Acute Lymphoblastic Leukemia Pts Research Articles

A Phase IB/II Study of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (alloBMT) Remission Maintenance

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, transplant-related toxicity and disease relapse limit survival. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates alternative allograft sources. Following PTCy, cellular immune reconstitution is favorable for strategies to augment anti-tumor immunity. Blinatumomab (blina) is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance post-transplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. A study of 21 B ALL pts demonstrated the feasibility of post-transplant blina but did not improve survival when pts universally remained on immunosuppression for at least 1 cycle of treatment (Gaballa. Blood. 2022). We present results of a phase Ib/II trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL in pts off immunosuppression. Methods: Pts ≥1 month-old with high risk CD19+ B ALL or ≥18 years-old with NHL who underwent alloBMT with PTCy were eligible. Pts had to be 60-180 days post-transplant with count recovery and in remission. Pts had to be off immunosuppression for ≥4 weeks prior to treatment, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Pts could receive 2 cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received 1 cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28. Results: The study closed to accrual on January 31, 2023 following enrollment of 42 pts (26 male/16 female) with a median age of 54 (Range 30-73). Among enrolled pts, 19 had Ph-negative B ALL and 23 had B-cell NHL. All pts underwent reduced-intensity conditioning alloBMT using a regimen of fludarabine, cyclophosphamide, and total body irradiation. Median prior lines of therapy were 2 (range 1-6). Additional transplant details are presented in Table 1. All B ALL pts were in an MRD-negative CR by flow cytometry at a sensitivity of 0.01% at alloBMT. All pts received a single cycle of therapy. Pts started blina a median of 137 days post-transplant (range, 90-182). Four pts failed to complete a full cycle due to G4 transaminitis (1), G4 neutropenia (1), relapse (1), and patient preference in the setting of tremors (1). Grade 3 or 4 adverse events felt to be at least possibly related to the study drug included G3 neutropenia (7%), G4 neutropenia (19%), anemia (5%), G3 ALT (5%), G4 AST (2%), G3 AST (2%), and neurotoxicity (7%). Two pts (5%) developed chronic GVHD following blina requiring the resumption of immunosuppression. At a median follow-up of 40 months post-alloBMT, the 3-year relapse-free survival is 73% (95% CI 54-85%) due to a 24% (95% CI 12-39%) incidence of relapse and a 4% (95% CI 0-17%) incidence of non-relapse mortality, as shown in Figure 2. All 3 (100%) relapsed B ALL pts and 2/6 (33%) relapsed B NHL pts presented with CNS involvement. Four pts with CNS relapse (80%) had CNS involvement prior to alloBMT. Among 2 pts who died without relapse, 1 was unrelated to alloBMT, while the other died of therapy-related myeloid neoplasm. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented. Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity in pts off immunosuppression. Initial survival outcomes are promising with the majority of relapses involving the CNS. A randomized trial of maintenance with blina after alloBMT with PTCy is needed to confirm efficacy in this high-risk population.

Achievement of Undetectable BCR::ABL1 (uBCR::ABL1) Is Predictive of Improved Survival in Philadelphia Chromosome Positive (Ph+ve) Acute Lymphoblastic Leukemia (ALL) Patients Not Receiving Allogeneic Stem Cell Transplantation

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.

Venous Thromboembolism in Adolescents and Young Adults with Acute Lymphoblastic Leukemia Treated on a Pediatric-Inspired Regimen

Introduction Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) can be effectively treated with pediatric-inspired ALL regimens which incorporate asparaginase (ASP). Asparaginase is associated with increased venous thromboembolic (VTE) complications. We examined the incidence of and risk factors for VTE events as well as the impact of VTE events on outcomes of AYA pts treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocols. Methods We identified pts aged 15-50 years diagnosed with Philadelphia chromosome negative (Ph-neg) ALL treated on 4 multicenter DFCI Consortium protocols (Pediatric 00-001, Pediatric 05-001, Adult 01-175, and Adult 06-254), or treated as per these protocols between 2000-2021. All regimens included an ASP containing induction, 30 weeks of continuous ASP exposure during consolidation and a continuation phase without ASP. The use of a pegylated vs non-pegylated ASP formulation varied between protocols. As ASP exposure is associated with both VTE and survival, it may confound the association between VTE and survival; thus, to ameliorate confounding, all survival associated outcomes were conducted on pts who remained on protocol for at least 1 year (encompassing ASP exposure). Overall survival (OS) and event free survival (EFS) were presented with Kaplan Meier curves and comparisons were made by the log-rank test. Cumulative incidence of VTE, relapse (CIR) and non-relapse mortality (NRM) were estimated by the cumulative incidence method with the appropriate competing risks, and comparisons were made by the Gray test. Cox regression analysis was fit to evaluate the effect of covariates on OS and EFS. Results Among 341 Ph-neg AYA ALL pts aged 15-50 years, 109 (32%) experienced one or more VTE events. The baseline characteristics did not differ between pts who experienced a VTE and those who did not experience a VTE, except for a higher rate of VTE among overweight/obese pts (BMI≥25 kg/m 2, n=56, 38%) vs normal BMI (n=53, 27%, p=0.04) and a lower rate of VTE in patients with hyperdiploid vs non-hyperdiploid karyotype (n=4, 12% vs n=105, 34%, p<0.01). Of the 109 pts with VTE, 9 (8%) experienced sinus vein thrombosis (2.6% in the overall cohort) and 19 (17%) experienced at least one additional VTE. Most initial VTE events occurred during consolidation (n=78, 72%), followed by induction (n=22, 20%), and continuation/follow-up (n=9, 8%). The 2-yr cumulative incidence of VTE was 32% (95% CI, 27%-37%) and was similar between patients who were treated with non-pegylated ASP vs. pegylated ASP (n=43, 30% vs n=65, 35%, p=0.35). The 2-yr cumulative incidence of VTE was higher in the BMI ≥ 25 kg/m 2 group compared to those with normal BMI (38% vs 28%, p=0.035, Figure 1) and was the only covariate associated with increased VTE risk in the univariate regression model (HR 1.49, 95% CI, 1.03-2.17). Among pts who completed ≥ 1 year of protocol therapy (n=220), the 4-year OS was 92%, and did not differ between pts who experienced VTE vs. not (94% vs 90%, p=0.99, Figure 2). Similarly, there were no differences in 4-year CIR (14% vs 11%, p=0.50), NRM (0% vs 3%, p=0.37), and EFS (86% vs 86%, p=0.79). In univariate analysis for OS, obese BMI (>30 kg/m 2), higher WBC, B-cell immunophenotype, and fewer weeks on ASP therapy were associated with worse OS; all remained predictive in the multivariable model. In the uni- and multivariable analysis for EFS, higher WBC and B-cell immunophenotype were associated with worse EFS. Notably, VTE was not associated with worse OS or EFS in all regression analyses. Conclusion Among AYAs treated on DFCI ALL Consortium protocols, VTE events were frequent, occurred mostly during consolidation phase and were more common among pts with overweight/obese BMI vs normal BMI. Sinus vein thrombosis was rare. VTE incidence did not impact CIR, NRM, EFS or OS, suggesting that VTE is a manageable toxicity.

Adverse events during chimeric antigen receptor T-cell (CAR-T) therapy for hematologic malignancies (HM): Real-world, US patient experience.

e18891 Background: CAR-T therapy represents the most significant advancement in the treatment of HM in the past 5 years. Life-threatening complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may occur leading to significant morbidity and mortality. We aimed to describes the frequency of CRS and ICANS and the time to onset of each post CAR-T therapy administration in real-world, U.S. patients. Methods: Patients (pts) with HM who received any FDA-approved CAR-T therapy were identified from a U.S. EMR database containing de-identified healthcare data for > 40M patients from > 500 hospitals and 30 healthcare systems (including academic centers). Confirmation of CAR-t treatment was based on ≥1 procedure code for general administration of CAR-T therapy (e.g., XW033C3, introduction of engineered autologous chimeric antigen receptor t-cell immunotherapy into peripheral vein) or a specific approved CAR-T (I.e., XW033K7, introduction of idecabtagene vicleucel immunotherapy into peripheral vein) between 2017 and 2022. Diagnosis of CRS or any ICAN was based ≥1 related ICD-10 diagnosis code (e.g., CRS = D89.83X). Frequency of occurrence of CRS, symptoms of CRS, ICANS symptoms, and severity of CRS or ICANS is described (severity based on validated clinical algorithm). Time to CRS and ICANS was calculated as the interval from CAR-T administration to first reported diagnosis, respectively. Results: 212 pts met the study criteria including 77 b-cell lymphoma, 64 multiple myeloma, 47 follicular lymphoma, 13 mantle cell lymphoma and 11 acute lymphoblastic leukemia pts. The majority were male (54.7%); median age was 60 years. Overall, 100 (47.2%) pts were diagnosed with CRS (any grade) while 82 (38.7%) pts experienced any ICAN symptoms. The top three CRS symptoms were fever (57.5%), hypotension (31.1%) and tachycardia (21.2%). The top three ICANS symptoms were obtundation (18.4%), confusion (12.7%), and delirium (12.7%). Of CRS pts, 25.0% experienced severe symptoms, including renal insufficiency (10.0%), atrial fibrillation (9.0%), ventricular tachycardia (7.0%), and cardiac failure (2.0%). The median time to development of CRS was 2 days (range 0-23 days). Of pts. experiencing ICANS, 72.0% experienced any mild symptom and 53.7% experienced any severe symptom, including obtundation (47.6%), aphasia (13.4%), and seizures (1.2%). The median time to development of ICANS post CAR-T therapy was 6 days (range 0-26 days). Conclusions: Our study is the first real-world, U.S. evaluation of the frequency and time to toxicities associated with CAR-t therapy across multiple hematologic malignancies. While well-described in RCTs these data highlight the need for the continued development of clinical and therapeutic approaches to minimize their impact on the effectiveness of CAR-T.

