Dinner, Shira

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 E1910 randomized pts with ALL aged 30-70 years who were measurable residual disease negative (MRD-) by multi-color flow cytometry (FC) after intensification to conventional chemotherapy (chemo) with or without blinatumomab (blina). The addition of blina resulted in improved overall survival (OS) (Litzow, NEJM 2024) and led to a new standard of care. Older ALL pts have inferior outcomes when compared to younger pts in part due to increased treatment toxicity. In E1910, exposure to dexamethasone and pegasparagase was reduced for older pts (age >55 years). We present results of subgroup analyses describing outcomes of older pts enrolled in E1910. Methods Details of the E1910 protocol remission induction (step 1), high dose methotrexate with pegaspargase intensification (step 2), blina randomization (step 3), and maintenance (step 4) or allogeneic hematopoietic stem cell transplant (HCT) were previously presented (Litzow, NEJM 2024). MRD status was determined after step 2 centrally with 6-color FC with MRD- defined as <0.01% in the bone marrow (BM). Following approval of blina in the US for MRD positive (MRD+) disease in 2018, MRD+ pts were assigned to the blina arm and no longer randomized. The primary objective was to compare the OS and relapse free survival (RFS) among older pts aged >55 years (pre-specified stratification factor) who received chemo + blina to that of pts who received chemo alone (step 3 treatment). Estimates of OS and RFS were calculated using the Kaplan-Meier method. Comparison of OS and RFS between treatment arms was conducted using the two-sided stratified log-rank test and Cox model with CD20 status, rituximab use, and whether pts intended to receive HCT or not as stratification factors. Stratified Multivariate Cox models of OS and RFS were used to further evaluate the effect of step 3 treatment, adjusted by gender, white blood cell count (WBC), platelets, hemoglobin, peripheral blood blasts, BM blasts, performance status and combined molecular risk category. Results Among the 488 enrolled pts, 211 were ≥55 years old with median age of 61 (range 55-70). Among older pts, 49.3% were female and 83.4% were white, 17 (8.1%) pts had WBC >30.000/uL at the time of diagnosis. 156 (73.9%) pts had CD10+ early B-ALL and 46 (21.8%) had CD10- B-ALL immunophenotype. The most common genetic subgroups were low hypodiploid (n=58, 27.5%), BCR::ABL1-like (n=34, 16.1%) and KMT2A rearranged (n=26, 12.3%). 8.1% of pts had low, 9.0% intermediate, 63.5% high combined molecular risk disease and in 19.4% of pts risk could not be assigned. Baseline characteristics were not significantly different in chemo + blina and chemo only pts. The median follow-up for this analysis from step 1 registration was 54.6 months. Complete response with (CR) or without (CRi) count recovery after induction was observed in 174 (82.5%) pts (167 CR, 7 CRi). 93 (44%) pts were MRD-. 32 (15.1%) pts received HCT on study and 24 (11.4%) pts received it off study. Among MRD- pts (n=93), 46 were randomized to and 45 received blina: 6 (13.3%) pts had 1, 14 (31.1%) had 2, 2 (4.4%) had 3 and 23 (51.1%) had 4 cycles. 3-year OS were 71% and 67% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.37-1.50; multivariate model: HR 0.56, 95% CI: 0.25-1.27). 3-year RFS were 69% and 59% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.39-1.45; multivariate model: HR 0.67, 95% CI: 0.32-1.42). Among MRD+ pts (n=25), 14 were randomized to and 11 received blina: 7 (63.6%) pts had 2, and 4 (36.4%) had 4 cycles. 3-year OS were 66% and 44% for the blina vs the chemo only arm (univariate model: HR 0.66, 95% CI: 0.12-3.64). 3-year RFS were 64% and 31% for the blina vs the chemo only arm (univariate model: HR 0.64, 95% CI: 0.15-2.74). Frequency of treatment-related toxicities among older pts during different study phases and treatment assignments will be presented. Conclusion Despite evidence of improved outcomes in the whole study cohort, the addition of blina to consolidation chemo for older pts with ALL was not associated with statistically significant improvement of OS or RFS in this exploratory analysis not powered to detect the difference in subgroups. This is possibly due to sample size but may be due to biologic differences in the older adult population. Further studies are needed to definitively determine tolerance and benefit of blina addition to consolidation for older pts with ALL.

