Publications by authors named "Naval Daver"

278 Publications

Impact of splicing mutations in acute myeloid leukemia treated with hypomethylating agents combined with venetoclax.

Blood Adv 2021 Apr;5(8):2173-2183

Department of Leukemia and.

Spliceosome mutations (SRSF2, SF3B1, U2AF1, ZRSR2), are encountered in ∼50% of secondary acute myeloid leukemia cases (sAML) and define a molecular subgroup with outcomes similar to sAML in de novo AML patients treated with intensive chemotherapy. Outcomes in patients with spliceosome mutations treated with hypomethylating agents in combination with venetoclax (HMA+VEN) remains unknown. The primary objective was to compare outcomes in patients with spliceosome mutations vs wild-type patients treated with HMA+VEN. Secondary objectives included analysis of the mutational landscape of the spliceosome cohort and assessing the impact of co-occurring mutations. We performed a retrospective cohort analysis of patients treated with HMA+VEN-based regimens at The University of Texas MD Anderson Cancer Center. A total of 119 patients (spliceosome mutated n = 39 [SRSF2, n = 24; SF3B1, n = 8; U2AF1, n = 7]; wild-type, n = 80) were included. Similar responses were observed between spliceosome and wild-type cohorts for composite complete response (CRc; 79% vs 75%, P = .65), and measurable residual disease-negative CRc (48% vs 60%, P = .34). Median overall survival for spliceosome vs wild-type patients was 35 vs 14 months (P = .58), and was not reached; 35 months and 8 months for patients with SRSF2, SF3B1, and U2AF1 mutations, respectively. IDH2 mutations were enriched in patients with SRSF2 mutations and associated with favorable outcomes (1- and 2-year overall survival [OS] of 100% and 88%). RAS mutations were enriched in patients with U2AF1 mutations and associated with inferior outcomes (median OS, 8 months). Comparable outcomes were observed between patients with vs without spliceosome mutations treated with HMA+VEN regimens, with specific co-mutation pairs demonstrating favorable outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020004173DOI Listing
April 2021

Single-center experience with venetoclax combinations in patients with newly diagnosed and relapsed AML evolving from MPNs.

Blood Adv 2021 Apr;5(8):2156-2164

In patients with acute myeloid leukemia evolving from myeloproliferative neoplasms (post-MPN-AML), the clinical activity of the B-cell lymphoma 2 inhibitor venetoclax remains to be determined. We review our experience with venetoclax-based regimens in 14 newly diagnosed (frontline [FL]) and 17 relapsed/refractory (R/R) post-MPN-AML patients. Venetoclax was used in combination with hypomethylating agents in 58% of cases and in 19% with intensive chemotherapy (treatment including cytarabine ≥1 g/m2 or CPX-351); the remaining patients received cladribine and low-dose cytarabine or isocitrate dehydrogenase 1/2 inhibitors. The median dose of venetoclax during the initial cycle was 100 mg in all patients (range, 50-800 mg) and 200 mg (range, 100-800 mg) for FL patients. The venetoclax dose was adjusted when used concomitantly with azole antifungal agents. In FL patients, complete remission with and without count recovery in 6 patients (median duration of 6.4 months) and partial remission in 1 patient was noted, with a median overall survival of 7 months. In R/R patients, no formal responses were seen, with a median overall survival of 3 months. Hematologic toxicities and adverse events were frequent; 83% of patients developed grade 3 or higher infection during the initial cycle. Severe hemorrhagic complications were observed in 14 patients, including 6 cases of intracranial and subdural hemorrhage. Overall 4-week and 8-week mortality were 10% and 32%, respectively. Given the substantial treatment-associated hematologic toxicity and mortality, and modest short-lived responses only in newly diagnosed patients with venetoclax-based regimens, additional treatment options are urgently needed for these patients.
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http://dx.doi.org/10.1182/bloodadvances.2020003934DOI Listing
April 2021

A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome.

