Bhatt, Vijaya Raj

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. 1 The NCCN Guidelines Panel for AML convenes annually to update recommendations for the diagnosis and treatment of AML in adults. These recommendations are based on a review of recently published clinical trials that have led to significant improvements in treatment or have yielded new information regarding biologic factors that may have prognostic importance. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding the monitoring and management of measurable (minimal) residual disease.

Abstract Despite concerns about the toxicity of allogeneic hematopoietic cell transplantation (alloHCT) in older patients, prospective data characterizing prevalence or risk stratification for geriatric morbidity such as disability or frailty are limited. We prospectively assessed the prognostic impact of the novel composite health assessment risk model (CHARM), a score established to predict 1-year nonrelapse mortality (NRM), among 1105 patients aged ≥60 years enrolled on the Bone Marrow Transplant Clinical Trials Network Study 1704. Secondary end points were assessed post-alloHCT at day 100 (D100), D180, and D365 in multivariable models adjusted with predetermined clinical variables. Among alloHCT survivors, the prevalence of disability by instrumental activities of daily living (IADL), frailty by the Physical Frailty Phenotype, and physical function impairment by Patient Reported Measurement Information System (PROMIS) was highest at D100 and lower on D180 and D365. Higher CHARM scores were independently associated with greater disability (coefficient, −0.64; 95% confidence interval [CI], −0.85 to −0.43; P< .001), increased frailty (coefficient, 0.19; CI, 0.081-0.31; P< .001), worse PROMIS physical function, greater PROMIS depression, increased serious organ toxicity by D100, more cognitive decline at D100, and higher mortality after acute graft-versus-host disease (GVHD) but not significantly associated with PROMIS anxiety or acute GVHD. Higher CHARM scores predicted worse disability-free survival (odds ratio [OR], 2.03; CI, 1.66-2.48; P< .001) and lower frailty-free survival (OR, 2.00; CI, 1.61-2.49). In summary, CHARM is an independent prognostic scoring system not only for NRM but also for geriatric morbidity and functional limitation–free survival through 1 year after alloHCT. Pre-alloHCT CHARM is a novel tool to aid shared decision-making for older patients. This trial was registered at www.clinicaltrials.gov as #NCT03992352.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models’ performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P < .0001) and worse OS (HR, 2.09; P < .0001). Bootstrap bias–corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.

Abstract The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 patients with prior allogeneic stem cell transplantation had a dose-limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%), and dyspnea (15%). In AML, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.

Background: Venetoclax in combination with hypomethylating agents (HMA) or low dose cytarabine is the standard of care for patients (pts) with newly diagnosed AML ineligible for intensive chemotherapy. However, responses are transient, and loss of response is associated with poor outcome. The antiapoptotic protein Mcl-1 promotes cell survival in AML and its overexpression is associated with resistance to venetoclax. Voruciclib, a potent oral CDK9 inhibitor (CDK9i), indirectly decreases Mcl-1 protein expression, and has synergistic activity with venetoclax in AML preclinical models. In the initial part of this study in 40 pts with R/R AML and B-cell malignancies, voruciclib at doses up to 200 mg administered on days 1-14 in a 28-day cycle was well tolerated, had no dose limiting toxicities (DLTs), and showed biologic and clinical activity in heavily pretreated pts (Blood 2023:142; Supp 1:4286). We hypothesized that voruciclib in combination with venetoclax may achieve greater antileukemic effect. Methods: Pts with R/R AML were eligible if aged ≥18 years, ECOG performance status ≤1, adequate organ function, and no prior CDK9i therapy. Dose escalation followed a 3+3 design, and DLTs were assessed in Cycle 1. Voruciclib was administered at 7 dose levels between 50 mg and 300 mg on days 1-14 of 28-day cycles. Venetoclax was administered at 200 mg on days 1-21 and 400 mg on days 22-28. Disease response was assessed by the 2017 ELN criteria. Mcl-1 protein expression and phosphorylation of RNA Pol IISer2 were evaluated in PBMC in cycle 1. The study is registered at clinicaltrials.gov (NCT03547115). Results: Enrollment in this portion of the study is complete with 41 pts. Median age was 67 years (range 34-89). Median number of prior lines of therapy was 2 (range 1-7), with 93% of pts having received venetoclax and HMAs, 51% having received an anthracycline, and 20% having had prior allogeneic hematopoietic stem cell transplant (HSCT). 2017 ELN risk was adverse in 73% of pts and intermediate in 17%. The median duration on therapy was 1.5 months (range 0.2 to 9+). No DLTs were observed, and based on PK/PD analysis, dose escalation was stopped at 300 mg without reaching the maximum tolerated dose. The most common adverse events (all grades/grade ≥3) were nausea (32%/0%), febrile neutropenia (27%/24%), dyspnea (22%/2%) diarrhea (22%/2%), hypokalemia (22%/5%) and thrombocytopenia (22%/20%). Seven pts died during treatment, 5 due to an infection and 2 due to hemorrhagic events. Anti-leukemic activity was observed in 10 (31%) of 32 pts treated with voruciclib at doses from 100-300 mg; 2 pts had CRi (one referred to HSCT and one with 6 months of remission prior to progression), 1 pt had MLFS (ongoing at 9 months), and 7 pts had stable disease lasting ≥3 months. Among 25 pts with circulating peripheral blood blasts, 18 (75%) showed a significant reduction of circulating blasts by day 14 of the first cycle; however, circulating blasts increased again in 8 of 18 pts during single agent venetoclax administration on days 15 to 28. Voruciclib pharmacokinetics (PK) was dose proportional. At 300 mg steady state, mean AUC0-24 was 21,526 ng x hr/mL and mean Ctrough was 644 ng/mL, exceeding concentrations needed for target inhibition in preclinical models. Voruciclib did not affect venetoclax PK. Pharmacodynamic studies including Mcl-1 protein expression and RNA Pol IISer2 phosphorylation in PBMC by flow cytometry showed on target effects and is reported separately. Conclusion: The combination of voruciclib with venetoclax is well-tolerated and has activity in pts with AML and disease progression after venetoclax. Because of the rebound in peripheral blasts after 14 days off voruciclib, voruciclib administered on days 1-21 per cycle merits further evaluation.