Background: Patients with acute lymphoblastic leukemia (ALL) receiving L-asparaginase (ASP) based induction therapy have a high risk of venous thromboembolism (VTE). Studies investigating universal thromboprophylaxis strategies have yielded sub-optimal results. Risk prediction models are needed to identify high-risk patients who would be candidates for intensification of thromboprophylaxis, and lower risk patients who are unlikely to benefit. Aims: Derive and externally validate a risk prediction model for VTE in patients with ALL receiving ASP therapy. Methods: We conducted a multicenter, international, cohort study of patients with newly-diagnosed ALL receiving ASP-based induction therapy (≥18yrs). The derivation and external validation cohorts included 306 and 97 patients without VTE prior to ASP therapy, respectively. Patients on therapeutic anticoagulation at index were excluded. Patients were followed from date of first ASP dose for 100 days post ALL diagnosis or until VTE, therapeutic anticoagulation or death. Candidate predictors were documented at ALL diagnosis and included demographics, disease and treatment characteristics, VTE history, comorbidities, thromboprophylaxis, complete blood count, fibrinogen and d-dimer. D-dimer was only analyzed within the 7 derivation cohort centers who routinely tested this at ALL diagnosis with <20% missing values. Primary outcome was VTE at any site (centrally confirmed). Secondary outcomes included major bleeding by ISTH criteria. Cause-specific Cox proportional hazard regression was performed to identify VTE risk factors in the derivation cohort while treating death as a competing event. Variables with p-value <0.1 on univariable analysis were included in a multivariable model and subsequently used in the risk model if p-value <0.05. Lastly, the derived VTE risk prediction model was tested in the external validation cohort for association with time to VTE using cause-specific Cox proportional hazard model. All analyses were stratified by center and use of low molecular weight heparin prophylaxis (at any dose on the date of first ASP dose). Results: The cumulative incidence of VTE in the derivation cohort was 17% at 30 days (95% confidence interval [CI] 13% - 21%) and 22% at 90 days (95% CI 17% - 27%). The multivariable model included hyperlipidemia (hazard ratio [HR] 1.35; 95% CI 0.56 - 3.27), body mass index ≥ 25 kg/m² (HR 1.49; 95% CI 0.75 - 2.95), platelet count ≥ 25 x 10⁹/L (HR 1.42; 95% CI 0.67 - 3.00), increasing hemoglobin per 1 g/dL (HR 1.17; 95% CI 1.03 - 1.32) and d-dimer ≥ 1 µg FEU/mL (HR 2.68; 95% CI 1.08 - 6.66). Hemoglobin as a continuous variable and d-dimer ≥ 1 µg FEU/mL were included in the final model and used to create a risk score which was weighted by estimated log-HR sum of these risk factors. The lowest risk quartile (risk score below 2.1) successfully differentiated between a lower 30-day cumulative VTE incidence (4%, 95% CI 0.72% - 12%) compared with the other quartiles (20%, 95% CI 14% - 27%; HR 4.40, 95% CI 1.54 - 12.5) which were defined as high risk (score ≥2.1). The risk score's negative predictive value (NPV) for VTE at 30 days was 96% and positive predictive value (PPV) was 20%. The validation cohort (n=97 from 3 external cohorts with routine d-dimer measurement) included 16 (16.5%) patients in the low-risk group and 81 (83.5%) in the high-risk group, with a 30-day VTE incidence of 6.3% (95% CI 0% - 17%) and 21% (95% CI 12% - 30%), respectively (HR 6.22; 95% CI 0.85 - 45.8; p = 0.073)). The NPV (93.7%) and PPV (21%) were comparable to the derivation cohort. The 30-day incidence of major bleeding was 0% (95% CI NR - NR) in low-risk patients (HR 1.36; 95% CI 0.27 - 6.77) and 2.0% (95% CI 0.55% - 5.4%) in the high-risk group. Conclusion: Patients with ALL receiving ASP induction therapy have a 17% VTE risk at 30 days. We derived and externally validated a VTE risk prediction model based upon d-dimer and hemoglobin. This model successfully identifies at least 16.5% of patients with ALL who have a low VTE risk after ASP treatment. Using this model, novel prevention strategies which may be associated with cost and risk could now be tailored to patients with higher risk. Prospective studies are needed to validate the model's performance and role in VTE risk management.

