Median Duration Of Complete Remission Research Articles

Kinetics of Complete Remission (CR) and CR Duration and Its Impact on Overall Survival (OS) and Event-Free Survival (EFS) in Quantum-First

Background Results from the phase 3 QuANTUM-First study (NCT02668653) showed that in patients (pts) with newly diagnosed (nd) acute myeloid leukemia (AML) and positive for FMS-like tyrosine kinase 3-internal tandem duplication ( FLT3-ITD+), the addition of the oral, highly potent, and selective, type 2 FLT3 inhibitor quizartinib (Quiz) to standard chemotherapy ± allogeneic hematopoietic cell transplantation (allo-HCT), followed by continuation monotherapy for up to 3 years, decreased the relative risk of death by 22.4% vs placebo (PBO) (PMID: 37116523). We assessed 1) the impact of CR duration on OS and EFS and 2) the kinetics of CR achievement over time after induction. Methods QuANTUM-First enrolled pts aged 18-75 years with FLT3-ITD+ nd AML, randomized to receive standard induction chemotherapy with either Quiz (40 mg/d) or PBO, and stratified by region (Europe, North America, or Asia/Australia/South America), age (<60 years, ≥60 years), and white blood cell count (WBC; <40×10 9/L, ≥40×10 9/L) at diagnosis. Pts who achieved CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine combined with Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 years (36 cycles) of continuation therapy with Quiz (30-60 mg/d) or PBO. OS was the primary endpoint, EFS and rates of CR and composite complete remission (CRc) were secondary endpoints; CR duration was an exploratory endpoint. The impact of CR duration on OS was analyzed by extended Cox regression model stratified by region, age, and WBC count at diagnosis and included treatment group and CR duration status (time-dependent covariate). CR duration status was 0 for pts who did not achieve CR, 1 for CR pts throughout the duration of sustained CR, and 0 for CR pts after they relapsed. Results Of the 539 randomized pts enrolled in QuANTUM-First (Quiz, n=268; PBO, n=271), there were 297 CR pts (Quiz, n=147; PBO, n=150) based on independent review committee assessment after 1 to 2 courses of induction. Among 533 treated pts, 20% had 2 induction cycles. Baseline characteristics in CR pts were well balanced between arms: median age in years (range), 56.0 (23-75) vs 55.5 (20-74); females, 55.8% vs 60.0%; ECOG ≥1, 64.6% vs 63.3%; mutated NPM1 / CEBPA,66.7% vs 64.7% / 25.9% vs 23.3%; variant allele frequency (VAF) >25%, 68.7% vs 66.7%; and WBC count at diagnosis ≥40×10 9/L, 55.8% vs 49.3%. Median OS in CR pts was not reached (95% CI 48.6 months-NE) in the Quiz arm vs 35.4 (95% CI 15.1-NE) months in the PBO arm (HR 0.572, 95% CI 0.400-0.816; Figure 1). Although CR rates were similar between arms (55% in both), median CR duration was longer with Quiz vs PBO (38.6 months, 95% CI 21.9-NE vs 12.4 months, 95% CI 8.8-22.7; HR 0.621, 95% CI 0.451-0.857). Based on the extended Cox model, CR duration status covariate was strongly predictive for OS (HR 0.156, 95% CI 0.113-0.216; nominal P<0.0001; Figure 2). Importantly, the HR for Quiz vs PBO effect on OS in the model with the time-dependent covariate CR duration status was higher (HR 0.851, 95% CI 0.672-1.076) vs the HR of the primary OS analysis (HR 0.776, 95% CI 0.615-0.979), implying that a substantial fraction of OS benefit was mediated through its effects on achieving a durable CR (Figure 2). EFS favored Quiz over PBO when induction treatment failure (ITF) was defined as not achieving CRc or CR, by the end of induction up to day 56 from the last induction cycle, with HR 0.729 (95% CI 0.592-0.897; nominal P=0.0031) and 0.818 (95% CI 0.669-0.999; nominal P=0.032), respectively. EFS was similar between arms when ITF was defined, according to FDA guidance, as not achieving CR by day 42 from the start of the last induction cycle (HR 0.916, 95% CI 0.754-1.114; P=0.24; primary EFS analysis). Between day 42 and the end of the induction phase, there were 51 pts who achieved CR (Quiz, n=33; PBO, n=18), and they were considered as ITF with EFS event on day 1 in the primary analysis of EFS. Among these 51 pts, 9 (Quiz, n=5; PBO, n=4) had CRi by day 42 and became CR after day 42 in the induction phase. Conclusions These analyses demonstrated that in QuANTUM-First: 1) a substantial fraction of the estimated effect of Quiz on OS was mediated through its effect on achieving a durable CR and 2) more pts in the Quiz arm vs the PBO arm achieved CR after day 42 of the last induction cycle, suggesting that there was a delay in CR achievement with Quiz. Longer EFS was observed in Quiz over PBO based on the EFS definition including CRs between day 42 and end of induction.

Oncogenetic-Driven Targeted Therapy for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia : A French ALL-Target Observatory Report

Introduction T-cell acute lymphoblastic leukemia (T-ALL) is an orphan disease diagnosed mostly in adolescent and young adults. In adult population, 5-10% of T-ALL patients (pts) will be primary refractory and 30-40% will relapse. In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration. On behalf of the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia), we launched the ALL-TARGET project combining a precision medicine platform dedicated to R/R T-ALL and T-cell lymphoblastic lymphoma (T-LL), and an observatory to evaluate therapeutic proposals based on mutational profile and intracellular signaling pathways alterations. Objectives and methods Leukemic samples from pts with R/R T-ALL/LL were shipped to the GRAALL T-ALL central laboratory in France (V. Asnafi, Hôpital Necker). Biological characterization comprised oncogenetic, phenotypic and in some cases functional analysis. Clinical data from R/R T-ALL/LL pts were collected in a real-life observatory (NCT05832125). Adults pts were eligible if an oncogenetic characterization was available at diagnosis or relapse, and if they received a salvage, either with conventional therapy or with a targeted therapeutic option (TTO). For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7R ALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3K ALT). The ALL-TARGET Observatory primary endpoint was overall response rate (ORR) including complete remission (CR), CR with incomplete hematological recovery and partial response. We report here the results of the first pts included, with a focus on those who received TTOs as salvage therapy. Results Eighty-nine were analyzed, including 80 T-ALL and 9 T-LL. Sex ratio was 3 and median age at diagnosis was 37.5y, and 51y at the time of the first TTO. Seventy-one pts were in relapse (79.7%) and 18 primary refractory (20.2%). Relapses occurred after a median first CR duration of 16.6 months (range: 2.5-92), with 62.8% in bone marrow, 30% in CNS and 30.3% in other extramedullary sites. Phenotype at diagnosis was available for 68 pts, including 36 Early T-cell Precursor (ETP or near-ETP) (52.9%), 6 immature non-ETP (8.8%), 20 cortical (29.4%) and 6 mature phenotype (8.8%). IL7R-expression was available for 53 pts, of whom 40 were IL7R+ (75.5%) and 13 IL7R- (24.5%). Out of 50 samples with available BCL2-expression, 47 were BCL2+ (94%) and 3 BCL2- (6%). IL7R ALT were evidenced in 41 pts (48.2%), PI3K ALT in 21 pts (24.7%), RAS pathway alterations (RAS ALT) in 19 pts (22.4%) and epigenetic dysregulation in 42 pts (49.4%). Ten pts harbored TP53/ATM mutations (11.7%) . These different alterations could coexist. At relapse, 33 phenotypes were reported, showing 22 ETP (66.6%), 2 immature non-ETP (6%) and 9 cortical (27.3%). IL7R-expression was available for 26 pts, among which 21 were IL7R+ (63.6%) and 5 IL7R- (19.2%). NGS was performed in 24 patients, revealing IL7R ALT in 9 pts (37.5%), PI3K ALT in 6 pts (25%), RAS ALT in 5 pts (20.8%) and epigenetic dysregulation in 15 pts (62.5%). Nine patients had TP53 mutations (37.5%). Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%). Among these, 8 were in first salvage (32%), 10 in 2 nd (40%), and 6 in 3 rd/4 th salvage (28%). Of note, 14 patients received Ven associated with chemotherapy, including 4 Nelarabine-Ven, and 3 Ven in monotherapy. By 3 months, the cumulative incidence of response under the chosen TTO was 70.7% (95%CI:51-88) (Figure). Ten of 14 patients were in response after Aza/Ven (ORR 71.4%), 4 of 8 patients after Tofa/Ven (50%) and 2 of 2 patients treated with Tem/Erw/Ven (100%). Five patients were bridged to allogeneic stem cell transplantation. Conclusion Our results demonstrate the feasibility of the ALL-TARGET project. A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL.

