-3. Consolidation was cladribine (5 mg/m) and cytarabine (1 g/m for patients aged <60 years and 0·75 g/m for patients aged ≥60 years) on days 1-3 and idarubicin (8 mg/m) on days 1-2. Venetoclax (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin or gilteritinib. The primary outcome was composite complete response (complete response plus complete response with incomplete blood count recovery). Secondary outcomes were overall response, duration of response, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT02115295.

Findings: Between Feb 25, 2019, and March 23, 2021, 77 patients were assessed for eligibility, 50 of whom were enrolled. Median age was 48 years (IQR 37-56). 47 (94% [95% CI 83-98]) patients had composite complete response, with the same proportion also having an overall response; two (4% [1-14]) patients did not respond, and one (2% [0-11]) patient died during induction. 37 (82% [95% CI 68-92]) of 45 patients had undetectable measurable residual disease (MRD). At a median follow-up of 13·5 months (IQR 6·4-19·5), the median duration of response, event-free survival, and overall survival were not reached. At 12 months, the estimated duration of response was 74% (95% CI 60-92), event-free survival was 68% (54-85), and overall survival was 85% (75-97). The most common adverse events of grade 3 or worse were febrile neutropenia (42 [84%] patients), infection (six [12%]), and alanine aminotransferase elevations (six [12%]). There was one death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor. Two patients died of infectious complications while in complete response in consolidation cycles, both of whom had FLT3-mutated acute myeloid leukaemia and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related.

Interpretation: Venetoclax added to CLIA was safe and active in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, producing high rates of durable MRD-negative remissions and encouraging event-free survival and overall survival.

Funding: MD Anderson Cancer Center.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(21)00192-7DOI Listing
August 2021

Outcomes in patients with newly diagnosed TP53-mutated acute myeloid leukemia with or without venetoclax-based therapy.

Cancer 2021 Oct 28;127(19):3541-3551. Epub 2021 Jun 28.

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

Background: Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53 ) over standard therapy is undefined.

Methods: In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53 AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN-based (n = 58) and non-VEN-based (n = 180) regimens.

Results: Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens. Compared with patients who received non-VEN-based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse-free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN-based regimens, regardless of age or intensity of treatment.

Conclusions: The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53 AML. These data highlight the need for novel therapies beyond VEN to improve the outcome of patients with TP53 AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33675DOI Listing
October 2021

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.

Leukemia 2021 Jun 25. Epub 2021 Jun 25.

H3 Biomedicine, Cambridge, MA, USA.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01328-9DOI Listing
June 2021

A phase 1b/2 study of azacitidine with PD-L1 antibody avelumab in relapsed/refractory acute myeloid leukemia.

Cancer 2021 Jun 25. Epub 2021 Jun 25.

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

Background: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. In preclinical models of AML, inhibition of the PD-1/PD-L1 axis demonstrated antileukemic activity. Avelumab is an anti-PD-L1 immune checkpoint inhibitor (ICI) approved in multiple solid tumors. The authors conducted a phase 1b/2 clinical trial to assess the safety and efficacy of azacitidine with avelumab in patients with R/R AML.

Methods: Patients aged ≥18 years who had R/R AML received azacitidine 75 mg/m on days 1 through 7 and avelumab on days 1 and 14 of 28-day cycles.

Results: Nineteen patients were treated. The median age was 66 years (range, 22-83 years), 100% had European LeukemiaNet 2017 adverse-risk disease, and 63% had prior exposure to a hypomethylating agent. Avelumab was dosed at 3 mg/kg for the first 7 patients and at 10 mg/kg for the subsequent 12 patients. The most common grade ≥3 treatment-related adverse events were neutropenia and anemia in 2 patients each. Two patients experienced immune-related adverse events of grade 2 and grade 3 pneumonitis, respectively. The overall complete remission rate was 10.5%, and both were complete remission with residual thrombocytopenia. The median overall survival was 4.8 months. Bone marrow blasts were analyzed for immune-related markers by mass cytometry and demonstrated significantly higher expression of PD-L2 compared with PD-L1 both pretherapy and at all time points during therapy, with increasing PD-L2 expression on therapy.

Conclusions: Although the combination of azacitidine and avelumab was well tolerated, clinical activity was limited. High expression of PD-L2 on bone marrow blasts may be an important mechanism of resistance to anti-PD-L1 therapy in AML.

