Dinner, Shira

Abstract Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

7012 Background: DLBCL with expression of MYC and BCL2 (double expressor lymphoma, DEL), has an adverse prognosis. Venetoclax, an inhibitor of BCL2, was previously studied in combination with R-CHOP. A051701 is a phase II/III randomized trial of chemoimmunotherapy +/- venetoclax in DEL and double hit lymphoma cohorts. Here we report initial phase II results from the DEL cohort. Methods: Patients (pts) age ≥ 18 years (y) with untreated DEL were randomized 1:1 to R-CHOP (Arm 1) or R-CHOP-venetoclax (Arm 2). DEL was defined as MYC expression ≥40% and BCL2 expression ≥50%, without double hit cytogenetics. Enrollment was based on local pathology results that were centrally confirmed. Venetoclax 800 mg was given orally days 4-8 of cycle 1 and days 1-5 of subsequent cycles for up to 6 cycles. All cycles were supported by GCSF or peg-GCSF. The primary endpoint was progression-free survival (PFS) with 84% power to detect a HR of 0.518 corresponding to 2y PFS rate of 65% in Arm 1 and 80% in Arm 2 (1-sided α=0.20). Results: 119 DEL pts were enrolled: 60 Arm 1; 59 Arm 2. Analyses were performed for the modified intent-to-treat population, defined as eligible pts with confirmed DEL histology (n=113; 56 Arm 1, 57 Arm 2). Median age was 64 y (range 22-85); baseline demographic factors were well balanced except for advanced stage (more common in Arm 1; (77% vs 60%, p=0.051). Most pts were non-germinal center B cell-like by immunohistochemistry (Arm 1 72%, Arm 2 58%), high-intermediate/high risk IPI (Arm 1 54%, Arm 2 51%) and ECOG performance status 0-1 (Arm 1 95%, Arm 2 86%). BCL2 rearrangements were detected in 25% and 33% of pts on Arm 1 and Arm 2, respectively. Most pts completed therapy per protocol (84% Arm 1, 75% Arm 2). Median follow up is 27 months (m). No difference in PFS was observed with 12-m PFS estimates of 77% in Arm 1, 76% in Arm 2 [HR = 0.98 (95% CI: 0.48 – 2.01), p=0.95]. The end of treatment (EOT) overall and complete response rates among patients with an EOT assessment were 87.5% and 70% in Arm 1, and 90% and 82% in Arm 2. Overall survival (OS) was not statistically significantly different with 12-mo OS estimates of 94% in Arm 1 and 79% in Arm 2 [HR = 1.27 (95% CI: 0.57 – 2.79), p=0.56]. Grade ≥3 adverse events (AEs) occurred more frequently in Arm 2 (42% vs 76%). The most commonly increased grade ≥3 AEs included neutropenia (20% vs 47%), anemia (4% vs 25.5%), thrombocytopenia (5.5% vs 24%), febrile neutropenia (7% vs 16%) and fatigue (0% vs 11%). No grade 5 AEs on treatment were reported on Arm 1, and 3 were reported on Arm 2 (lung infection and sudden death NOS, both possibly related; respiratory failure, unlikely related). Conclusions: Adding venetoclax to R-CHOP in DEL pts did not improve PFS and resulted in increased toxicity. The study did not meet its primary endpoint in phase II, and so did not proceed to phase III. Clinical trial information: NCT03984448 .

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.

