Stem Cell Transplantation Consolidation Research Articles

Rising Prevalence of Low-Frequency PPM1D Gene Mutations after Second HDCT in Multiple Myeloma.

Multiple myeloma (MM) first-line treatment algorithms include immuno-chemotherapy (ICT) induction, high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) consolidation, followed by lenalidomide maintenance. After these initial therapies, most patients suffer a disease relapse and require subsequent treatment lines including ICT, additional HDCT and ASCT, or novel immunotherapies. The presence of somatic mutations in peripheral blood cells has been associated with adverse outcomes in a variety of hematological malignancies. Nonsense and frameshift mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to the gain-of-function of Wip1 phosphatase, which may impair the p53-dependent G1 checkpoint and promote cell proliferation. Here, we determined the presence of PPM1D gene mutations in peripheral blood cells of 75 subsequent myeloma patients in remission after first or second HDCT/ASCT. The prevalence of truncating PPM1D gene mutations emerged at 1.3% after first HDCT/ASCT, and 7.3% after second HDCT/ASCT, with variant allele frequencies (VAF) of 0.01 to 0.05. Clinical outcomes were inferior in the PPM1D-mutated (PPM1Dmut) subset with median progression-free survival (PFS) of 15 vs. 37 months (p = 0.0002) and median overall survival (OS) of 36 vs. 156 months (p = 0.001) for the PPM1Dmut and PPM1Dwt population, respectively. Our data suggest that the occurrence of PPM1D gene mutations in peripheral blood cells correlates with inferior outcomes after ASCT in patients with multiple myeloma.

Obecabtagene autoleucel (obe-cel, AUTO1) in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): Overall survival (OS), event-free survival (EFS) and the potential impact of chimeric antigen receptor (CAR)-T cell persistency and consolidative stem cell transplantation (SCT) in the open-label, single-arm FELIX phase Ib/II study.

6504 Background: Obe-cel is an autologous CAR-T cell product with a fast off-rate CD19 binder designed to mitigate immunotoxicity and improve expansion/persistence. Pooled results from the pivotal FELIX phase Ib/II study (NCT04404660) of obe-cel in adults with R/R B-ALL were recently presented (Roddie C et al. Blood 2023;142[Suppl 1]:222). Here, OS and EFS in all patients (pts) treated with obe-cel are reported, alongside the impact of CAR-T cell persistency and consolidative SCT for pts in remission. Methods: Pts aged ≥18 yrs with R/R B-ALL were enrolled. CAR-T products were generated via an automated process (Roddie C et al. Blood 2023;142[Suppl 1]:222). Pts received bridging therapy as appropriate and underwent lymphodepletion (fludarabine, 4×30mg/m2; cyclophosphamide, 2×500mg/m2), followed by obe-cel split dose infusions on Days 1 and 10 based on pre-lymphodepletion leukemic burden at a target dose of 410×106 CAR-T cells. Results: A total of 127/153 (83%) enrolled pts were infused. At screening, pts’ median age was 47 yrs; 42%/31%/44% had received prior blinatumomab/inotuzumab ozogamicin/allogeneic SCT; median bone marrow blast burden was 36% (range: 0−100). At data cut-off (13 September 2023), median follow-up was 16.6 mos (range 3.7−36.6 mos). The overall complete remission or complete remission with incomplete count recovery rate among infused pts was 78%. Among responding pts, 17/99 (17%) proceeded to consolidative SCT while in remission; all 17 (100%) were in measurable residual disease (MRD)-negative remission (≤10–4 leukemic blasts) and 10/17 (59%) showed CAR-T cell persistency prior to SCT. Loss of CAR-T cell persistency was associated with a hazard risk of relapse or death 2.9 times compared with pts who had ongoing CAR-T cell persistency. Pts who experienced B-cell recovery had a hazard risk of relapse or death 1.7 times compared with pts without B-cell recovery. At 12 mos, the EFS rate was 50% and 43% with or without censoring for consolidative SCT or new therapies, respectively; the OS rate was 61% and 59% with or without censoring for SCT, respectively. Conclusions: Ongoing CAR-T cell persistency and B-cell aplasia were associated with improved EFS without further consolidation post-obe-cel. At the current follow-up, consolidative SCT for pts in MRD-negative remission post-obe-cel did not improve EFS or OS. Clinical trial information: NCT04404660 .

Hematopoietic stem cell transplant for adults with mixed phenotypic acute leukemia.

6517 Background: Mixed phenotype acute leukemia (MPAL) is a rare acute leukemia subtype characterized by expression of lymphoid and myeloid lineage markers on blasts. Consequently, the role of hematopoietic stem cell transplant (HCT) consolidation is unclear. We conducted a retrospective study of MPAL patients treated at our institution integrating the impact of transplant status, chemotherapy, and initial response on survival. Methods: We evaluated patients with MPAL at Fred Hutchinson Cancer Center from 1/2005 – 9/2022, some of whom were previously reported (Huang et al, ASH 2023). Independent pathology review using 2022 WHO criteria verified MPAL diagnosis. Potentially transplant eligible patients were defined as those <75 years of age, diagnosed at least 6 months prior to data retrieval date, and alive 100 days after diagnosis with an evaluable induction response. Log-rank and Cox proportional hazard models were used to compare survival and adjust for baseline covariates. Survival was landmarked at 100 days. Results: Of 55 total patients, 42 were potentially HCT eligible and 30 received HCT (71.4%; 20/30 myeloablative). Patients who did not complete HCT were similar in age (median 46.2, range 18-70 vs median 50.3, range 24 – 74, p = ns) and had similar ECOG (ECOG 0-1 86.6% vs 75.0%, p = ns) at diagnosis. Nine of 12 non-transplanted patients had age-adjusted HCT-CI score ≤ 3. Patients receiving a HCT had better progression free survival (PFS) (p = 0.025) and were more likely to be alive at 48 months (61.6% vs. 32.4%, p = 0.011) with a median overall survival (mOS) of not reached (NR) (95% CI, 43 months – NR) compared to a mOS of 13 months (95% CI, 9 months – NR) for those not transplanted. Given that our prior work showed that the type of induction chemotherapy did not influence OS (p = 0.40) or remission status (p = 0.16) (Huang et al. ASH 2023), we investigated impact of remission status at the time of transplant. Differences in PFS and OS persisted when stratifying patients by induction response status with HCT status (PFS p = 0.0048; OS p < 0.0001). Patients who had a complete response (CR) followed by HCT had the longest mOS = NR (17 of 24 patients alive after 48 mo). Patients who had resistant disease (RD) and completed HCT had mOS = 43 months (95% CI, 43 months– NR). Patients who achieved CR but did not undergo HCT had mOS = 19 months (95% CI, 11 months – NR). Patients who had RD and did not undergo HCT had median OS of 6 months (95% CI, 6 – NR). The hazard ratio for death among patients who underwent HCT was 0.28 (95% CI 0.077 – 0.99, p = 0.049). Conclusions: HCT consolidation was significantly correlated with improved survival (p = 0.011). While potentially biased by selection and limited by small sample size, patients benefitted from undergoing a HCT regardless of response to prior therapy (p < 0.0001). This study suggests that patients with MPAL in CR after induction chemotherapy as well as those with less than complete responses should be considered for HCT consolidation.

A phase III, randomized study of daratumumab, cyclophosphamide, bortezomib and dexamethasone (DARA-VCD) induction followed by autologous stem cell transplant or DARA-VCD consolidation and daratumumab maintenance in patients with newly diagnosed AL amyloidosis.

