Race/ethnic associations with comprehensive cancer center access and clinical trial enrollment for acute leukemia.

BACKGROUND: Clinical trial participation at Comprehensive Cancer Centers (CCC) is inequitable for minoritized race/ethnic groups with acute leukemia. CCCs care for a high proportion of adults with acute leukemia. It is unclear if participation inequities are due to CCC access, post-access enrollment, or both. METHODS: We conducted a retrospective cohort study of adults with acute leukemia (2010-2019) residing within Massachusetts, the designated catchment area of the Dana-Farber/Harvard Cancer Center (DF/HCC). Individuals were categorized as non-Hispanic Asian (NHA), Black (NHB), White (NHW), Hispanic White (HW), or Other. Decomposition analyses assessed covariate contributions to disparities in (1) access to DF/HCC care and (2) post-access enrollment. RESULTS: Of 3698 individuals with acute leukemia, 85.9% were NHW, 4.5% HW, 4.3% NHB, 3.7% NHA, and 1.3% Other. Access was lower for HW (age- and sex-adjusted OR 0.64 95%CI 0.45,0.90) and reduced post-access enrollment for HW (aOR 0.54 95%CI 0.34,0.86) and NHB (aOR 0.60 95%CI 0.39,0.92) compared to NHW. Payor and socioeconomic status (SES) accounted for 25.2% and 21.2% of the +1.1% absolute difference in HW access. Marital status and SES accounted for 8.0% and 7.0% of the -8.8% absolute disparity in HW enrollment; 76.4% of the disparity was unexplained. SES and marital status accounted for 8.2% and 7.1% of the -9.1% absolute disparity in NHB enrollment; 73.0% of the disparity was unexplained. CONCLUSIONS: A substantial proportion of race/ethnic inequities in acute leukemia trial enrollment at CCCs are from post-access enrollment, the majority of which was not explained by sociodemographic factors.

Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients.

The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38-0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.

Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.

PURPOSE: Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD- and TKD-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML. METHODS: Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m2) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m2 or idarubicin 12 mg/m2, once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m2 twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant. RESULTS: Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD, and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3-mutant clones were detected at relapse in patients completing consolidation. CONCLUSION: Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.

Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML.

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.

Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL.

ABSTRACT: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Treatment completion, asparaginase completion, and oncologic outcomes among children, adolescents and young adults with acute lymphoblastic leukemia treated with DFCI Consortium Protocols.

Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) face worse outcomes than children. While pediatric-inspired protocols have improved outcomes, the ability of patients to complete these intensive regimens and the reasons for discontinuation are unknown. We analyzed a cohort of 332 AYA patients (aged 15-49 years) and 1159 children (aged 1-14 years) with Ph-negative ALL treated on DFCI consortium protocols. We found that AYA patients completed treatment at lower rates than children (60.8% vs. 89.7%, p < 0.001), primarily due to higher rates of early treatment failure (14.5% vs. 2.4%, p < 0.001). Withdrawal from treatment for toxicity, social/personal, or unknown reasons was uncommon, but higher among AYA patients (9.3% vs 4.7%, p = 0.001). Patients who remained on assigned therapy for one year had favorable overall survival (AYA 5-year OS 88.9%; children 5-year OS 96.4%; p < 0.001). Among patients who continued treatment for 1 year, AYA patients completed asparaginase (defined as receiving 26+ weeks) at lower rates than children (79.1% vs. 89.6%, p < 0.001). Patients who received more weeks of consolidation asparaginase had higher overall and event-free survival. Efforts should focus on identifying patients at risk for early treatment failure and optimizing asparaginase delivery.

Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML.

ABSTRACT: We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT) after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% with prior Ven exposure, and 96% with positive molecular measurable residual disease), 22 received maintenance therapy with Aza 36 mg/m2 intravenously on days 1 to 5, and Ven 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% confidence interval [CI], 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, nonrelapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. Immune monitoring demonstrated no significant impact on T-cell expansion but identified reduced B-cell expansion compared with controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered for patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT03613532.

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia.

ABSTRACT: CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/-VEN in combination. The recommended phase 2 dose of TAG was 12 µg/kg/day for 3 days, with 7-day AZA +/- 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643.

Optimization of Advanced Molecular Genetic Testing Utilization in Hematopathology: A Goldilocks Approach to Bone Marrow Testing.

PURPOSE: This study investigated the effectiveness of algorithmic testing in hematopathology at the Brigham and Women's Hospital and Dana-Farber Cancer Institute (DFCI). The algorithm was predicated on test selection after an initial pathologic evaluation to maximize cost-effective testing, especially for expensive molecular and cytogenetic assays. MATERIALS AND METHODS: Standard ordering protocols (SOPs) for 17 disease categories were developed and encoded in a decision support application. Six months of retrospective data from application beta testing was obtained and compared with actual testing practices during that timeframe. In addition, 2 years of prospective data were also obtained from patients at one community satellite site. RESULTS: A total of 460 retrospective cases (before introduction of algorithmic testing) and 109 prospective cases (following introduction) were analyzed. In the retrospective data, 61.7% of tests (509 of 825) were concordant with the SOPs while 38.3% (316 of 825) were overordered and 30.8% (227 of 736) of SOP-recommended tests were omitted. In the prospective data, 98.8% of testing was concordant (244 of 247 total tests) with only 1.2% overordered tests (3 of 247) and 7.6% omitted tests (20 of 264 SOP-recommended tests; overall P < .001). The cost of overordered tests before implementing SOP indicates a potential annualized saving of $1,347,520 in US dollars (USD) in overordered testing at Brigham and Women's Hospital/DFCI. Only two of 316 overordered tests (0.6%) returned any additional information, both for extremely rare clinical circumstances. CONCLUSION: Implementation of SOPs dramatically improved test ordering practices, with a just right number of ancillary tests that minimizes cost and has no significant impact on acquiring key informative test results.