Background: The anti-apoptotic protein Mcl-1 contributes to the pathophysiology of certain B-cell malignancies and AML, and dependence on Mcl-1 is associated with resistance to venetoclax. Efforts to target Mcl-1 through direct inhibition have faced challenges due to cardiovascular toxicities. Voruciclib, a potent oral CDK9 inhibitor (CDK9i), was shown to indirectly downregulate Mcl-1 protein levels and synergize with venetoclax in preclinical models in lymphoid and myeloid malignancies. In solid tumors, voruciclib maximum tolerated dose (MTD) was defined as 350 mg with continuous daily dosing, and 600 mg when used on days 1-14 on a 21-day cycle. This phase 1 study is the first to evaluate the safety, dose-limiting toxicities (DLT), preliminary efficacy, pharmacokinetics, and pharmacodynamics of voruciclib in R/R hematologic malignancies (NCT03547115). Methods: Patients (pts) with relapsed B-cell NHL, CLL, or AML aged ≥18 years who had ECOG performance status ≤1, disease progression after standard therapies, adequate hepatic and renal function, and no prior CDK9i were eligible. The study followed a 3+3 design and DLTs were assessed in Cycle 1. Voruciclib was administered daily continuously at a starting dose of 50 mg on a 28-day cycle (Cohort I). After 2 DLTs were observed at 100 mg in AML pts, dosing was changed to daily on days 1-14 on a 28-day cycle (Cohort II). Also, pts with prior allogeneic transplant were excluded and dose escalation (100, 150, 200 mg) proceeded separately in AML and B-cell malignancies. Disease response was assessed by investigators using the Lugano, 2008 iwCLL, and 2017 ELN criteria. Results: 40 pts were enrolled: 21 AML, 19 NHL (9 DLBCL, 3 CLL, 3 MCL, 3 FL and 1 MZL). Cohort I enrolled 16 pts, 8 each at 50 mg and 100 mg. Cohort II enrolled 24 pts (17 AML and 7 B-cell malignancies), including 6 at 100 mg, 7 at 150 mg, and 11 at 200 mg. Dose escalation in Cohort II did not reach the MTD and was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition. Median age was 70 years (range 40-90), 72.5% of pts were ≥65 years, and 77.5% had ECOG performance status = 1. Pts had a median of 3 prior therapies (range, 1-8). Median duration on drug was 5 weeks (range 1-22). Drug-related serious adverse events (AEs) were reported in Cohort I only. Two pts with AML had a DLT of Grade (Gr) 3 interstitial pneumonitis at 100 mg; both had had allogeneic transplant and active graft versus host disease, one of whom also had a concurrent Gr 3 differentiation syndrome. One pt with DLBCL at 50 mg had Gr 3 hypoxemic respiratory failure in Cycle 4. In Cohort II, no DLTs were observed and there were no non-hematologic Gr 3-5 drug-related AEs. In the overall population, the most common AEs were diarrhea (30%), nausea (25%), anemia (22.5%), fatigue (22.5%), constipation (17.5%), dizziness (15%) and dyspnea (15%) [Table 1). One pt with AML had Gr 3 hyperbilirubinemia. There was no evidence of drug-related neutropenia in pts with NHL. No significant cardiovascular AEs were observed. One pt with AML in Cohort I achieved a morphologic leukemia-free state. At 200 mg, 5 of 10 AML pts (50%) had stable disease. Voruciclib pharmacokinetics was dose proportional, mean accumulation ratio was 2.4, mean T max was 4 hours, and at 200 mg, steady state C max was 925 ng/mL and mean C trough was 442 ng/mL (~1 microM). Analysis of Mcl-1 protein expression in normal lymphocytes by flow cytometry showed a trend of decrease in on-treatment samples compared to pre-treatment. Consistent with this, RNA-Seq analysis of 3 paired CLL samples confirmed rapid (after 6 hours) downregulation of Mcl-1 mRNA transcript in the malignant B-cells. Furthermore, scRNA-Seq analysis of 2 longitudinal AML samples demonstrated downregulation of MYC transcriptional program and oxidative phosphorylation in circulating AML blasts, both evident 24 hours after start of voruciclib and ongoing at C1D15. Conclusions: Voruciclib at doses up to 200 mg administered on 14 consecutive days on a 28-day cycle was well tolerated, with no DLTs observed, and no cardiovascular toxicities. There was no significant myelosuppression in pts with B-cell malignancies. As the safety profile suggested non-overlapping toxicities with venetoclax, the study is now evaluating voruciclib in combination with venetoclax in pts with R/R AML to exploit dual inhibition of Bcl-2 and Mcl-1.