TPS7575 Background: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved depth of hematologic and organ responses. However, this approach has not yet demonstrated an overall survival (OS) benefit with short follow-up. Autologous stem cell transplant (ASCT) consolidation remains safe and is associated with deep and durable hematologic responses with an 83% 2-year progression free survival (PFS) and up to 72% of patients achieving a VGPR or better, comparable to Dara-VCD (79%). In multiple myeloma, ASCT improved PFS even in patients who are MRD negative at the end of standard induction therapy. It is thus reasonable to consider that ASCT might provide similar benefits in AL patients. No randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD. Methods: This randomized phase 3 SWOG led intergroup trial will accrue a total of 143 participants per arm and compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving Dara-VCD consolidation following uniform Dara-VCD induction. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematological PFS, cardiac and renal responses and progression, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. This trial was activated on 12/1/2023. Funding: NIH/NCI/NCTN grants and in part by Janssen Pharmaceuticals. Clinical trial information: NCT06022939 . [Table: see text]

1p and 1q: Partners in crime in multiple myeloma.

7571 Background: Cytogenetic abnormalities in multiple myeloma (MM) highly influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) among others are secondary CA. Gain (3 copies) and amplification (>3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of novel therapies. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients with chromosome 1 abnormalities, mainly del 1p, treated with autologous stem cell transplant (ASCT) consolidation at our institution. Methods: We conducted a retrospective study of all NDMM patients who were treated with ASCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) were defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC CA. Results: Of 511 pts transplanted, 453 had cytogenetic data at the time of diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amplification 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of progression-free survival (PFS) (HR 1.35; 95% CI 1.06-1.73, p=0.016), time to next treatment (TTNT) (HR 1.84; 95% CI 1.40-2.42, p<0.001) and overall survival (OS) (HR 1.47; 95% CI 1.06-2.02, p=0.02) compared to those without, consistent with published literature. The median PFS, TTNT and OS from ASCT in pts with gain/amp 1q were 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from the time of ASCT compared to those without del(1p). Conclusions: In our study of NDMM patients that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite induction therapy involving novel drugs and ASCT consolidation, patients with del(1p) at diagnosis continue to have inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.

Bendamustine Plus Brentuximab Has Superior Efficacy to Brentuximab Monotherapy As Third-Line Treatment for Classical Hodgkin Lymphoma: A Real-World, Multicentre UK Analysis

Purpose: The introduction of targeted agents has been a major advance in the treatment of classical Hodgkin lymphoma (HL) but the optimal application and sequencing of these agents is unclear. The CD30-targeted antibody-drug conjugate brentuximab vedotin (BV) is licensed for treatment of relapsed and refractory (R/R) HL as monotherapy and is available in the United Kingdom as third-line (3L) therapy for HL. BV has been evaluated in combination with chemotherapy in single-arm trials with very promising results, but randomised data are lacking. The aim of this analysis was to compare the efficacy of BV monotherapy with BV plus bendamustine (BVB) as 3L treatment of HL in a real-world UK cohort. Methods: Data were retrospectively collectively for consecutive patients receiving treatment for R/R HL with intent to consolidate with stem cell transplant (SCT) between 01/2015 and 12/2019 at 11 UK centres. Use of BVB was principally determined by availability, due to regional differences in BV funding in the UK, rather than patient disposition. Response was assessed by PET according to the Lugano Classification. Most analyses use descriptive statistics. Time-to-event analyses are measured from the start of 3L treatment until the first event (death for overall survival and death or further therapy for treatment failure) with groups compared using Kaplan Meier survival analysis and Cox regression. Results: 96 patients received BV and 30 received BVB. Baseline demographics are provided in the Table. Patients receiving BVB were slightly younger in age at diagnosis (p=0.031), but a slightly higher proportion had primary refractory disease (p=0.16) and failed to respond to second-line therapy (p=0.034). Numerically fewer patients in the BVB arm had received prior SCT (p=0.16). Patients received a median of 4 cycles of BV monotherapy (range 3 - 5). Patients treated with BVB received a median of 3 cycles of bendamustine (IQR 2 - 4) and 4 cycles of BV (IQR 3 - 5); 2 patients discontinued bendamustine after 1 cycle due to adverse reactions. Complete metabolic response was achieved in 34 patients (37.4%) with BV and 22 patients (73.3%) with BVB, with overall response rates of 57.3% and 93.3%, respectively (OR 9.2; 95% CI: 2.06 - 40.86; p=0.004). SCT consolidation was performed after 3L treatment in 33 patients (34.4%) following BV (26 autologous, 7 allogeneic) and 22 patients (73.3%) after BVB (17 autologous, 5 allogeneic). Median follow-up was 30.1 months after BV (IQR: 15.3 - 46.8) and 18.1 months after BVB (15.4 - 29.8). Freedom-from-treatment-failure (FFTF) rates at 18 months were 41.5% (95% CI: 30.8 - 51.8) after BV and 62.9% (39.3 - 79.4) after BVB (HR 0.45, 95% CI 0.23 - 0.88; p=0.019; see Figure). Overall survival rates at 18 months were 76.9% (66.0 - 84.7) after BV and 88.4% (68.1 - 96.1) after BVB (HR 0.37, 95% CI 11 - 1.23; p=0.11. There were 29 deaths following BV, including 17 (17.7%) due to HL, 6 (6.3%) due to toxicity of SCT or subsequent treatment and 6 (6.3%) due to other causes/unknown. There were 3 deaths following BVB, all due to toxicity of SCT or subsequent treatment (10%). Eight patients received single-agent bendamustine after failure of BV monotherapy, at a median of 2.4 months after commencing BV. The median number of bendamustine cycles delivered was 2 (range 1 - 6). The overall response rates was 62.5%. Two patients (25%) achieved complete metabolic response; both underwent subsequent SCT. Conclusion: In this retrospective analysis, use of BVB as 3L treatment for R/R HL was associated with higher response rates, transplant rates and FFTF compared with BV monotherapy. Although toxicity data were not available, our results are otherwise consistent with phase 2 trial data with BVB as second-line therapy (LaCasce, Blood 2018;132:40, Broccoli, Blood Cancer Journal 2019;9:100). These data demonstrate that BVB is a highly effective regimen in R/R HL, and support its use in transplant-fit patients.

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Truly Refractory Hodgkin Lymphoma Patients Is Highly Effective and Responses Are Mediated By NK Cells