Lay Summary: This report describes the results of a phase 1b/2 study of azacitidine with the anti-PD-L1 immune checkpoint inhibitor avelumab for patients with relapsed/refractory acute myeloid leukemia (AML). The clinical activity of the combination therapy was modest, with an overall response rate of 10.5%. However, mass cytometry analysis revealed significantly higher expression of PD-L2 compared with PD-L1 on AML blasts from all patients who were analyzed at all time points. These data suggest a novel potential role for PD-L2 as a means of AML immune escape.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33690DOI Listing
June 2021

Only SF3B1 mutation involving K700E independently predicts overall survival in myelodysplastic syndromes.

Cancer 2021 Oct 23;127(19):3552-3565. Epub 2021 Jun 23.

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

Background: SF3B1 mutations (SF3B1 ) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700E SF3B1 is uncertain.

Methods: The authors analyzed the clinicopathological features and outcomes of a single-institution series of 94 treatment-naive SF3B1 MDS patients (18%) and 415 treatment-naive SF3B1 MDS patients and explored the differences between K700E and non-K700E SF3B1 MDS.

Results: Fifty-five patients (59%) carried K700E. Recurrent non-K700E mutations (39 [41%]) included R625, H662, and K666. Compared with SF3B1 K700E patients, non-K700E patients had a lower median absolute neutrophil count (1.8 vs 2.4; P = .005) and were frequently "high" according to the Revised International Prognostic Scoring System (19% vs 4%; P = .031). Non-K700E MDS was associated frequently with RUNX1 (26% vs 7%; P = .012) and exclusively with BCOR, IDH2, and SRSF2 mutations. A splicing analysis showed the differential distribution of alternatively spliced events and gene expression profiles between K700 and non-K700E MDS patients. The majority (at least 80%) of SF3B1 K700E, SF3B1 non-K700E, and SF3B1 patients were treated with hypomethylating agents. Over a median follow-up of 16 months, SF3B1 had superior overall survival (OS) in comparison with SF3B1 in all MDS patients (not reached vs 25.2 months; P = .0003), in patients with low-grade MDS, and in patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS). Compared with SF3B1 , SF3B1 K700E had superior outcomes in all MDS (median OS, 25 months vs not reached; P = .0001), in low-grade MDS (median OS, 41.3 months vs not reached; P = .0015), and in MDS-RS (median OS, 22.3 months vs not reached; P = .0001), but no significant difference was seen between non-K700E and SF3B1 MDS. By multivariable analysis, the absence of SF3B1 K700E mutations was independently associated with the prognosis.

Conclusions: This study highlights the importance of the SF3B1 mutation subtype in MDS risk assessment.

Lay Summary: Myelodysplastic syndromes (MDS) with SF3B1 mutations are regarded as having a favorable prognosis by both the World Health Organization and the International Working Group for the Prognosis of Myelodysplastic Syndromes. However, this article shows that only MDS patients with SF3B1 K700E mutations have a favorable prognosis (and not MDS patients with SF3B1 mutations involving other codons). This has important implications for refining future MDS subclassification and risk assessment criteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33745DOI Listing
October 2021

Hyper-CVAD plus ofatumumab versus hyper-CVAD plus rituximab as frontline therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: A propensity score analysis.

Cancer 2021 Sep 17;127(18):3381-3389. Epub 2021 Jun 17.

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

Background: The outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD + ofatumumab (hyper-CVAD + ofatumumab) has not been compared with the outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD plus rituximab (hyper-CVAD + Rituximab) in Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in a randomized clinical trial.

Methods: The authors compared the outcomes of 69 patients treated with hyper-CVAD + ofatumumab and 95 historical-control patients treated with hyper-CVAD + Rituximab. Historical-control patients were treated with hyper-CVAD + Rituximab if they had CD20 expression ≥ 20%. Ofatumumab (day 1 of course 1, 300 mg intravenously; subsequent doses, 2000 mg intravenously) was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of 8 doses. A propensity score analysis with inverse probability of treatment weighting (IPTW) was performed to adjust for baseline covariates between groups.

Results: The median event-free survival with stem cell transplantation (SCT) censoring was 33 and 65 months with hyper-CVAD + Rituximab and hyper-CVAD + ofatumumab, respectively (crude P = .064; IPTW P = .054). The median overall survival with SCT censoring was 52 months and not reached, respectively (crude P = .087; IPTW P = .097).