Haematologica 2021 Apr 15. Epub 2021 Apr 15.

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

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.
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http://dx.doi.org/10.3324/haematol.2020.263392DOI Listing
April 2021

Outcome of patients with chronic myeloid leukemia in lymphoid blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with hyper-CVAD and dasatinib.

Cancer 2021 Apr 6. Epub 2021 Apr 6.

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

Background: Dasatinib monotherapy has demonstrated modest clinical activity in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP). The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has dramatically improved with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with tyrosine kinase inhibitors (TKIs).

Methods: The authors reviewed 85 patients (23 with CML-LBP and 62 with newly diagnosed Ph-positive ALL) who received hyper-CVAD plus dasatinib.

Results: In the CML-LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML-LBP. The BCR-ABL1 transcript was p210 in 22 patients (96%) and p190 in 1 patient (4%). In the Ph-positive ALL cohort, p210 and p190 transcripts were detected in 13 patients (21%) and 48 patients (77%), respectively. Patients with CML-LBP were less likely to achieve deep molecular remission than patients with Ph-positive ALL: the major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). Survival outcomes were similar for CML-LBP and Ph-positive ALL: the 5-year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML-LBP (5-year OS rate, 88% vs 57%; P = .04). In Ph-positive ALL, the outcome was driven by deeper molecular remission: the 5-year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002).

Conclusions: The outcome of CML-LBP has improved with hyper-CVAD plus dasatinib therapy with survival comparable to that of Ph-positive ALL. Further improvement may be achieved with the use of novel TKIs and targeted agents.
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http://dx.doi.org/10.1002/cncr.33539DOI Listing
April 2021

Duration of cytopenias with concomitant venetoclax and azole antifungals in acute myeloid leukemia.

Cancer 2021 Apr 1. Epub 2021 Apr 1.

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

Background: Venetoclax (VEN) combined with the hypomethylating agent (HMA) azacitidine improves survival in patients aged ≥75 years with newly diagnosed acute myeloid leukemia (AML). VEN and HMA treatment can result in prolonged and often profound neutropenia, and this warrants antifungal prophylaxis. Azole antifungals inhibit cytochrome P450 3A4, the primary enzyme responsible for VEN metabolism; this results in VEN dose reductions for each concomitant antifungal. Limited clinical data exist on outcomes for patients treated with VEN, an HMA, and various azoles.

Methods: The time to neutrophil recovery (absolute neutrophil count [ANC] > 1000 cells/mm ) and platelet (PLT) recovery (PLT count > 100,000 cells/mm ) in 64 patients with newly diagnosed AML who achieved a response after course 1 of VEN plus an HMA were evaluated. HMA therapy included azacitidine (75 mg/m intravenously/subcutaneously for 7 days) or decitabine (20 mg/m intravenously for 5 or 10 days).

Results: Forty-seven patients (73%) received an azole: posaconazole (n = 17; 27%), voriconazole (n = 9; 14%), isavuconazole (n = 20; 31%), or fluconazole (n = 1; 2%). The median time to ANC recovery were similar for patients who did receive an azole (37 days; 95% confidence interval [CI], 34-38 days) and patients who did not receive an azole (39 days; 95% CI, 30 days to not estimable; P = .8). The median time to PLT recovery was significantly longer for patients receiving azoles (28 vs 22 days; P = .01). The median times to ANC recovery (35 vs 38 days) and PLT recovery (26 vs 32 days) were similar with posaconazole and voriconazole.

Conclusions: VEN plus an HMA resulted in neutropenia and thrombocytopenia, with the latter prolonged in patients receiving concomitant azoles. Concomitant posaconazole or voriconazole and VEN (100 mg) resulted in similar ANC and PLT recovery times, suggesting the safety of these dosage combinations during course 1.
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http://dx.doi.org/10.1002/cncr.33508DOI Listing
April 2021

Prognostic factors for progression in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in complete molecular response within 3 months of therapy with tyrosine kinase inhibitors.