Introduction: The BMT CTN 1704 study developed and validated the CHARM that stratified risk for non-relapse mortality and overall mortality among older adults, performing better than the HCT-CI alone (Artz A et al, Blood. 2023;142:109) and equally to two machine learning models. CHARM assigns a total score for 7 health variables: increasing age, higher HCT-CI scores, lower albumin, higher C-reactive protein, higher percent of weight loss over the preceding year, lower patient-reported performance status scores, and lower cognitive score per Montreal cognitive assessment (MoCA). A CHARM calculator is available at:https://cibmtr.org/CIBMTR/OffNav/DevSandbox/CHARM-Risk-NRM-Calculator No multi-institutional prospective data exist on functional trajectories and morbidity after HCT in older patients. We now report on the association of CHARM to trajectories of secondary morbidity outcomes among allo-HCT survivors of this large, prospective study. Patients and Methods: Allo-HCT candidates, aged ≥60 years (yrs), were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. The primary analysis includes 1105 patients proceeding to allo-HCT on study and secondary endpoints were assessed at day (D) 100, 180 and 365 except MoCA and organ toxicity were restricted to D100 and frailty had inadequate data for D100. A sequential multiple imputation strategy was implemented to impute endpoints for survivors at each time point with missing data. Analyses on multiply imputed datasets were conducted and the results combined using Rubin's rule. Associations between CHARM scores and secondary outcomes were analyzed using a multivariable Cox, Fine-Gray, Generalized Estimating Equations, and logistic regression model for survival, competing risks, continuous, and binary outcomes, respectively, with latter two focused on surviving patients. Models were adjusted for other variables including conditioning intensity, graft-versus-host disease (GVHD) prophylaxis regimen, disease-risk index, donor-recipient gender match, ethnicity, baseline value of the dependent variable, and visit timepoints. Results: Higher CHARM scores were associated with development of serious organ toxicities by D100 (OR: 2.05, [1.52-2.78], p<0.0001) and ≥2 worsening score on the MoCA (odds ratio (OR) 1.55 [1.16-2.1], p=0.003). Among survivors at all timepoints, higher CHARM scores were associated with greater disability by instrumental activities of daily living (IADL) (Slope -0.640 [-0.433-0.846], p<0.001) and worsening Patient-Reported Outcomes Measurement Reporting System (PROMIS) physical function (Slope -0.981 [-0.057 - -1.904], p=0.037), depression (Slope 0.763 [0.042-1.484], p=0.038) and in a lesser magnitude anxiety (Slope 0.659, p=0.076). Among survivors at D180 and D365, higher CHARM scores were associated with worse frailty (Slope 0.193 [0.081-0.305], p<0.001). CHARM scores were not associated with development of acute GVHD grades 2-4 or 3-4 but were associated with post-GVHD increased mortality (HR: 1.61, [1.25-2.08], p=0.0002). Higher CHARM scores are associated with a lower incidence of chronic GVHD (HR: 0.83, p=0.026), likely due to the effect of CHARM on the competing risk of death leaving fewer patients at risk for chronic GVHD. Conclusions: The novel primary CHARM, originally developed to predict risks of NRM, also predicts worse frailty, disability, cognitive decline, and serious organ toxicities; outcomes that are critically important to older recipients of allo-HCT. CHARM therefore informs risks of transplant morbidity, separate from risks of developing acute GVHD. Results further support adopting CHARM in practice to counsel patients, expedite HCT referrals for lower risk CHARM, and design trials for high CHARM score patients.