Background In the relapsed/refractory Hodgkin Lymphoma (HL) setting (RHL), the achievement of complete remission (CR) is fundamental in order to proceed with allogeneic stem cell transplantation (HSCT) consolidation. Immune checkpoint inhibitors (CI) have demonstrated clinical activity in patients relapsing after ASCT, although only 20% CR rate is observed. In order to improve the efficacy of CI in RHL, we previously reported a salvage treatment based on early CI therapy following post-autologous stem cell transplantation (ASCT) with the reinfusion of unselected autologous lymphocytes infusions (ALI). The rationale of this approach is based on the achievement of a disease debulking through ASCT conditioning. Early administration of CI (nivolumab) is performed on a minimal disease burden, while reinfusions of ALI reduce post ASCT immune depression eliciting CI efficacy. Aims The aim of this study was to evaluate the efficacy of the procedure in terms of CR rates and overall survival (OS) after an extended follow up. Biological endpoint was to investigate the lymphocyte subpopulations involved in the mechanism of response and investigate the role of NK-cells mediating anti tumor responses in HL. Methods Patient were eligible to this study after failure to respond to first line treatment (i.e. positive PET2 or PET6 scan) and underwent autologous lymphocyte apheresis upon enrollment. All patients received conventional 2nd line chemo followed by 3rd line chemo-immunotherapy with Brentuximab-Vedotin (BV) in non-responding patients. Patient failing to achieve CR after BV were enrolled in the treatment arm and proceeded to ASCT + CI and ALI, whereas patients responding to 2nd- or 3rd treatment received ASCT followed by ALI alone, as a control cohort (figure 1A). NK cell degranulation assay was evaluated by staining for CD107a (LAMP-1) expression on healthy-donors derived NK cells exposed to HL cell lines (L428 and L250), in the presence or absence of monoclonal antibodies targeting inhibitory or activating receptors. Surface and intracellular staining was performed prior to flow cytometry and analysis was performed on the CD3-/CD56+ gated population. Results Twenty-one patients with RHL (median age 32 years; range 18-65) underwent lymphocyte apheresis after failure of 1st line chemo and then proceeded to salvage therapy. Thirteen patients failed to respond to 2nd and 3rd line therapy and thus received early post-transplant CI supported with four ALI. Eight patients responded to 2nd line chemo (n=6) or 3rd line BV (n=2) and received ASCT followed by ALI alone. No adverse events were recorded, specifically, no immune-related toxicity was observed. All patients receiving ALI + CI (treated patients) achieved negative PET scan CR. Eight of them received HSCT consolidation. One patient refusing HSCT after achieving CR in this study relapsed and responded to CI re treatment followed by HSCT. All patients in the treatment arm are alive and disease-free after a median follow-up of 32 months (95% CI 26.4-51.0). Median disease-free survival (DFS) was not reached in treatment arm (Fig 1B). Four of the patients in the control arm relapsed (50%). Three of them responded to 3rd line therapy and proceeded to HSCT. One patient achieved CR with conventional CI treatment but refused HSCT and the other relapsing patient died because of progressive lymphoma after failure to achieve CR with conventional single agent CI. Median DFS in the control arm was 22 months (Fig 1B). NK cells showed higher expansion and a faster maturation in the treatment arm, compared to the control arm (p<0.05). As expected, HL cells lines do not express HLA class I and II, but express activating NK cells receptors (aNKG2D, aNKp30, aNKp46, aDNAM-1). In vitro, the activation of each of those receptors was able to trigger NK cells degranulation. Similarly, PD-L1 and PD-L2 blockade on HL cell lines significantly increased NK cell degranulation (p<0.05). Taken together, those observations support the role of NK cells in this setting. Conclusions Our data show very high anti-tumor activity of ALI + CI for RHL, allowing most patients to proceed to HSCT. RHL patients in the treatment arm had an excellent outcome if compared to the control arm, which included patient who did respond to conventional treatment. Biological data suggests that this approach may accelerate NK cell development/maturation and suggest that NK cells may mediate response to CI in HL.

Survival of Hodgkin Lymphoma Patients Treated with Novel Immunotherapies after Autologous Stem Cell Transplantation Failure: A Retrospective Analysis of the Italian Lymphoma Foundation (FIL)

Background: Classical Hodgkin lymphoma (HL) is considered a highly curable disease and nearly 80-90% of patients (pts) may achieve complete remission (CR) with standard chemotherapy (Engert et. al. NEJM 2010).However up to 30% of HL pts experience primary refractory disease or eventually relapse after first-line treatment (Barrington et. al. Blood 2016, Press O et al. Clin Oncol 2016). High-dose chemotherapy followed by autologous hemopoietic stem cell transplantation (autoHSCT) has been showed to be an active salvage treatment in approximately 50% pts with chemosensitive relapse. Before the advent of novel immunotherapies, the median survival duration for pts failing autoHSCT was only 10 months (Vose et. al. Blood 1992). In this setting the introduction of Brentuximab Vedotin (BV) (Younes et. al. JCO 2012) and of the checkpoint inhibitors (CPI) Nivolumab (nivo) (Herrera et. al. Blood 2018) or Pembrolizumab (Chen et.al. Blood 2019) have shown to significant therapeutic active. Aims: To assess the therapeutic effects of BV and CPI in prolonging PFS and OS in patients with HL r/r post autoHSCT. Methods: This is an observational, retrospective, multicentric study from 15 centers of the Fondazione Italiana Linfomi (FIL). Adult patients who received salvage treatment with BV or CPI for post autoHSCT r/r HL from January 2015 to June 2018 were included in the analysis; the times of observation was censored in December 2020. Patients that had received pre-autoHSCT BV or CPI, were excluded from the analysis. Results: 40 pts, 25 treated with BV and 15 with nivo were included into the study. Patients' main characteristics at diagnosis are summarize in Table 1. Overall response was achieved in 23 (56%) pts treated with BV and in 9 (60%) with nivo, respectively. 14 (35%) out of 40 responsive to BV (10 pts) or nivo (4 pts) received allogeneic hemopoietic stem cell transplantation (alloHSCT) consolidation. The median follow-up time from the time of autoHSCT failure of the entire cohort was 36 months (range 2-70). At last follow-up, 32 (80%) pts were in CR, 1 (2%) in PR, while 2 (5%) and 5 (13%) were in SD and PD, respectively. 34 (85%) pts were alive and 6 (15%) have died. In the entire cohort, the median PFS and OS from the time of autoHSCT failure was 36 months and not reached, respectively; the 36-months projected PFS and OS of 50% and 86%, respectively. The median PFS and the 36-months projected OS of pts who received or not received alloHSCT were superimposable (Figure 1). Conclusion: In this retrospective analysis of pts with HL failing autoHSCT, BV or nivo resulted very active therapeutic salvage therapies. The comparison with historical results of the pre BV/CPI era suggests a major significant improvement both in PFS and OS. A significant proportion of pts received post BV or nivo alloHSCT but the effect of this treatment in prolonging PFS and OS should be further evaluated.

Project Evolve, Evaluation of Lineage Switch (LS), an International Initiative: Preliminary Results Reveal Dismal Outcomes in Patients with LS

