Narra, Ravi

Abstract Introduction: Clinical outcomes for patients (pts) with Philadelphia chromosome positive (Ph+) B-cell precursor Acute Lymphoblastic Leukemia (B-ALL) have significantly improved with the incorporation of tyrosine kinase inhibitors (TKI) and immunotherapy. Although the incidence of central nervous system (CNS) relapse in Ph+ B-ALL is rare, it has become an emerging challenge with chemotherapy-free approaches. While IKZF1, CDKN2A/B and emergence of T315I kinase domain mutations in ABL1 have been associated with worse outcomes (Foà R, JCO, 2024),further characterization of patients with CNS relapse could prove useful in risk stratification and optimizing treatment intensification. Currently, high white blood cell count (WBC) is being assessed as a marker to identify pts who may benefit from addition of CNS penetrant chemotherapy (ex. cytarabine or high-dose methotrexate (HD-MTX)) to TKI and immunotherapy protocols (Short NJ, J Hematol Oncol, 2025). Methods This is a multicenter retrospective study of relapsed/refractory Ph+ B-ALL pts under the COMMAND consortium. Age, gender, induction regimen and TKI of choice during induction were descriptively reported for the entire cohort. Categorical variables were compared, using Fisher's exact test, between pts with CNS relapse and pts with systemic relapse. Variables of interest were the presence of IKZF1 or CDKN2A/B alterations, emergence of T3151 mutation, CNS disease at diagnosis (dx), WBC >70K/microliter at dx, use of high-dose methotrexate (HD-MTX) during induction or consolidation, and use of TKI as part of the induction regimen. Odds ratio (OR) and 95% confidence intervals (CI) were reported for each variable. Results A total of 654 Ph+ B-ALL pts were initially identified across multiple centers in the United States, of whom 20 (3%) experienced a CNS relapse and 157 (24%) experienced a systemic relapse on median follow up of 29 months (range, 0-207). A total of 15 pts with CNS relapse and 114 pts with systemic relapse were used for this analysis after exclusion of pts without molecular data. The median age for the 129 pt cohort was 55 years (range 22-85), of whom 65 pts (50%) were male. Induction regimens used were intensive chemotherapy (IC)+TKI for 79 pts (61%), low-intensity chemotherapy or steroids (LDC-S)+TKI for 40 pts (31%), IC without TKI during induction for 5 pts (4%) and blinatumomab+TKI for 1 pt (1%). TKI of choice during induction included second-generation TKIs (dasatinib, nilotinib) for 77 pts (60%), imatinib for 30 pts (23%), ponatinib for 15 pts (12%) and none during induction for 5 pts (4%). CNS disease at dx was found in 6/15 pts (40%) with CNS relapse and 9/114 pts (8%) with systemic relapse, which was a statistically significant difference (p=0.002, OR= 7.57, 95% CI= 1.81 - 31.08). The systemic treatment regimens for the 15 pts with CNS disease at x were IC+TKI for 10 pts (66%) and LDC-S+TKI for 5 pts (33%), 9 of the pts (60%) received HD-MTX during induction. Intrathecal (IT) chemotherapy administration data at dx was available for 8 pts (53%) with CNS disease at dx, of whom 2 pts received <9 doses, 4 pts received 9-12 doses and 2 pts received >12 doses of IT chemotherapy. Although not statistically significant, pts with CNS relapse were more likely to have IKZF1 or CDKN2A/B alterations (p = 0.648, OR= 1.44, 95% CI= 0.14-7.78), WBC >70K/mcl (p = 0.472, OR= 1.73, 95% CI= 0.34-7.41), emergence of T3151 mutations (p = 0.123, OR= 2.54, 95% CI= 0.72-8.84) and use of HD-MTX during induction or consolidation (p = 0.262, OR= 2.15, 95% CI= 0.61-8.61); while they were less likely to have received a TKI during induction (p = 0.106, OR= 0.18, 95% CI= 0.02-2.34). Conclusion This data confirms that the presence of CNS disease at dx is associated with CNS relapse. Despite recent incorporation into clinical trials, WBC≥70K/mcl and omission of HD-MTX were not seen more frequently in pts with CNS relapse in this cohort. However, this analysis is limited by the small number of pts who experienced CNS relapse. With the rising use of chemotherapy-free regimens, prospectively trialing treatment intensification, such as with additional IT chemotherapy or HD-MTX, could be prospectively trialed in pts with CNS disease at dx to potentially improve outcomes for this subset of pts. The impact of increasing IT chemotherapy doses or additional cycles of systemic chemotherapy in this pt population is yet to be elucidated.