Conclusions: Hyper-CVAD + ofatumumab was associated with better outcomes than hyper-CVAD + Rituximab among patients with newly diagnosed Philadelphia chromosome-negative ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33655DOI Listing
September 2021

Donor clonal hematopoiesis increases risk of acute graft versus host disease after matched sibling transplantation.

Leukemia 2021 Jun 16. Epub 2021 Jun 16.

Department of Genomics Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Clonal hematopoiesis (CH) is associated with older age and an increased risk of myeloid malignancies and cardiovascular complications. We analyzed donor DNA samples in patients with AML/MDS who underwent first allogeneic stem cell transplant (SCT) to investigate the association between donor CH and transplant outcomes. We performed targeted deep sequencing of 300 genes on donor blood samples and identified CH with the minimum variant allele frequency of 2%. Among 363 donors, 65 (18%) had CH. The most frequently mutated genes were DNMT3A (31 of 65; 48%), TET2 (16 of 65; 25%), PPM1D (5 of 65, 8%), and ASXL1 (7 of 65; 11%). Transplant outcomes: time to neutrophil and platelet recovery, relapse incidence, transplant-related mortality and progression-free survival, were comparable by donor CH. However, risk of grade II-IV and III-IV acute graft versus host disease (aGvHD) at 6 months after transplant was higher with donor CH vs. without donor CH (hazard ratio (HR) = 2.4, 95% Confidence Interval (CI) = 1.6-3.6, p < 0.001 and HR = 3.8, 95% CI = 1.6-8.9, p = 0.003). In this homogenous population of AML/MDS patients, donor CH was associated with increased risk of grade II-IV and III-IV aGvHD. Further studies to investigate the mechanisms of increased aGvHD and therapeutic interventions to improve aGvHD in the context of donor CH are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01312-3DOI Listing
June 2021

Incidental identification of inv(16)(p13.1q22)/- variant transcript in a patient with therapy-related acute myeloid leukemia by routine leukemia translocation panel screen: implications for diagnosis and therapy.

Cold Spring Harb Mol Case Stud 2021 06 11;7(3). Epub 2021 Jun 11.

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

A 52-yr-old woman presented with therapy-related acute myeloid leukemia. A bone marrow biopsy showed 21% blasts with a myeloid phenotype and no other notable features such as abnormal eosinophils. Routine nanofluidics-based reverse transcriptase polymerase chain reaction (PCR) leukemia translocation panel designed to screen for recurrent genetic abnormalities in acute leukemia detected an inversion 16 transcript variant E. This prompted rereview of karyotype and fluorescence in situ hybridization studies, which confirmed inv(16), leading to appropriate prognostication and modification of treatment. This case underscores the utility of a powerful molecular screening method for the routine detection of recurrent genetic abnormalities of acute myeloid leukemia. It was especially useful in this case because of the lack of characteristic morphologic findings seen in inversion 16 and the difficulty in its detection by conventional karyotype analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a006084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208042PMC
June 2021

Clonal Dynamics and clinical implications of Post-Remission Clonal Hematopoiesis in Acute Myeloid Leukemia (AML).

Blood 2021 Jun 3. Epub 2021 Jun 3.

The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

While clonal hematopoiesis (CH) can precede the development of acute myeloid leukemia (AML), it can also persist after achieving remission. Long-term clonal dynamics and clinical implications of persistent CH are not well understood. Here, we studied the prevalence, dynamics and clinical implications of post-remission CH in 164 AML patients who attained complete remission after induction chemotherapies. Post-remission CH was identified in 79 (49%) patients. Post-remission CH persisted long-term in 91% of the trackable patients despite treatment with various types of consolidation and maintenance therapies. Post-remission CH was eradicated in 20 out of 21 (95%) patients who underwent allogeneic stem cell transplant. While patients with post-remission CH as a group had comparable hematopoiesis with those without it, patients with persistent TET2 mutations showed significant neutropenia long-term. Post-remission CH had little impact on relapse risk, non-relapse mortality, and incidence of atherosclerotic cardiovascular disease, although the clinical impact of post-CR CH was heterogeneous among different mutations. These data suggest that while residual clonal hematopoietic stem cells (HSCs) are generally resistant to consolidation and maintenance therapies, they retain the ability to maintain normal hematopoiesis and have little impact on clinical outcomes, although larger study is needed to dissect the gene-specific heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020010483DOI Listing
June 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2021.1938028DOI Listing
June 2021

Targeting health-related quality of life in patients with myelodysplastic syndromes - Current knowledge and lessons to be learned.