Mini-hyper-CVD with venetoclax (Ven) for patients with relapsed/refractory (R/R) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL): A phase II study.

e19039 Background: In preclinical studies, Ven has shown promising clinical activity in patients (pts) with R/R ALL. The combination of Ven with low intensity mini-HCVD chemotherapy could improve outcomes in ALL pts. Methods: Pts ≥18 years with R/R Ph-negative B- or T-cell ALL received mini-HCVD alternating with methotrexate and cytarabine for up to 8 cycles. Ven was given at a dose of 400 mg/d on Days (D) 1-14 of Cycle (C) 1 and on D1-7 of C2-8. Rituximab (if CD20+ B-ALL) and prophylactic IT chemotherapy x8 doses were given for the first 4 cycles. Pts with T-ALL received additional 2 cycles of nelarabine and peg-asparaginase during consolidation without Ven, and 2 cycles during maintenance. Maintenance with vincristine, prednisone and Ven was given for up to 2 years. Results: Between 6/2019 and 2/2021, 23 pts were treated, with a median age of 45 years (range, 20-70). 18 (78%) pts had B-ALL and 5 (22%) T-ALL, including 1 pt with ETP ALL. Among the 23 pts, the median number of prior therapies was 2 (range, 1-6) and 13 (57%) had undergone prior allogeneic stem cell transplant (ASCT). Among the 18 B-ALL pts, 16 (89%) had received prior blinatumomab and 7 (39%) prior inotuzumab. Among 23 pts, 1 was in CR at enrollment. Overall, 12 of 22 (55%) pts responded to therapy (complete response, n=9), of whom 9 achieved best response after C1 and 3 after C2. An additional pt achieved partial response. The overall response rate among the 18 pts who had at least a bone marrow assessment after C1 was 67%. The median duration of follow-up was 26 months (range, 2-35). Among the 13 responders (including the pt in CR at start), 6 (46%) relapsed, 5 (39%) underwent ASCT (4 subsequently relapsed), and 2 (15%) died in remission. The median RFS and OS were 6.4 and 8.1 months, respectively, and the 1-year RFS and OS rates were 15% and 37%, respectively. Survival was worse in pts with adverse cytogenetics versus others (median OS, 6 vs 12 months; 1-yr OS rate, 17% vs 44%; P=0.15). In C1, the median time to platelet recovery was 27 days (range, 0-81) and neutrophil recovery was 21 days (range, 0-36); in C2+, median times to recovery were 25 days (range, 0-76) and 15 days (range, 0-26), respectively. The 30-day and 60-day mortality rates were 0% and 13%, respectively. Conclusions: The combination of low-intensity chemotherapy mini-HCVD with Ven in pts with R/R Ph-negative ALL was well-tolerated and resulted in a response rate of 67%. Further studies examining the role of Ven-based therapies in ALL are needed for newly diagnosed and R/R pts. Clinical trial information: NCT03808610 . [Table: see text]

First report of PhALLCON: A phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

398868 Background: The standard of care in patients (pts) with newly diagnosed (dx) Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy (chemo) or steroids. Treated with 1st- or 2nd-generation TKIs, pts eventually progress due to emergence of resistance. Multiple studies have reported promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with pon in combination with chemo or chemo-free regimens. PhALLCON (NCT03589326), the first randomized study comparing TKIs in pts with Ph+ALL, evaluates pon vs im in combination with reduced-intensity chemo. Methods: This phase 3 open-label trial randomized adult newly dx Ph+ALL pts 2:1 to receive pon (30 mg once daily [QD]) or im (600 mg QD) with reduced-intensity chemo through end of induction (EOI; Cycles 1–3), consolidation (Cycles 4–9), and post-consolidation (Cycles 10–20). After Cycle 20, pts received single-agent pon or im until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% ) complete remission (CR) for 4 weeks at EOI. Event-free survival (EFS: any cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. Results: 245 pts were randomized to pon (n=164) or im (n=81); median age was 54 y (37% ≥60 y). At data cutoff (Aug 2022), 78 pts (pon vs im: 42% vs 12%) were on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (31% vs 37%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). Median follow-up was 20 mo vs 18 mo (pon vs im). The primary endpoint was met (Table) by significantly higher MRD-neg CR rate for pon vs im (34.4% vs 16.7%; p=0.0021). Survival data were not mature; however, the median EFS was reached in im and not in pon, with a trend toward improvement (HR=0.652, 95% CI 0.385–1.104). Time to treatment failure reported an improvement as well (HR=0.455). The treatment-emergent adverse event (TEAE) rates (any grade [Gr] and Gr3/4/5) were comparable between treatment arms. Arterial occlusive events (AOEs) were infrequent and similar between the arms (Table). Conclusions: Pon was superior to im in combination with reduced-intensity chemo in pts with newly dx Ph+ALL, with a significantly higher MRD-neg CR rate at the EOI. Pon was associated with deeper and more durable responses, with a trend toward improved EFS and comparable safety vs im. Clinical trial information: NCT03589326 . [Table: see text]

The First Report of Third-Generation TKI Olverembatinib in Adult Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia with T315I Mutation and Relapsed Disease

Background Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients(pts) with Ph/BCR-ABL1-positive (Ph/BCR-ABL1+) acute lymphoblastic leukemia (ALL). However, mutations in the ABL1 kinase domain, especially T315I, are the main mechanism of resistance to the first- or second-generation TKIs. Olverembatinib is a novel third-generation TKI developed in China and approved in Dec. 2021, which has been demonstrated great efficacy and safety in clinical trials of CML with T315I mutation. Our study is the first application of Olverembatinib in adult Ph/BCR-ABL1+ ALL with T315I mutation. Herein, we report the preliminary results. Methods In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40 mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone) in our institution. Efficacy was assessed by complete remission (CR) rate, MRDneg (<0.01%) rate by multiparameter flow cytometry (MFC) and CMR (BCR-ABL1 transcript<10-5) rate by real-time quantitative polymerase chain reaction (RT-qPCR). Safety profiles were also monitored in this study. Results From December 2021 to June 2022, 10 Ph/BCR-ABL1+ ALL pts were treated with olverembatinib due to T315I mutation or disease recurrence, after prior TKIs combined with chemotherapy. Median age was 60.5 years (range, 37-65), and 6/10 were males. 5 pts had received 2 types of TKIs previously, of which 2 pts relapsed after ponatinib (Table 1). Among 10 pts, 6 were still in CR1 (pt 1-6), their T315I mutations were detected during regular follow-up. 4/6 pts were persistently molecular positive, while the other 2 had molecular relapse. Median time from diagnosis to the administration of olverembatinib was 5 months (range, 3-17). Among the 4 pts with hematologic relapse (pt 7-10), 2 (pt 7, 8) had T315I mutation. Because of the successive occurrence of G250E, Y253H, L248V mutations and L248 K274del, the 3rd one (pt 9) relapsed twice and failed to response to two kinds of TKIs and chemotherapy. As for the last pt (pt 10), although no ABL1 mutations were found, she was in 3rd relapse with CNS and BM involvement. Median time from diagnosis to the start of olverembatinib for these 4 relapsed pts was 28 months (range, 5-41). Among 6 pts with T315I mutation and persistent molecular diseases or molecular relapse, the CMR rate was 66.7%, with a median time of 3 months (range, 1-4) to achieve CMR. Then 2 pts underwent allo-HSCT (pt3, 4), who were still in CR. Among 4 hematological relapsed pts, the CR rate was 75%. 1 pt (pt8) with T315I was unresponsive, while another T315I positive patient achieved MRDneg by MFC after 1 month of treatment, with a complete disappearance of T315I mutation (pt7), though the BCR-ABL1 transcript was still positive. The remaining 2 relapsed pts without T315I mutation achieved hematologic CR after 1 month of olverembatinib monotherapy (pt9,10). Totally, overall response rate (ORR) was 70% and MRDneg rate by MFC was 71.4% (5/7), while the CMR rate by PCR was 57.1% (4/7). Notably, olverembatinib was ineffective in neither of the 2 pts who have been previously treated by ponatinib. Meanwhile, the olverembatinib-based therapy was well-tolerated, and the main adverse events of the third-generation TKIs, such as cytopenia, elevated transaminases, hypertension, and cardiovascular events, were less frequent than those reported relating to ponatinib. In addition, 4 patients developed grade 1 skin pigmentation (pt2,3,6,9). There were no drug-related death or permanent discontinuation due to toxicity. Conclusion This work suggests that Olverembatinib is a very promising 3rd-generation TKI. It is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with extremely poor prognosis, especially in T315I mutated or relapsed pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract CT027: Exploration of association of leukemic molecular profile with efficacy in patients (pts) with relapsed/refractory acute lymphoblastic leukemia (ALL) treated with inotuzumab ozogamicin (InO) in the phase 3 INO-VATE trial