Background While central nervous system (CNS) disease is found in minority of patients (pts) at diagnosis of Ph+ ALL, later relapses can occur in pts despite adequate CNS prophylaxis. CNS disease can be managed with varying combinations of systemic, radiation, and intrathecal (IT) therapy and can be associated with significant toxicity, especially in older pts. While there are more durable systemic responses with 2nd or 3rd generation tyrosine kinase inhibitors (TKIs) based combinations, CNS penetration can vary by TKI. In this large multi-center study, we analyze the incidence of CNS disease in Ph+ ALL in the context of induction therapies and survival post relapse. Methods We conducted a multicenter observational study in collaboration with 10 U.S. academic centers under the COMMAND consortium and reviewed the incidence of CNS relapse in 505 Ph+ ALL pts. We evaluated baseline characteristics, treatment given prior to CNS relapse, and outcome post relapse. Results Baseline characteristics, initial treatment and outcome prior to CNS relapse Eighteen (3.56%) pts were identified to have CNS disease at relapse. Median age of the pts in years (yrs) was 51 (range [R], 22-75), median white blood cell (WBC) was 33.3 x 10(9)/L (R, 2.1-200) and 6 (33%) pts had additional cytogenetic abnormalities at diagnosis. Sixty-one percent (n= 11) of pts received intensive chemotherapy (IC) during induction; 2 (11%), 14 (78%) and 2(11%) of pts received 1st, 2nd or 3rd generation TKI-based combination during induction, respectively. All of pts achieved complete remission (CR), 45.5% achieved complete molecular remission (CMR) at 3 months from the time of diagnosis. Five (28%) pts received allogeneic stem cell transplantation (allo-HCT) as a consolidation therapy. Treatment received at CNS relapse and response The median time to CNS relapse after induction was 10.8 months (mo) (R, 2-79). All pts except 1 had isolated CNS relapse after CR1, 4/18 (22%) pts had T315I mutation at relapse. Twelve (67%) and 6 (33%) pts received intrathecal chemotherapy (IT) with TKI and systemic chemotherapy + TKI in addition to IT, respectively. Eleven (61%) pts received dasatinib, 5 (28%) pts received ponatinib and one (6%) pts each received bosutinib and imatinib at relapse. Ninety-three percent of pts achieved CR (n=3, not evaluable). Six (33%) pts underwent allo-HCT after CNS relapse, one of these transplanted pts had second allo-HCT. Survival after CNS relapse The median relapse free survival (RFS) and overall survival (OS) after CNS relapse was 9.8 (95% CI: 3.80-15.76) and 13.87 (95% CI: 4.08-23.65) mo, respectively. In subset analysis, we compared survival outcome among pts who had relapse without CNS involvement (n= 160/505 [32%]). The median RFS (9.9 vs 9.8, p= 0.88) and OS (31.53 vs 28.80, p= 0.57) after relapse was not significantly different among pts who had relapse with or without CNS involvement, respectively. We also compared OS among pts without relapse to those with relapse. The median OS was not reached (NR; 73% alive at 5 years), 28.80 and 31.53 months (p= <0.001) among pts with no relapse, relapse with CNS and without CNS involvement, respectively. Conclusion Our retrospective analysis from a large database showed that CNS relapses were uncommon (3.56%) in adult pts with Ph+ ALL. A majority of pts (89%) received a 2nd or a 3rd generation TKI during induction. Approximately one quarter of pts with CNS relapse had emergence of T315I mutation. While almost all pts achieved CR, the RFS was relatively short. We did not see significant differences in survival among pts who had relapse with or without CNS involvement.

Summary Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T ( n = 24) or BsAb ( n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT.