A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML.

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).

Prediction of risk for myeloid malignancy in clonal hematopoiesis.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) ≥ 0.02, in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults and defining predictors of MN risk would aid clinical management and research. Methods: We analyzed sequenced exomes of healthy UK Biobank (UKB) participants (n = 438,890) in separate derivation and validation cohorts. Genetic mutations, laboratory values, and MN outcomes were used in conditional probability-based recursive partitioning and Cox regression to determine predictors of incident MN. Combined statistical weights defined a clonal hematopoiesis risk score (CHRS). Independent CHIP/CCUS patient cohorts were used to test prognostic capability of the CHRS in the clinical setting. Results: Recursive partitioning distinguished CHIP/CCUS cases with 10-year probabilities of MN ranging from 0.0078 - 0.85. Multivariable analysis validated partitioning variables as predictors of MN. Key features, including single DNMT3A mutations, high risk mutations, ≥ 2 mutations, VAF ≥ 0.2, age ≥ 65 years, CCUS vs CHIP and red blood cell indices, influenced MN risk in variable direction. The CHRS defined low risk (n = 10018, 88.4%), intermediate risk (n = 1196, 10.5%), and high risk (n = 123, 1.1%) groups. In clinical cohorts, most MN events occurred in high risk CHIP/CCUS patients. Conclusions: The CHRS provides simple prognostic framework for CHIP/CCUS, distinguishing a high risk minority from the majority of CHIP/CCUS which has minimal risk for progression to MN.

Effect of BMI on toxicities and survival among adolescents and young adults treated on DFCI Consortium ALL trials.

Adolescent and young adults (AYAs) with acute lymphoblastic leukemia (ALL) treated with asparaginase-containing pediatric regimens are commonly overweight or obese. We studied the association of body mass index (BMI) on outcomes of 388 AYAs aged 15 to 50 years treated on Dana-Farber Cancer Institute (DFCI) consortium regimens (2008-2021). BMI was normal in 207 (53.3%) and overweight/obese in 181 (46.7%). Patients who were overweight or obese experienced higher nonrelapse mortality (NRM; 4-year, 11.7% vs 2.8%, P = .006), worse event-free survival (4-year, 63% vs 77%, P = .003), and worse overall survival (OS; 4-year, 64% vs 83%, P = .0001). Because younger (aged 15-29 years) AYAs more frequently had a normal BMI (79% vs 20%, P < .0001), we conducted separate analyses in each BMI group. We found excellent OS among younger and older (30-50 years) AYAs with normal BMI (4-year OS, 83% vs 85%, P = .89). Conversely, in AYAs who were overweight/obese, worse outcomes were seen in older AYAs (4-year OS, 55% vs 73%, P = .023). Regarding toxicity, AYAs who were overweight/obese experienced higher rates of grade 3/4 hepatotoxicity and hyperglycemia (60.7% vs 42.2%, P = .0005, and 36.4% vs 24.4%, P = .014, respectively) but had comparable rates of hypertriglyceridemia (29.5% vs 24.4%, P = .29). In a multivariable analysis, higher BMI was associated with worse OS, hypertriglyceridemia was associated with improved OS, and age was not associated with OS. In conclusion, among AYAs treated on DFCI Consortium ALL regimens, elevated BMI was associated with increased toxicity, increased NRM, and decreased OS. The deleterious effect of elevated BMI was more pronounced in older AYAs.

Incidence and predictors of anthracycline-related left ventricular dysfunction in acute myeloid leukemia.

INTRODUCTION: Anthracycline-related left ventricular dysfunction (ARLVD) is a concern in patients with acute myeloid leukemia (AML) undergoing anthracyclinecontaining induction chemotherapy. However, the incidence of ARLVD in the modern era of routine pretreatment left ventricular ejection fraction (LVEF) echocardiographic assessment, as well as the clinical and genetic predictors of ARLVD are not well understood. METHODS: Consecutive adult patients with AML receiving anthracycline-containing induction chemotherapy at the Dana-Farber Cancer Institute from 2014 to 2022 were studied. Inclusion criteria included availability of a pre and post chemotherapy echocardiogram to assess the LVEF, pre-treatment LVEF > 50 %, as well as comprehensive diagnostic next generation sequencing assessing for the presence of myeloid mutations. The primary endpoint was the incidence of ARLVD defined as LVEF < 50 % post-induction. RESULTS: Out of 419 patients meeting inclusion criteria, 34 (8%) patients developed ARLVD. Among the 122/419 patients who did not undergo planned allogeneic stem cell transplantation (allo-SCT), ARLVD was the deciding factor for ineligibility in 4 patients (1%). Baseline cardiovascular comorbidities (hypertension, diabetes mellitus, hyperlipidemia, smoking and coronary artery disease) and cumulative anthracycline dose were not predictive of post-induction ARLVD. However, the presence of a JAK2 mutation (but not other myeloid mutations) was associated with an increased risk of ARLVD in multivariable analysis (OR 8.34, 95 % CI 1.55-39.3, p = 0.007). DISCUSSION: In a group of AML patients with normal LVEF prior to anthracycline-containing induction chemotherapy, ARLVD was infrequent and did not commonly preclude post-remission allo-SCT consolidation. Genetic predictors of ARLVD require further investigation in a larger patient cohort.

Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.