Introduction: Lineage switch (LS) refers to the transformation of acute leukemia from one cell lineage to another (e.g., lymphoid (ALL) to myeloid (AML)). This rare phenomenon, distinct from treatment induced malignancy (i.e., t-AML) and mixed phenotype acute leukemia (MPAL), is increasingly being observed following cell surface antigen targeting. Given challenges in the diagnosis and treatment of LS, Project EVOLVE was developed to globally identify cases of LS following immunotherapy. Methods: A protocol and data collection form for this IRB exempt study was widely disseminated to capture deidentified LS case information across multiple centers and cancer consortia. This included collection of data from published reports of LS, with authors contacted to obtain additional information. For this analysis, LS was defined by the emergence of cell-surface markers warranting reclassification of the original leukemia as a different lineage derivation based on the immunophenotype, including cases of AML emerging alongside the original ALL. “Confirmed” LS cases included those where retention of original cytogenetic or molecular aberrations and/or the clonal immunoglobulin rearrangement patterns were verified to confirm the clonal relationship. “Suspected” LS cases included those where samples to confirm clonality marker retention could not be obtained, but the clinical presentation was consistent with LS. The term “transition” was applied when immunophenotypic shifts were transient. Cases with new cytogenetic abnormalities unrelated to the original diagnosis and compatible with t-AML were excluded. Statistical analysis was primarily descriptive. Data cut-off was July 26, 2023. Results: A total of 58 cases were identified, including 19 cases referenced in prior publications. Of the 58, 11 cases were excluded from this initial analysis, including: 4 cases of t-AML, 2 cases of T-ALL to AML, and 5 “transition” cases. Collectively, 47 cases of LS (43 “confirmed”; 4 “suspected”), spanning across 3 continents and 8 countries, were analyzed. (Fig. 1A) Cases included transition from B-ALL to AML in 36 (76.6%) and to MPAL/biphenotypic/ambiguous lineage in 11 (23.4%). Two likely had MPAL at diagnosis and a third with chronic myeloid leukemia. The median age at initial diagnosis was 8.4 years (range, 1 day-76.5 years); median age at LS presentation was 11.0 years (range 0.4-77.3 years). Twenty-three (48.9%) were male and 19 (40.4%) had prior stem cell transplant (SCT). Baseline cytogenetics showed KMT2A rearrangement in 27 (57.4%). Baseline myeloid antigen co-expression was seen in 22 of 23 patients with submitted data, but variation in degree of expression across patients and antigens was substantial. The most proximal immunotherapy prior to development of LS was CAR T-cells in 23 (48.9%) and blinatumomab in 24 (51.1%). The median time from the most proximal immunotherapy to development of LS was 1.6 months (range, 7 days-36.5 months). In 7 (29.2%) patients receiving blinatumomab, LS developed during the infusion. LS presented as isolated marrow relapse in 27 (57.4%), isolated CNS in 2 (4.3%), isolated non-CNS extramedullary disease in 3 (6.4%), combined relapse in 14 (29.8%) and unreported in 1. First line treatment for LS was chemotherapy induction in 31 (66.0%), palliative care/no therapy in 8 (17.0%), and alternative therapies in the remaining 8 (17.0%). In 35 (74.5%) patients, remission induction was the goal of first line therapy. Fifteen (31.9%) achieved a complete remission (CR) of whom 2 were treated with palliative intent. Across all patients, 8 (17.0%) are alive in remission, the longest being 4.7 years from LS diagnosis; 2 (4.3%) are alive with active LS and 37 (78.7%) died from LS, their original disease, or complications of treatment of LS (Fig 1B). For those alive in CR (n=8), 7 (87.5%) proceeded to a consolidative SCT for treatment of LS and 1 patient, an octogenarian remains in remission after AML directed therapy. Conclusions: LS is emerging as an important mechanism of immune escape following immunotherapy. Project EVOLVE provides the largest dataset of patients with LS to date. This systematic, international effort reveals substantial complexity and variability in diagnosing and managing LS. Unfortunately, outcomes following LS are grim, underscoring the critical need to identify risk factors of and optimal therapies for this leukemia transformation.

Nivolumab and Ibrutinib for Treatment of Patients with Refractory or Relapsed Central Nervous System Lymphoma

Background: Central Nervous System (CNS) lymphoma is a distinct entity of large B-cell lymphoma (LBCL) with a unique genomic profile with similarities to the activated B-cell (ABC) subtype, which may offer potential targets for therapy. These aberrancies commonly include MYD88 mutations, which enhances sensitivity to Bruton's tyrosine kinase (BTK) inhibitors, and translocation or copy number alterations of 9p24, which may associate with sensitivity with programmed death (PD)-targeted therapies. Expression of PD-L1 is common in CNS lymphoma and tumor infiltrating lymphocytes, and the majority of CNS lymphomas have a copy gain of 9p24.1. This suggests an attenuated immune response against CNS lymphoma. Ibrutinib in combination with nivolumab has shown safety and clinical activity in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia in a phase 1/2 trial, and therefore we hypothesized that this combination may be active in CNS lymphoma. Methods: We conducted an investigator-initiated, open label, single center, phase 2 clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Adult patients were eligible if they had CNS lymphoma (primary or secondary) refractory to or relapsed after at least 1 prior CNS directed therapy, with adequate organ and bone marrow function, without prior ibrutinib or PD1 inhibitor therapy, and did not require persistent high dose steroids. The trial had two sequentially enrolled cohorts: Cohort A included ibrutinib 560mg oral daily for one cycle (28-days per cycle), followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B included ibrutinib and nivolumab during the first cycle. Patients with a partial response or greater after 6 cycles of combined ibrutinib and nivolumab could continue therapy for up to 2 years or until progression of disease or unacceptable toxicity occurs. The primary objective was to determine the best overall response rate (ORR) of ibrutinib and nivolumab. Secondary objectives included the ORR of ibrutinib as a lead in prior to the combination, best complete response (CR) rate, landmark survival outcomes, and the safety of the combination. The trial planned to enroll 20 patients in both cohort A and B, but closed early due to slow accrual, due in part to the COVID19 pandemic. Results: The trial accrued 18 patients from February 2019 to June 2022, with all patients evaluable for response. The median age was 63 years (range 43-88), 33% were >70 years, and 78% were female. 89% had primary CNS lymphoma, 50% had non-GCB, 22% had GCB, and 28% were unable to be classified due to missing components of the Hans algorithm. The median number of prior lines of therapy was 2 (range, 1-4), 55% had refractory disease, 17% had prior stem cell transplant, and 11% had prior CAR T-cell therapy. 10 patients were enrolled to Cohort A (ibrutinib lead in), and 8 patients were enrolled to Cohort B (initial combination therapy). Adverse events included 50% with fatigue, 33% with nausea, and 28% with mucositis. For both cohorts, the best ORR was 77.8% (95% CI: 52~94%) and the best CR rate was 50% (95% CI: 26-74%). In cohort A, the ORR of ibrutinib as a lead in after 1 cycle was 90% (95% CI: 55.5-99.7%), and the CR rate was 60%. In GCB patients (n = 4), the ORR and CR rates were 25%. In non-GCB patients (n =9), the ORR and CR rates were 100% and 56%, respectively. With a median follow up time of 34.6 months, the median overall survival (OS) was 25.4 months (95% CI 12.5-NR), and the OS rate at 12 months was 70%. The median progression free survival (PFS) was 6.6 months (95% CI: 2.9 - NR), and the PFS rate at 18 months was 47%. 4 patients withdrew from protocol therapy in CR, including 2 who proceeded to stem cell transplant consolidation, and 2 who stopped due to fatigue. 3 patients withdrew from protocol therapy in PR, 2 due to mucositis and 1 due to arthralgias. 1 patient died of COVID19 infection with a CR after 4 cycles of therapy. Conclusion: Ibrutinib and Nivolumab resulted in significant clinical activity in patients with refractory/relapsed CNS lymphoma. Our trial is limited by small patient numbers but suggests the potential for targeted therapy combinations in future larger clinical studies.

