CR Pts Research Articles

End of Phase 1 Results from Zuma-6: Axicabtagene Ciloleucel (Axi-Cel) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma

Background Axi-cel is a US FDA-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for treatment of adult patients (pts) with relapsed or refractory large B cell lymphoma (LBCL) after ≥ 2 prior lines of therapy. The checkpoint proteins PD-1 and PD-L1 are expressed on CAR T cells and in the tumor microenvironment, and are upregulated after CAR T cell infusion (Cherkassky, et al. J Clin Invest. 2016; Galon, et al. ASCO 2017. #3025). This suggests that PD-L1 blockade could augment axi-cel activity. This end of Phase 1 analysis of ZUMA-6 examines the safety and preliminary efficacy of axi-cel in combination with the anti–PD-L1 antibody atezolizumab (atezo) in pts with refractory LBCL (NCT02926833). Methods Eligible pts (≥ 18 years) with refractory DLBCL must have received prior CD20-targeting and anthracycline-containing regimen and had ECOG ≤ 1 and adequate bone marrow and organ function. Pts received low-dose conditioning followed by axi-cel infusion (target dose of 2 × 106 cells/kg). Atezo was administered at 1200 mg every 21 days for 4 doses starting on Day 21, 14, and 1 post–axi-cel infusion for Cohorts 1, 2, and 3, respectively. Incidence of dose-limiting toxicities (DLTs) was the primary endpoint. Secondary endpoints included the frequency of adverse events (AEs), disease response, and pharmacokinetics. Results As of January 19, 2018, 12 pts have received axi-cel and ≥1 dose of atezo (3 in Cohort 1; 3 in Cohort 2, 6 in Cohort 3). Median age was 55 years (range, 30 – 66); median follow-up from axi-cel infusion was 4.4 months (range, 0.8 – 12.6). One pt in Cohort 3 experienced a DLT of Grade 4 thrombocytopenia and neutropenia lasting >30 days. All pts experienced at least 1 AE (92% Grade ≥ 3), with no apparent exacerbation or recurrence of axi-cel–related AE following atezo infusion. The most common grade ≥ 3 AEs were anemia (9/12, 75%), encephalopathy (5/12, 42%), and neutropenia (5/12, 42%). Grade ≥ 3 CRS and neurologic events occurred in 3 (25%) and 6 (50%) pts, respectively. The ORR in evaluable pts was 9/10 (90%), with 6 pts (60%) in CR and 3 (30%) in partial response (PR); 2/6 pts (33%) had converted to CR at month 6 and month 9 after initially achieving a PR. CAR T cell expansion (area under the curveD0-28) in pts with DLBCL was >2-fold higher in ZUMA-6 than the median observed in pts treated with axi-cel alone in ZUMA-1 (ZUMA-6: median, 823 cells/µL × days, range, 99 – 2301; ZUMA-1: median, 357 cells/µL × days, range, 5 – 11,507). Median CAR T cell levels remained higher than ZUMA-1 beyond 28 days. Conclusions PD-L1 blockade with atezo following axi-cel infusion has a manageable safety profile, with a low incidence of DLTs and no clinically significant increase in incidence of AEs. Encouraging efficacy results support the opening of Phase 2 of ZUMA-6 in which 22 pts will be treated according to the Cohort 3 schedule. Pharmacokinetic data suggest the potential for enhanced CAR T cell expansion.

Evaluation of Sustained Minimal Residual Disease (MRD) Negativity in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Daratumumab in Combination with Lenalidomide Plus Dexamethasone (D-Rd) or Bortezomib Plus Dexamethasone (D-Vd): Analysis of Pollux and Castor

Evaluation of Sustained Minimal Residual Disease (MRD) Negativity in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Daratumumab in Combination with Lenalidomide Plus Dexamethasone (D-Rd) or Bortezomib Plus Dexamethasone (D-Vd): Analysis of Pollux and Castor

The MRD-Negativity Rate Measured By Flow Cytometry after the 1st and the 2nd Induction Course Among CR AML Patients from Different Cytogenetic Subgroups Does Not Differ Though the Morphological CR Achievement Does