Introduction: Based on a donor versus no-donor analysis, UKALLXII/E2993 showed a survival benefit for adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR1) compared to consolidation/maintenance chemotherapy alone. The follow-up phase 3 E1910 trial (NCT02003222) randomized BCR::ABL1-negative B-lineage ALL patients (pts) aged 30-70 years in measurable residual disease (MRD)-negative CR1 after intensification to conventional chemotherapy (CC) +/- blinatumomab (blin) and demonstrated significantly improved overall survival (OS) with blin (Litzow, NEJM 2024). The current exploratory subgroup analysis evaluates outcomes of MRD-negative pts randomized on E1910 who underwent alloHCT on trial. Methods: Among pts enrolled on E1910, pts in MRD-negative CR1 by 6-color flow cytometry after intensification who were randomized to CC +/- blin and subsequently underwent alloHCT were identified. We compared baseline characteristics, MRD status post induction, relapse-free survival (RFS) and OS using the Kaplan-Meier method and the two-sided log-rank test and Cox model. A multivariable analysis was performed with alloHCT included as a time-varying covariate as well as a landmark analysis comparing the outcome of pts with unfavorable risk on the CC + blin arm who underwent alloHCT versus those who did not. Results: Of 224 MRD-negative randomized pts, 44 underwent alloHCT on trial: 22 in each arm. The median time from randomization to transplant was 3.2 months (mos). The median follow-up from initial registration was 57.8 mos. Baseline demographics including age (median 55 years), gender (53% male), race (89% white) and ethnicity (89% non-Hispanic/Latino) were equally distributed. Compared to CC + blin, the median peripheral blood white cell (WBC) count and blast percentage at diagnosis were higher in the CC arm at 6,640 vs 3,740/uL and 55 vs 9%, respectively, while median marrow blast percentage and overall unfavorable risk as defined in E1910 (55% vs 64%) were similar. Of the 44 MRD-negative pts who proceeded to alloHCT on study, 77% in the CC arm and 64% in the CC+ blin arm were MRD-negative after induction. Myeloablative conditioning was given to the majority of pts (68% CC arm and 73% CC+blin arm) and the most common graft versus host disease prophylaxis was tacrolimus-based on both arms. Among the 44 pts who underwent alloHCT, the observed hazard ratio (HR) comparing relative risk of death between pts randomized to CC+blin or CC only was 0.59 (95% CI: 0.12-2.11) with a 3-year OS rate of 82% versus 71% and the HR comparing relative risk of relapse/death was 0.52 (CI: 0.15-1.79) with a 3-year RFS rate of 82% versus 67%. For patients with unfavorable risk, 3-year OS and 3-year RFS in each treatment arm were both 71% versus 65%. Among 50 pts with unfavorable risk in MRD-negative CR after intensification who were randomized to CC + blin, a landmark analysis performed at 5 mos post randomization showed 3-year OS and RFS rates of 71% versus 90% and 71% versus 86% between the 14 pts who underwent alloHCT and those who did not, respectively. Receipt of alloHCT was a time-varying covariate in a multivariable analysis with gender, WBC count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status, and combined molecular risk category. Age, CD20 status, rituximab use, and intention to receive alloHCT were used as stratification factors. In the entire cohort of MRD-negative pts who were randomized, there was a significant association between improved OS and the receipt of CC+blin vs CC alone (HR 0.46, 95% CI: 0.26 - 0.82; p=0.009), better performance status of 0-1 vs ≥2 and favorable vs unfavorable risk ALL. In contrast, the receipt of alloHCT had no significant effect on OS (HR 1.00, 95% CI: 0.49 - 2.01). Conclusions: Within the constraints of small numbers, this exploratory subgroup analysis demonstrates that in pts with newly diagnosed BCR::ABL1-negative B-ALL treated on E1910 who achieved MRD-negativity after intensification, alloHCT outcomes did not appear to be different with or without blin in consolidation. In a multivariate analysis of all MRD-negative pts, receipt of blin but not alloHCT was associated with improved OS. Further investigation is warranted to characterize the relative benefit of blinatumomab in pts receiving alloHCT in frontline consolidation.