Survival Outcomes of Rural Patients with Mantle Cell Lymphoma

Background Mantle cell lymphoma (MCL) is a rare and aggressive malignancy, representing approximately 6-8% of all non-Hodgkin lymphomas, and is generally associated with poor outcomes. Patients (pts) with MCL often require intensive up-front treatment with consideration for stem cell transplant consolidation. Due to geographic limitations, pts living in rural areas with MCL may not have access to specialized treatment centers experienced in managing this rare disease. There is a paucity of data available evaluating the impact of rurality in MCL, and it is unknown how population density and access to major metropolitan centers and their healthcare systems may impact survival outcomes. Methods The National Cancer Database was used to identify MCL pts diagnosed from 2004-2020. Demographic and treatment characteristics were compared by county level measures of rurality and urban influence, categorized into metropolitan (metro), non-metropolitan urban (urban), and non-metropolitan rural (rural) counties. These data are provided from the 2013 Department of Agriculture Economic Research service data Rural-Urban Continuum Codes which uses population, population density, and commuting distance to determine these codes. Pts without rurality data or who were not treated at the reporting facility were excluded. Kaplan Meier and adjusted Cox regression survival analysis were used to compare overall survival by rural-urban codes. Results Of the 29,464 pts with MCL identified, 83.4% (N= 24,849) resided in metro counties, 14.6% (N=4,356) resided in urban counties, 1.9% (N=573) resided in rural counties. Non-metro pts were more likely to be male (70.7% male metro vs 73.0% and 72.1% for urban and rural counties, respectively), with similar age at diagnosis across county types (median age of 68 for metro pts and 69 for rural pts). Rural pts had a higher burden of comorbidities, as determined by the Charlson-Deyo comorbidity index (11.3% of rural pts with a score of 2 or greater, compared to 8.7% urban, and 7.9% of metro pts). Pts from metro counties were more likely to have private insurance (38.5% metro vs. 32.4% for urban and 28.6% for rural pts), where non-metro pts were more often uninsured (3.3% of rural, vs 2.4% of metro) or Medicare insured (61.6% rural vs 53.4% of metro pts). Notably, pts were less likely to be managed with active surveillance if they were from a rural county (4.8% vs 6.9% of metro pts), and were more likely to receive systemic disease related therapy at diagnosis (90.6% rural vs 85.2% metro). With a median follow up of 42 months, pts from metro counties had a median overall survival (OS) of 70.6 months (95% confidence interval (CI) 68.6-72.7), which was significantly longer than those from urban (61.1 months [95% CI 56.4-65.9], p<0.001) and rural counties (59.8 months [95% CI 54.0-65.6], p<0.001). The survival disparity was persistent for metro, urban, rural pts at 1-year (81%, 80%, and 78% respectively, p<0.001), 5-years (54%, 50%, 50% respectively, p<0.001) and 10-years (36%, 30%, 29% respectively, p=0.066). When referenced to pts from metro counties on Cox regression, non-metro counties had a greater risk of all-cause mortality, with hazard ratio (HR) of 1.13 (95% CI 1.08-1.18; p<0.001) for urban and 1.14 (95% CI 1.02-1.28; p=0.024) for rural pts. When adjusted for age and Charlson-Deyo comorbidity score this survival disparity persisted, with a HR of 1.12 (95% CI 1.07-1.17), p<0.001 for urban pts and HR 1.05 (95% CI 0.94-1.18), p=0.408, for rural pts, when referenced to pts from metro counties. Discussion We demonstrate a population density-based survival disparity in MCL pts, finding that pts living in more rural counties have worse survival outcomes. Rural pts had a higher comorbidity burden and were more likely to be underinsured. Additionally, they received less active surveillance, which may indicate delays in diagnosis and/or consultation with an oncologist. Given the rapidly evolving treatment landscape of MCL, these data support the need for efforts to improve healthcare access for MCL pts, such as earlier referrals to academic centers with expertise in MCL management, expanded access to telehealth, rural partnerships with academic medical centers, and programs that support patient and family travel.

Mutational Burden in High Risk Genes Do Not Affect Remission Rates and MRD Clearance in Elderly AML Patients Receiving CPX-351 Induction

Background: CPX-351 has recently been approved for the treatment of patients diagnosed with Acute Myeloid Leukemia (AML) arising from a previous myelodisplastic syndrome (s-AML) or secondary to chemotherapy (t-AML) as per former WHO 2016 classification. Minimal residual disease (MRD) assessment is a strong prognostic factor for relapse and shorter survival in AML patients undergoing intensive induction chemotherapy. Recent studies explored the role of genomic profile of AML influencing clinical outcome. In particular, Papaemmanuil et al showed that mutations in critical genes such as TP53, ASXL1, SRSF2 and RUNX1 are independently associated with a worse prognosis; moreover, co-occurrence of different high-risk mutations are predictors of dismal outcome when conventional chemotherapy is administered. Adverse risk mutations are particularly frequent in s-AML and t-AML. As clinical trials evaluating the prognostic relevance of MRD in the context of different molecular subsets mainly involve younger patients affected by de novo AML and receiving conventional 3+7 chemotherapy, there is a lack of data to define the impact of specific mutations on MRD clearance and prognosis in elderly s- AML and t-AML patients receiving CPX-351 induction. Aims: The aim of this study was to evaluate the prognostic impact of recurrent genic mutations and mutational burden at diagnosis on CR probability, MRD clearance and prognosis in a cohort of elderly s-AML or t-AML patients treated with CPX-351 induction chemotherapy. Methods: The study included 67 elderly patients (>60 year, median age 69, range 60-77) with a diagnosis of s-AML or t-AML according to WHO2016 classification, treated in our Center with CPX-351. Next generation sequencing (NGS) was performed using the Myeloid Solution panel by SOPHiA Genetics, encompassing 34 critical genes mutations. Sample have been processed on a Illumina MiSeq platform and the analysis performed with SOPHiA DDM® Software. MRD was analysed in all patients achieving complete remission (CR) with multicolour flow-cytometry, with a threshold of 0.1%. Results: AML patients were re-classified according to ELN 2022 risk score which was adverse, intermediate and favourable in 35, 29 and 3 patients, respectively. Median number of mutations for single patient (mutational burden) by NGS was 4 (range 2-9). Most frequent mutations involved: RUNX1 (44%), ASXL1 (37%), TP53 (33%), IDH1 (18%), IDH2 (14%), DNMT3A (14%), TET2 (8%). Four patients died before response assessment, mainly due to infections. Fifty-four patients (81%) achieved complete remission (CR) after first induction cycle; MRD evaluation was negative in 28/54 responding patients (52%). Univariate and multivariate analysis showed that factors traditionally associated with poor outcome such as ELN risk group, leukocytosis at diagnosis or previous treatment with hypomethylating agents did not affect the probability of CR rate and MRD negativity. Interestingly, having any high risk mutation, the combination of ≥2 high risk mutations or high mutational burden (having ≥ 4) did not affect CR probability and MRD negativity rate both in univariate and multivariate analysis. After cycle 2, the cumulative CR rate was 56/67 (84%), with 33/56 (59%) responding patients obtaining MFC MRD negativity. After a median follow up of 36 months (CI 95%; 22.4 -48.5 months), median OS was 19 months (CI 95% 13-24), whereas 2 year OS was 24%. Multivariate OS analysis revealed that negative MRD was the strongest independent predictor of longer survival (p<0.05). Notably, OS was not affected by mutational burden (29.2% and 27.6% for patients with less or more than 4 mutations, respectively, p=n.s, Fig.1). In landmark analysis, patients achieving CR and proceeding to allogeneic stem cell transplantation consolidation (HSCT) within 3 months from CR (N=13) had a significantly better outcome if compared to CR patients who did not receive HSCT or proceeded to transplant later (N= 41, 2-year OS: 84.6% and 31.7, respectively, p<0.03, Fig. 2). Conclusion : CPX-351 is able to induce good quality remission with high CR rate and MRD negativity, regardless of mutational burden, allowing a high number of elderly AML patients to undergo to HSCT. MRD evaluation has proven to be a strong prognostic tool also in the setting of elderly s-AML and t-AML patients receiving CPX-351. The prognostic value of high risk mutation seems to be less relevant in CPX-351 treated patients.