Introduction: AutoHCT is an effective therapy for patients (pts) with DLBCL who are refractory or relapse following first-line chemotherapy, but long term outcomes remain suboptimal. The BTK inhibitor ibrutinib has shown promising activity in pts with ABC-DLBCL (Wilson et al, Nat Med 2015). In 2016 we launched a randomized phase III clinical trial to evaluate the addition of ibrutinib to AutoHCT as part of conditioning and as consolidation therapy for pts with relapsed/refractory ABC-DLBCL. Patients and Methods: Following assessment of open-label treatment in a safety cohort of 6 pts, we randomly assigned pts with chemotherapy-sensitive persistent or relapsed ABC-DLBCL to receive ibrutinib 560 mg [Arm A] or placebo [Arm B] concurrently with conditioning on days -6 to -1 of AutoHCT (Cycle 1). Following count recovery and resolution of acute toxicities, pts continued ibrutinib 560 mg in Arm A or placebo in Arm B for 12 additional 28-day cycles. Crossover to Arm A using single agent ibrutinib was allowed for pts progressing on Arm B. Central pathology review was performed for disease confirmation and subtype assignment. Initially, ABC subtype assignment was performed using the Nanostring Lymphoma Subtyping Test (LST) but the study was amended to use the IHC-based Hans classifier for non-GCB on 8/15/19. Other key eligibility criteria included receipt of no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no prior progression on Ibrutinib. Pts were stratified by time to relapse (<=12 mos vs >12 mos), type of conditioning (BEAM or CBV) and prior ibrutinib use. The original design required 296 patients with 82% power to detect a difference in 2-year progression-free survival (PFS) rates of 67% vs. 50% with a two-sided alpha of 0.05. A revised statistical design allowed an interim futility analysis to be conducted after 40 pts were enrolled and followed for 2 years. Even though the study met criteria to continue accrual to a target of 160 pts, we decided to close it early due to declining accrual on 12/20/2022. We hereby present the primary analysis of the evaluable patients enrolled (data as of 07/17/2023). Results: Between 2/6/17 and 8/24/18, we screened 255 pts but enrolled only 34 (13%) largely due to long assay turnaround times and performance characteristics with the LST. Following the switch to the IHC-based Hans classifier (after 8/15/19), 60 out of 110 pts screened were enrolled (54%) in line with our a priori expectation. In total, 45 pts were randomized to Arm A vs. 43 to Arm B, with 39 and 38, respectively, being evaluable for the primary endpoint at this time. Median age was 61 years (range 20-75 years), median number of prior lines of therapy was 2, 46% of the pts were female, 21% were refractory or had early relapse, 94% were planned to receive BEAM conditioning. Overall, 87% of pts in Arm A and 88% in Arm B underwent conditioning while 70% and 67% respectively, started maintenance therapy. The median number of cycles received was 6 in Arm A vs. 5 in Arm B. The primary endpoint of 2-year PFS was 57.6% (95% CI: 42.1%, 78.8%) in Arm A vs. 40.8% (95% CI: 26.5, 62.8%) in Arm B (HR=0.54; 95% CI: 0.26, 1.10; log-rank p = 0.087). Median PFS was 26.5 months (95% CI: 10.2, not reached [NR]) in Arm A vs. 8.1 months (95% CI: 5.4, NR) in Arm B. Only one pt crossed over to Arm A after progression on Arm B. The most common grade 3-4 AEs in each of the arms were: neutropenia (A: 14%, B: 14%), febrile neutropenia (A: 11%, B: 9%), and thrombocytopenia (A: 11%, B: 7%). Rates of any grade atrial fibrillation were similar between arms (12.8% in Arm A vs. 10.5% in Arm B); one patient had grade 3 and one patient had grade 4 atrial fibrillation, both in Arm B. Six pts had reported grade 5 events (Arm A: 2 sepsis, 1 COVID-19, 1 respiratory failure and 1 disease progression and Arm B: 1 disease progression) but only one grade 5 event (sepsis, Arm A) was deemed probably related to treatment. Conclusions: Despite an early high rate of screen failures and declining accruals due to competition with CAR-T cell therapy, the primary analysis suggests that ibrutinib with and following AutoHCT in relapsed/refractory ABC-DLBCL is well-tolerated and may improve PFS in this high-risk patient population. This trial was supported by: U10CA180821, U10CA180882, U24CA196171; U10CA180820, UG1CA233234 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG) ClinicalTrials.gov Identifier: NCT02443077 https://acknowledgments.alliancefound.org