Efficacy and Safety of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naive, Higher-Risk Myelodysplastic Syndromes

Introduction: Azacitidine (Aza) has been shown to prolong survival in patients with treatment-naive, higher-risk myelodysplastic syndrome (HR MDS) compared to lower-intensity, conventional treatment regimens; however, improvement in clinical outcomes are needed. Clinical data on the synergy of Aza with venetoclax (Ven)-a selective, potent BCL-2 inhibitor-in the treatment of myeloid malignancies and the unmet need in HR MDS provide a rationale to evaluate Ven in combination with Aza in treatment-naive HR MDS. Here, we report efficacy and safety data in patients with treatment-naive HR MDS treated with Ven+Aza at the recommended Phase 2 dose (RP2D) in the safety expansion part of the Phase 1b study (NCT02942290). Methods: Adult patients were enrolled with de novo treatment-naive HR MDS defined by the Revised International Prognostic Scoring System (IPSS-R) score of >3 with an Eastern Cooperative Oncology Group performance status of ≤2, and bone marrow (BM) blasts <20% at baseline. Patients received Ven 400 mg orally daily on Days 1-14 and Aza 75 mg/m 2 intravenously or subcutaneously on Days 1-7 or on Days 1-5, 8, and 9 of each 28-day cycle (RP2D). The primary objective was to assess the complete remission (CR) rate. Key secondary objectives included determining marrow CR (mCR), overall response rate (ORR), hematologic improvement (HI), postbaseline red blood cell (RBC) and platelet transfusion independence (TI), overall survival (OS), duration of CR, time to next treatment (TTNT), transformation to acute myeloid leukemia (AML), and time to AML transformation. Responses were assessed by International Working Group 2006 criteria. Prophylactic antibiotics were mandated in Cycle 1 and recommended for Grade ≥3 neutropenia thereafter. Safety was analyzed in patients who received ≥1 dose of study treatment. Results: At thedata cutoff of May 31, 2023, 107 patients had received Ven+Aza at the RP2D. Key baseline characteristics for all treated patients are shown in Table 1A. Median age was 68 years (range, 26-87), 64% of patients had intermediate or poor cytogenetic risk, and >89% had ≥5% BM blasts. Median number of treatment cycles before transplantation was 3.0 (range, 1.0-11.0). At the median follow-up of 31.9 months (95% CI, 30.4-42.5), CR rate was 29.9% (95% CI, 21.4-39.5), with a median CR duration of 16.6 months (95% CI, 10.0-not reached [NR], Table 1B). Median OS was 26 months (95% CI, 18.1-51.5), with an estimated 12-month OS of 71.2% (95% CI, 61.4-78.9)and 24-month OS of 51.3% (95% CI, 41.2-60.5). Median OS for CR was NR. Median TTNT including transplantation was 6.8 months (95% CI, 5.6-8.3). Sixty-two (57.9%) patients received subsequent treatment, including transplantation in 42 (39.3%) patients; the median time to transplantation was 4.8 months (range, 1.4-16.8). Among patients who received transplantation post-study, 17 were transplant ineligible at study entry. Postbaseline TI rate was 61.7% for RBC and 72.0% for platelets. Median maximal duration of TI achieved was 5.4 months (range, 1.8-50.8) and 5.4 months (range, 1.9-56.0) for RBC and platelets, respectively. Postbaseline overall hematologic improvement (HI) was achieved in 51 (49.0%) of 104 evaluable patients, and specific responses included erythroid (40/93; 43.0%), platelet (32/74; 43.2%) and neutrophil (10/57; 17.5%) indices. All patients experienced ≥1 treatment-emergent adverse event (TEAE), with 94.4% of patients reporting grade ≥3 TEAEs. Serious adverse events (SAEs) occurred in 68.2% of patients. Common TEAEs of any grade were constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), diarrhea (41.1%), anemia (39.3%), vomiting (36.4%), and hypokalemia (26.2%). Grade ≥3 TEAEs reported in ≥20% of patients were neutropenia (48.6%), thrombocytopenia (43.0%), febrile neutropenia (42.1%), and anemia (34.6%). Infections were reported in 57% of patients, including SAEs in 40.2% of patients. Of the 59 deaths (55.1%) reported, 23 (21.5%) were due to disease progression and 7 (6.5%) to adverse events. Within 60 days after study start, 7 deaths (6.5%) were reported. Conclusion: Ven 400 mg for 14 days plus Aza combination was well tolerated with favorable responses of CR+PR+mCR in >80% and HI in nearly 50% of patients with treatment-naïve HR MDS. A separate Phase 3 study of this combination is ongoing to confirm survival benefit.

Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia

To evaluate the clinical efficacy and safety of decitabine combined with modified CAG regimen (D-CAG regimen) in patients aged ≥70 years with newly diagnosed acute myeloid leukemia (AML). The clinical data of 59 AML patients (≥70 years old) who were newly diagnosed and treated in the Hematology Department of the First Affiliated Hospital of Nanjing Medical University from November 2010 to June 2021 were retrospectively analyzed. Among the 59 AML patients, 28 were males and 31 were females, with a median age of 74 (70-86) years. The complete remission (CR) rate was 69.4% (34/49), and the median duration of CR was 10.7 (0.6-125.4) months after 2 courses of D-CAG treatment. According to the British Medical Research Council (MRC) classification, there was only one patient in the favorable-risk group, and the CR rate was 71.8% (28/39) in the intermediate-risk group, and 55.6% (5/9) in the adverse-risk group, respectively. There was no statistical difference in the CR rate between the intermediate-risk and adverse-risk group. Referring to ELN 2017 genetic risk classification, CR rate was 88.2% (15/17) in the favorable-risk group, 45.5% (5/11) in the intermediate-risk group, and 66.7% (14/21) in the adverse-risk group. There was no significant difference in CR rate between the favorable-risk and adverse-risk categories, but both were significantly higher than that in the intermediate-risk group (P <0.05). Next-generation sequencing (NGS) analysis showed that 11 gene mutations with a frequency of more than 10%, including TET2 mutation (35.6%), ASXL1 mutation (30.5%), NPM1 mutation (28.8%), FLT3-ITD mutation (27.1%), DNMT3A mutation (22.0%), IDH1 mutation (15.3%), CEBPA single mutation (13.6%), TP53 mutation (13.6%), IDH2 mutation (11.9%), RUNX1 mutation (11.9%), and NRAS mutation (10.2%). There were no statistical differences in mutation frequency of these 11 genes between CR group and non-CR group. Compared with normal karyotypes, patients with complex karyotypes were more likely to develop TP53 mutations (P <0.001), while FLT3-ITD and DNMT3A mutations were more likely to occur in patients with normal karyotypes (P =0.04, P =0.047). The median follow-up, overall survival (OS), and event-free survival (EFS) of all the patients was 11.7 (1.5-128.2) months, 12.3 (1.5-128.2) months, and 8.5 (1.5-128.2) months, respectively. The median OS and EFS of CR patients were 19.8 and 13.3 months, respectively, which were significantly longer than 6.4 and 5.7 months in patients experiencing treatment failure (P < 0.001, P =0.009). In regard to genes with mutation frequency >10%, there were no statistical differences in CR rate, median OS, and median EFS between mutated and wild-type patients by Chi-square test and survival analysis. Univariate analysis showed that age, hemoglobin, lactate dehydrogenase, cytogenetics and CR were factors affecting prognosis, while multivariate analysis showed that only CR failure was an independent adverse prognostic factor for OS. The major adverse reactions to D-CAG regimen were grade 3-4 myelosuppression, pulmonary infection, and fever (infection focus was not identified). D-CAG regimen is safe and effective in the treatment of AML patients ≥70 years old, and can partially improve the prognosis of elderly and high-risk patients.

Combination of Mitoxantrone Hydrochloride Liposome with Cyclophosphamide, Vincristine and Prednisone (CMOP) in Treatment-Naïve Patients with Peripheral T-Cell Lymphoma: A Multicenter, Open-Label, Single-Arm, Phase Ib Clinical Trial

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas accounting for 25% to 30% of non-Hodgkin lymphomas in China. Although CHOP remains backbone of frontline treatment in PTCL, outcomes are typically poor. Front-line treatment with brentuximab vedotin plus CHP only provided moderate improvement in CD30-positive PTCL. Therefore, the development of novel agents for this population is still urgently needed. In 2020 ASH annual meeting (Abstracts 42), we reported mitoxantrone hydrochloride liposome (PLM60) monotherapy yielded effective antitumor activity, durable response with mild toxicity in patients with relapsed or refractory PTCL for the first time. This trial aimed to explore the safety, efficacy and pharmacokinetics (PK) of PLM60 plus cyclophosphamide, vincristine and prednisone in patients with treatment-naïve PTCL (TN-PTCL). Methods: Patients aged 18-75 years with histologically confirmed treatment-naïve PTCL (including PTCL-NOS, AITL, ALCL- ALK+/-; other subtypes that investigators consider to be appropriate), ECOG performance score 0-1 and avid-FDG PTCL by PET/CT were recruited. Main exclusion criteria were patients with ENKTL, MF/SS, primary cutaneous-ALCL and ATLL, central nervous system involvement, hemophagocytic syndrome. This study consisted of two parts. In part 1, 3+3 dose-escalation design with four dose levels of PLM60 (12, 15, 18 and 21 mg/m2) was used to identify the MTD, DLT and recommended Phase II dosage (RP2D) of PLM60 plus cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2 with maximum dose of2 mg) on day 1 and prednisone 100 mg orally administered on day 1-5 (CMOP) of every cycle (28 days) for 6 cycles. Part 2 was dose expansion at the RP2D. The primary endpoints were safety. Adverse events were defined according to the CTCAE 5.0. The secondary endpoint was efficacy including complete response (CR) rate, duration of complete remission (DoCR), objective response rate (ORR) and progression-free survival (PFS) assessed according to Lugano 2014 criteria and PK profile. This trial is registered at ClinicalTrials.gov (NCT04548700). Results: At the cut-off data of June 23, 2022, 31 patients were screened in the 6 institutions in China, of which 26 eligible patients (19 males) with a median age of 51.5 (range, 28-70) were enrolled in phase Ib study. Enrolled patients included the following PTCL subtypes: AITL (53.8%), PTCL-NOS (15.4%), ALCL-ALK+ (7.7%), ALCL-ALK- (7.7%) and other subtypes (15.4%). 10 patients (38.5%) presented with B symptom and 20 patients (76.9%) were at the stage III or IV. No dose-limiting toxicities occurred, RP2D was 18 mg/m2. Treatment-related adverse events (TRAEs) of any grade occurred in all 26 patients, in which 22 (84.6%) were ≥ grade 3. The most common ≥ grade 3 TRAEs was neutropenia (73.1%), leucopenia (73.1%), lymphocytopenia (38.5%), thrombocytopenia (11.5%), febrile neutropenia (11.5%), infectious pneumonia (7.7%), anemia (7.7%). After a median follow-up of 10.8 (range 1.6-16.9) months, 25 patients were evaluable for response. CR rate and ORR of the whole cohort were 52.0% (13/25) and 84.0% (21/25). While ORR were 92.3% (12/13), 75.0% (3/4), 50.0% (1/2), 50.0% (1/2), 100.0% (4/4) and the CR rates were 76.9% (10/13), 25.0% (1/4), 50.0% (1/2), 50.0% (1/2), 0% (0/6) for AITL, PTCL-NOS, ALCL ALK+, ALCL ALK-, and other subtypes, respectively. Median DoCR was 6.1 months (3.45-NA), median PFS was 8.8 months (7.26-10.71), and 6-month PFS rate were 78.2%. Conclude: This was the first clinical study demonstrated that new combination of CMOP showed promising antitumor activity in TN-PTCL with manageable safety profiles and dose expansion study at RP2D is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Outcomes of a Clinical Trial of Molecular and Functional Drug Screening for Individualized Therapy in Relapsed and Refractory (R/R) Acute Leukemia (AL)