Multicenter Study of Mantle Cell Lymphoma Outcomes Following First-Line Bendamustine-Rituximab and Second-Line Bruton's Tyrosine Kinase Inhibitor Therapy

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL and Blast Phase CML in Adults

Introduction:Oral ABL1 kinase inhibitors rapidly produce deep remissions in BCR::ABL1+ acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC). Second generation TKIs such as dasatinib (DAS) are more effective than imatinib (Foa et al. Blood 2011) but patients may develop resistance. Asciminib (ASC), previously ABL001, is a STAMP (Specifically Targeting the ABL Myristoyl Pocket) allosteric ABL1 inhibitor that binds to a site spatially distinct from ATP-competitive TKIs. Combination treatment with an allosteric and an ATP-competitive TKI may deepen clinical responses and limit mutational resistance as supported by a cell line xenograft model of CML (Wylie et al. Nature 2017) and patient-derived xenograft models of BCR::ABL1+ ALL. We hypothesized that dual ABL blockade with catalytic domain and allosteric inhibitors would be tolerable and active in BCR::ABL1+ ALL and CML-LBC. Methods: This investigator initiated, phase I study (NCT03595917) of asciminib (ASC) in combination with DAS plus prednisone (pred) for BCR::ABL1+ ALL studied ASC in escalating doses in a 3+3 design with the primary objective to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D); a 10 patient (pt) expansion cohort was then accrued. Secondary objectives define the depth and durability of responses. Pts with BCR::ABL1+ ALL or CML-LBC newly diagnosed ≥ 50 years (yrs), or unfit; or relapsed/refractory (no prior DAS or ASC) were eligible in dose escalation; all pts ≥18 yrs were eligible in dose expansion. Pts received DAS 140 mg/day(d) and pred 60 mg/m 2/d 1-24 (max 120 mg/d, tapered d 25-32) with escalating daily doses of ASC (DL1: 40 mg; DL2: 80 mg; DL3: 160 mg). DAS and ASC were given in 28-d cycles indefinitely in setting of clinical benefit, with allogeneic stem cell transplant (SCT) consolidation after d85 per treating physician. Dose-limiting toxicity (DLT) was initially defined as CTCAEv4 non-heme toxicity grade (gr) 3+; the study was amended to assess DLT via CTCAEv5. Correlative science efforts seek to define biomarkers of response and resistance to dual ABL1 blockade. Results:The study enrolled 25 pts (48% female), with 14 in dose escalation (13 evaluable), and 11 in expansion (10 evaluable). Most (92%) had new ALL (p190: 15/23, p210: 8/23; 8% had CML-LBC. Median age was 65 yrs (range 33 - 85; 8 pts 70+). Median WBC was 15.1 K/μL (range 0.9 - 251.9 K/μL). No pt had CNS disease. DL1 and DL2 enrolled 3 pts each without DLT. Two of 3 pts at DL3 developed asymptomatic CTCAEv4 gr 3 amylase elevation during C1 meeting original DLT criteria. A 4 th pt enrolled on re-opened DL3 under an amendment defining asymptomatic CTCAEv4 gr 3 amylase/lipase elevations persisting ≤5d to not be a DLT. This pt experienced an asymptomatic CTCAEv4 gr 3 lipase elevation meeting DLT criteria. Thus, the study de-escalated to DL2, re-opening under an amendment assessing DLTs via CTCAEv5. Of note, all DLTs at DL3 would be gr <3 per CTCAEv5. Four more pts (3 evaluable) enrolled at DL2 without a DLT. Thus, ASC 80 mg/d was declared the RP2D, and 11 pts age ≥18 yrs enrolled in an expansion cohort, 10 of whom initiated study treatment. No pt had symptomatic pancreatitis. Rates of molecular response after 3 cycles among all evaluable patients were 58.3% (14/24) for MRD 3.0 and 25.0% (6/24) for MRD 4.0. Evaluable pts with new ALL treated at the RP2D achieved molecular response rates after 3 cycles of 78.6% (11/14) for MRD 3.0 and 42.9% (6/14) for MRD 4.0. Both patients with imatinib-refractory CML-LBC progressed (C9, C3). Of those with ALL, 8 bridged to SCT after 2-8 cycles; 2 elected local care (C5, C7); 1 transitioned to ponatinib for inadequate response plus recurrent DAS pulmonary toxicity (C4); 6 remained on study treatment until disease progression (C4 - MRD+, C45, C11, C11); 3 remain on study. Correlative science evaluation of serial pt biospecimens in pursuit of predictive biomarkers will be shared at the meeting. Conclusion: Dual ABL1 kinase inhibition with ASC and DAS plus pred in BCR::ABL1+ ALL and CML-LBC is feasible and tolerable in adults with BCR::ABL1+ ALL and CML-LBC. DLTs at ASC 160 mg/d were asymptomatic amylase and lipase elevation, without clinical sequelae. ASC 80 mg/day was declared the RP2D, and an expansion cohort of 10 pts was completed. High rates of molecular response and bridging to transplant highlight encouraging preliminary activity. A phase II expansion cohort incorporating blinatumomab is now open.

Blinatumomab with Tyrosine Kinase Inhibitor for Ph-Positive B-Acute Lymphoblastic Leukemia (B-ALL): Multicenter Retrospective Review

Background: Ph-positive B-ALL has long been considered an adverse cytogenetic abnormality in ALL, and it is generally recommended to proceed with a stem cell transplant (SCT) in first remission. Historically, the addition of Tyrosine Kinase Inhibitors (TKI) to the stander chemotherapy backbone improved long-term survival, with better results noted in the second-generation than in first-generation TKIs. Recent reports on a non-chemotherapy-based approach with the combination of immunotherapy (Blinatumomab) and TKI showed encouraging results and potentially eliminated the need for consolidative SCT (Foà NEJM 2020, Jabbour Lancet Haematol 2023). In this retrospective analysis, we reviewed all Ph-positive B-ALL treated with blinatumomab and TKI at two major academic centers. Methods: A retrospective review of adolescents and adults (14 years or older) with Ph-positive B-ALL patients who received blinatumomab with TKI at two major institutions (KFSHRC & KFMC) between 7/2018 and 7/2023. Patients who received up to 3 cycles of chemotherapy before being transitioned to therapy with blinatumomab and TKI were considered as frontline if there was no history of relapsed disease. Relapse/refractory patients with Ph-positive B-ALL treated with blinatumomab and TKI were also included in the R/R cohort, excluding patients with prior single-agent exposure to blinatumomab or ponatinib. Patients with a history of CNS disease were included. Chronic myeloid leukemia in a lymphoid blast phase (LBP-CML) treated with blinatumomab and TKI were also included. Patients were assessed for toxicity as well as for efficacy. Results: We identified 17 patients, with a median age of 40 yrs (range, 15-78): 9 pts (53%) were frontline Ph-positive B-ALL, 5 (29%) pts were relapsed/refractory Ph-positive B-ALL, and 3 (18%) were LBP-CML patients. Pt characteristics and outcomes by cohort are outlined in Table. All patients in all the cohorts achieved complete remission and were included in the RFS analysis [ Figure]. Of 7 evaluable pts in the frontline cohort, all patients achieved complete molecular response (CMR) using PCR for BCR::ABL (CMR=100%). No relapse was documented, with a median follow-up of 6.9 months. In the relapse/refractory cohort, all patients achieved complete molecular response (CMR) using PCR for BCR::ABL (CMR=100%). No relapse was documented, with a median follow-up of 6.7 months. In 3 patients with LBP-CML, two patients achieved complete molecular response (CMR) using PCR for BCR::ABL, and one patient achieved MMR (0.036%). No relapse was documented, with a median follow-up of 19.7 months. Only four patients proceeded to SCT, two with LBP-CML and two with newly diagnosed Ph-positive B-ALL. All patients proceeded with SCT in CMR except one with LBP-CML with positive PCR for BCR::ABL at 0.03%, although with undetectable MRD by flow cytometry (<0.01%). Patients were treated with dasatinib (4 patients) and ponatinib (13 patients). The median number of blinatumomab cycles was 4 (1-5). One death occurred at seven months in a patient treated with dasatinib and blinatumomab. The patient presented to the emergency department with pleural effusion and cardiac tamponade and died during her ICU stay with infectious complication. The death is likely contributed to by dasatinib. Conclusion: Although with short follow-up, combining TKI with blinatumomab seems to have a high complete molecular response rate in patients with newly diagnosed and relapsed/refractory Ph-positive B-ALL. Similar to prior reports, patients with newly diagnosed Ph-positive B-ALL perhaps they could be spared the toxicities associated with chemotherapy and the need for allogeneic hematopoietic stem-cell transplantation in the first remission using this approach. Further evaluation of this novel strategy is warranted.