Introduction: ECOG ACRIN E1910 is a randomized phase III trial that showed that adults with newly diagnosed BCR::ABL1 negative acute lymphoblastic leukemia (ALL) who become MRD negative (<0.01%) after induction chemo who receive blinatumomab with conventional chemotherapy (chemo) have improved survival compared with those who received chemo only (Litzow et al, Blood (2022) 140: Supplement 2, LBA-1). However, not all pts were able to receive all four planned cycles of blinatumomab in consolidation. In this report we assessed outcomes of pts in the blinatumomab arm of the trial who received all 4 cycles of blinatumomab compared to those who received 1-2 cycles. Methods: Patient between the ages of 30 and 70 with newly diagnosed BCR::ABL1 negative B-lineage ALL were enrolled and initially received 2.5 months of combination induction chemo utilizing a BFM-like regimen adapted from the E2993/UKALLXII clinical trial, with pegaspargase (after induction only for patients >=55 years of age) and addition of rituximab for CD20 positive patients. After remission induction (step 1) pts in morphologic complete remission (CR/CRi) received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). At the conclusion of step 2, remission and MRD status were determined centrally by 6-color flow cytometry with MRD negativity defined as <0.01%. In the primary analysis subset, MRD negative patients were randomized to receive an additional 4cycles of consolidation chemo or 2 cycles of blinatumomab at 28 mcg/day (flat dose) for 28 days each cycle followed by 3 cycles of consolidation chemo, another 4-week cycle of blinatumomab (3rd cycle of blinatumomab) followed by an additional cycle of chemo and then a 4th cycle of blinatumomab (step 3). Following completion of consolidation chemo +/- blinatumomab, pts were given 2.5 years of POMP maintenance therapy timed from the start of the intensification cycle (step 4). Estimates of OS were calculated using the Kaplan-Meier method. Comparison of OS between treatment arms were conducted using the stratified log-rank test and Cox proportional-hazards model with age, CD20 status, rituximab use, and whether pts intend to receive HSCT or not as stratification factors. As the number of cycles needed to optimize outcome has not been studied, an unplanned landmark analysis was used to compare OS of pts in the blinatumomab arm who received all 4 cycles o those who received 1-2 cycles. Time 0 was chosen as 9 months post step 3 randomization (the time that patients were supposed to complete 4 cycles of blina). Four pts who received blinatumomab but died within 9 months post step 3 randomization were therefore excluded from this analysis. Results: The study was activated on December 17, 2013 and closed to enrollment on October 15, 2019. 772 pts were screened for the trial and 488 were enrolled on step 1 induction therapy. The median age of the pts was 51 years (range 30-70). 224 MRD negative pts were randomized, 112 pts to each arm. In the blinatumomab arm 12 pts received 1 cycle (11%), 32 pts received 2 cycles (29%), 4 pts received 3 cycles (4%) and 63 pts received 4 cycles (57%). The OS of pts who received 1-2 cycles of blinatumomab was compared to control (Figure 1) The difference was not significant (hazard ratio 0.62, 95% CI 0.28 to 1.34, p=0.22). Fig 2 compares the survival of those who received 1-2 cycles to those who received 4 cycles ( (HR: 0.39, 95% CI 0.12 to 1.16, p=0.076). Conclusion: The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival compared to chemotherapy alone in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification. This represents a new standard of care for pts aged 30-70 years with BCR::ABL1 negative ALL. The optimal dose and number of cycles is however unknown. In this unplanned subgroup analysis we demonstrate that a survival benefit can only be confirmed in patients who receive the intended 4 cycles of blinatumomab during consolidation. Further studies will be needed to determine if fewer cycles can provide a similar benefit.