Background. Outcome of patients (pts) with R/R AL is dismal. While traditional precision medicine basket trials have assigned treatment based on targeted inhibitors for certain mutations, this approach has limited use for pts without such mutations or with co-occurring mutations. In contrast, we developed a clinical trial for which treatment was assigned based on molecular characteristics and functional drug testing. Patient cell samples were analyzed for 194 recurring mutations and by high throughput screening (HTS) for a custom panel of drugs and drug combinations to comprehensively select the best treatment for each individual patient. Here we report the final analysis and long-term outcomes of this individualized approach. (NCT02551718) Methods. Eligibility criteria included diagnosis of AL, relapsed or refractory to at least 2 lines of treatment, ECOG <4 and adequate organ function. Blood/bone marrow (BM) and/or fluid or tissue involved by leukemic blasts was subjected to cell enrichment using magnetic beads, then assayed for drug sensitivity using the CLIA approved Cancer Drug Sensitivity Test (CDST) performed at the University of Washington Quellos High Throughput Core (method described in Lee et al. Nat Commun 2018), mutations by MyAML®, RNAseq and single cell mutation analysis (MissionBio). The HTS included 170 drugs and drug combinations, both FDA-approved and investigational. Drug recommendations were provided by the study to the patient's physician based on the lowest IC50, percentile rankings compared to other tested patients, no history of failed prior use, and insurance authorization. The patient's physician made the final decision about treatment. Results. 60 pts were enrolled: 51 acute myeloid leukemia (AML), 7 acute lymphoblastic leukemia (ALL), 1 undifferentiated, 1 mixed phenotype. The median age was 58 years (range 22-82). For AML pts, ELN 2017 was favorable, intermediate and adverse in 8 (16%), 14 (28%) and 28 (56%) pts, respectively. Median prior lines of therapy were 4 (range 1-8); 15 pts (25%) had primary induction failure and 23 pts (40%) had relapsed post allogeneic transplant, 10 in the first 100 days (d). For those who had relapsed disease, median duration of 1st CR was 6.8 months (range 0.5-52.6). Final HTS test results were obtained within 5 d (4-13), and each patient exhibited a unique pattern of drug response (Figure 1). 35 patients were treated with a single drug (N=12) or combination (2-4 agents; N=23) recommended by the trial. 25 of the patients did not complete treatment on this study because of transition to supportive care (6), treatment with other therapy (10), travel out of state to local care (4), participation on another trial (CAR-T cell-2, investigational agent-2), and pneumonia (1). 30 patients had at least 1 mutation for which targeted inhibitors [FLT3 (11), KIT (2), IDH1/2 (7), NRAS/KRAS (20), ABL1 (3), JAK2 (1)] were available, and seven patients received one. Additionally, 35 pts (4 had more than 1) had a mutation that could now be considered for investigational therapy, including TP53 (12), NPM1 (8), KMT2A rearrangement (4), WT1 (10), or spliceosome mutation (5). Median follow up duration was 2.7 months (range 0.3-36.3). Of 27 pts for whom a post-treatment BM was performed, overall response rate was 33% including 2 complete remission (CR), 1 CR with incomplete count recovery (CRi) and 6 partial remissions (PRs). Of 22 pts with circulating blasts, 21 (95%) exhibited decline with chosen regimen, and 7 (31.8%) exhibited resolution. Median overall survival (OS) for those receiving assay guided therapy was 135 days (d) (95%CI 79-213), compared to 34 d (95%CI 26-63) for enrolled patients not treated on study with corresponding 100 day-OS of 57% (95%CI 39-72%) and 24% (95%CI 10-42), respectively (P<0.001) (Figure 2). Median survival post consent was 109 d (95%CI 79-341) for the subset of post-allogeneic transplant relapsed pts who then received assay guided therapy vs. 30 d (95%CI 8-92) for the those not treated on this trial (P 0.003). Assay guided therapy can decrease risk of death by 83% after adjusted by age, sex, type of leukemia, cytogenetic risk, number of lines of previous treatment (HR 0.17, 95%CI 0.08-0.35, P <0.001) for this group of pts with extensive prior therapy. Conclusion. Genomic analysis and functional screening of enriched leukemia cells can comprehensively predict in vivo efficacy and individualize optimal treatment for patients with R/R AL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-464 Tolerability and Efficacy of the First-In-Class Anti-CD47 Antibody Magrolimab Combined With Azacitidine in Frontline Patients With TP53-Mutated Acute Myeloid Leukemia (AML): Phase 1b Results

Patients with TP53-mutated AML have a poor prognosis. Magrolimab is an antibody blocking CD47, a "don't eat me" signal on cancer cells, which induces tumor phagocytosis and is synergistic with azacitidine. Report final tolerability and efficacy data. Ph1b single-arm trial of magrolimab+azacitidine (NCT03248479). 72 frontline patients with TP53-mutated AML unsuitable for intensive chemotherapy. Magrolimab IV 1-mg/kg (priming) then 30-mg/kg ramp-up QW/Q2W (maintenance). Azacitidine 75 mg/m2 IV/SC days 1-7 (each 28-day cycle). Primary endpoints were safety/tolerability and complete remission (CR) rate. Common treatment-emergent adverse events (TEAEs) were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Common grade (G)≥3 TEAEs were febrile neutropenia (37.5%), anemia (29.2%; G3, 26.4%; G4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). G3 hemolysis was reported in 1 patient; no G4 hemolysis was reported. Objective response rate was 48.6% (CR, 33.3%; CR with incomplete hematologic recovery [CRi]/CR with partial hematologic recovery [CRh], 8.3%; morphologic leukemia-free state [MLFS], 1.4%; partial remission, 5.6%). 16.7% and 5.6% of patients had stable disease and progressive disease (PD), respectively; 30- and 60-day mortality rates were 8.3% and 18.1%, respectively. Response assessments were unavailable in 4.2% (discontinued due to AEs) and 6.9% (other) of patients prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (range, 1.7-7.2) and CR was 3.0 months (range, 1.8-9.6); 14/31 (45.2%) evaluable patients with CR/CRi/CRh/MLFS achieved negative MRD. 8/24 patients with CR had a longitudinal TP53 variant-allele-frequency (VAF) assessment; 5/8 (63%) had ≤5% VAF. Treatment was stopped due to stem cell transplant (9 [12.5%]), PD (26 [36.1%]), death (8 [11.1%]), AE (13 [18.1%]), or other (14 [19.4%]). Median durations of CR and CR/CRi were 7.7 (95% CI, 4.7-10.9) and 8.7 (95% CI, 5.3-10.9) months, respectively. Median overall survival was 10.8 months (95% CI, 6.8-12.8; 8.3-month median follow-up). Magrolimab+azacitidine showed durable responses and encouraging overall survival in frontline patients with TP53-mutated AML unsuitable for intensive chemotherapy. A Ph3 trial of magrolimab+azacitidine vs standard-of-care in TP53-mutated AML (ENHANCE-2; NCT04778397) is ongoing.

FDA Approval Summary: Brexucabtagene Autoleucel for Treatment of Adults With Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia.

In October 2021, the FDA approved brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL). Approval was based on the phase II portion of ZUMA-3, a single-arm, open-label, multicenter trial that evaluated a single infusion of brexu-cel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine, in this population. Efficacy was established on the basis of complete remission (CR) within 3 months after infusion and the duration of CR (DOCR). Among 54 patients in the efficacy analysis population, the CR rate was 52% (95% CI: 38, 66) with a median time-to-response of 56 days. With a median follow-up for responders of 7.1 months, the median DOCR was not reached. For all leukapheresed patients in the phase II portion of this trial (n = 71), the CR rate was 41% (95% CI: 29, 53). Among the 78 patients treated with the approved dose of brexu-cel, serious adverse reactions occurred in 79% and fatal adverse reactions occurred in 5% and included cerebral edema and infections. Cytokine release syndrome occurred in 92% (grade ≥3, 26%) and neurologic toxicities occurred in 87% (grade ≥3, 35%), leading to implementation of a risk evaluation and mitigation strategy (REMS). Postmarketing study with 15 years of follow-up will further evaluate long-term safety in adult patients with relapsed or refractory B-ALL.

Elective Checkpoint Inhibitor Discontinuation in Metastatic Solid Tumor Patients: A Case Series.