Optimal Duration of CPX-351 Treatment and Best Timing for Consolidation with Allogeneic Stem Cell Transplantation: Evidence from a Large Real-World Italian Study

Background: CPX-351, has been approved for the treatment of patients diagnosed with Acute Myeloid Leukemia (AML) arising from a previous myelodysplastic syndrome (s-AML) or secondary to chemotherapy (t-AML) as per former WHO 2016 classification, following results from the phase III trial (Lancet et al, JCO2018). Long term results from the trial confirmed that the benefit from CPX-351 over conventional 3+7 induction was maintained both in patients proceeding or not to allogeneic stem cell transplantation consolidation (HSCT). However, the information on the optimal duration of treatment with CPX-351 or the best timing for HSCT consolidation are still incomplete. Furthermore, there is also scarce data on the efficacy of CPX-351 among NPM1 or FLT3-ITD mutated AML or in patient with low risk AML according to European Leukemia Net (ELN) classification, as those subgroups are rare among t-AML and s-AML. Aims: The aim of this study is to analyze the outcome of CPX-351 treatment in a large cohort of patient who received commercially available treatment in Italy since the approval of the drug, in order to identify the optimal duration of treatment, the best timing for HSCT and to evaluate the efficacy among more rare secondary AML subtypes. Methods: 513 elderly (median age 65.6 years, range 19-79) s-AML or t-AML patients who received CPX-351 treatment in 38 Italian Centers since January 2019 were retrospectively included in this study. All patients received CPX-351 as per Italian Drug Authority (AIFA) approval, allowing up to two induction cycles and up to two consolidation. Diagnostic workup was performed as per internal standard in all patients. Eligible patients proceeded to HSCT consolidation as per internal standard of each Center. 108 (21.1%) and 405 (78.9%) patients were diagnosed with t-AML or s-AML, respectively. NPM1 mutation were found in 31 patients (6%), FLT3-ITD mutation was present in 24 patients (4.6%). ELN 2017 score was favorable, intermediate or high in 27 (5.2%), 177 (34.5%) and 309 (60.3%) patients, respectively. Most patients had relevant comorbidities (84%), mainly cardiovascular disease (43%), type II diabetes (39%). After induction 1, 297/513 patients (58%) achieved a complete remission (CR). 72 patients failing to achieve CR received induction 2. After induction 2, CR was achieved in 340/513 patients (66.3%). CR rate was significantly higher among NPM1 mutated patients (p <0.05) and among ELN 2017 favorable risk patients if compared to intermediate or high risk (p<0.05), whereas was not affected by FLT3-ITD mutations. Among responding patients, 118 (34.7%), 137 (40.3%) and 85 (25%) received none, one or two consolidation cycles, respectively. HSCT consolidation in first CR was performed in 166/340 responding patients (48.8%). 30 and 60-days mortality were 5.2 and 8.2%, respectively. After a median follow-up of 23.66 months (CI 95% 23.11 - 26.01), median OS was 16.23 months (CI 95% 13.6 - 18.9). OS was significantly influenced by NPM1 mutational status (p<0.05) and ELN 2017 risk score (p<0.05, Fig. 1A). Of note, NPM1 mutated patients and ELN 2017 low-risk patients showed a very good outcome (Median OS 24.6 months for NPM1 mutated patients and not reached in ELN 2017 favorable risk patients). In a landmark analysis including patients alive and in CR at day 90, HSCT was the strongest predictor of longer survival (Median OS not reached and 16.3 months for patients receiving or not HSCT, respectively, p<0.05). In the same landmark model, completion of all allowed CPX-351 treatment was beneficial only in patients not proceeding to HSCT (median OS 20.36 and 12.2 months in patients receiving 2 or less CPX-351 consolidation without HSCT, respectively, p<0.05, Fig. 1B), whereas in patients receiving HSCT consolidation further CPX-351 treatment after cycle 1 did not improve results (Median OS not reached, 35 and 28.4 months in HSCT patients receiving 0, 1 or 2 CPX-351 consolidations, respectively, p=n.s.) Conclusions: Our large cohort confirms the efficacy of CPX-351 treatment and suggests that CPX-351 may be beneficial also in NPM1 mutated and ELN 2017 favorable risk patients. In eligible patients, HSCT should probably be performed as soon as a CR is achieved, whereas patients not proceeding to HSCT may still have a long survival if two consolidations are administered. In a future perspective, maintenance strategies may further improve the results.

Performance of baseline FDG-PET/CT radiomics for prediction of bone marrow minimal residual disease status in the LyMa-101 trial

The prognostic value of 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) at baseline or the predictive value of minimal residual disease (MRD) detection appear as potential tools to improve mantle cell lymphoma (MCL) patients’ management. The LyMa-101, a phase 2 trial of the LYSA group (ClinicalTrials.gov:NCT02896582) reported induction therapy with obinutuzumab, a CD20 monoclonal antibody. Herein, we investigated the added prognostic value of radiomic features (RF) derived from FDG-PET/CT at diagnosis for MRD value prediction. FDG-PET/CT of 59 MCL patients included in the LyMa-101 trial have been independently, blindly and centrally reviewed. RF were extracted from the disease area with the highest uptake and from the total metabolic tumor volume (TMTV). Two models of machine learning were used to compare several combinations for prediction of MRD before autologous stem cell transplant consolidation (ASCT). Each algorithm was generated with or without constrained feature selections for clinical and laboratory parameters. Both algorithms showed better discrimination performances for negative vs positive MRD in the lesion with the highest uptake than in the TMTV. The constrained use of clinical and biological features showed a clear loss in sensitivity for the prediction of MRD status before ASCT, regardless of the machine learning model. These data plead for the importance of FDG-PET/CT RF compared to clinical and laboratory parameters and also reinforced the previously made hypothesis that the prognosis of the disease in MCL patients is linked to the most aggressive contingent, within the lesion with the highest uptake.

Craniospinal Irradiation for CNS Leukemia: Rates of Response and Durability of CNS Control.