Cancer 2021 Apr 1. Epub 2021 Apr 1.

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

Background: The achievement of a 3-month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs).

Methods: The authors reviewed 204 patients with Ph-positive ALL who were treated between January 2001 and December 2018 using the combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients [22%]; dasatinib, 88 patients [43%]; or ponatinib, 72 patients [35%]). Progression-free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow-up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow-up.

Results: Overall, a 3-month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow-up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3-month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5-year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166-0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149-0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis.

Conclusions: In patients with Ph-positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3-month CMR is achieved.
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http://dx.doi.org/10.1002/cncr.33529DOI Listing
April 2021

Taking aim at IDH in fitter patients with AML.

Blood 2021 Apr;137(13):1706-1707

MD Anderson Cancer Center.

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http://dx.doi.org/10.1182/blood.2020009361DOI Listing
April 2021

Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia.

Blood Adv 2021 Apr;5(7):1876-1883

Department of Leukemia.

Assessment of measurable residual disease (MRD) provides prognostic information in acute myeloid leukemia (AML). However, the utility of MRD with venetoclax-based lower intensity regimens is unknown. We analyzed the prognostic value of achieving a negative MRD in older/"unfit" patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. MRD was evaluated in bone marrow specimens using multicolor flow cytometry (sensitivity 0.1%). Ninety-seven patients achieving either a complete remission (CR) or CR with incomplete hematologic recovery (CRi) or morphologic leukemia-free state were included. Median age was 72 years (interquartile range, 68-78 years), and 64% had adverse-risk AML. Eighty-three patients achieved CR/CRi, and 52 (54%) became MRD negative. Median time to becoming MRD negative was 2.0 months (interquartile range, 0.9-3.1 months). Patients becoming MRD negative by 2 months had longer relapse-free survival (RFS) compared with those remaining MRD positive (median RFS, not reached vs 5.2 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.12-0.78; P = .004), longer event-free survival (EFS) (median EFS, not reached vs 5.8 months; HR, 0.25; 95% CI, 0.12-0.55; P < .001), as well as longer overall survival (OS) (median OS, 25.1 vs 7.1 months; HR, 0.23; 95% CI, 0.11-0.51; P < .001). Patients achieving an MRD-negative CR had longer OS compared with those with an inferior response (median OS, 25.1 vs 11.6 months; HR, 0.33; 95% CI, 0.19-0.58; P < .0005). Patients becoming MRD negative within 1 month had an improved OS compared with MRD-positive patients (median OS, 25.1 vs 3.4 months; HR, 0.15; 95% CI, 0.03-0.64; P < .0001). Differential impact of MRD status on survival outcomes persisted at a later 4-month time point of evaluation. In conclusion, MRD-negative status at 1, 2, and 4 months after starting therapy confers significantly better survival in older/unfit patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT03404193.
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http://dx.doi.org/10.1182/bloodadvances.2020003717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045494PMC
April 2021

High-throughput proteomic profiling reveals mechanisms of action of AMG925, a dual FLT3-CDK4/6 kinase inhibitor targeting AML and AML stem/progenitor cells.

Ann Hematol 2021 Mar 31. Epub 2021 Mar 31.