Checkpoint inhibitor (CKI) therapy has markedly altered the survival of patients with many solid tumors. It appears clear that 10-40% of patients with a number of metastatic cancers can achieve lengthy remissions following CKI therapy. The optimal duration of treatment or whether treatment can ever be safely stopped is still controversial. Based on melanoma-derived data, we tested whether CKI treatment could safely be discontinued in patients with other solid tumors. A retrospective analysis was performed in adults with metastatic solid tumors treated with CKI-based therapy. Patients with solid tumors who achieved complete remission on 2 sequential scans at least 3 months apart during ongoing treatment were identified from our computerized patient database. Patient data was analyzed for patient characteristics, as well as progression-free and overall survival. A total of 69 non-melanoma solid tumor patients were treated with CKI-based regimens in our clinic and 14 achieved complete remission (20.3%). Five patients were female (35.7%) and the remaining nine were male (64.3%). A 100% progression-free survival was observed for these patients. The median duration of complete remission was over 20 months from the time of elective treatment discontinuation. Median overall survival was not reached in this cohort. One patient died of no cancer-related causes. Based on this retrospective case series, elective treatment discontinuation in patients who achieved complete remission appears feasible. All patients remained in a durable complete remission after treatment discontinuation. We hypothesize that appropriate selection of patients for early treatment discontinuation may decrease their economic burden related to ongoing treatment, limit potential toxicity, and improve quality of life.

S132: TOLERABILITY AND EFFICACY OF THE FIRST-IN-CLASS ANTI-CD47 ANTIBODY MAGROLIMAB COMBINED WITH AZACITIDINE IN FRONTLINE PATIENTS WITH TP53-MUTATED ACUTE MYELOID LEUKEMIA: PHASE 1B RESULTS

Background: Patients (pts) with TP53-mutated acute myeloid leukemia (AML) have a poor prognosis, with limited responses to currently available therapies and low survival outcomes, representing a significant unmet medical need. Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cells in cancers such as AML. This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. Aims: To report tolerability and efficacy data from a phase 1b trial of magrolimab + AZA in frontline pts with TP53-mutated AML unsuitable for intensive chemotherapy (NCT03248479). Methods: Frontline pts with AML not suitable for intensive chemotherapy received magrolimab IV starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as the maintenance dose. AZA 75 mg/m2 was given IV or SC on days 1-7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by European LeukemiaNet (ELN) 2017 criteria. Results: 72 pts with TP53-mutated AML were treated (Table). Common all-grade treatment-emergent adverse events (TEAEs) were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common grade ≥3 TEAEs were febrile neutropenia (37.5%), anemia (29.2%; grade 3, 26.4%; grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Grade 3 hemolysis was reported in 1 pt (1.4%); no grade 4 hemolysis was reported. Objective response rate by intent to treat was 48.6% (CR, 33.3%; CR with incomplete hematologic recovery [CRi]/CR with partial hematologic recovery [CRh], 8.3%; morphologic leukemia-free state [MLFS], 1.4%; partial remission, 5.6%). Stable disease and progressive disease (PD) were reported in 16.7% and 5.6% of pts, respectively; 30- and 60-day mortality rates were 8.3% and 18.1%, respectively. Response assessments were unavailable in an additional 4.2% of pts who discontinued due to AEs and 6.9% due to other reasons, prior to the cycle 3 day 1 assessment. Median time to CR/CRi was 2.2 months (range, 1.7-7.2 months) and to CR was 3.0 months (range, 1.8-9.6 months); 14 of 31 (45.2%) evaluable pts with CR/CRi/CRh/MLFS achieved negative MRD by flow cytometry (investigator reported). Of 24 pts with CR, 8 had a longitudinal TP53 variant allele frequency (VAF) assessment and 5 of 8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to stem cell transplant (9 [12.5%]), PD (26 [36.1%]), death (8 [11.1%]), AE (13 [18.1%]), and other (14 [19.4%]). Median durations of CR and CR/CRi were 7.7 months (95% CI, 4.7-10.9 months) and 8.7 months (95% CI, 5.3-10.9 months), respectively. Median overall survival (OS) in 72 pts was 10.8 months (95% CI, 6.8-12.8 months) (figure), with median follow-up of 8.3 months. - Table. Baseline characteristics N=72 Age (range), years 73 (31-89) ECOG, n (%) 0-1 61 (84.7) 2 11 (15.3) ELN cytogenetic risk, n (%) Favorable 1 (1.4) Intermediate 2 (2.8) Adverse 57 (79.2) Unknown 12 (16.7) AML with MDS-related changes, n (%) 34 (47.2) Therapy-related AML, n (%) 15 (20.8) ECOG, Eastern Cooperative Oncology Group; MDS, myelodysplastic syndrome. Image:Summary/Conclusion: In high-risk frontline pts with TP53-mutated AML unsuitable for intensive chemotherapy, magrolimab + AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial of this combination vs standard of care in TP53-mutated AML (ENHANCE-2; NCT04778397) is ongoing.

P500: A REAL WORLD MULTI CENTRE STUDY OF CPX-351 REVEALS NO DIFFERENCE IN OVERALL SURVIVAL WHEN COMPARED WITH FLAG-IDA AND 3 + 7 IN HIGH RISK AML.

Background: CPX-351 is a liposomal formulation of daunorubicin and cytarabine in a fixed synergistic ratio of 5:1. It has been approved by both the FDA and EMA for use in high-risk AML including therapy related AML (t-AML) and AML with myelodysplastic related change (AML-MRC). However, this is little data of CPX-351 in a real-world setting. There is also no data comparing CPX-351 to FLAG-IDA which is used in our institution front line for high-risk AML Aims: The objective of our multi-centre study was to assess outcomes of CPX-351 and then compare these outcomes in patients who received FLAG-IDA and 3 + 7 for high risk AML(tAML and AML-MRC). Methods: Patients aged 18 and over who were treated with induction chemotherapy and who met the WHO criteria for t-AML and AML-MRC were included in the study. Retrospective data was collected from 10 centres throughout Canada for CPX-351. The Princess Margaret Cancer Centre database was used to collect data for patients who received induction with FLAG-IDA and 3 + 7. Targeted sequencing was performed on DNA samples using the TruSight Myeloid Sequencing Panel. Overall survival (OS) and progression free survival (PFS) rates were calculated using the Kaplan-Meier method. Results: 76 patients treated with CPX-351 were identified with baseline characteristics seen on Table 1. Targeted sequencing was performed on 72% of patients (55/76) and the average number of mutations was 2(0-7). RUNX1 was the most commonly mutated gene found in 22% (12/55), followed by ASXL1 mutated in 19% (10/55) and SRSF2 in 15%. Assessing treatment responses, 53% (38/76) of patients achieved a complete remission (CR) or a complete remission with incomplete recovery (CRi). The median CR duration was short at 7.3 months. Median follow up was 7.78 months (range 0.2 to 20 months). OS was 57% at 12 months and 38% at 18 months. PFS was 40% at 12 months and 23% at 18 months. There were no differences in OS when stratified by ELN risk (p=0.46), adverse risk cytogenetics (p=0.1485), or poor risk mutations such as RUNX1 (p=0.73), ASXL1 (p=0.47) or TP53(p=0.53).Patients who received an ASCT had significant improvement of OS of 82% at 18 months compared to those who did not receive a transplant of 15% at 18 months (Fig 2; p=0.0001). Patients who received 3 + 7 and FLAG-IDA for the same indications as CPX-351 (tAML and AML-MRC) were identified. Baseline characteristics are shown in Table 1. 69% of patients receiving FLAG-IDA and 67% of those receiving 3 + 7 had adverse ELN risk stratification. CR rates were highest with FLAG IDA with 75% achieving a CR or CRi. 68% of patients who received CPX-351 proceeded to ASCT compared with 59% with FLAG-IDA and 57% with 3 + 7. OS at 18 months was 42% for FLAG-IDA and 39% for 3 + 7. There was no statistical difference in OS when comparing CPX-351 to FLAG-IDA and 3 + 7 (p=0.855) (Figure 1). Similarly, there was no difference in PFS when comparing all 3 inductions (p=0.26). Patients who received a ASCT had significant improvement of OS of 59% at 18 months compared to those who did not receive a transplant of 24% at 18 months (p=<0.0001)irrespective of what induction was used. Image:Summary/Conclusion: High risk AML remains an unmet clinical need which is supported by our study which reveals no difference in OS or PFS when treated with either CPX-351, FLAG-IDA or 3 + 7. Unsurprisingly, ASCT improved OS across all patients irrespective of induction type. Further study with a prospective randomised control trial is required.

Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: Phase 1b results.

7020 Background: Magrolimab is a monoclonal antibody blocking CD47, a “don’t eat me” signal overexpressed on cancer cells such as acute myeloid leukemia (AML). This blockade induces phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. We report data from a Phase 1b trial of magrolimab+AZA in frontline TP53-mutant ( TP53m) AML. Methods: Patients (pts) with frontline AML not suitable for intensive chemotherapy received IV magrolimab starting with a priming dose (1 mg/kg) followed by ramp-up to 30 mg/kg QW or Q2W as maintenance dose. AZA 75 mg/m2 was given IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate by ELN 2017 criteria. Results: 72 TP53m AML pts were treated (Table). Common all-grade TEAEs were constipation (52.8%), diarrhea (47.2%), febrile neutropenia (45.8%), nausea (43.1%), fatigue (37.5%), decreased appetite (37.5%), thrombocytopenia (31.9%), peripheral edema (30.6%), and cough (30.6%). Most common Grade 3+ TEAEs were febrile neutropenia (37.5%), anemia (29.2%; Grade 3, 26.4%; Grade 4, 2.8%), thrombocytopenia (29.2%), pneumonia (26.4%), and neutropenia (20.8%). Objective response rate (ORR) by intent-to-treat was 48.6% (33.3% CR, 8.3% CR with incomplete hematologic recovery [CRi] / CR with partial hematologic recovery [CRh], 1.4% morphologic leukemia-free state [MLFS], 5.6% partial response). Stable disease was reported in 16.7%, progressive disease (PD) in 5.6%. 30- and 60-day mortalities were 8.3% and 18.1%, respectively. Response assessment was unavailable in 4.2% who discontinued due to AEs and 6.9% due to other, prior to the C3D1 assessment. Median time to CR/CRi was 2.2 months (mos; range 1.7–7.2) and to CR was 3.0 mos (range 1.8–9.6). 45.2% (14/31) of evaluable CR/CRi/CRh/MLFS pts achieved negative MRD by flow cytometry (investigator reported). Of 24 CR patients, 8 had a longitudinal TP53 VAF assessment, and 5/8 (63%) had VAF decreased to ≤5%. Treatment was stopped due to SCT in 9 pts (12.5%), PD 26 (36.1%), death 8 (11.1%), AE 13 (18.1%), and other 14 (19.4%). Median durations of CR and CR/CRi were 7.7 mos (95% CI: 4.7, 10.9) and 8.7 mos (95% CI: 5.3, 10.9), respectively. Median overall survival (OS) for the 72 pts was 10.8 mos (95% CI: 6.8, 12.8) with median follow up 8.3 mos. Conclusions: In high-risk frontline TP53m AML pts unsuitable for intensive chemotherapy, magrolimab+AZA showed durable responses and encouraging OS in a single-arm study. A Phase 3 trial in TP53m AML (ENHANCE-2; NCT04778397) of this combination vs standard of care is ongoing. Clinical trial information: NCT03248479. [Table: see text]

CD19 or CD20 CAR T Cell Therapy Demonstrates Durable Antitumor Efficacy in Patients with Central Nervous System Lymphoma.

Patients with central nervous system (CNS) lymphomas have a poor prognosis. Chimeric antigen receptor-modified (CAR) T cells have shown remarkable efficacy for B-cell non-Hodgkin's lymphoma. However, few studies have reported the effects of CAR T cells in the treatment of CNS lymphoma, and the duration of remission is short. In this study, seven CNS lymphoma patients (six patients with secondary CNS lymphomas and one patient with primary CNS lymphoma) were treated with CD19 or CD20 CAR T cell therapy, and the clinical efficacy and toxicity profiles were evaluated. All patients responded to CAR T cell therapy. Four patients achieved complete remission (CR), while three demonstrated partial remission. We also found that either CD19 or CD20 CAR T cells could be detected in the cerebrospinal fluid of four patients. The median progression-free survival and median overall survival were not assessed. The median duration of CR was 22.4 months. Five patients (5/7) in this cohort received combination therapy (bridging with autologous hematopoietic stem cell transplantation and programmed death-1 inhibitor for maintenance treatment) and three (3/7) received CAR T cell therapy as soon as possible after the relapse of CNS lymphoma. This could help explain why these patients achieved long-term remission. After a median follow-up of 10.4 months, three patients demonstrated disease progression, and the antigen loss of CD20 was confirmed as the reason for relapse in one patient. The results of this study suggest that CD19 or CD20 CAR T cells are effective against CNS lymphoma. This research was registered at http://www.chictr.org.cn (No. ChiCTR2000036350).

Long term follow-up of a phase II study of cladribine with concurrent rituximab with hairy cell leukemia variant

AbstractHairy cell leukemia variant (HCLv) responds poorly to purine analogue monotherapy. Rituximab concurrent with cladribine (CDAR) improves response rates, but long-term outcomes are unknown. We report final results of a phase 2 study of CDAR for patients with HCLv. Twenty patients with 0 to 1 prior courses of cladribine and/or rituximab, including 8 who were previously untreated, received cladribine 0.15 mg/kg on days 1 to 5 with 8 weekly rituximab doses of 375 mg/m2 beginning day 1. Patients received a second rituximab course ≥6 months after cladribine, if and when minimal residual disease (MRD) was detected in blood. The complete remission (CR) rate from CDAR was 95% (95% confidence interval, 75-100). Sixteen (80%) of 20 patients (95% confidence interval, 56-94) became MRD negative according to bone marrow at 6 months. The median duration of MRD-negative CR was 70.1 months, and 7 of 16 are still MRD negative up to 120 months. With a median follow-up of 69.7 months, 11 patients received delayed rituximab, and the 5-year progression-free survival (PFS) and overall survival (OS) were 63.3% and 73.9%, respectively. Five patients with TP53 mutations had shorter PFS (median, 36.4 months vs unreached; P = .0024) and OS (median, 52.4 months vs unreached; P = .032). MRD-negative CR at 6 months was significantly associated with longer PFS (unreached vs 17.4 months; P < .0001) and OS (unreached vs 38.2 months; P < .0001). Lack of MRD in blood at 6 months was also predictive of longer PFS and OS (P < .0001). After progression following CDAR, median OS was 29.7 months. CDAR is effective in HCLv, with better outcomes in patients who achieve MRD-negative CR. This trial is registered at www.clinicaltrials.gov as #NCT00923013.