Background With the advent of tyrosine kinase inhibitor (TKI)-based therapy the outcome of Philadelphia chromosome-positive (Ph +) acute lymphoblastic leukemia (ALL) has significantly improved. Moreover, patients (pts) who achieved undetectable (u) BCR::ABL1 at 3 months (mo) from the time of initiating therapy, tend to have improved outcomes (Short et al. Blood 2016; 128 [4];504-507). We conducted a retrospective multicenter study to analyze the predictors of achieving uBCR::ABL1 in adult (> 18 years) Ph + ALL pts. Methods A total of 458 adult Ph + ALL pts from 10 US academic institutions, who were diagnosed between May 2003 and April 2023, were evaluated to assess the rates of uBCR::ABL1 at 3 mo after initiating therapy and factors that predict the achievement of molecular response. Continuous variables were summarized as median (range), while categorical variables were reported as frequency (percentage). Unadjusted comparisons of patient/ treatment related characteristics and molecular response were made using a non-parametric test (continuous variables) or Fisher's exact test (categorical variables). Survival curves were estimated using the Kaplan-Meier method and compared between molecular responses via the log-rank test. Results Baseline characteristics The median age of the pts was 53 years (range [R] 19-85), median white blood cell count (WBC) was 17.6 (10 9/L) (R, 1.2-571), 249 (55%) pts had additional cytogenetic (CG) abnormalities, 98 (22%) pts had p210 fusion protein, and 35 (8%) pts had CNS disease at diagnosis. A higher proportion of pts received TKI in combination with intensive chemotherapy (IC) (69%), than TKI + steroids (15%), TKI + low intensity chemotherapy (LC; combination of vincristine, steroids +/- rituximab) (9%), TKI + blinatumomab (3%) and IC without TKI (4%) during induction. During induction, the highest proportion of pts received 2 nd generation TKI combinations (67%; majority dasatinib 98%), compared to imatinib (19%) or ponatinib (10%): 4% of pts did not receive TKI with induction. The complete remission (CR) rate was 94%; measurable residual disease (MRD) negative by flow cytometry 51% (181/352 evaluable pts) and 58.5% (209/354 evaluable pts) of pts had uBCR::ABL1 by PCR at 3 mo from induction. A total of 212 (46%) pts received allogeneic stem cell transplantation (allo-HCT) in CR1, among them 61% of pts received TKI maintenance post allo-HCT. Predictors of uBCR::ABL1 at 3 months Predictors for uBCR::ABL1 at 3 mo are summarized in Table 1. The proportion of pts with WBC > 100 (45% vs 60%, p= 0.04), p210 fusion protein (35% vs 85%, p= <0.001), additional CG abnormality with monosomy 7 (40% vs 61%, p= 0.03), additional somatic myeloid co-mutation (39% vs 61%, p= 0.09; 94 pts evaluable), received induction with steroid plus TKI (41% vs 63%, p= 0.002) or received imatinib based induction (47% vs 61%,p= 0.07) had inferior uBCR::ABL1 rates at 3 mo. Conversely pts who received ponatinib based induction had significantly better uBCR::ABL1 rates (79% vs 57%, p= 0.009). Survival The median relapse free survival (RFS) was 72.3 mo (95% CI; 50.1-94.4), RFS was numerically higher among pts who achieved uBCR::ABL1 at 3 mo but not statistically significant (84.2 mo vs 62.9 mo, p= 0.20). The median overall survival (OS) was 129.2 mo (95% CI; 81.2-177.2), OS was not significantly different among pts who achieved uBCR::ABL1 at 3 mo (129.2) versus no uBCR::ABL1 (not reached; 50% alive at 94 mo), p= 0.47. In sub-set analysis, among non-transplanted pts, RFS was not statistically significant between those who achieved uBCR::ABL1 vs those who did not (38.9 vs 22.0 mo, respectively p= 0.24). However, the median OS was significantly higher in pts who achieved uBCR::ABL1 at 3 mo compared to pts who did not achieve uBCR::ABL1 at 3 mo: 149.3 vs 77.5 mo, p= 0.04 ( Figure 1). Conclusion In this large multicenter study, we observed significantly inferior uBCR::ABL1 rates among pts with WBC > 100, p210 fusion protein, monosomy 7 CG abnormality, pts receiving induction with steroid plus TKI or imatinib based induction. Conversely, uBCR::ABL1 rates were significantly better in pts receiving ponatinib based induction therapy. Overall, we did not see significant impact of uBCR::ABL1 at 3 mo, on RFS or OS. It is likely subsequent therapies and allo-HCT abrogates the negative impact of not achieving uBCR::ABL1 at 3 mo. However, among non-transplanted pts achievement of uBCR::ABL1 at 3 mo showed a significantly improved OS.

Abstract Waldenström macroglobulinemia (WM) is a rare B‐cell lymphoproliferative malignancy. Autologous hematopoietic cell transplantation (auto‐HCT) is considered in a subset of WM patients with relapsed disease. While registry data has shown a benefit for auto‐HCT in relapsed WM, there is a paucity of data on outcomes of patients relapsing after auto‐HCT. Eligibility criteria included adult patients with relapsed/refractory WM who underwent auto‐HCT between 2007 and 2017. The primary endpoint was post‐relapse overall survival (PR‐OS). Secondary endpoints were to identify factors prognostic of PR‐OS. Of the 48 patients with WM who underwent auto‐HCT, 22 (46%) experienced relapse following auto‐HCT. Median PR‐OS of relapsed WM patients after auto‐HCT ( n = 22) was not reached (NR) (95% confidence interval [CI]: 17.5 months‐NR). Among patients who relapsed <1 year versus ≥1 year from auto‐HCT, the median PR‐OS was 18.4 months (95%CI: 0.8‐NR) months and NR (95%CI: 17.5‐NR), respectively ( p = 0.06). Of note, disease status at the time of transplant, CR/VGPR versus partial remission did not appear to impact PR‐OS. The median PR‐OS was significantly longer in patients who received ibrutinib in the post‐transplant setting compared to those who did not (NR vs. 18.4 months, 95%CI: 9.1‐NR, p = 0.02). On univariable analysis, the presence of complex karyotype (RR = 4.87, 95% CI = 1.22–19.53) and a higher number of prior lines of therapy (RR = 1.81, 95% CI = 1.23–2.67) were associated with a significantly higher risk of relapse. This is the only study to date that evaluated outcomes of WM patients who relapsed following auto‐HCT and provides a benchmark for future trials evaluating survival following auto‐HCT relapse.