Background. The recent ELN recommendations (2017) have introduced new criteria of response in AML - complete remission with MRD-negativity (CR/MRD-neg). It's a well-known fact that AML with different cytogenetics has different chemosensitivity, and so - CR rate in patients with favorable, intermediate or poor cytogenetic markers substantially differs. MRD negativity corresponds to more favorable long-term results in CR patients, but it's not clear whether the MRD-negativity rate is the same in favorable, intermediate or poor risk AML pts. As it is still poorly understood whether the high risk AML patients need classical «7+3» induction, we introduced a new approach for this cohort of patients - prolonged low-dose cytostatic exposure after hypomethylating priming.Aim. To evaluate the MRD-negativity in CR AML patients from different cytogenetic subgroups after the first classical non-intensive induction: «7+3», «Aza+7+3», «Aza-Ida-Ara-C», and the second induction differed by intensity.Materials and patients. 83 AML patients with a median age of 37 y.o. (17-59), m/f 31/52, after achieving CR (69 pts) were included in the MRD study in the National Research Center for Hematology. From March 2016 till Dec 2017, 49 pts disregarding cytogenetic risk were treated with «7+3» as the first induction course (Dauno 60 mg/m2 1-3 days, Ara-C 100 mg/m2 bid 1-7 days). The second induction course for these pts was «7+3» with continuous Ara-C infusion (200 mg/m2 1-7 days). Since Dec 2017 till July 2018 in all patients epigenetic priming with 3 days of Azacitidine (75 mg/m2) was applied additionally in order to obtain the cytogenetic results prior to cytostatic exposure. All patients were tested by molecular markers (FLT3, CEBPa, mNPM1) but this data did not influence the treatment choice. 8 pts from favorable/intermediate cytogenetic risk group after Aza-prephase have got «7+3» (Dauno 60 mg/m2 4-6 days, Ara-C 200 mg/m2 by continuous infusion, 4-10 days), and 13 pts from poor cytogenetic risk group (complex, -7,-5, inv3, monosomy) after Aza-priming received prolonged low-dose schedule (Ida 3 mg/m2 4-10 days, Ara-C 10 mg/m2 bid sc 4-17 days). The second induction course for favorable/intermediate risk group was FLAG-Ida, for poor risk group - the same as the 1st induction. MRD testing was performed by 6-color flow cуtometry with FACS Canto II (BD) machine after 1st and 2nd chemotherapy courses. The rate of MRD-negativity was calculated among CR patients.Results. Totally among 83 patients CR was achieved in 83%, early death was registered in 6% and refractory AML was diagnosed in 11%. The induction and MRD testing results after the 1st and the 2nd induction course according to prognostic group and treatment arm are demonstrated in the Table.1. Morphological CR rate differs substantially in patients from favorable/intermediate and poor risk by any treatment approach (p=0,04). The prolonged low-dose induction with Aza-prephase induced the same numbers of CRs as the classical «7+3»: 69% vs 46% (p=0,42). Epigenetic priming provided identical MRD-negative CRs in all treatment and cytogenetic groups: 75% vs 62% in favorable/intermediate risk group (p=0,29), 67% vs 50% in poor risk (p=0,62). The second intensive induction with Flag-Ida in favorable/intermediate risk group did not increase the portion of MRD-neg CR pts in comparison with «7+3»: 88% vs 71% (р=0,14). Early relapse rate through all groups showed comparable results.Conclusion. Though the morphological CR achievement is highly influenced by cytogenetic subgroup in AML, the MRD-negativity rate among CR pts by flow cytometry after the 1st and the 2nd induction course is similar. The de-intensification of induction for poor risk group did not lead to the deterioration of therapy efficacy and provided the same rate of MRD-negativity. The 2nd intensified induction after «7+3» did not increase the MRD-negativity in CR pts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

BeEAM (Bendamustine, Etoposide, Cytarabine, Melphalan) Prior to Autologous Stem Cell Transplant for Chemosensitive Relapses in Patients with Follicular Lymphoma: A Prospective Multicenter Phase II Study from Lymphoma Study Association (LYSA) Centers