Blood Rev 2021 May 14:100851. Epub 2021 May 14.

Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Using a range of health-related quality of life (HRQoL) instruments, most - but not all - studies of myelodysplastic syndromes (MDS) have reported that lower hemoglobin levels and red blood cell transfusion dependency are associated with worse HRQoL. In addition, some MDS treatments may significantly improve HRQoL, particularly among those patients who respond to therapy; however, the majority of these studies were underpowered for this secondary endpoint. Furthermore, decreased HRQoL has been associated with worse survival outcomes, and HRQoL scores can be used to refine classical prognostic systems. Despite the subjective nature of HRQoL, the importance and validity of measuring it in trials and clinical practice are increasingly being recognized, but properly validated MDS-specific instruments are required. We describe what is currently known about HRQoL in patients with MDS, and the limitations of measuring HRQoL, and we provide some recommendations to improve the measurement of this outcome in future trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.blre.2021.100851DOI Listing
May 2021

Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia.

J Clin Oncol 2021 Sep 27;39(25):2768-2778. Epub 2021 May 27.

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

Purpose: Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML.

Materials And Methods: The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML.

Results: Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease-negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML.

Conclusion: Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.03736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407653PMC
September 2021

Immunotherapy in Acute Myeloid Leukemia: Where We Stand.

Front Oncol 2021 10;11:656218. Epub 2021 May 10.

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.

In the past few years, our improved knowledge of acute myeloid leukemia (AML) pathogenesis has led to the accelerated discovery of new drugs and the development of innovative therapeutic approaches. The role of the immune system in AML development, growth and recurrence has gained increasing interest. A better understanding of immunological escape and systemic tolerance induced by AML blasts has been achieved. The extraordinary successes of immune therapies that harness the power of T cells in solid tumors and certain hematological malignancies have provided new in this area of research. Accordingly, major efforts have been made to develop immune therapies for the treatment of AML patients. The persistence of leukemia stem cells, representing the most relevant cause of relapse, even after allogeneic stem cell transplant (allo-SCT), remains a major hurdle in the path to cure for AML patients. Several clinical trials with immune-based therapies are currently ongoing in the frontline, relapsed/refractory, post-allo-SCT and minimal residual disease/maintenance setting, with the aim to improve survival of AML patients. This review summarizes the available data with immune-based therapeutic modalities such as monoclonal antibodies (naked and conjugated), T cell engagers, adoptive T-cell therapy, adoptive-NK therapy, checkpoint blockade PD-1/PD-L1, CTLA4, TIM3 and macrophage checkpoint blockade the CD47/SIRPa axis, and leukemia vaccines. Combining clinical results with biological immunological findings, possibly coupled with the discovery of biomarkers predictive for response, will hopefully allow us to determine the best approaches to immunotherapy in AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.656218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143531PMC
May 2021

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.

Blood Cancer J 2021 May 20;11(5):98. Epub 2021 May 20.

The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-021-00487-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138012PMC
May 2021

Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia.

Nat Commun 2021 05 10;12(1):2607. Epub 2021 May 10.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22874-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110775PMC
May 2021

Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia.

Cancer 2021 Sep 29;127(17):3113-3124. Epub 2021 Apr 29.

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

Background: There are limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML).

Methods: The authors evaluated the clinicopathologic features, outcomes, and responses to therapy of 65 patients with aCML. The median age was 67 years (range, 46-89 years).

Results: The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 appeared at variant allele frequencies (VAFs) greater than 40%, whereas other RAS pathway mutations were more likely to appear at low VAFs. The acquisition of new, previously undetectable mutations at transformation was observed in 63% of the evaluable patients, with the most common involving signaling pathway mutations. Hypomethylating agents (HMAs) were associated with the highest response rates but with a short duration of response (median, 2.7 months). Therapy with ruxolitinib was not associated with clinically significant responses as a single agent or in combination with an HMA. Allogeneic stem cell transplantation was the only therapy associated with improved outcomes (hazard ratio, 0.144; 95% CI, 0.035-0.593; P = .007). Age, platelet counts, bone marrow blast percentages, and serum lactate dehydrogenase (LDH) levels were independent predictors of survival and were integrated in a multivariable model that allowed the prediction of 1- and 3-year survival.