Introduction: Preclinical studies have suggested synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a master transcriptional factor that regulates myeloma cell survival. Single agent oral IBR combined with dexamethasone proved well tolerated and active in advanced, steroid refractory relapsed MM as part of a large Phase1/2 study in 60 patients, with durable stabilization and minimal response seen in most evaluable patients (Richardson PG et al, BJH 2018). LEN is considered a standard of care in newly diagnosed MM, as maintenance and in relapsed disease, and a backbone of oral therapy in the MM treatment paradigm (Laubach JP et al, Leukemia 2016). Methods: We therefore conducted a 3+3 phase I trial to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least 2 prior lines of therapy. Three dose levels (DL) were planned. Cycle length was 28 days. IBR was administered orally daily at 560mg on DL1-2 and 840mg on DL3, LEN orally days 1-21 at 15mg on DL1 and 25mg on DL2-3, and DEX orally days 1, 8, 15, and 22 at 40 mg if age < 75 or 20 mg if ≥75 for DL1-3. Patients with GFR ≥ 30 and < 60 were treated according to manufacturer's instructions with lenalidomide dosed at 10mg/d. Dose limiting toxicities (DLT) included grade 4 thrombocytopenia; grade 4 neutropenia lasting more than 5 days or febrile neutropenia; grade 4 nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; grade 3-4 hyperglycemia or thrombotic/embolic event, treatment delays ≥ 21 days for toxicity; and treatment related death. Due to changes in standard of care during the study, eligibility was modified to allow the enrollment of patients with RRMM who had at least 1 prior line of therapy. Response was assessed using IMWG/Uniform Criteria. Results: Fourteen patients (DL1-6 pts; DL2-3 pts; DL3-5 pts) registered to the study from March 2019 to May 2023, prior to its closure due to slow accrual. One patient on DL3 cancelled participation prior to start of treatment due to disease progression (PD). The remaining 13 patients are included in summary of toxicities and response but 2 patients on DL3 are excluded from determination of MTD due to discontinuing cycle 1 treatment due to COVID and receiving 280 mg/day of IBR instead of assigned 840 mg/day dose during cycle 1, respectfully. Twelve patients were evaluable for response. The median number of prior lines of therapy was 3 (range: 2-9), reflecting a heavily pretreated relapsed and refractory population. One of the 6 patient on DL1 developed a DLT, grade 3 non-viral hepatitis. None of the 3 patients on DL2 or the 2 patients on DL3 had a DLT. One patient on DL1 remains on treatment with stable disease for 42+ cycles. The median number of cycles administered was 3 (range: 1-42+). Severe toxicities reported included grade 3 lymphocytopenia (3), anemia (2), alanine aminotransferase increase (1), aspartate aminotransferase increase (1), blood bilirubin increase (1), hypocalcemia (1), hypokalemia (1) hypophosphatemia (1), febrile neutropenia (1), chronic kidney disease (1), non-viral hepatitis (1), soft tissue infection (1), and fatigue (1); grade 4 lymphocytopenia (1), and grade 5 sepsis (1). End of treatment reasons included: PD (7), toxicity (2), death [soft tissue infection that turned into sepsis considered to be likely related to DEX] (1), and concomitant conditions (2). Stable disease (SD) or better was achieved in 10 of 12 evaluable patients (83%), including one patient who achieved disease control for over 3.5 years. One patient (8%) on DL3 had a complete response (CR) but stopped treatment after 2 cycles due to reversible toxicity and comorbid conditions, based upon physician advice and patient choice. Conclusions: The combination of lenalidomide with Ibrutinib as an all-oral approach in RR MM proved feasible and generally tolerable, with the majority of discontinuation seen in this Phase I study due to disease progression. No COVID related - mortality was seen. SD or better was achieved in 83% of patients, including one CR. Potential future directions include combination approaches with next generation IMids such as pomalidomide, as well as other orally bioavailable novel agents with potent immune activating properties, such as CelMoDs. Support: AFT; Pharmacyclics; Clinicaltrials.gov Identifier: NCT03702725