Introduction: Health disparities negatively impact outcomes of patients (pts) with hematologic malignancies. Limited retrospective data correlating health disparities with lymphoma outcomes prohibit proper identification of reversible causes and elaboration of potential interventions. We present data from a coordinated effort between the National Clinical Trials Network (NCTN) cooperative groups (Alliance for Clinical Trials in Oncology [Alliance], Eastern Cooperative Oncology Group [ECOG], and the Southwest Oncology Group [SWOG]) to catalog the racial, ethnic, and socioeconomic characteristics of pts with lymphoma to better understand the quality of data collected, analyze selected health disparity indicators, and develop a prospective data collection tool. Methods: We conducted a retrospective analysis of demographic data from pts with lymphoma enrolled on 32 cooperative group therapeutic trials between 2005 and 2020. Special focus was placed on data regarding race, ethnicity, and proxies that help identify socioeconomic status (health insurance, residential zip code, Social Deprivation Index [SDI]). These were evaluated in relation to histology-based metrics from the Surveillance, Epidemiology, and End Results Program (SEER) Program with reported data through 2022. Here, our focus is to characterize baseline demographic and disparities data on the collection of these 32 NCTN lymphoma trials. Results: A total of 3,897 pts were included, with 3,406 non-Hodgkin lymphoma (87.4%) - 1,644 diffuse large B-cell (DLBCL, 48.3%), 905 follicular (26.6%), 669 mantle cell (19.6%), 113 primary central nervous system (3.3%), 75 T-cell (2.2%) - and 491 Hodgkin lymphoma (12.6%). Age at registration was available for 3,891 pts with median age 57.1 years (range: 18-92). The majority of patients were male (58.8%; one pt missing biological sex data). Race data were available for all but one patient, where most pts were white (W, 86.6%), followed by 246 African American (AA, 6.3%), 99 Asian (A, 2.5%), 13 American Indian or Alaska Native (AI, 0.3%), 8 Native Hawaiian or Pacific Islander (PI, 0.2%), 11 with more than 1 race reported (0.3%), and 145 with unknown/not reported race. Ethnicity data were unknown for 327 pts (8.4%) with 179 Hispanic or Latino (Hisp, 4.6%). Combined race/ethnicity data showed 3,010 non-Hisp white (NHW, 77.2%) and 219 non-Hisp black (NHB, 5.6%). For comparison, in the SEER database, 84.7% of all lymphoma cases were W, with 8.6% AA, 5.2% A/PI, 0.4% AI, and 1.1% unknown race, and with 13.9% of pts reported as Hisp. When focusing on the 804 pts enrolled on Alliance CALGB 50303 and ECOG-ACRIN 1412 studies, two randomized DLBCL studies, there was a more proportional representation of W and AA pts with DLBCL - 82.1% and 9.8% compared 84.6% and 7.7%, respectively, at SEER database, with 5.3% Hisp (with another 5.3% unknown) compared to 14.9% at SEER. Insurance information was missing in 113 pts. Of the remainder, 2,102 pts had private insurance only (55.6%), 549 with a mix of private and public (14.5%), 701 public only (18.5%, including 11.4% Medicare, 4.5% Medicaid, 0.8% both), and 166 self-pay (4.4%). Year-matched SDI score was available in 2,885 pts, where higher SDI scores = higher social deprivation. The total mean SDI score for the overall cohort was 42.5 with significant differences observed based on race/ethnicity and insurance type. Specifically, NHW were from less deprived areas (mean SDI=38.8) than NHB (66.4) or Hisp (65.5) (p<0.0001). Those without insurance (mean SDI=52.6) or only public insurance (48.9) were located in areas associated with greater deprivation compared to pts with private (40.1) or public+private (38.8) insurance (p<0.0001). Conclusion: To our knowledge, this is the largest retrospective catalog of racial, ethnic, and socioeconomic characteristics of pts with lymphoma enrolled on cooperative group therapeutic trials. The scope of NCTN cooperative group lymphoma studies provides a unique opportunity to assess novel therapeutic outcomes for patients representing racial, ethnic and socioeconomic subgroups with both common and rare lymphoma subtypes. From this resource, additional analyses on relationships between SDI, race/ethnicity, insurance coverage, disease subtype, and temporal trends will be presented. Support: U10CA180821, U10CA180882, UG1CA189823