Abstract Background: INO-VATE (NCT01564784) demonstrated higher rates of remission, MRD-negativity, and improved overall survival (hazard ratio 0.75, one-sided P=0.01) for pts with R/R ALL who received InO vs standard chemotherapy (SC). Here we explore the potential association between leukemic molecular profiles and efficacy of InO. Methods: Pts with CD22+ ALL due to receive salvage treatment were randomized to InO or SC; clinical methods and results were published previously (Kantarjian HM, et al. N Engl J Med 2016; PMID: 27292104). Bone marrow samples collected at screening post protocol amendment 2 underwent RNA-sequencing with analysis of gene expression profile, fusions, and genomic alterations. Data cutoff: Jan 4, 2017. Results: Of 326 pts in the INO-VATE intent-to-treat (ITT) population, 91 (InO, 43; SC, 48) had samples evaluable for molecular profiling. Baseline characteristics were similar in the evaluable pts vs the ITT population. Most common (≥5%) ALL subtypes were BCR-ABL1-positive (14%), low hypodiploidy (12%), Philadelphia chromosome (Ph)-like (11%), KMT2A-rearranged (9%), and DUX4-rearranged (6%); 29% (26/91) of pts could not be subtyped due to low blast counts. Most common (≥5%) non-BCR-ABL1 oncogenic fusions detected were IGH-CRLF2 (8%), and KMT2A-AFF1 (6%). Among non-fusion genomic alterations, those involving chromatin modifying genes featured prominently (e.g. KMT2D, 18%; CREBBP, 12%; KMT2C, 11%; ARID2, 9%; ARID1A, 8%; SET2D, 7%; EP300, 6%). Other commonly altered (≥9%) genes included TP53 (14%), NOTCH1 (11%), KRAS (9%), and PAX5 (9%). Similar to the overall findings of INO-VATE, complete remission (CR)/CR with incomplete count recovery (CRi) rates were numerically higher with InO vs SC across ALL subtypes, including but not limited to, low hypodiploidy (67% [2/3] vs 13% [1/8], P=0.15), Ph-like (83% [5/6] vs 0% [0/4], P=0.02), and KMT2A (100% [2/2] vs 17% [1/6], P=0.11), although not in BCR-ABL1-positive (67% [4/6] vs 57% [4/7], P=0.59). Within pts bearing common non-BCR-ABL1 oncogenic fusions, CR/CRi was seen for InO including for IGH-CRLF2 (50% [1/2] vs 20% [1/5] for SC), KMT2A-AFF1 (100% [1/1] vs 25% [1/4] for SC), and IGH-DUX4 (100% [3/3] vs 0% [0/1] for SC). Consistent with a previous report (Yang X, et al. Blood 2019; 134 [Suppl 1]: 3888) CR/CRi rates were high for InO in pts with TP53 alterations (100% [5/5] vs 13% [1/8] for SC, P=0.0047). Conclusions: This retrospective, exploratory analysis of INO-VATE demonstrated potential for benefit with InO for ALL pts across leukemic subtypes, including Ph-like, and for those bearing diverse fusions. Further exploration of Ph-like subtype or TP53 alterations as candidate predictive biomarkers for InO in pts with R/R ALL is warranted. Citation Format: Yaqi Zhao, A Douglas Laird, Kathryn Roberts, Rolla Yafawi, Hagop Kantarjian, Daniel J. DeAngelo, Matthias Stelljes, Michaela Liedtke, Wendy Stock, Nicola Gökbuget, Susan O'Brien, Elias Jabbour, Ryan D. Cassaday, Melanie R. Loyd, Scott Olsen, Geoffrey Neale, Xueli Liu, Erik Vandendries, Charles G. Mullighan, Anjali Advani. Exploration of association of leukemic molecular profile with efficacy in patients (pts) with relapsed/refractory acute lymphoblastic leukemia (ALL) treated with inotuzumab ozogamicin (InO) in the phase 3 INO-VATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT027.

Efficacy and safety of daratumumab (DARA) in pediatric and young adult patients (pts) with relapsed/refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL): Results from the phase 2 DELPHINUS study.

10001 Background: Approximately 15-20% of pediatric pts with ALL or LL will be refractory to/relapse after frontline treatment; relapsed disease is associated with poor outcomes. In a phase 2 study, 2 of 7 (28.6%) pts with T-cell ALL in first relapse achieved a complete response (CR) using the vincristine, prednisone, PEG-asparaginase, and doxorubicin (VPLD) reinduction backbone. DARA, a human IgGκ monoclonal antibody targeting CD38 approved for treating multiple myeloma, has shown preclinical efficacy in ALL models. We report the initial results of DARA plus VPLD in pediatric and young adult pts with relapsed/refractory T-cell ALL or LL enrolled in the phase 2, open-label DELPHINUS study. Methods: Eligible pts were aged 1-30 y, had T-cell ALL or LL in first relapse or refractory to 1 prior induction/consolidation regimen, and had a performance status ≥70. DARA (16 mg/kg IV QW) was given with VPLD in Cycle 1 and with methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine in Cycle 2. Pts received age/risk-adjusted intrathecal therapy. Response was measured at the end of each cycle by local bone marrow morphology. The primary endpoint for ALL pts was CR rate in pediatric pts at the end of Cycle 1. Pts achieving CR after Cycles 1 or 2 could proceed to allogeneic HSCT off study. Overall response rate (ORR) was defined as CR or CR with incomplete hematological recovery (CRi) at any time before start of subsequent therapy or HSCT. Minimal residual disease (MRD) negativity (&lt; 0.01%) at any time before disease progression, start of subsequent therapy, or HSCT was centrally reviewed by flow cytometry. Results: Twenty-four pediatric (age 1-17 y) and 5 young adult (age 18-30 y) ALL pts and 10 LL pts (age 1-30 y) received ≥1 DARA dose. Median (range) age was 10.0 (2-25) y (ALL) and 14.5 (5-22) y (LL); median (range) time from initial diagnosis to first study treatment was 2.0 (0.1-6.1) y (ALL) and 0.8 (0.5-6.0) y (LL). Pediatric ALL pts received a median (range) of 2 (1-3) treatment cycles; young adult ALL pts and LL pts each received 2 (1-2). Among pediatric ALL pts, 10 (41.7%) pts (90% CI, 24.6-60.3) achieved CR at the end of Cycle 1. ORR was 83.3% (CR, 13 [54.2%] pts; CRi, 7 [29.2%] pts) in pediatric and 60.0% (all CR) in young adult ALL pts and 40.0% (all CR) in LL pts. Ten (41.7%) pediatric ALL pts achieved MRD negativity. All pediatric ALL pts had a grade 3/4 TEAE. No pediatric ALL pt discontinued DARA primarily due to AEs and 1 (4.2%) died due to TEAEs (brain edema and hepatic failure) attributed to study treatment but unrelated to DARA. Conclusions: The addition of DARA to VPLD in pediatric and young adult pts with relapsed/refractory T-cell ALL or LL showed initial activity, generating improved response rates compared to those achieved with backbone therapy alone, with a manageable safety profile. Clinical trial information: NCT03384654.

Isatuximab in Combination with Chemotherapy in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia (ISAKIDS): Interim Analysis

Introduction: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, representing ~25% of cancer diagnoses in children. Approximately 20% of childhood leukemias are of myeloid origin with the majority being acute. Isatuximab (Isa) is a monoclonal antibody that binds to a specific epitope of CD38 and exerts anti-multiple myeloma (MM) effects through several modes of action. Isa is approved for use in MM in adults. CD38 expression is high in some acute leukemia subsets in pediatric patients, making CD38 a potential target for acute leukemia treatment in children.Methods: ISAKIDS (NCT03860844) is a Phase 2, single-arm, multicenter, open-label study evaluating the antitumor activity, safety, and pharmacokinetics (PK) of Isa in combination with standard salvage chemotherapies in children with relapsed or refractory (R/R) leukemia in first or second relapse; including both T-ALL and B-ALL and acute myeloid leukemia (AML), conducted in 3 separate cohorts. Children from 2 years (yrs) to <18 yrs of age were eligible for inclusion. In all cohorts, participants received 20 mg/kg Isa as a single agent on Day 1 and then weekly for 5 weeks in the ALL groups or weekly for 3 weeks in the AML groups. Combination chemotherapy was added on Day 8 (modified UKALL R3 and fludarabine, cytarabine, G-CSF induction for ALL and AML patients (pts), respectively) unless it was judged necessary to start chemotherapy earlier than Day 8. The primary endpoint was complete response (CR) rate, defined as the proportion of pts with CR or CR with incomplete peripheral recovery (CRi). Secondary endpoints included duration of response, event-free survival, overall survival, and overall response rate. CD38 receptor density was assessed at baseline and CD38 occupancy was assessed at Day 15. Descriptive statistics were carried out on the evaluable population. Confidence intervals were computed using the Clopper-Pearson method. For this first interim analysis, PK parameters for Isa were assessed in the first 20 pts to confirm Isa dose and schedule in very young pts. Safety analyses included treatment-emergent adverse events (TEAEs) of all grades.Results: 24 pts were enrolled (10, B-ALL; 7, T-ALL; 7, AML) and treated. Baseline characteristics were comparable between cohorts; median age (range) B-ALL 6.5 (3-14) yrs; T-ALL 10.0 (7-16) yrs; AML 7.0 (2-17) yrs. Males (4/10 B-ALL; 6/7 T-ALL; 3/7 AML). Evaluable Lansky scores of 90 - 100 (9/10 B-ALL; 3/4 T-ALL; 4/6 AML). Mean (standard deviation) time from initial diagnosis to first dose of investigational medicinal product (IMP) was 2.6 (1.0) yrs, 1.2 (0.6) yrs, and 1.0 (0.3) yrs for the B-ALL, T-ALL, and AML groups, respectively. Number of prior regimens, median (range) was 6 (1-≥8), 3 (1-≥8), 4 (1-≥8) for the B-ALL, T-ALL, and AML groups, respectively, corresponding to inclusion of pts with very advanced disease. Three pts presented with hyperleukocytosis >20 x 10 9/L. Among 23 pts assessed for CD38 expression, all except 2 (1 B-ALL and 1 AML) were CD38 positive. There were 17 evaluable pts with valid response data collected up to the cutoff date (May 11, 2021). Of the evaluable participants, CR+CRi were observed for: 3/7 (42.9%) in the B-ALL cohort, 2/6 (33.3%) in the T-ALL cohort, and 2/4 (50.0%) in the AML cohort (Table). Safety data showed that Grade ≥3 TEAEs occurred in 17 pts (Table). Infusion reactions (majority Grade 1 or 2) occurred in 9/24 pts (2/10 B-ALL; 4/7 T-ALL; 3/7 AML). Three pts had Grade 5 TEAEs (deaths: 1 B-ALL and 2 AML). One subject in the AML cohort had cytokine-release syndrome (CRS) related to IMP with progressive disease as a confounding factor. The other 2 deaths were not treatment related. One subject in the AML cohort had cellulitis Grade 5 and 1 subject in the B-ALL cohort had septic shock Grade 5 as cause of death. Preliminary PK analysis on 18 pts (>2 yrs) showed that Isa PK parameters including exposure PK parameters in children with ALL or AML are consistent with those observed in adult ALL pts. PK modeling approaches predict a slightly lower exposure (<20%) in pts <2 yrs old (4-12 kg) compared with exposure achieved in adults (51-100 kg) at the same dose.Conclusions: In a poor prognostic relapsed population, 7/17 (41.2%) pts achieved CR+CRi. Safety profile and exposure is consistent with the available data for adults. Enrollment will be opened for pts <2 yrs of age with R/R ALL or AML. [Display omitted] DisclosuresBaruchel: Kite/Gilead: Other: Investigator; Novartis, Servier, Celgene, Jazz, Janssen, Sanofi, Amgen,Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: Satellite symposium; Shire Servier: Research Funding. Abrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Nysom: Bayer, Y-mAbs, EUSA Pharma: Consultancy, Honoraria. Rizzari: Sobi: Other: personal fees; Jazz Pharmaceuticals: Other: Personal fees; Amgen: Other: Personal fees; Medac: Other: Grants and personal fees; Shire: Other: Grants and personal fees. Cesaro: Sobi: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Duarte: Amgen: Consultancy, Other: Advisory Board; Novartis: Consultancy; Jazz Pharma: Research Funding. Kang: Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kattamis: Agios Pharmaceuticals: Consultancy; IONIS: Consultancy; VIFOR: Consultancy; CRISPR/Vertex: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Tøndel: Sanofi: Research Funding. Ivanina: Sanofi: Current Employment. Brillac: Sanofi: Current Employment. Wang: Sanofi: Current Employment. Oprea: Sanofi: Current Employment, Other: may have stock options . Abbadessa: Sanofi: Current Employment. Zwaan: Sanofi: Consultancy.