Conclusions: aCML is characterized by high frequencies of ASXL1, SRSF2, and SETBP1 mutations and is associated with a high risk of acute myeloid leukemia transformation. Response and survival outcomes with current therapies remain poor. The incorporation of age, platelet counts, bone marrow blast percentages, and LDH levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33622DOI Listing
September 2021

Response to Hypomethylating Agents in Myelodysplastic Syndrome Is Associated With Emergence of Novel TCR Clonotypes.

Front Immunol 2021 12;12:659625. Epub 2021 Apr 12.

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

Aberrant T-cell function is implicated in the pathogenesis of myelodysplastic syndrome (MDS). Monitoring the T-cell receptor (TCR) repertoire can provide insights into T-cell adaptive immunity. Previous studies found skewed TCR repertoires in MDS compared to healthy patients; however these studies that leverage mRNA-based spectratyping have limitations. Furthermore, evaluating the TCR repertoire in context of hypomethylating agents (HMAs) treatment can provide insights into the dynamics of T-cell mediated responses in MDS. We conducted immunosequencing of the CDR3 regions of TCRβ chains in bone marrows of 11 MDS patients prior to treatment (n=11 bone marrows prior to treatment), and in at least 2 timepoints for each patient following treatment (n=26 bone marrow aspirates post-treatment) with (HMA), alongside analyzing bone marrows from 4 healthy donors as controls. TCR repertoires in MDS patients were more clonal and less diverse than healthy donors. However, unlike previous reports, we did not observe significant skewness in CDR3 length or spectratyping. The global metrics of TCR profiling including richness, clonality, overlaps were not significantly changed in responders or non-responders following treatment with HMAs. However, we found an emergence of novel clonotypes in MDS patients who responded to treatment, while non-responders had a higher frequency of contracted clonotypes following treatment. By applying GLIPH2 for antigen prediction, we found rare TCR specificity clusters shared by TCR clonotypes from different patients at pre- or following treatment. Our data show clear differences in TCR repertoires of MDS compared with healthy patients and that novel TCR clonotype emergence in response to HMA therapy was correlated with response. This suggests that response to HMA therapy may be partially driven by T-cell mediated immunity and that the immune-based therapies, which target the adaptive immune system, may play a significant role in select patients with MDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.659625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072464PMC
April 2021

Long-term results of low-intensity chemotherapy with clofarabine or cladribine combined with low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia.

Am J Hematol 2021 08 26;96(8):914-924. Epub 2021 May 26.

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

The treatment of older patients with newly diagnosed acute myeloid leukemia (AML) using intensive chemotherapy is associated with treatment intolerance and poor survival. We evaluated two new lower-intensity regimens with clofarabine (n = 119) or cladribine (n = 129) combined with low-dose cytarabine (LDAC) alternating with decitabine. We reviewed response rates by subgroup and long term outcomes of 248 patients with newly diagnosed non core-binding-factor AML treated on two clinical trials investigating double nucleoside-analogue therapy (DNT) alternating with HMA from October, 2008 to April, 2018. Of 248 patients with a median age of 69 years (range, 49-85 years), 102 patients (41%) were ≥ 70 years, and 108 (44%) had adverse karyotype. Overall, 164 patients (66%) responded: 147 (59%) complete remission (CR) and 17 (7%) CR with incomplete count recovery (CRi). With a median follow up of 60 months, median relapse-free and overall survival (OS) were 10.8 and 12.5 months, respectively. The 2-year OS was 29%. Among patients with normal karyotype, the CR/CRi rate was 79% and the median OS 19.9 months. High response rates and OS were observed in patients with mutations in NPM1, FLT3, IDH2, and RUNX1. The 4- and 8-week mortality rates were 2% and 11%, respectively. The backbone of clofarabine or cladribine and LDAC alternating with decitabine was effective and safe for the treatment of older patients with newly diagnosed AML. Incorporating targeted therapies could extend the efficacy of this approach and provide more curative therapeutic options in this AML population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26206DOI Listing
August 2021
-->