Mantle cell lymphoma (MCL) is a rare lymphoma with a median age at diagnosis of 60-70 years. Front line therapy has traditionally been bendamustine-rituximab (BR) in older patients and then Bruton Tyrosine kinase inhibitors (BTKi) for relapsed disease. Due to their efficacy, BTKi are now being combined with chemotherapy as induction treatment. The TRIANGLE trial of R-CHOP/R-DHAP +/- ibrutinib +/- transplant showed the benefit of adding a BTKi in young patients (Dreyling M, 2022). The SHINE trial, a phase III trial of BR +/- ibrutinib in patients >65 years, showed a significant improvement in median PFS (81 months vs. 53 months) (Wang M, 2022). However, this came with an increase in toxicity with more treatment related deaths in the ibrutinib arm (11% vs. 6%) and no difference in overall survival. Therefore, a better tolerated approach is still needed in older patients. A phase II study of rituximab + indefinite ibrutinib in 50 patients >65 years demonstrated efficacy of frontline BTKi with a 96% ORR and 71% CR (Jain P, 2021). However, a disadvantage of BTKi therapy is continuous treatment until disease progression or intolerance. In this study half of patients required dose reductions and almost a third of patients stopped treatment due to drug toxicity, most frequently atrial fibrillation or bleeding. If front line intermittent BTKi therapy is as effective as continuous therapy, it could minimize cumulative toxicity. A052101 (NCT05976763), an Alliance for Clinical Trials in Oncology trial, is a randomized phase 3 multicenter trial of upfront zanubrutinib that asks the question “in older patients with previously untreated MCL who obtain a CR with zanubrutinib-rituximab, is it safe and equally effective to stop treatment and restart it upon disease progression rather than continuing indefinitely?” The A052101 trial is enrolling pts with previously untreated MCL who are either >70 years old or 60-69 years old but are not transplant candidates due to cardiac ejection fraction <45%, DLCO <60% of predicted, creatinine clearance <70, Eastern Cooperative Oncology Group (ECOG) performance status of >2, or a Cumulative Illness Rating Scales score of >6. Key exclusion criteria include: history of a severe bleeding disorder or clinically significant cardiac arrhythmias. Patients will take zanubrutinib 320 mg daily and rituximab/rituximab biosimilar once monthly for 6 cycles. Patients with less than partial response after 6 cycles will go off study treatment. Patients with a complete remission will be randomized in a 1:1 manner to intermittent treatment versus continuous treatment. Randomization will be stratified by age (60-69 years vs ≥70 years) and MIPI score. Those randomized to the continuous arm will receive zanubrutinib until intolerance or disease progression. Those randomized to the intermittent arm will stop all study drugs after those initial 6 cycles and will restart zanubrutinib at first disease progression and continue it until intolerance or second disease progression. In order to make the study results generalizable to clinical practice, disease progression will be defined by clinical parameters rather than minimal residual disease testing. The primary objective of this study is to compare time from randomization to first progression or death (PFS1) in the continuous treatment arm to the time to second progression or death (PFS2) in the intermittent treatment arm. The primary evaluation will be to determine whether, for patients in a CR, active monitoring followed by retreatment with zanubrutinib therapy upon disease progression will result in non-inferior clinical outcomes compared to indefinite zanubrutinib. Serial quality of life testing and adverse event monitoring will be performed throughout the study to gain a full understanding of the impact of continuous vs intermittent zanubrutinib on patients' lives. A052101 has the potential to change management of older patients with previously untreated MCL. If our study demonstrates that the time to second progression/death when using the stop and retreat strategy is non-inferior to time to first progression/death when using continuous BTK therapy, then it might lead to a new standard of care in this patient population. This could result in decreased health care costs, decreased toxicity and improved quality of life for older patients with mantle cell lymphoma. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org

