Park, Jae H.

Abstract Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase–activating mutation in >95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor–based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.

Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Abstract Background: Relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) remain challenging to treat, particularly in older patients and those with a T-cell phenotype. Venetoclax (VEN), a selective BCL-2 inhibitor, has shown preclinical synergy with vincristine (VCR) in multiple preclinical ALL models. Following the previously reported establishment of the recommended Phase II dose (RP2D), we now report the results of the Phase II (Ph2) portion of EA9152 (VEN 600 mg daily with weekly L-VCR 2.25 mg/m² IV or VCR 1.5 mg/m2 IV capped at 2 mg), evaluating efficacy and safety in this high-risk population. Methods: This open-label, multicenter Phase II study enrolled adults (≥18 years) with R/R B- or T-cell ALL or LL. The phase II portion of this trial was a single-arm, open-label study evaluating the combination of VEN (600 mg po D1–28) with either L-VCR (2.25 mg/m² IV weekly x4) or vincristine sulfate (VCR) (1.4 mg/m² IV weekly x4). Following the market withdrawal of L-VCR in the United States in April 2022, no new patients were initiated on this formulation and patients already receiving L-VCR were transitioned to VCR at the start of their next treatment cycle or sooner if necessitated by drug availability. Prior VCR but not VEN exposure was permitted in Ph2. The primary endpoint was achievement of a complete response or complete response with incomplete count recovery CR + CRi rate by end of cycle 3. Secondary endpoints included measurable residual disease (MRD) response, progression free survival (PFS), overall survival (OS), and safety. The association of phenotype with response and time-to-event were evaluated using Fisher's exact test and the Cox proportional hazards model, respectively. Results: Twenty-one eligible patients were treated (B-cell ALL/LL: n=12; T-cell ALL/LL: n=9). The trial was terminated early after 22/56 patients were accrued on account of withdrawal of sponsor support. Median age was 50 years and 76.2% were male. Performance status was 0–1 in 85.7%. All patients had received prior chemotherapy; 47.6% had undergone prior transplant. Median number of treatment cycles was 1 (2 for B-cell, 1 for T-cell). By end of cycle 3, no patients in the B-cell cohort (0/12; 90% CI, 0.00–0.22) achieved CR or CRi, 8 had stable disease (SD). In the T-cell cohort, 1 of 9 patients (11.1%; 90% CI, 0.01–0.43) achieved CR, 1 achieved PR and 1 had SD. There was no statistically significant difference in CR + CRi rate between phenotypes (p=0.43). None of the patients achieved an MRD-negative CR/CRi by flow cytometry or molecular methods. At the time of this analysis, 16 of 21 patients had died. Median overall survival (OS) was 4.3 months (95% CI, 1.5–22.0) for B-cell and 10.2 months (95% CI, 2.0–16.4) for T-cell patients (HR 1.32, p=0.60). Median PFS was 2.9 months (95% CI, 1.7–3.7) for B-cell and 1.2 months (95% CI, 0.7–4.6) for T-cell cohorts (HR 2.18, p=0.18). Grade 3–5 treatment-related adverse events occurred in most patients. One T-cell patient experienced grade 5 respiratory failure. Among 16 patients enrolled under the revised protocol using VCR, only 1 experienced grade 3 peripheral motor neuropathy, and no peripheral sensory neuropathy was reported (combined AE rate 0.06; 90% CI, 0.00–0.26). Tumor lysis syndrome was not observed in this cohort. Conclusions: The combination of VEN at the established RP2D and L-VCR/VCR was feasible and had an acceptable safety profile in heavily pretreated patients with R/R ALL/LL. However, response rates, including CR/CRi and MRD negativity, were limited, particularly in the B-cell cohort. Median OS and PFS remain poor in both subtypes, highlighting the need for improved strategies in this high-risk population. Venetoclax, in combination with other chemotherapy regimens, has shown encouraging response rates warranting continued exploration of its benefit in ALL.

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity. Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America. We defined complete remission (CR) as < 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up. Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate. Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p < 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel. We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts < 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p < 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005). Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6). Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

Introduction: Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts >65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database. Methodology: ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in <60 yo; p=0.004). Pre-apheresis, 33 pts (45%) had active disease (>5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts <60 yo (MRD-negative CR 66%; r/r disease of 9%). The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts <60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in <60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and <60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts <60 yo. With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts <60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the <60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts <60, p=0.001). Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in <60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in <60, p=0.18). Conclusion: This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

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.

Abstract The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). With a median follow-up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS; P = .013) and overall survival (OS; P = .006) in univariate analyses; however, prior InO exposure did not influence PFS (hazard ratio, 1.20; 95% confidence interval, 0.71-2.03) in multivariate models. Within InO-exposed patients, InO responders had superior PFS (P = .002) and OS (P < .0001) relative to InO-refractory patients. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (P = .51) and OS (P = .86) for patients receiving InO as bridging therapy or before apheresis. In conclusion, although InO exposure was associated with inferior survival outcomes after brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively affects brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.