Phase 2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

In children with relapsed ALL, salvage options are sub-optimal and relapse remains the leading cause of death. Achieving subsequent complete remission (CR) after relapse is a critical first step to cure, without which, survival is unlikely. A phase 1b trial evaluating carfilzomib combined with VXLD (vincristine, dexamethasone, PEG-asparaginase, daunorubicin) in children with relapsed ALL showed preliminary safety and efficacy in highly advanced pediatric ALL (Burke, ASH 2019). The phase 1b portion of this trial was recently completed and a recommended phase 2 dose determined. Patients (pts) were heterogeneous with respect to number of relapses (>1, n = 7), refractory relapse (n = 7), prior stem cell transplant (n = 8) and duration of first remission (<18 mo, n = 15), or none of these risk factors (n = 3). CR with incomplete hematologic recovery or better occurred in 50% overall after 1 cycle of induction (9 of 13 [69%] with B-ALL; 3 of 11 [27%] with T-ALL) and increased to 58% after consolidation (B-ALL, 9 of 13 [69%]; T-ALL, 5 of 11 [45%]). Herein, we describe the design of the phase 2 study (NCT02303821) which is currently enrolling.This multicenter (~120 sites) phase 2 trial is designed to evaluate the efficacy and safety of carfilzomib in combination with VXLD re-induction when compared with an external control arm in children with relapsed ALL. Eligible pts include those aged ≥1 mo to 21 y originally diagnosed before age 18 with T- or B-cell ALL with bone marrow relapse (≥5% leukemic blasts) or refractory relapse with or without extramedullary disease. Pts with B-cell ALL must have received prior therapy with a targeted B-cell immune agent (blinatumomab, inotuzumab, chimeric antigen receptor T cell [CAR-T] therapy). Major exclusion criteria include prior treatment with carfilzomib or other proteasome inhibitor within <3 mo of enrollment, use of VXLD or similar regimen within 2 mo of enrollment, or allogeneic hematopoietic stem cell transplantation within 3 mo of enrollment.Pts receive a 28-day cycle of induction therapy. Pts aged >12 mo not progressing may go on to receive an optional cycle of modified Berlin-Frankfurt-Munster consolidation therapy. Carfilzomib will be administered at 20 mg/m 2 on day 1 followed by 56 mg/m 2 on days 2, 8, 9, 15, and 16 of re-induction and 56 mg/m 2 on days 1, 2, 8, 9, 15, and 16 of consolidation. For pts aged ≥12 mo, VXLD re-induction includes vincristine 1.5 mg/m 2 per dose on days 1, 8, 15, and 22, daunorubicin 60 mg/m 2 per dose IV on day 2, PEG-asparaginase 2500 U/m 2 per dose IV on days 4 and 18, and dexamethasone 3 mg/m 2 per dose twice daily on days 1-21. Pts <12 mo receive a modified induction and optional consolidation regimen based on the Interfant-06 chemotherapy backbone. All pts receive intrathecal therapy based on CNS status at time of enrollment. Alternate anthracycline and asparaginase agents may be substituted as part of VXLD per country availability and local practice. Investigators may delete anthracycline therapy based on specified pt risk factors.The primary objective is to compare the CR rate of carfilzomib-VXLD after 1 cycle of re-induction to an appropriate control arm receiving standard of care re-induction chemotherapy. A minimum of 100 pts with R/R ALL are planned to be treated (T-cell, ~60; B-cell, ~40) in order to provide ≥70% power for showing superiority with a 95% CI for odds ratio that excludes 1 at a 2-sided significance level of 0.05. Analyses will be done separately for pts with T-cell and B-cell ALL. The control arm data will be collected by detailed retrospective chart abstraction at participating centers from the Therapeutic Advances for Childhood Leukemia/Lymphoma consortium for a minimum of 150 B-cell ALL and 70 T-cell ALL pts who fulfil the inclusion/exclusion criteria for the phase 2 trial. These pt data are collected as part of a larger retrospective observational study and do not require pt consent. Secondary objectives include evaluation of safety; CR after consolidation; CR without platelet recovery, CR with partial hematologic recovery, and CR with incomplete hematologic recovery at the end of induction therapy and after consolidation therapy, respectively; minimal residual disease; event free and overall survival; duration of response; proportion of pts able to proceed to stem cell transplant or CAR-T therapy; and pharmacokinetic parameters.This phase 2 trial is currently enrolling pts globally. DisclosuresZiegler: Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Gore: Roche/Genentech: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Anchiano: Current equity holder in publicly-traded company; Blueprint Medicines: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Clovis: Current equity holder in publicly-traded company; Mirati: Current equity holder in publicly-traded company; Sanofi Paris: Current equity holder in publicly-traded company. Locatelli: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Miltenyl: Honoraria. O'Brien: Pfizer: Honoraria, Research Funding; Jazz: Honoraria. Kim: Amgen: Current Employment, Current equity holder in publicly-traded company. Obreja: Amgen: Current Employment, Current equity holder in publicly-traded company. Morris: Amgen: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure:Carfilzomib is approved in the United States for the treatment of adult patients with relapsed or refractory multiple myeloma. It has not been approved for use in pediatric patients with ALL.