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

FLT3 mutations, which are found in a third of patients with acute myeloid leukemia (AML), are associated with poor prognosis. Responses to currently available FLT3 inhibitors in AML patients are typically transient and followed by disease recurrence. Thus, FLT3 inhibitors with new inhibitory mechanisms are needed to improve therapeutic outcomes. AMG925 is a novel, potent, small-molecule dual inhibitor of FLT3 and CDK4/6. In this study. we determined the antileukemic effects and mechanisms of action of AMG925 in AML cell lines and primary samples, in particular AML stem/progenitor cells. AMG925 inhibited cell growth and promoted apoptosis in AML cells with or without FLT3 mutations. Reverse-phase protein array profiling confirmed its on-target effects on FLT3-CDK4/6-regulated pathways and identified unrevealed signaling network alterations in AML blasts and stem/progenitor cells in response to AMG925. Mass cytometry identified pathways that may confer resistance to AMG925 in phenotypically defined AML stem/progenitor cells and demonstrated that combined blockade of FLT3-CDK4/6 and AKT/mTOR signaling facilitated stem cell death. Our findings provide a rationale for the mechanism-based inhibition of FLT3-CDK4/6 and for combinatorial approaches to improve the efficacy of FLT3 inhibition in both FLT3 wild-type and FLT3-mutated AML.
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http://dx.doi.org/10.1007/s00277-021-04493-0DOI Listing
March 2021

Immune checkpoint inhibitors in acute myeloid leukemia.

Authors:
Naval Daver

Best Pract Res Clin Haematol 2021 Mar 30;34(1):101247. Epub 2021 Jan 30.

Leukemia Research Alliance Program, Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Understanding the immune biology of AML and designing rational approaches to target or harness the immune environment to improve outcomes is an area of intense research in AML. There are two primary immune checkpoint harnessing modalities under clinical evaluation in AML: T-cell (such as PD1 inhibitors nivolumab and pembrolizumab) and macrophage (such as the anti-CD47 antibody magrolimab) These work synergistically with hypomethylating agents. Patients who do not achieve complete or partial responses based on IWG criteria often achieve durable stable disease or hematologic improvement, which may provide meaningful benefit for patients, even in the absence of traditional response unlike cytotoxic therapies. Patients should ideally be prospectively selected for CPI based therapies based on pre-treatment biomarkers, as there are definite populations that are more likely to respond. Immune toxicities are often mistaken for infection or other adverse event; however, if identified and treated early and aggressively with steroids, immune toxicity outcomes can be improved. Therefore, in the formative stage of development ideally only centers with experience in immune therapies should perform CPI studies in AML.
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http://dx.doi.org/10.1016/j.beha.2021.101247DOI Listing
March 2021

Long-term follow-up of salvage therapy using a combination of inotuzumab ozogamicin and mini-hyper-CVD with or without blinatumomab in relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia.

Cancer 2021 Mar 19. Epub 2021 Mar 19.

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

Background: The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low-intensity mini-hyper-CVD (mini-hyper-CVD; cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL.

Methods: We used lower intensity chemotherapy, mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m x 4 doses) compared to conventional hyper-CVAD.

Results: Ninety-six patients with a median age of 37 years (range, 18-87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty-four (46%) patients underwent later allogeneic stem cell transplantation. Veno-occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower-dose inotuzumab and sequential blinatumomab. With a median follow-up of 36 months, the median overall survival (OS) was 13.4 months, with 3-year OS rates of 33%. The 3-year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%.

Conclusion: The combination of inotuzumab and low-intensity mini-hyper-CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL.
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http://dx.doi.org/10.1002/cncr.33469DOI Listing
March 2021

Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.

Blood Cancer Discov 2021 Mar 6;2(2):125-134. Epub 2020 Dec 6.

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

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with -mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target , epigenetic modifiers, pathway, and less frequently , and . and D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment mutated patients, pretreatment cohort level variant allelic frequencies for were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in -mutated AML treated with type I versus II FLT3i.
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http://dx.doi.org/10.1158/2643-3230.bcd-20-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935111PMC
March 2021

Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation.

J Immunother Cancer 2021 Feb;9(2)

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: Immune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.

Methods: A retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.

Results: Four patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2-4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).

Conclusions: ICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.
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http://dx.doi.org/10.1136/jitc-2020-001818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919586PMC
February 2021

An Update on the Clinical Evaluation of Antibody-Based Therapeutics in Acute Myeloid Leukemia.