Abstract We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Introduction: Allogeneic hematopoietic cell transplantation (HCT) remains the only therapy for long-term disease control for many high-risk hematologic malignancies (HM). HCT use in older HM patients (pts) continues to increase. However, concerns of excessive transplant-related morbidity and non-relapse mortality (NRM) limit referrals and broader application of curative intent HCT. The HCT-comorbidity index (HCT-CI) was initially developed to improve risk-stratification of NRM. More recently, geriatric assessment (GA) and biomarkers have emerged as promising additional tools that may refine estimates of these risks. We hypothesized that a combination of health assessments by GA and biomarkers would constitute a robust and valid model, CHARM, for accurate personalized estimation of one-year (1-yr) NRM. Here, we report the results of the largest, first of its kind, prospective study of older recipients of HCT through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1704 study (NCT03992352). Patients and Methods: Adults aged ≥60 years (yrs) with HM institutionally eligible for HCT were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. Within 21 days of conditioning, 13 prospectively identified older pt.-specific health variables, informed from prior studies, were collected: age, HCT-CI, % of weight loss over the past yr, pt reported Karnofsky performance status, PROMIS physical function scale, instrumental activities of daily living (IADL), number of falls, PROMIS depression scale, number of prescribed medications, 4-meter walk speed, cognition by the Montreal Cognitive Assessment (MoCA), C-reactive protein (CRP) and albumin. The CHARM score to predict NRM within 1 yr was built using a multivariable (MVA) Fine-Gray model, with multiple imputation to handle modest missingness in covariates and grouped penalized variable selection using SCAD to identify variables to retain in the model. Final variables were used as continuous. The model further considered adjustment for conditioning intensity, CMV serostatus, and donor type. Area under the ROC curve (AUC) was calculated to validate the CHARM and compare to HCT-CI alone, with bootstrap sampling to correct for optimism in the within-sample AUC. MVA of overall survival (OS) within 1 yr used the CHARM score and adjusted for other significant variables derived from stepwise regression. Results: The primary analysis included 1105 pts who were confirmed eligible and proceeded to transplant. Median age was 67 (range 60-82) and 32% were ≥ 70 yrs. AML (45%) and MDS (30%) were the most common indications and matched donors the most frequent donor type at 72%. Reduced intensity conditioning with fludarabine (flu)-melphalan (38%) and flu-busulfan (20%) were the most common regimens. Baseline geriatric vulnerabilities among evaluable pts were frequent including slow walk speed (<0.8 meter/second) in 22%, any IADL limitation in 37%, and cognitive impairment (MoCA < 23) in 12%. 1-yr NRM was lower than expected at 14.4% with 1-yr OS of 72%. In the MVA model, albumin, CRP, HCT-CI, and weight loss were independently associated with NRM (Table) and comprised the CHARM. Of note, increasing age did not significantly affect NRM. The CHARM had within sample and bootstrap corrected AUC of 0.641 and 0.607 whereas the HCT-CI alone achieved corresponding AUC values of 0.601 and 0.598. NRM by tertiles is shown in Figure. Each point increase in the CHARM (median -2.2504, range -3.6327 to 0.1381), was associated with a hazard ratio (HR) of 2.83 (95% CI 2.12 - 3.78, p < 0.0001) for NRM. The CHARM also predicted overall mortality within 1-yr with a HR of 2.04 (1.65- 2.53, p <0.0001) per one point increase, independent of the disease risk index, which had a HR of 1.5 (95% CI 1.12 - 1.99, p =0.0059) for high/very high vs low/intermediate categories. Conclusions: We report on the first prospectively established tool, CHARM, to risk-stratify older adult HCT comprised of simple and readily available parameters in transplant and oncology clinics. Adopting CHARM in practice may promote HCT referrals and access for older pts, given low risks of NRM among CHARM lower 2/3 rd tertiles. Identifying high-risk CHARM pts pre-HCT will promote developing novel strategies to reduce NRM. Further analysis of the impacts of the 13 health assessment variables on geriatric morbidity such as disability trajectories is in-process.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.