Prognostic Impact of Pregnancy on Long-Term Outcome in Acute Leukemias Patients

BackgroundAcute leukemia (AL) during pregnancy - is a rare clinical condition that limits the possibility to conduct large prospective clinical studies. All publications present small retrospective data and case reports. Most of them conclude that pregnancy doesn't affect the prognosis of AL.AimTo assess the pregnancy, as independent prognostic factor, in AL-patients (pts), prospectively treated within Russian AL multicenter studies.MethodsFrom 1990 to 2017 the Russian AL-study group has treated 73 pregnant women with de novo AL 18-42 yrs (Me-27y): acute myeloid leukemia (AML) - 35, acute lymphoblastic leukemia (ALL)- 27 and acute promyelocytic leukemia (APL) - 11. AL was diagnosed at the different gestation age with 89% - in the IInd-IIIrd trimesters.In 8 pts at the 1st trimester medical abortion was conducted. 17 pts delivered at the 34-40 weeks before chemotherapy (CT) and 48 (66%) pregnant women received CT, that was started at 23 (14-32) weeks of gestation.Pregnancy was not an exclusion criteria for standard AL-treatment approach. APL-pts were treated by 7+3 (Dauno 60 mg/m2)+ATRA or AIDA-protocol. ALL-pts were included in the Multicenter ALL-2009 trial (NCT01193933). In AML pts standard 7+3 was applied: either with Dauno 45-60 mg/m2 (NCT01587430), or Mito10 mg/m2, or Ida 12 mg/m2 according to the on-going study-protocol.The control group consisted of the childbearing age women (15-51y) with the same type of AL, who were treated by the same protocols within 2011-2017 yy in NRCH (16 APL, 28 AML and 129 ALL).Results54,5% (n=6) of APL-pts were referred to the low/intermediate (L<10*109/l; Plt<>100*109/l) and 45,5% (n=5) to the high risk (HR) group (L>10*109/l). In the control group the distribution of the APL-pts according to the risk factors was similar: 75% and 25%, rsp.The cytogenetic risk group was estimated in 27/35 pregnant women with AML. 52% (n=14) were referred to the intermediate and 48% (n=13) to the HR group. The HR group comprised complex karyotype (n=5), -7/del7 (n=4), MLL gene translocations (n=2), inv3/-7 (n=1) and AML with normal karyotype, FLT-3+ (n=1). In AML non-pregnant women HR was detected in much less pts - 7% (p=0,001*).In ALL 37% of pregnant women (n=10) were referred to the standard and 63% (n=17) - to the HR group (BI, L>30,TI,II,IV, L>100, LDH>2N, t(4;11) and t(9;22)). There were no differences in comparison with non-pregnant ALL pts: 28,2% and 72,1%, respectively.Overall induction results in pregnant and non-pregnant women treated according the standard CT protocols were comparable in all AL subtypes (Tab.1). It should be noted that early death rate in APL pregnant women was slightly higher than in the control cohort. And in AML - despite the high portion of HR cytogenetics - CR rate was similar to the control.All differences appeared at the long-term follow-up (Tab.2). High relapse rate was noted in APL pregnant women (n=3), and the main reason for that were the refusals of 2 pts to continue CT due to postpartum psychological problems. 5-y OS for APL pregnant pts constituted 54,5%, DFS - 40,9%. APL-pts in the control group are alive in CR.The long term outcome in ALL pts represented the same results in both cohorts. 5-y OS and DFS were 70% and 55% in the pregnant ALL pts, and 60% and 65% - the control group. So we may assume that in ALL pregnancy does not affect the prognosis.On the contrary in AML we registered very unsatisfactory long term results. For AML pregnant pts 5-y OS was 23,5% and DFS -21,3% in comparison with 58,6% and 59% in the control group. The differences are highly significant though the same treatment protocols were applied. In order to evaluated the role of allo-HSCT in AML-pts, we performed a landmark analysis (land-mark = 6 mo of CR - median time to allo-HSCT). We note, that if allo-HSCT was performed in the 1st CR in AML pts, diagnosed while pregnancy, all those pts are alive; in contrast - 5-y OS without allo-HSCT constituted only 11,9% (p=0,03). In a multivariate analysis pregnancy and allo-HSCT in the 1st CR became the independent prognostic factor for AML, diagnosed in women during pregnancy.ConclusionThe long term results in APL-pregnant women in our study were somewhat worse than in non-pregnant women, mostly due to the poor adherence to the treatment after delivery. The survival of ALL-pregnant women did not differ from the general population. And AML diagnosed during pregnancy was characterized by extremely poor outcome, and these pts are the candidates for allo- HSCT in 1st CR. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Human Herpes-Virus 6 Infection in Immunocompromised Patients after Chemotherapy and Autologous Stem Cell Transplantation

Introduction.The ubiquitous spreading of human herpes viruses (HHV) in nature, the variety of ways and methods of their transmission, ability of lifelong persistence in the host and pantropism lead to almost total infection of the adult population. In immunocompromised patients (pts) with blood system diseases HHV infections are characterized by severe complications and may cause death without proper diagnostics and treatment. HHV-6 is widely explored in pts after allogenic transplantation but its role in pts after chemotherapy (ChT) courses and autologous stem cell transplantation (ASCT) is not investigated enough.Aims. To determine the rate of HHV-6 reactivation in pts with hematological diseases. To investigate the role of HHV-6 infection in pts with immunodeficiency after ChT and ASCT to define treatment tactics.Methods. From January 2013 to July 2017 in hematology department of National Research Center retrospectively analyzed 273 pts with newly diagnosed hematology diseases (72-with acute lymphoblastic leukemia (ALL), 141 - acute myeloblastic leukemia (AML), 15-with high-grade B-cell lymphoma (BCL), 45 - aplastic anemia (AA). ALL was treated according to ALL 2009 protocol, AML - with standart «7+3» ChT, AA - with Antithymocyte Globulin or cyclosporine, BCLs - with R-EPOCH/R-HMA or R-EPOCH. We performed real time polymerase chain reaction (RT-PCR) for detecting HHV-6 DNA in cases of any clinical complication after ChT, in period of febrile neutropenia and post-transplant. The investigation included the samples of blood, cerebrospinal fluid, urine, feces, bone marrow, bronchoalveolar lavage (BAL), saliva, pulmonary effusion. Diagnostically significant criterion was the DNA detection of more than 500 copies/ml.Results. HHV-6 reactivation was detected in 90 pts out of 273 (32,9%): 38% in AML pts (54 out of 141), 33% - in ALL pts (24 out of 72), in group of AA - 15,5% (7 out of 45), BCL - in 5 pts (33%). Twenty-five pts (19 with ALL, 6 - BCL) underwent ASCT. HHV-6 DNA was revealed in 44% cases of pts after ASCT, but only 24% of these pts received antiviral therapy because they had clinical symptoms of HHV-6 infection. The most severe infection was encephalitis. Among AML pts after ChT, manifestations of HHV-6 infections were detected in 14 out of 141 (10%), among ALL without ASCT- in 9,4% (5 out of 53). Before stating the HHV-6 infection and starting special treatment all other reasons of complications were excluded (bacterial and fungal). All pts with clinical symptoms of viral contagion received iv ganciclovir (10mg/kg/day) with further prophylaxis of valganciclovir (900mg/day) during 2-9 weeks. Almost all clinical symptoms regressed after 3-5 days of the treatment but DNA copies in samples stayed much longer (2-6 weeks) and early stop of treatment (1-2 weeks) in some cases caused the increasing of HHV-6 copies. Interestingly, that pts with AA didn't have clinical symptoms though had reactivation of HHV-6 and nobody of them needed antiviral treatment.Conclusion. HHV-6 reactivation is quite common in immunocompromised pts (see table 1) but development of HHV- 6 infection requires treatment only in 9,5% (26 pts out of 273) of them (including pts after ASCT). The most severe complications associated with HHV-6 included encephalitis, enteropathy, urinary infection and pneumonia. More frequently HHV-6 was detected in blood samples and feces.The HHV-6 infection needs to be diagnosed when bacterial and fungal infections are excluded. In case without clinical symptoms there is no need to start specific treatment. When stated, HHV-6 infection requires continual antiviral curing until complete disappearing of DNA copies from biological liquids. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Blinatumomab in B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease: Initial Results of a Phase II Trial

Background: Chemoimmunotherapy offers excellent response rates for acute lymphoblastic leukemia (ALL). Persistence of minimal residual disease (MRD), delayed MRD negativity, and recurrence of MRD positivity portend higher risk of relapse and worse survival. Blinatumomab is a CD19/CD3 bispecific T-cell engager antibody construct which simultaneously engages CD3+ cytotoxic T cells and CD19+ ALL blasts enabling T-cell recognition and elimination of these leukemic cells. The BLAST study (Goekbuget, et al. Blood 2014;124:379) suggested the potential role of blinatumomab in eradicating MRD in precursor B-ALL. We aimed to evaluate blinatumomab in patients with pre-B ALL and positive MRD by multicolor flow cytometry and in patients with Philadelphia chromosome-positive (Ph+) ALL with positive MRD defined by polymerase chain reaction (PCR).Methods: This was an open-label, single-arm, phase II trial. Pts with B-lineage ALL in hematologic complete remission (CR) who had either not achieved MRD negativity or had MRD-positive relapse, starting any time after ≥3 months (mo) of frontline therapy, or in CR2 and beyond at any time point after 1 mo of salvage therapy, and pts with prior allogeneic stem-cell transplantation (ASCT) were eligible for inclusion. MRD was defined as ≥1 x10-4 by 6-color multiparameter flow cytometry. MRD for Ph+ ALL pts was defined as BCR-ABL1 to ABL1 transcripts of ≥0.1% International Scale by Real-Time qRT-PCR. Pts received continuous IV infusion of blinatumomab 28 µg/day over 4 weeks (wk) followed by 2 wk treatment-free interval. For the first cycle (cy), blinatumomab was initiated at 9 µg/day for 1 wk and then escalated to 28 µg/day, if tolerated. A TKI of treating physician's choice was added to the regimen for pts with Ph+ ALL. Responders could receive up to 4 additional consolidation cy, and subsequent ASCT was offered depending on donor availability. The primary endpoint was to evaluate the efficacy of blinatumomab in this population in terms of relapse free survival (RFS). Secondary endpoints were MRD negativity rate overall and after cy 1, overall survival (OS), and event-free survival.Results: Between 12/2015 and 05/2017 we enrolled 12 pts with precursor-B ALL in CR. 3 pts (25%) had Philadelphia-like ALL and 2 pts (17%) had Ph+ ALL. Baseline characteristics are shown in Table 1. 9 pts (75%) were in CR1. Pts received a median of 2 cy (range, 1-4) of blinatumomab. 9 pts (75%) achieved MRD-negative status at a median time of 41 days (range, 38-92), and 3 pts did not achieve a response after 2 cy. 8 pts (67%) responded after first cy and 1 pt (8%) responded after second cy. 5 pts (42%) who responded, proceeded to ASCT with median time from enrollment to ASCT being 12.6 wk (range, 8.4-27.3). 5 pts (33%) have discontinued therapy, and 1 pt (8%) with response is currently receiving therapy on trial. Reasons for discontinuation were lack of response in 3 pts, toxicity in 1 pt (grade 3 psychosis and grade 2 encephalopathy), and loss of response in 1 pt. Out of the 3 pts who discontinued therapy due to lack of response, 1 pt underwent ASCT in MRD-positive CR, 1 pt is receiving blinatumomab outside of the clinical trial with vincristine and prednisone, and 1 pt is being evaluated for ASCT and is currently in MRD-positive CR. 1 pt who discontinued due to loss of response, underwent ASCT in morphologic relapse with 6% bone marrow blasts. Therapy was well tolerated and 8 pts (67%) have not had any adverse events. Toxicities encountered include grade 2 cytokine release syndrome in 2 pts, grade 1/2 peripheral neuropathy in 1 pt, and grade 3 psychosis and grade 2 encephalopathy in 1 pt. With a median follow-up of 8 mo (range, 2.3-19.1), 10 pts (83%) are alive. Out of the 2 pts who died, 1 pt did not respond to blinatumomab and died on day +25 post-ASCT from disseminated adenovirus infection, and 1 pt who had responded to blinatumomab but discontinued due to toxicity, died from sepsis in the setting of ALL relapse after ASCT. MRD negativity rates overall and after cy 1 were 75% and 67%, respectively. The 6 mo OS and RFS were 89% and 88%, respectively (fig. 1). The median OS and RFS have not been reached.Conclusion: Blinatumomab is well-tolerated and is highly effective in eradicating MRD in pts with B-lineage ALL who have persistent MRD after intensive chemotherapy.Clinical trial registration information: NCT02458014 [Display omitted] DisclosuresKantarjian:Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Daver:Immunogen: Research Funding; Kiromic: Research Funding; Pfizer Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Incyte Corporation: Honoraria, Research Funding; Jazz: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy. Thompson:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jain:BMS: Research Funding; Verastem: Research Funding; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. O'Brien:Celgene: Consultancy; AbbVie: Consultancy; Acerta: Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; GSK: Consultancy; Sunesis: Consultancy; Janssen: Consultancy; Alexion: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; ProNAI: Other: Research Support: Honorarium, Research Funding; Astellas: Consultancy; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; Amgen: Consultancy; Aptose Biosciences, Inc.: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees. Jabbour:Bristol-Myers Squibb: Consultancy.