ABCL-454: CheckMate 436: Extended Follow-Up from the Phase 2 Study Investigating Nivolumab Plus Brentuximab Vedotin (BV) for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma (R/R PMBL)

Context R/R PMBL has limited treatment options. CheckMate 436 (NCT02581631), an open-label phase 1/2 study, assessed combination nivolumab (anti–PD-1) and brentuximab vedotin (anti-CD30) in patients with R/R PMBL; the primary analysis (median follow-up 11.1 months) showed an objective response rate (ORR) of 73% and complete remission (CR) rate of 37%. Objective Report extended follow-up data from CheckMate 436. Patients Cohort of patients with R/R PMBL after autologous hematopoietic cell transplantation (auto-HCT) or ≥2 prior multi-agent chemotherapy regimens if ineligible for auto-HCT. Interventions Nivolumab (240 mg IV) + BV (1.8 mg/kg IV) every 3 weeks until disease progression or unacceptable toxicity. Outcome Measure(s) Primary: investigator-assessed ORR (Lugano 2014) and safety. Secondary: duration of response (DOR), CR rate and duration, progression-free survival (PFS), and overall survival (OS). Results Among 30 patients with a median follow-up of 33.7 months, ORR was 73% (95% CI, 54–88; CR, 37%). Median DOR was 31.6 months (95% CI, 23.3–not estimable [NE]), and median duration of CR was not reached. Estimated median PFS was 26.0 months (95% CI, 2.6–NE). Among patients censored in the PFS analysis, 13/17 received consolidation therapy, including auto-HCT (n=6) or allogeneic HCT (n=6) +/- radiotherapy, and radiotherapy alone (n=1). Four patients remained progression free in follow-up for 5+, 9+, 12+, and 20+ months after discontinuation of nivolumab + BV (maximum clinical benefit, n=3; study drug toxicity, n=1) without subsequent therapy. OS was 79% (95% CI, 59–90) at 12 months and 76% (95% CI, 55–88) at 24 months; median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 83% of patients, most frequently neutropenia (30%; all grade 3/4) and peripheral neuropathy (27%; 10% grade 3/4). Six patients discontinued due to TRAEs. Eight patients died, 5 due to disease progression, and none was considered related to treatment. Conclusions Nivolumab + BV demonstrated durable responses and long-term survival benefits; 4 patients remained progression-free without consolidation after nivolumab + BV. Safety was consistent with prior findings. These results further support nivolumab + BV as a treatment option for patients with R/R PMBL. Funding BMS. Previous Presentation: ICML 2021

Phase II Study of High Dose Cytarabine Followed By Pembrolizumab in Relapsed/Refractory Acute Myeloid Leukemia (AML)

Introduction: Outcomes are dismal for patients (pts) with relapsed/refractory (R/R) AML. Innate and adaptive immune aberrations exist in AML pts leading to immune escape. We have previously shown that there is an increased expression of multiple co-inhibitory molecules including programmed death-1 (PD-1) in the peripheral blood of AML pts at diagnosis, and these levels persist in pts with refractory disease (Knaus H, et al. Blood [Abstract] 2015). We hypothesized that administration of pembrolizumab after high dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T-cell mediated anti-leukemic immune response leading to improved efficacy in R/R AML.Methods: A multicenter phase II study of age-adjusted HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; >=60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14 is being conducted in R/R AML pts 18-70 years. The primary endpoint of this study is the rate of complete remission (CR)/CR with incomplete recovery (CRi) after HiDAC followed by pembrolizumab. The study design is a Simon's like two-stage design (n=37 pts) with relaxed stopping for futility. Relaxed stopping refers to overall response rate (CR/CRi+partial remission [PR]) when stopping rule for futility is applied in the first stage. The null hypothesis that the CR/CRi rate for HiDAC followed by pembrolizumab is 20% will be tested against a one-sided alternative hypothesis yielding a type 1 error rate = 5% and power = 84% when the CR/CRi rate of HiDAC followed by pembrolizumab = 40%. Continuous monitoring for toxicity will be performed to assess for unacceptable toxicity. Overall responders will receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until relapse/progression. Pts can proceed to allogeneic stem cell transplant (SCT) before or after maintenance phase (SCT must be >=30 days from last dose of pembrolizumab). Correlative studies include serial peripheral blood and bone marrow flow cytometry, mRNA-sequencing, and T cell receptor (TCR) clonality studies to determine predictive biomarkers of response.Results: 13 pts enrolled on this study between August, 2016-July, 2017 (Table 1). There have been 0 unacceptable toxicities to date. Immune-related adverse events have included grade 2 hyperbilirubinemia (n=1), grade 3 hepatic enzymes (n=1), both resolved promptly after systemic corticosteroids, as well as self-resolving grade 3 rash (n=1). Additionally, 1 pt developed grade 3 pulmonary edema without evidence of pneumonitis that resolved spontaneously without steroids. Of the 10 evaluable pts (as of July 1, 2017), overall response rate = 50% (CR/CRi: 4/10= 40%; PR = 1/10=10%), meeting the threshold to proceed to stage 2. Two pts have proceeded to a myeloablative allogeneic SCT in CR (one of whom received 2 cycles of maintenance pembrolizumab) and remain in CR. Post-SCT, both pts developed steroid-responsive acute GVHD of skin, one pt developed a transient increase in hepatic enzymes that was responsive to steroids, and one pt developed moderate chronic GVHD. Four pts have received maintenance pembrolizumab: 2 pts relapsed (median duration of CR = 3.9 months; range: 2-5.7 months), one pt proceeded to SCT after 2 cycles, and one pt initially achieved a PR and remains with stable disease after 11 cycles of maintenance pembrolizumab. No pts have died in remission. 30-day and 60-day mortality = 0% and 10%, respectively. Preliminary findings from the first 6 pts (3 responders vs. 3 non-responders) revealed increased diversity of TCR Vβ repertoire from pre-treatment peripheral blood CD8+ T-cells in responders when compared with non-responders using Shannon entropy analysis (p=0.0058; Figure 1).Conclusions: Early results of a multicenter phase II study demonstrate the feasibility of adding immune checkpoint blockade with pembrolizumab after HiDAC chemotherapy in R/R AML. An overall response rate of 50% is encouraging in a high-risk R/R AML cohort though ongoing findings are imperative to evaluate the efficacy and future role of pembrolizumab in AML. Interestingly, in a small cohort of patients, broadening of the immune repertoire, perhaps by increasing T cell responses beyond endogenous viral responses, was associated with response to PD-1 blockade. Future directions include a comprehensive immune biomarker discovery approach to determine predictors of response to immune checkpoint blockade in AML. [Display omitted] DisclosuresZeidner:Tolero Pharmaceuticals: Honoraria; Agios: Honoraria; Merck: Research Funding; Takeda: Research Funding; Tolero Pharmaceuticals: Research Funding; Celgene: Honoraria. Vincent:Merck: Research Funding; Pharmacyclics: Research Funding; Nanostring: Membership on an entity's Board of Directors or advisory committees. Foster:Shire: Honoraria; Incyte: Honoraria; Macrogenics: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Pfizer: Research Funding; Celator: Research Funding. Coombs:Pharmacyclics: Honoraria; H3 Biomedicine: Honoraria. Gojo:Merck: Research Funding; Amgen: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Serody:Merck: Research Funding.