Curr Hematol Malig Rep 2021 Feb 25;16(1):89-96. Epub 2021 Feb 25.

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

Purpose Of Review: The advent of several targeted agents has revolutionized the treatment of acute myeloid leukemia (AML) in recent times; however, majority of patients are still not cured. In the ongoing quest for rationally targeted treatment strategies in AML, scientific endeavors have focused on identifying new antigen targets on the leukemic cells for therapeutic exploitation including strategies to directly deliver toxins into the leukemic blasts as well as strategies that harness host immunity to favorably impact clinical outcomes. Gemtuzumab ozogamicin, a CD33 directed antibody-drug conjugate, has provided the proof of concept for the potential efficacy of monoclonal antibody-based therapies in AML. This article provides an overview of immunologically relevant antigen targets expressed on the leukemic cells and synopsizes the clinical results evaluating targeted antibody-based therapeutic approach in AML.

Recent Findings: AML blasts and leukemic stem cells express several antigens, including CD33, CD47, CD70, CD123, and CLEC12A. The past several years have seen the burgeoning of cell-specific immunotherapy concepts, including checkpoint inhibitors, antibody-toxin conjugates, and bispecific antibodies in the treatment of AML. The first-in-class anti-CD47 antibody magrolimab and anti-CD70 antibody cusatuzumab in combination with hypomethylating agent (HMA) azacitidine, in newly diagnosed AML, and flotetuzumab, a bispecific DART® (dual-affinity retargeting) antibody to CD3ε and CD123 as salvage option in relapsed/refractory AML appear promising. The development of antibody-based immunotherapeutic approach in AML has been encouraging. Ongoing research will define the choice of an appropriate complementary therapeutic agent in antibody-based combination therapy, and whether one or more than one antigen should be simultaneously targeted. Further studies will likely refine the role of antibody-based therapy in post hematopoietic cell transplant setting.
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http://dx.doi.org/10.1007/s11899-021-00612-wDOI Listing
February 2021

Acute myeloid leukemia: current progress and future directions.

Blood Cancer J 2021 Feb 22;11(2):41. Epub 2021 Feb 22.

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

Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.
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http://dx.doi.org/10.1038/s41408-021-00425-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900255PMC
February 2021

Flow cytometric immunophenotypic alterations of persistent clonal haematopoiesis in remission bone marrows of patients with NPM1-mutated acute myeloid leukaemia.

Br J Haematol 2021 Mar 22;192(6):1054-1063. Epub 2021 Feb 22.

The Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA.

Clonal haematopoiesis (CH) in patients with acute myeloid leukaemia (AML) may persist beyond attaining complete remission. From a consecutive cohort of 67 patients with nucleophosmin 1-mutated (NPM1 ) AML, we identified 50 who achieved NPM1 clearance and had parallel multicolour flow cytometry (MFC) and next generation sequencing (NGS). In total, 13 (26%) cleared all mutations, 37 (74%) had persistent CH frequently involving DNA methyltransferase 3α (DNMT3A,70%), tet methylcytosine dioxygenase 2 (TET2, 27%), isocitrate dehydrogenase 2 (IDH2, 19%) and IDH1 (11%). A small number (<1%) of aberrant CD34 myeloblasts, but immunophenotypically different from original AML blasts [herein referred to as a pre-leukaemic (PL) phenotype], was detected in 17 (49%) patients with CH, but not in any patients with complete clearance of all mutations (P = 0·0037). A PL phenotype was associated with higher mutation burden (P = 0·005). Persistent IDH2 and serine and arginine-rich splicing factor 2 (SRSF2) mutations were exclusively observed in PL CH cases (P = 0·016). Persistent dysplasia was seen exclusively in cases with a PL phenotype (29% vs. none; P = 0·04). The PL phenotype did not correlate with age, intensity of induction therapy or relapse-free survival. Post-remission CH in the setting of NPM1 clearance is common and may result in immunophenotypic changes in myeloid progenitors. It is important to not misinterpret these cells as AML measurable residual disease (MRD).
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http://dx.doi.org/10.1111/bjh.17347DOI Listing
March 2021

Clinical Outcomes of Patients With Chronic Myeloid Leukemia With Concurrent Core Binding Factor Rearrangement and Philadelphia Chromosome.