Outcomes of Adults with Acute Lymphoblastic Leukemia (ALL) Following Relapse After First Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

AbstractAbstract 4215 Background:Outcomes of SCT in adult ALL have improved over the past decade. However, for patients (pts) who relapse after SCT, the prognosis is poor and treatment options are limited; the clinical course and prognostic factors affecting these pts are not well characterized. Methods:We retrospectively analyzed the outcomes of relapsed adult ALL pts who underwent first SCT between 1993–2011. The objectives of the study were to assess outcome after salvage therapy in these pts and to investigate the prognostic factors affecting outcome. Out of 365 ALL pts who underwent first SCT, 123 pts relapsed and received further treatment. Outcome was assessed since the date of relapse until death or last follow-up. Results:The median time to relapse was 4.4 months (mo.) (0.4–38.5 mo.) from first SCT. With a median follow up of 11 mo. (0.1 mo. -9 years) from time of relapse, the actuarial OS at 6 mo. was 35% (27–44%). First salvage treatments and median OS after relapse were: second SCT (n=19, OS 10 mo.) or donor lymphocyte infusion (DLI) (n=11, OS 6.5 mo.) with or without prior chemotherapy, radiation therapy for extramedullary only relapse (n=6, OS 3 mo.), cytoreductive chemotherapy (n=30, OS 4 mo.), mild chemotherapy (n=27, OS 4 mo.) and palliative care (n=23, OS 1 mo.). Mild chemotherapy was defined as combinations of steroids and vincristine, single cytotoxic agents such as clofarabine or nelarabine, tyrosine kinase inhibitors, hypomethylating agents, or monoclonal antibody therapies. Seven pts were lost to follow-up. Following the first salvage treatment, 47 pts (38%) went into complete remission (CR). The CR rate was higher in the HSCT, radiotherapy and DLI groups (84%, 83% and 64% respectively) compared with the mild chemotherapy (41%) and cytoreductive chemotherapy (27%) groups.In a univariate analysis for survival (Table 1), adverse factors included active disease at time of first SCT and short time to relapse from first SCT (<6 mo.). In pts who were not in active disease at SCT (n=83), the EBMT prognostic score (Spyridonidis et al, Leukemia 2012) was found to be highly prognostic of OS. Patients with 2/3 adverse factors (first SCT at CR2/3, relapse in <6.9 mo. and peripheral blast >10% at relapse) had significantly worse 6-mo. OS compared to pts with 0/1 adverse factor (p=0.009). Presence of isolated extra-medullary relapse was not associated with improved OS compared to pts with systemic relapse.Second SCT was found to be correlated with improved outcome compared with cytoreductive chemotherapy (p=0.003). Among the pts who received treatment and were evaluable for response (n=86), achievement of CR after first salvage was the most significant predictor of survival (p=0.001). In bivariate analysis, this benefit was shown to be independent of performing second SCT. Conclusion:Prognosis of ALL pts who relapse following SCT remains poor. However, second SCT may allow long term survival in a small subset of pts. Longer time to progression after first SCT and successful induction of CR following first salvage treatment are associated with improved survival post relapse. We corroborated the EBMT prognostic score for pts experiencing relapse after HSCT.Table 1Univariate analysis of factors influencing 6-month post relapse OSCovariatesN (123)HR95% CIP valueAge at HSCT (years)<=3055Ref.>30680.70.5–1.10.2SexFemale39Ref.Male841.71.01–2.80.05LineageB-cell85Ref.T-cell2810.6–1.70.99CytogeneticPh-71Ref.Ph+280.70.4–1.30.2Status at HSCTCR120Ref.PIF/CR2/CR3632.020.9–4.30.07Active disease403.11.4–6.70.005Preparative regimenRIC32Ref.HD911.10.6–1.80.8AllotypeMatched unrelated45Ref.Matched related650.70.5–1.20.2Cord blood70.80.3–2.20.6Haploidentical61.60.6–4.20.3Time to relapse (months)>642Ref.<=6812.051.2–3.40.007Site of relapseSystemic99Ref.Isolated extramedullary240.80.4–1.40.4First line salvage*Cytoreductive chemotherapy30Ref.Second SCT190.20.1–0.60.003Chemotherapy + DLI110.50.2–1.30.1Mild chemotherapy270.990.5–1.90.9Radiation therapy only60.90.3–3.10.9Response to first salvage**CR47Ref.NR392.91.6–5.40.001CR indicates complete remission; PIF, primary induction failure; RIC, reduced intensity conditioning; HD, high dose conditioning; NR, no response.*Palliative group was excluded.**Palliative group and non-evaluable pts excluded. Disclosures:No relevant conflicts of interest to declare.

Neuropsychiatric disorders in hospitalized patients undergoing chimeric antigen receptor T-cell therapy for aggressive lymphomas and acute lymphoblastic leukemia: A national study.

12118 Background: Chimeric antigen receptor T cell therapy (CART) has shown efficacy in acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), and primary mediastinal B cell lymphoma (PMBCL). While neurological toxicities of CART are known, neuropsychiatric disorders (NPD) in patients undergoing CART has not been well described. Our study assessed the prevalence of NPD in hospitalized patients (pts) undergoing CART, and explored association of NPD with clinical variables. Methods: Using the National Inpatient Sample database, we conducted a retrospective study of pts with ALL, DLBCL and PMLCL aged ≥ 18 years who underwent CART in 2018. Hospitalizations were selected using International Classification of Disease, Tenth Revision (ICD-10) codes. NPD of interest included anxiety, depression, adjustment disorder, insomnia, psychosis, dementia, bipolar disorder. Delirium was not included in the inventory of NPD since delirium is a neurotoxicity of CART, and inclusion of delirium as NPD would confound results. Patient, disease, and CART complications were extracted from hospitalization records. Regression analyses were used to assess association of NPD with clinical variables. Results: 945 CART procedures met the inclusion criteria (56 % males and 60% Caucasians). Majority of CART (88%) were performed for DLBCL and PMBCL. NPD was diagnosed in 31 % of pts. Anxiety was the most common NPD, followed by insomnia and depression. ALL pts were more likely to have NPD compared to pts with lymphoma (52% versus 28%, p&lt;0.05). More females had NPD compared to males (40% versus 25%, p&lt;0.05). Univariable analysis showed association of NPD with female gender [Odds ratio (OR)=2.03, 95% CI = 1.05-3.93] and ALL (OR=2.76, 95% CI = 1.03-7.43). In a multivariable model, NPD was associated with ALL (OR =3.57, 95% CI= 1.01-12.55), while the association of NPD with female gender was less certain (OR =1.41, 95% CI=0.73 - 2.74). There was no association between NPD and mortality, neurotoxicity, systemic inflammatory response syndrome or hemophagocytic lymphohistiocytosis. Conclusions: One in every 3 pts who underwent in-hospital CART for ALL or aggressive B cell lymphoma in 2018 had comorbid NPD. Females and ALL pts were at higher risk for NPD. As CART pts transition into longer follow up and survivorship, ours and similar results should inform the planning and allocation of psychosocial services.