Background: The rising incidence of PCNSL in the elderly represents an unmet need with an undefined standard approach [Villano Br J Cancer 2011]. High-dose methotrexate-based (HD-MTX) therapy is feasible and effective in older patients, but outcomes in this population remain poor. Despite high response rates to HD-MTX induction therapy, poor candidacy for intensive consolidative therapy results in transient disease control that may benefit from maintenance strategies [David Am J Hematol 2023]. Lenalidomide (len) has demonstrated activity in PCNSL even at low doses and represents a potential alternative to consolidation considering its extensive use in maintenance settings [Vu Br J Haematol 2019]. Anecdotal activity in PCNSL by checkpoint inhibitors such as nivolumab (nivo) has been reported [Nayak Blood 2017], and its immune response may be enhanced by len [Görgün Clin Cancer Res 2015]. A051901 evaluates the feasibility of the addition of len and nivo to rituximab (R) and HD-MTX as first line induction therapy followed by len-nivo maintenance in elderly patients with PCNSL not eligible for intensive consolidation. Study Design and Methods: This is a single-arm phase 1 multicenter US study (NCT04609046) conducted by the Alliance for Clinical Trials in Oncology with a traditional 3+3 design. Eligible patients are 18 years of age or older with untreated diffuse large B-cell lymphoma PCNSL diagnosed through brain biopsy or resection, or cerebrospinal (CSF) or vitreous fluid not considered candidates for high dose chemotherapy consolidation. This study is available to all eligible patients, regardless of race, gender, or ethnic origin. Patients must have adequate end-organ function including creatinine clearance of at least 50 mL/min. Use of systemic corticosteroids for disease control to be tapered after initiation of therapy is allowed. Induction consists of six 14-day cycles with rituximab 500 mg/m2 i.v. on day 1, HD-MTX 3g/m2 i.v. on day 2. In the most recent treatment schedule, a 5-day course of lenalidomide PO at different dose levels (dose level (DL) 1 = 10 mg, DL2 = 15 mg, DL3 = 20 mg) is initiated immediately after adequate clearance of HD-MTX. Once a maximum tolerated dose (MTD) of len is defined, a subsequent cohort will evaluate the addition of nivo 240 mg i.v. to the day 14 of the induction cycle of R-HD-MTX plus len at the MTD. Patients who present any clinical benefit from induction with at least stable disease by International PCNSL Collaborative Group response criteria are eligible for maintenance - twelve 28-day cycles of therapy with len 15 mg PO from day 1 to day 21 (regardless of dose during induction) +/- nivo 480 mg i.v. on day 1 (for those who received len and nivo during induction). The primary endpoint of the induction therapy is the MTD of len when given in combination with R-HD-MTX; the primary endpoint of maintenance is its feasibility, defined as the proportion of patients able to remain on maintenance for at least 6 cycles. As of July 2024, 16 patients have been enrolled with a maximum expected sample size of 47 patients with the assumption of 75% of patients being eligible to proceed with maintenance and 50% of those who begin maintenance not progressing in the first 6 cycles. Overall response, adverse events, progression-free and overall survival will be evaluated in all eligible patients with a focus on the outcome of patients treated at the MTD. For patients who consent to biobanking, diagnostic tissue, peripheral blood and CSF from different timepoints are collected and banked with planned exploratory analyses including whole exome sequencing, circulating tumor DNA, proteomics, metabolomics. Support: U10CA180821, U10CA180882. https://acknowledgments.alliancefound.org.