Clin Lymphoma Myeloma Leuk 2021 Jan 12. Epub 2021 Jan 12.

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

Background: Acquisition of additional cytogenetic abnormalities (ACAs) in addition to Philadelphia chromosome is frequently observed in patients with chronic myeloid leukemia (CML) in advanced phase. The presence of core binding factor (CBF) translocations determines the diagnosis of acute myeloid leukemia regardless of blast percentage, and CBF rearrangements are rarely identified as ACAs.

Patients And Methods: A retrospective chart review of patients with CML who had CBF rearrangement, t(8;21) or inv(16), in Philadelphia chromosome-positive clones was conducted. Additional cases of CML with CBF rearrangements were identified through literature review.

Results: Between August 1997 and December 2014, we identified 11 patients who had Philadelphia chromosome and CBF rearrangement in the same clones: 1 (9%) with t(8;21) and 10 (91%) with inv(16). Nine (82%) patients were in blast phase, and 2 (18%) in second chronic phase. Four (36%) patients received tyrosine kinase inhibitor monotherapy, 2 (18%) received tyrosine kinase inhibitor and chemotherapy, and 5 (45%) received chemotherapy only. Three (27%) patients achieved complete remission with incomplete count recovery, and 4 (36%) had no response after the initial therapy. Three (27%) patients underwent allogeneic stem cell transplantation. The median event-free survival and overall survival for the 11 patients were 2 months and 6 months, respectively. Literature review identified 14 patients with CML with CBF rearrangement with a median overall survival of 14 months.

Conclusion: Acquisition of CBF rearrangement in addition to Philadelphia chromosome is a rare phenomenon associated with poor prognosis. CBF rearrangements as ACAs in patients with CML can be considered high-risk features.
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http://dx.doi.org/10.1016/j.clml.2020.12.025DOI Listing
January 2021

Next-Generation Sequencing of in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations.

Front Oncol 2020 28;10:582213. Epub 2021 Jan 28.

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States.

Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline , individuals presenting with ≥1 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline "hot spots" are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline mutations, enabling timely and appropriate care.
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http://dx.doi.org/10.3389/fonc.2020.582213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878971PMC
January 2021

Distinct Immunophenotypes of T Cells in Bronchoalveolar Lavage Fluid From Leukemia Patients With Immune Checkpoint Inhibitors-Related Pulmonary Complications.

Front Immunol 2020 21;11:590494. Epub 2021 Jan 21.

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

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated with immune checkpoint inhibitors (ICIs) are at risk of pneumonitis as well as pneumonia (combined henceforth as ICI-related pulmonary complications). Little is known about the cellular and molecular mechanisms underlying ICI-related pulmonary complications. We characterized lymphocytes from bronchoalveolar lavage (BAL) fluid and peripheral blood from seven AML/MDS patients with pulmonary symptoms after ICI-based therapy (ICI group) and four ICI-naïve AML/MDS patients with extracellular bacterial or fungal pneumonias (controls). BAL T cells in the ICI group were clonally expanded, and BAL IFNγ IL-17 CD8 T and CXCR3 CCR6 Th17/Th1 cells were enriched in the ICI group. Our data suggest that these cells may play a critical role in the pathophysiology of ICI-related pulmonary complications. Understanding of these cell populations may also provide predictive and diagnostic biomarkers of ICI-related pulmonary complications, eventually enabling differentiation of pneumonitis from pneumonia in AML/MDS patients receiving ICI-based therapies.
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http://dx.doi.org/10.3389/fimmu.2020.590494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859512PMC
January 2021