Craniospinal irradiation (CSI) is used in the management of leukemia patients with central-nervous-system (CNS) involvement, though the data on response and local control are limited. Given the radioresponsiveness of leukemia, we hypothesized that response to CSI would be high, but CNS control would be influenced by control of systemic disease. This retrospective, single-institution analysis included consecutive pediatric and adult patients between 2009-2021 with leukemia that underwent CSI for CNS involvement, defined as presence of blasts (i.e., >0%) on CSF flow cytometry. Endpoints included CNS response rate (RR), CNS local recurrence (LR), progression-free survival (PFS), and overall survival (OS), which were estimated from start of CSI. The probability of CNS LR was summarized using a cumulative incidence estimate, where death without LR was considered a competing risk. The probabilities of OS and PFS were obtained using Kaplan-Meier estimates. Among the 39 eligible patients (43% AML, 49% ALL, 8% blast-phase CML), most were male (59%). All had CSF confirmation of disease. Median age at CSI was 31 years (range 7-67). CSI (protons 54%, photons 46%) was utilized early within the CNS disease course (median 0 CNS relapses prior to CSI). Twenty-five patients (64%) received CSI immediately prior to a stem-cell transplant (SCT), of which 21 (84%) had TBI conditioning to a median dose of 12 Gy (range 2-13.2). Patients treated with CSI alone received a higher CSI dose (median 18 Gy; range 10.8-24) than those treated with SCT consolidation (median 12 Gy; range 10.8-24). Fifteen patients had CSF-positive disease immediately prior to CSI; all 14 of those assessed for response (RR 100%) had confirmed clearance of blasts at a median of 23 days (range 7-197) from CSI start. With a median follow-up of 48 months (range 0.4-123) for survivors, 2-year PFS and OS estimates were 32% and 43%, respectively. Only 5 CNS relapses were noted (2-year CNS LR of 14%). All CNS relapses either occurred after (n = 4) or concurrently (n = 1) with a systemic relapse. In Cox regression univariate models, age, sex, time to CNS disease, positive CSF immediately prior to CSI, and SCT did not show demonstrable evidence of association with CNS LR. However, systemic relapse after CSI (HR 5.9, 95% CI 2.5-13.8, P<0.0001) and systemic disease at the time of CSI (HR 3.9, 95% CI 1.6-9.5, P = 0.003) were associated with higher risk of CNS LR. No grade-3+ acute toxicity was seen during CSI. CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Though CNS local recurrence was modest, there was a high risk of systemic relapse and/or death. Control of systemic disease, both before and after CSI, may be important for CNS local control, and raises consideration that CNS recurrence may reflect reseeding from the systemic space.

INFERIOR OUTCOMES WITH POLATUZUMAB VEDOTIN, BENDAMUSTINE AND RITUXIMAB FOR TREATMENT OF RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA AFTER &gt;1 PRIOR LINE OF THERAPY

In the pivotal trial, the addition of polatuzumab vedotin to bendamustine and rituximab (Pola-BR) improved overall survival (OS) for stem cell transplant (SCT)-ineligible patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, the optimal position of Pola-BR in the treatment pathway for patients who receive it as a ‘stand-alone’ treatment, without planned SCT consolidation or CAR T-cell therapy, remains an open question. 71% of patients in the pivotal trial received Pola-BR in 3rd line or beyond but detailed analysis of outcomes by lines of therapy were not presented and published real-world data for this cohort are lacking. We previously reported results of our real-world study of Pola-BR and we now present further analysis of efficacy according to prior treatment exposure. Methods: Retrospective data were collected for consecutive patients treated with Pola-BR at 28 UK hospitals via the UK Regulatory Agency’s Early Access to Medicines Scheme (EAMS) which ran from June 2019 to Jan 2020 prior to marketing authorisation. Patients with R/R LBCL after ≥1 prior treatment were eligible. Treatment was administered according to the marketing authorisation, dose reductions or delays were permitted according to physicians’ discretion. Responses were investigator assessed, time to event was measured from the start of Pola-BR. Results: Pola-BR was administered as stand-alone treatment for 76 of 106 patients who received it via EAMS, treatment intent for the remaining patients was bridge to CAR-T or SCT. Of the stand-alone cohort, 43 received it 2nd line (2L) and 33 at 3rd line or later (≥3L). The median age was 75 years (range 41-88), 71.1% were male. Patients in the ≥3L group were younger and tended to have later stage disease, other characteristics including sex, performance status, IPI and the presence of bulk were well balanced between the groups. 55.8% and 57.6% respectively, were refractory to their last treatment. The objective response rates (ORR) were 73.2% (95% CI 57.1–85.8) and 54.5% (95% CI 36.4%-71.9%) for the 2L and ≥3L groups respectively (p = 0.1). The complete response (CR) rates were 48.8% (32.9–64.9) and 30.3% (15.6-48.7) (p = 0.1). A best response of progressive disease to Pola-BR was found for 22.0% and 36.4% in the 2L and ≥3L groups respectively. The 6-month progression free survival (PFS) rates were 54.2% (95% CI 37.9–67.9) and 35.9% (95% CI 20.1–52.0) for the 2L and ≥3L groups respectively (HR 2.17 (95% CI 1.19–3.95), p = 0.01). The 6-month OS rate was 68.4% (95% CI 51.8–80.4) in the 2L group and 49.2% (95% CI 30.9–65.2) in the ≥3L group (HR 2.15 (95% CI 1.12–4.14), p = 0.02). Longer follow up will be presented. Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies Conflicts of interests pertinent to the abstract W. Osborne Honoraria: Roche R. Auer Honoraria: Beigene C. Burton Honoraria: Roche A. Davies Consultant or advisory role: Celgene, Roche, Gilead, Incyte, Abbvie Honoraria: Celgene, Roche, Gilead, Janssen, Acerta Pharma/AstraZeneca, ADC Therapeutics, Incyte, Abbvie Research funding: Celgene, Roche, Gilead, Janssen, Acerta Pharma/AstraZeneca, ADC Therapeutics, BioInvent Educational grants: Celgene, Roche D. El-Sharkawi Honoraria: Roche Educational grants: Roche C. Fox Consultant or advisory role: Abbvie, AstraZeneca, Atarabio, BMS, GenMab, Gilead/Kite, Incyte, Lilly, Morphosys, Ono, Roche, Takeda Research funding: Beigene Educational grants: Roche, BMS A. Kuhnl Consultant or advisory role: Kite/Gilead, Novartis, BMS Honoraria: Kite/Gilead, Novartis, BMS P. McKay Honoraria: Roche E. Phillips Honoraria: Takeda, Gilead Educational grants: Celgene, Takeda, Janssen W. Townsend Consultant or advisory role: Roche, Takeda, Gilead, Incyte, Honoraria: Roche, Gilead, Incyte Educational grants: Roche, Takeda

Current status of CAR-T cell therapy for pediatric hematologic malignancies

Acute lymphoblastic leukemia (ALL) is the most common cancer in the pediatric population, and the long-term survival can reach 90%. However, approximately, 20% of pediatric ALL patients experience relapse and require second-line chemotherapy. This is frequently followed by hematopoietic stem cell transplantation, which can cause long-term sequelae. Recent advances in immunotherapy, such as monoclonal antibody therapy and chimeric antigen receptor (CAR)-T cell therapy, have revolutionized the treatment of relapsed and refractory ALL. Anti-CD19 CAR-T cells successfully eliminate B cell malignancies such as ALL. Tisagenlecleucel (Kymriah®) is the first CAR-T cell immunotherapy approved by the FDA. CAR-T cell therapy can cause specific adverse events (AEs) such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which are defined and graded according to the consensus grading system and treated with supportive therapies along with tocilizumab and corticosteroids. Other AEs include prolonged bone marrow suppression and hypogammaglobulinemia. Severe AEs are less common in the real-world experience than in clinical trials, probably due to better management of the patient before and during CAR-T cell therapy. The biggest challenge in CAR-T cell therapy against ALL is relapse. A high tumor burden on infusion, early loss of B cell aplasia, and minimal residual disease positivity after CAR-T cell infusion are predictive of relapse. Consolidative stem cell transplantation may improve the long-term outcome. The success of CD19 CAR-T cell therapy against B cell malignancy prompted extensive research into the use of CAR-T cells against other hematologic malignancies such as T cell leukemia or myeloid leukemia.