Introduction: Inotuzumab ozogamicin (INO) is an antibody targeting CD22 conjugated with a cytotoxic antitumor antibiotic (calicheamicin) approved for treatment of relapsed/refractory CD22 positive B-cell acute lymphoblastic leukemia (ALL) (Kantarjian et al. NEJM 2017). CD22 is expressed on the surface of lymphoblasts in ALL (~95%). Young adult patients (pts) 18-39 years (yrs) treated on the pediatric regimen CALGB 10403 resulted in a 3-yr event-free survival (EFS) of 59% (95% CI: 52-67%) and an estimated 3-yr overall survival (OS) of 73% (95% CI: 68-78%) (Stock et al. Blood 2019). Alliance A041501(NCT03150693), a phase 3 NCTN sponsored cooperative group trial was conducted to determine if the addition of INO to the CALGB 10403 pediatric regimen would significantly improve EFS. Methods: Eligibility included pts 18-39 years with newly diagnosed CD22 positive ALL, defined as baseline expression in > 20% of lymphoblasts by local institution. Pts with Burkitt-type ALL, BCR::ABL1 positive ALL, or Down syndrome were excluded. Eligible pts received the CALGB 10403 regimen modified to omit extended induction, include dexamethasone as opposed to prednisone as steroid backbone, cap the pegaspargase dose to 3750 units, and adding rituximab for pts with CD20 expression (> 20%). An amendment added blinatumomab for minimal residual disease (MRD) positivity. Pts achieving a complete remission (CR/CRi) or partial remission (PR) were eligible for randomization. Following a 6 pt safety run-in with INO, pts were randomized 1:1 to receive INO or continue CALGB 10403 backbone. Two cycles of INO (1.5 mg/m2/cycle) were administered following induction in the experimental arm. Pts were stratified by age, disease status post induction (M0/M1 vs M2), CD20 status, and LDA Card, which tests for the Ph-like status. The primary endpoint was to determine if the addition of INO would improve the EFS of the pediatric regimen CALGB 10403 without censoring for stem cell transplant (SCT). Key secondary endpoints included the impact of INO on disease-free survival (DFS), OS, and MRD. The Alliance Data and Safety Monitoring Board halted enrollment after 273 out of a planned 341 pts were registered because of increased grade (gr) 5 events in the INO arm compared with the control arm. Results: 273 pts were enrolled between 6/15/2018, and 5/24/2022. Median age was 27.0 yrs, 65.2% were White, 30.4% were Hispanic, and 63.4% were male. Baseline CSF analysis revealed 14% with CNS-2/3 disease. The overall CR rate was 86.8% (82.8-90.8%). 46 pts were not randomized due to death (5), withdrawal (6), ineligibility (3), toxicity (5), receipt of non-protocol therapy (8), progression (5), and other (14). 227 eligible pts were randomized 1:1 to receive INO (N=111) or not (N=116)). For randomized pts, 92.5% achieved M0/M1 marrow status, 48.9% had a positive LDA Card defining Ph-like ALL, 50.7% were CD20 positive. Only 36 pts (13%) received a SCT. With a median follow up of 28.3 months for randomized pts, 3-yr EFS was 69.0% (59.1-80.5%) for the INO arm and 66.7% (57.1-78.1%) for the control (HR=0.97; 0.58-1.63). Similarly, the 3-yr OS was 79.4% (71.0-88.7%) for the INO arm and 80.3% (71.9-89.6%) for the control (HR=1.05; 0.55-2.01). The MRD undetectable rate at Course II Day 56 was 80.6% in the INO arm and 74.2% in the control arm. Univariate analysis suggests improved EFS with INO in pts with a positive LDA card (Ph-like ALL) and of Hispanic ethnicity. There were 22 gr 5 events, 7 occurred prior to randomization. Of the 15 gr 5 events on the randomized cohort, 12 were reported in the INO arm and 3 in the control arm. Of the 12 gr 5 events in the INO arm, all occurred during intensive consolidation courses complicated by prolonged pancytopenia infection/sepsis (8), hepato-biliary in setting of infection (2), multi-organ failure (1), or post-surgical complication (1). These events occurred after INO during Course II (3), Course III (5), or Course IV (4). Conclusions: Although this trial did not meet the primary EFS endpoint for the addition of INO to the pediatric regimen CALGB 10403, these data provide compelling evidence for continued use of pediatric regimens in young adults with ALL as the EFS and OS compares favorably with prior published results. INO may still be efficacious if late toxicity can be mitigated. A pilot study is planned that will decrease INO dose, add 2 cycles of blinatumomab and strict infectious prophylaxis guidelines. Support: U10CA180821, U10CA180882

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

AbstractIntroductionRelapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B‐ and T‐ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L‐VCR and VEN for patients with r/r B‐or T‐cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644).MethodsIn a 3+3 dose escalation design, r/r ALL subjects were given single‐agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L‐VCR at 2.25 mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination.ResultsAmong the 18 patients in phase I, grade ≥ 3 treatment‐related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose‐limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty‐two percent of evaluable patients (N = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD).ConclusionThe combination of VEN and L‐VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L‐VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.