The Role of Genetic Polymorphisms ofTPMTandNUDT15Genes in Adult Patients with Ph-Negative Acute Lymphoblastic Leukemia in Russia

Context: TPMTandNUDT15polymorphisms are involved in the toxicity and therapeutic efficacy of thiopurine drugs (6-mercaptopurine (6-MP)). The frequencies of polymorphisms of these genes are different across diverse populations. The role ofTPMTandNUDT15genes in adult patients (pts) with Ph-negative acute lymphoblastic leukemia (ALL) in Russia is still unclear. Objective:Evaluation of frequency and significance ofTPMTandNUDT15polymorphisms in the cohort of adult Ph-negative ALL pts treated by the RALL-2016 protocol. Design and Patients:Since April 2017 till July 2020 56 adult Ph-negative ALL patients treated by RALL-2016 protocol were included in the research ofTPMTandNUDT15polymorphisms. Median age was 32 у (range, 18-54), m/f: 39 (70%) / 17 (30%). B-ALL/LBL were diagnosed in 26 (46,4%) pts, T-ALL- in 26 (46,4%) and MPAL- in 4 (7,2%). Genomic DNA was extracted from peripheral blood samples of given pts. Genetic polymorphisms inNUDT15(*2, *3)and TPMT(*2, *3A, *3B, *3C)genes were detected using the allele-specific RT-PCR. The dose of 6-MP was calculated only for 54 pts from 56 (one of these pts stopped the therapy and another received the 1 st phase of induction by RALL-2016 without 6-MP). According to the RALL-2016 protocol 6-MP dose correction imply: if the level leukocytes&amp;lt;2,0*109/l, thrombocytes &amp;lt;100*109/l pts got 50% from the required dose. The therapy of 6-MP was stopped, if the level leukocytes &amp;lt;1,0*109/l, thrombocytes &amp;lt;50*109/l. On the 2 induction therapy by the protocol, the doses of 6-MP were calculated only for 47 pts with CR. The group of pts who didn't have remission on the 36 day by the protocol took the drug without corrections. Results:From 54 pts CR rate was 87 % (n=47) and resistance - 13% (n=7). One patient died in CR. The frequency ofTPMTandNUDT15polymorphisms in study group was 17,8 % (n=10): 6 (23%) of 26 pts with B-ALL, 3 (11,5 %) of 26 pts -T-ALL and 1 (25%) of 4 pts - MPAL. In our cohort these polymorphisms were found significantly more frequently in pts with B-ALL (p&amp;lt;0.001). These polymorphisms were detected in 8 (80%) men and 2 (20%) women (p=0.432). All detected polymorphisms were presented as heterozygous variants:NUDT15*3was in 2 (20%) pts,TPMT*2-1(10%),TPMT*3A-6 (60%),TPMT*3C-1 (10%). The doses of 6-MP in 5 pts withTPMTandNUDT15and 42 pts withWTwere 54% (27-89%) vs 71% (25-100%), respectively. Statistics analysis didn't show correlation between the 6-MP toxicity (difference of the fact dose of 6-MP therapy) and the polymorphisms in our cohort (fig.1). The frequency of resistance cases didn't different in cohort with/withoutTPMTandNUDT15polymorphisms in 3 (37, 5%) from 8 pts and 4 (10, 5%) from 42 pts, respectively. Only 1 patient with heterozygousTPMT*2died in CR due to toxicity and infection. Two-years overall survival (OS) in pts with the genetic polymorphisms was worse 75 % than in pts without them - 83,6% (p=0,67) (fig.2). Conclusions:In our study the frequency ofTPMTandNUDT15polymorphisms in adult pts with Ph-negative ALL was 17,8%. The statistical analysis showed that polymorphisms of these genes were detected more frequently in pts with В-ALL. Only one patient withTPMT*2had significant toxicity on the therapy of 6-MP and died in CR. However, we don't know whether this is due to deficient 6-MP metabolism. We didn't find a correlation between the 6-MP toxicity and the polymorphisms in our pts. There is a tendency that OS within 2-years in pts withoutTPMTandNUDT15polymorphisms is better than in the group of pts with them. But our cohorts are small and require further study. Keywords:acute lymphoblastic leukemia, toxicity, 6-mercaptopurine,TPMT,NUDT15 Disclosures No relevant conflicts of interest to declare.

Risk of Gvhd and Survival in Patients with Acute Leukemia Who Were Bridged to Allogeneic Stem Cell Transplantation (alloSCT) with Venetoclax- Based Therapy

Background: Venetoclax has shown a promising benefit in patients (pts) with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). There is paucity of information about the efficacy and risk of GVHD with alloSCT post venetoclax -based therapy. Methods: We conducted a retrospective analysis of 35 AML/ALL pts who received alloSCT following venetoclax-based therapies between 2013-2018 at MD Anderson Cancer Center. Results: Median age at alloSCT was 60 years and 23 (66%) pts had an age-adjusted HCT-CI score &amp;gt; 3. Disease diagnosis - AML (n=31; 89%), ALL (n=4; 11%). Disease status in pts with AML at study entry was CR1 (n=11; 35%), CR2/CR3 (n=6; 19%), Cri (n=2, 6%), hypoplastic marrow (n=2; 6%) or refractory disease (n=10; 32%). ALL pts were in CR1 (n=2) or CR2 (n=2). Sixteen (46%) pts were MRD-negative by flow cytometry on marrow samples pre-alloSCT, 7 (20%) were MRD-positive, and 10 (29%) had active disease; 2 pts had hypoplastic marrow. Median lines of prior therapies was 2 (range 1-7) and 6 (17%) pts had failed a prior alloSCT. Disease risk index was intermediate (n=18 of 34; 53%) or high/very-high (n=16 of 34; 47%). Venetoclax was provided in combination of hypomehylating (HMA) agents or other chemotherapies in 26 (74%) and 9 (26%) pts, respectively. Median duration of venetoclax-based treatment was 2.0 months (range 0.5- 4.6). Most pts (83%) continued their therapy as a bridge to alloSCT. Venetoclax was discontinued in 6 (17%) pts due to adverse events (n=4) or progression (n=2). Conditioning regimens were melphalan-based reduced intensity (n=26, 74%), or busulfan-fludarabine regimens (n=9; 26%). Donor source was matched unrelated (n=13, 37%), or related (n=9; 26%); haplo (n=12; 34%) and mismatched unrelated (n=1; 3%). Cell source was from peripheral blood (n=24; 69%) or bone marrow (n=11; 31%). GVHD prophylaxis consisted of tacrolimus with either post-transplant cyclophosphamide in 25 (71%) pts or methotrexate in 10 (29%) pts. Seven (20%) pts (3 with active disease, 2 MRD-positive and 2 were MRD-negative pre-alloSCT)) received maintenance therapy with agents other than venetoclax (Vidaza=2, Sorafenib =2, SGI =1, Ponatinib =1, Asparginase = 1) post alloSCT at a median of 3 months (range, 2-4 months). Median time to ANC &amp;gt;500 was 15.5 days (range, 10-24), and platelets counts &amp;gt;20 k was 22.5 days (range, 11-46). The cumulative incidence (CI) of acute 2-4 and 3-4 GVHD was 29% and 9%, respectively. Risks associated with 100 day-acute 2-4 GVHD were evaluated in univariate analyses. Factors evaluated were age, HCT-CI, # prior lines of therapies, prior alloSCT, type GVHD prophylaxis, donor type, cell source, female donor to male recipients, prior PD-1 therapy (n=3) , types of combination of venetoclax duration of treatment and timing of last venetoclax treatment to alloSCT. Only venetoclax timing to alloSCT was associated with significant risk. The CI of acute 2-4 GVHD in patients who discontinued venetoclax ≤ 2 weeks (n=11, 31%) vs &amp;gt; 2 weeks (n=24, 69%) was 55% vs 17% (P = 0.020; Figure 1), respectively [HR 0.24, 95% confidence interval 0.07-0.80; P = 0.020). . With a median follow up among surviving pts of 18.4 months (range 3.5-31.4), the 1-year rates of OS, PFS, and NRM were 72%, 57% and 12% respectively. Twelve patients died: 8 due to progression, 2 of GVHD, 1 of infection and 1 of unknown cause. Disease status was the only predictor of OS in univariate analysis. Pts who were MRD-negative pre-alloSCT had a 1-year OS of 92% while the 1-year OS in pts who were CR/MRD+ and those with active disease was 38% and 70%, respectively (Figure 2). No factor evaluated was significantly associated with NRM. Conclusions: Our data show that the use of venetoclax-based therapy as a bridge to alloSCT does not increase the risk of NRM or delayed engraftment. It does improve OS by inducing CR/MRD-negativity in high-risk acute leukemia. It may be prudent however to discontinue therapy &amp;gt; 2 weeks before alloSCT in order to avoid a higher risk of acute GVHD. Disclosures Jabbour: BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Daver:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:Cellectis: Research Funding; Reata Pharmaceutical Inc.;: Patents &amp; Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Ascentage: Research Funding; Agios: Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Ablynx: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding. DiNardo:Novartis: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria; Calithera: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; MedImmune: Honoraria; Jazz: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Ravandi:Orsenix: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding. Kadia:Pulmotec: Research Funding; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Ascentage: Research Funding; Novartis: Honoraria; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Astellas: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding. Alousi:Incyte: Honoraria, Research Funding; Alexion: Honoraria; Therakos: Research Funding. Oran:Arog Pharmaceuticals: Research Funding; Celgene: Consultancy; ASTEX: Research Funding. Kebriaei:Amgen: Other: Research Support; Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Jazz: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Kantarjian:Aptitute Health: Honoraria; BioAscend: Honoraria; Adaptive biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Oxford Biomedical: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Janssen: Honoraria; Delta Fly: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Champlin:Omeros: Consultancy; Actinium: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Genzyme: Speakers Bureau; Takeda: Patents &amp; Royalties; Johnson and Johnson: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Enhanced Risk Stratification of 21,178 Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia (ALL) Incorporating White Blood Count (WBC), Age, and Minimal Residual Disease (MRD) at Day 8 and 29 As Continuous Variables: A Children's Oncology Group (COG) Report