Presence of Post Induction Minimal Residual Disease (MRD) Is an Independent Predictor for Relapse and Is Associated with Inferior Survival in Acute Myeloid Leukemia (AML)

Background:Acute myeloid leukemia (AML) is a highly heterogenous condition. Current risk stratification based on cytogenetics and molecular genetic markers at point of diagnosis is used to predict treatment response and relapse risk. The conventional way of defining complete remission (CR) is based on morphological identification of ≤5% blasts seen in bone marrow. However, this does not provide adequate insight to the quality of response as there is still a high proportion of patients that relapse despite being in CR.A significant proportion of AML patients have detectable MRD post induction. There is increasing evidence to support MRD as a significant prognostic factor for clinical outcome. Despite this, MRD status has yet to become an important factor in deciding on subsequent allogeneic stem cell transplant (allo-SCT). This study assessed the role MRD in predicting risk of relapse and survival rates and also looked into the role of allo-SCT in abrogating the adverse risk of MRD.Methods:All AML cases excluding acute promyelocytic leukemia who underwent curative chemotherapy from year 2001 until 2015 were retrospectively identified. Clinical data was gathered from computerized patient data system. Baseline patients and disease characteristic were correlated with post induction MRD status. MRD was assessed by flow cytometry analysis of bone marrow samples taken on day 26-30 days of post-induction. Samples from year 2001 to 2011 were analyzed using 4 color flow, and from 2011 onward, all samples were analyzed using 8 color flow. Leukemia-associated antigens were identified at baseline and followed up for MRD. Data collected were analyzed using SPSS Statistic Desktop V22.0.Results:235 patients underwent intensive chemotherapy. 61.7% achieved complete remission (CR) after induction chemotherapy. Among those who achieved CR after induction, 41.3% have detectable MRD. 42.8% eventually relapsed, after a median follow-up of 36.6 months. Median duration of CR was 49.5 months. The presenting WBC, LDH, time taken for neutrophil count or platelet count recovery after induction, cytogenetic risk group and FLT3-ITD and NPM1 molecular status did not correlate with MRD status.Post induction MRD positive status was associated with higher relapse rate, 42.6% vs 22.4% for MRD positive and negative respectively, p=0.015, (OR = 1.9) (95% CI: 1.14-3.19).In the multivariate analysis that include presenting WBC, LDH, BM blasts, risk group and post induction MRD status, risk group and MRD status remained an independent predictor for relapse. HR 1.95 (95% CI: 1.00-3.79), p=0.049 for positive MRD status, while adverse risk group gave a HR of 7.15 (95%CI: 2.01-25.49), p=0.002.The 3-year Leukemia free survival (LFS) was 38.3% and 59.6% for MRD+ and MRD- group respectively (p=0.043) (figure 1), while the overall survival (OS) was 55.5% and 69.5% for MRD+ and MRD- group respectively (p=0.388).55 patients underwent allo-SCT, 26 in MRD+ group and 29 in MRD- group. There was no statistical significance in terms of LFS among those who underwent allo-SCT according to MRD status (Median LFS were 13.1 months for MRD+, 29.2 months for MRD-, p=0.328). In the intermediate or adverse risk group who did not undergone allo-SCT, the median LFS in MRD+ group was only 2.5 months (95%CI: 0.0-21.2) compared to MRD- group, 39.9 months (p=0.041), (figure 2).Conclusions:Post induction MRD+ was associated with higher relapse rate and reduced LFS. Post induction MRD- status was associated with excellent LFS among AML with intermediate and adverse risk even without allo-SCT. Allo-SCT may be able to abrogate the adverse outcome of MRD+ AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation.

On November 28, 2018, the FDA approved gilteritinib (Xospata; Astellas), a small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test. In the ADMIRAL study, patients were randomized 2:1 to receive gilteritinib or standard chemotherapy and stratified by response to first-line treatment and intensity of prespecified chemotherapy. Efficacy was established on interim analysis on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence to transfusion independence in 138 patients in the gilteritinib arm. With median follow-up of 4.6 months [95% confidence interval (CI), 2.8-15.8 months] at interim analysis, the CR + CRh rate was 21% (95% CI, 15%-29%), median duration of CR + CRh was 4.6 months (range, 0.1-15.8+), and conversion from transfusion dependence to transfusion independence was 31%. Revised labeling approved on May 29, 2019 included the results of the final analysis, showing an improvement in overall survival (OS) with gilteritinib compared with chemotherapy (HR, 0.64; 95% CI, 0.49-0.83; one-sided P = 0.0004; median OS, 9.3 vs. 5.6 months). The OS benefit was observed in both high and low chemotherapy intensity subgroups. Labeling includes a boxed warning for differentiation syndrome and warnings for posterior reversible encephalopathy syndrome, QT prolongation, pancreatitis, and embryo-fetal toxicity. Safe use requires frequent monitoring of electrocardiograms and blood chemistries. Assessments of long-term safety are pending.

Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience: Presented in part at the American Society of Hematology meeting, New Orleans, LA, December 1999.

AbstractAcute megakaryocytic leukemia (AMegL) is a rare subtype of acute myeloid leukemia (AML) evolving from primitive megakaryoblasts. Because of its rarity and the lack of precise diagnostic criteria in the past, few series of adults treated with contemporary therapy have been reported. Twenty among 1649 (1.2%) patients with newly diagnosed AML entered on Eastern Cooperative Oncology Group (ECOG) trials between 1984 and 1997 were found to have AMegL. The median age was 42.5 years (range 18-70). Marrow fibrosis, usually extensive, was present in the bone marrow. Of the 8 patients who had cytogenetic studies performed, abnormalities of chromosome 3 were the most frequent. The most consistent immunophenotypic finding was absence of myeloperoxidase in blast cells from 5 patients. In the most typical 3 cases, the leukemic cells were positive for one to 2 platelet-specific antigens in addition to lacking myeloperoxidase or an antigen consistent with a lymphoid leukemia. Myeloid antigens other than myeloperoxidase and selected T-cell antigens (CD7 and/or CD2) were frequently expressed. Induction therapy included an anthracycline and cytarabine in all cases. Complete remission (CR) was achieved in 10 of 20 patients (50%). Two patients remain alive, one in CR at 160+ months. Resistant disease was the cause of induction failure in all but 3 patients. The median CR duration was 10.6 months (range 1-160+ months). The median survival for all patients was 10.4 months (range 1-160+ months). Although half of the patients achieved CR, the long-term outcome is extremely poor, primarily attributable to resistant disease. New therapeutic strategies are needed.

Combination Chemotherapy of Advanced Non-Hodgkin Lymphoma with Bleomycin, Adriamycin, Cyclophosphamide, Vincristine, and Prednisone (BACOP)

Seventy-three patients with advanced non-Hodgkin lymphoma were treated with bleomycin, Adriamycin, cyclophosphamide, vincristine (Oncovin) and prednisone (BACOP), administered intensively during a 7-wk induction course followed by intermittent cycles every 3 wk for a total of 28 wk. The objective response in 44 evaluable nonleukemic patients with diffuse histology was 86%, with 66% achieving a complete remission (CR), varying from 80% for diffuse poorly differentiated lymphocytic (DPDL) to 56% for diffuse histiocytic (DH) lymphoma. In patients with nodular histology 89% (8/9) achieved a CR with a projected 75% of patiients in CR at 14 mo. Median follow-up from time of CR for nodular histology was 17 mo. The projected median duration of CR in diffuse histology was 14 mo. with median survival 14 mo. Patients with a partial response survived a median of 7 mo, compared to 3 mo for nonresponders. Of 29 patients with diffuse histology, 17 (59%) have remained disease free for 5-34 mo with a median follow-up of 12 mo. Survival beyond 20 mo has been projected for 42% of patients with diffuse histology (58% with DPDL and 32% with DH). The central nervous system (CNS) was involved in a total of 11/44 (25%) patients with diffuse histology, including 5 with primary CNS relapse. BACOP resulted in a higher CR rate and longer survival than a previous three-drug program (COP), especially in patients with diffuse histology.