Current risk stratification for COG ALL patients (pts) relies on National Cancer Institute (NCI) risk group (RG) at diagnosis, somatic genetics, and early response to therapy as measured by specific thresholds of minimal residual disease (MRD) using flow cytometry on day 8 peripheral blood (D8 PB) and day 29 bone marrow (D29 BM). NCI RG is defined as age 1-10 years (yrs) and white blood cell count (WBC) &amp;lt;50,000/uL (Standard Risk, SR); all other non-infant patients are high risk (HR). Using COG risk stratification, current therapies for SR and HR patients are based on 5-year projected event-free survival (EFS) of 92-97%, and 65-86%. Currently, two subsets, Ph-like and very high risk (VHR) ALL are identified with additional assays-genomic sequencing for Ph-like, and persistent BM MRD on D29 and at end of consolidation for VHR, and are eligible for different treatments. However, as UK investigators recently published (O'Connor, JCO 2018; Enshaei, Blood 2020), using multiple continuous variables as threshold-defined categorical data may diminish the power of accurately predicting relapse, and thus prescribe inappropriate post induction therapy. We tested the UK approach of transforming categorical variables into continuous data on 13,870 NCI SR and 7308 NCI HR B-ALL pts treated on two generations of COG trials: AALL0331 (SR; n=5094), AALL0932 (SR; n=8776), AALL0232 (HR; n=2883), and AALL1131 (HR; n=4425). Down syndrome and Ph+ pts were excluded from analysis. Clinical characteristics are listed in Table 1. ETV6-RUNX1 (25.24%) and double trisomies of chromosome 4, 10 (DT) (23.77%) comprised the favorable risk genetic RG (FRG) group (48.15% of risk classified) while KTM2A rearranged (1.71%), hypodiploidy (1.67%), and iAMP21 (2.56%) comprised the unfavorable risk genetic RG (URG) (6.26%). All others with genetic information were classified as intermediate risk genetic RG (IRG) (45.59% of risk classified). Among 4873 pts tested, 20.46% had Ph-like ALL. D8 PB and D29 BM MRD data were available for 76.42% and 96.69% pts, respectively. We first log transformed WBC, D8 and D29 MRD and displayed these by treatment protocol, NCI RG, and FRG/URG (separating out Ph-like independently). Age and WBC followed the normal expected distribution with the median age of SR pts 4.0 yrs (range 1-9) and HR 12 yrs (range 1-30). Transformed MRD was displayed as a variable t(MRD), corresponding to the negative log; max t(D29 MRD) was 13.82, corresponding to MRD &amp;lt;1.0 x 10-5.The great majority of pts were MRD-positive at D8 (mean t(D8 MRD) 7.42); but there was broad distribution of values, with NCI SR and FRG pts having lower t(D8 MRD) (mean 7.52 and 8.08) than NCI HR and URG pts (mean 7.20 and 6.56) (p &amp;lt; 0.001) . The great majority of pts were D29 MRD-negative (mean t(D29 MRD) 12.08), with NCI SR and FRG pts achieving lower D29 MRD (mean t(D29 MRD) 12.43 and 12.73) than NCI HR and URG pts (mean 11.40 and 10.95) (p&amp;lt; 0.0001). Ph-like ALL pts had a mean t(D8 MRD) and t(D29 MRD) of 6.22 and 9.37. We next conducted a univariate analysis for risk factors for relapse, including sex, age, WBClog, CNS status, protocol-defined rapid early response status, FRG, URG, t(D8 MRD), and t(D29 MRD); all variables except CNS status were significant p &amp;lt; 0.0001). Multivariable modeling showed that WBClog, FRG, URG, t(D8 MRD), t(D29 MRD) retained significance (p &amp;lt; 0.0001). Finally, we applied the UK Prognostic Index (PIUKALL) equation [t(d29 MRD) x -0.218 + CYTO-GR x -0.440 + CYTO-HR x 1.066 + WBClog x 0.138] to the COG data using protocol, NCI RG, FRG, URG, IRG, or Ph-like RG in the model and validated the trends for relapse-free survival (RFS), which were similar in our groups with an overall median PIUKALL of -2.63 (mean -2.32, SD -.90, min -3.54, max 1.79). We next added in t(D8 MRD) to define a PICOG and determined that D8 PB MRD added significantly to the model, mostly through discriminating between the hazard ratios of the FRG and the URG RGs. Importantly, the D8 PB MRD led to a qualitatively more distinctive group with a potentially lower predicted RFS in NCI SR pts, a group that has been more difficult to predict in the past, and yet comprises nearly half of all relapse events. Our analyses of 21,178 COG B-ALL pts confirm and extend the utility of integrating WBC and MRD as continuous rather than categorical values to refine risk stratification for patient treatment and trial design. Disclosures Loh: Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. Mattano:Melinta Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Hunger:Amgen: Current equity holder in publicly-traded company, Honoraria; Novartis: Consultancy. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; AbbVie, Inc.: Research Funding.

Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. These regimens, which rely heavily on corticosteroids and asparaginase (asp), are known to increase the risk of osteonecrosis (ON). In children older than 10 years (yrs), reported rates of symptomatic ON range from 5-25% (Mattano JCO 2000, Mattano Lancet Onc 2012, Toft Eur J Haematol 2016, Larsen JCO 2016). In adults, the frequency of ON and fractures (fx) are not well described including among those treated on pediatric regimens. In the recently reported C10403 trial (Stock Blood 2019), a 4% rate of ON was reported among patients aged 17-39 yrs. Here, we describe the orthopedic toxicities of AYA pts treated on sequential Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: Pts aged 1-50 yrs were treated on four sequential multi-center DFCI ALL Consortium protocols between 2000 and 2018. Additional pts treated as per these protocols at DFCI, Massachusetts General Hospital (MGH), and Boston Children's Hospital (BCH) were identified by chart review. Earlier pts were enrolled on parallel Pediatric 00-001 (2000-2004) and Adult 01-175 (2002-2008) trials while later pts were enrolled on parallel Pediatric 05-001 (2005-2011) and Adult 06-254 (2007-2011) trials. Protocol 00-001 randomized pts between dexamethasone (dex) and prednisone (pred) during consolidation, while the other three trials used dex (all trials used pred during induction). Both 00-001 and 01-175 used native E.Coli asp, while later protocols (05-001, 06-254) used PEG asp for some (05-001, randomized) or all (06-254) pts. All pts were intended to receive 30 weeks of asp during consolidation. Pts aged 15-50 yrs were included in this study. Orthopedic toxicities were extracted from case report forms for trial pts and by chart review for those not on trial. Additional chart review was performed on all pts treated at DFCI, MGH, and BCH to identify surgical events. All pts were combined in the modeling based on the treatment backbone. The 5-yr cumulative incidences (CIs) of ON and fx were estimated and compared using the Gray test. Univariate and multivariable competing risk regression models were constructed with death as a competing risk. Results: A total of 367 pts with a median age of 23 yrs (68% &amp;lt; 30 yrs) were identified. The majority (61%) of pts were male and the median BMI was 24.5 kg/m2 (46% overweight or obese). The median follow-up for pts remaining alive was 5 yrs (range, 0.01-14.1). In total, 60 pts experienced ON (5-yr CI 17%, [95% CI 13-22]) and 40 pts experienced fx (5-yr CI 12%, [8-15]). The median time to develop ON was 1.6 yrs (range, 0.5-7.7). The median time to fx was 1.4 yrs (range, 0.2-5.2). Pts &amp;lt; 30 yrs were significantly more likely to be diagnosed with ON (21%, [16-27]) compared to those aged 30-50 yrs (8%, [4-14], univariate HR 2.77 [1.35-5.65]; p=0.005). Pts treated on PEG-asp based protocols were significantly more likely to be diagnosed with ON (5-yr CI 24% [18-30]) compared to those treated on earlier trials with native E.coli asp (5-yr CI 5% [2-10], HR 5.28 [95% CI 2.24-12.48], p&amp;lt;0.001). These results remained statistically significant in multivariate analysis including treatment backbone, age, BMI, and sex. BMI and sex were not associated with orthopedic toxicity, although there was a trend toward fewer fx in male pts (HR 0.55, [0.29-1.02]). Of the 54 ONs for which adequate information was available, surgery was performed in 25 (46%) and total joint replacement in 18 (33%). Of the 9 fx with adequate information, 3 (33%) required surgery. Conclusions: In a large cohort of AYA ALL pts aged 15-50 yrs treated on a pediatric regimen, orthopedic toxicities were common (17% for ON, 12% for fx at 5 yrs). Younger pts (&amp;lt; 30 yrs) experienced higher rates of ON, as well as pts treated on later-generation PEG-asp protocols which combined dex and PEG asp. Increased rates of orthopedic toxicity in later generation protocols may be driven by the pharmacokinetic drug interaction between PEG asp and dex, leading to higher dex exposure (Yan JCO 2008, Panetta Clin Pharmacol Ther 2009). Increased awareness may be useful in early identification of orthopedic toxicities. Future efforts should focus on further understanding the pathophysiology and risk factors for orthopedic toxicity in ALL AYA regimens and developing prophylactic interventions. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board. Brunner:Acceleron Pharma Inc.: Consultancy; Biogen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Forty-Seven: Consultancy; Jazz: Consultancy; Incyte Corporation: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy; Autolos: Consultancy; Agios: Consultancy; Pfizer: Consultancy.