Introduction: high dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) is an effective treatment in relapsed follicular lymphoma (FL). Alternative regimens including bendamustine based conditioning (BeEAM) had been developed to improve lymphoma outcome. Visani et al. showed in a phase I/II for relapsed aggressive lymphomas and relapsed Hodgkin lymphomas that bendamustine used at a dose of 200mg/m2, 2 days in combination with cytarabine (400 mg/m2, day-5 to day-2), etoposide (200 mg/m2, day-5 to day-2) and melphalan (140 mg/m2, day-1) was well tolerated with promising efficacy results. We designed a single arm, multicenter, phase II study for first and second chemosensitive relapses in FL patients (pts) evaluating this conditioning regimen.Methods: The primary endpoint is the efficacy of BeEAM by measuring the 2-year event-free survival (2-year EFS) rate defines by relapse, progression, death from any cause and initiation of a new therapy. The hypothesis was the improvement of 2-year EFS rate from 70% (H0) to 85% (H1). Based on a Fleming-A'Hern single-stage design, 50 pts are needed. Secondary endpoints are: overall response rate (ORR) at day 100 according to 2007 Cheson criteria; progression-free survival (PFS); overall survival (OS) and safety profile of BeEAM. Main eligible criteria are: histologically confirmed FL relapsed (WHO grade 1, 2, 3a); aged 18-65 years; first or second chemosensitive relapses after salvage immunochemotherapy based on 2007 Cheson criteria with a complete (CR) or a partial response (PR) before the BeEAM; eligibility for ASCT; signed informed consent. This trial was funded by the French government PHRC program 2012.Results: Twenty-one pts were included between July 2014 and November 2016 in 7 LYSA centers. One patient did not receive the treatment. The final analysis was based on 20 pts. Inclusion were performed for 16 (80%) and 3 (15%) pts at 1st and 2nd relapses, respectively. One patient (5%) was included at 3rd relapse and is considered as protocol minor deviation. The median time between the initial diagnostic and the 1st relapse was 3.6 years (0.7-12.9). In first-line therapy, 17/20 pts (85%) were treated with immunochemotherapy. At the relapse allowing inclusion, the FLIPI score were 0-1, 2, ≥3 for 6 (32%), 7 (36%), 6 (32%) pts, respectively. Salvage treatments were rituximab (R) associated with, dexamethasone, cytarabine, and platin in 19 pts and R-CHOP in one patient. The median age at inclusion was 57 years (range, 39-63); 16 (80%) and 4 (20%) pts were in CR and PR before BeEAM. After 18 included pts, the protocol was amended due to unexpected toxicities especially two hepatic veino-occlusive diseases (VOD), leading to the reduction of bendamustine dosage. Finally, 17 and 3 pts were respectively treated at 200mg/m2, 2 days and 160mg/m2, 2 days. The median time for neutrophil>0.5 G/L and platelet recoveries>20 G/L were 7.5 (0-11) and 7 (2-18) days. Patients received a median of 4 (0-12) packed red blood cell units and 6 (3-21) platelet units until J100. The median duration of hospital stay duration was 27 days (20-50). Response evaluation at J100 showed 19 CR pts and one patient in progressive disease. The ORR was 95.0% (95%CI, 75.1-99.9). Six pts progressed with two deaths of the FL (Figure 1A). With a median follow-up of 31 months (16-42), the 2-year EFS rate was 59.6% (95%CI, 35.1-77.4) but two events correspond to unplanned rituximab maintenance in two CR pts (Figure 1B). The PFS and OS rates were 69.6% (95%CI, 44.5-85.1) and 90% (95%CI, 65.6-97.4), respectively (Figure 1C). Fifteen pts (75%) had infectious complications until J100 that needed treatments for more than 7 days. Grade ≥3 toxicities were infections (N=18, 90%), gastrointestinal disorders (N=14, 70%), mucositis (N=12, 60%); atrial flutter (N=1, 5%); acute renal failure (N=2, 10%); HHV6 reactivation (N=3, 15%). In total, 29 serious adverse events (SAE) were declared for 16 pts. Two pts experienced VOD classified as unexpected SAE; one of them needed a hepatic transplantation. No patient presented toxic death.Conclusions: the prospective evaluation of BeEAM conditioning in FL pts with a chemosensitive relapses showed excessive toxicities especially infectious complications, cases of VOD leading to premature termination of the trial. Based on the 20 treated pts, the outcome seems not improve with the use of BeEAM. Our study does not encourage the use of BeEAM conditioning in relapsed FL pts. DisclosuresGhesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy. Le Bras:Amgen: Consultancy. Le Gouill:Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria. Cartron:Celgene: Consultancy, Honoraria; Gilead Sciences: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria.

Multivariable Modeling of Disease and Treatment Characteristics of Adults with B-ALL in MRD-Negative CR after CD19 CAR-T Cells Identifies Factors Impacting Disease-Free Survival

Multivariable Modeling of Disease and Treatment Characteristics of Adults with B-ALL in MRD-Negative CR after CD19 CAR-T Cells Identifies Factors Impacting Disease-Free Survival

Genomics Reveal Potential Biomarkers of Response to Pembrolizumab after High Dose Cytarabine in an Ongoing Phase II Trial in Relapsed/Refractory AML

Background: Outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Programmed Death-1 (PD-1), an inhibitory receptor on T and B cells, suppresses immune activation. We hypothesized that administration of pembrolizumab, a monoclonal antibody targeting PD-1, 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: We are conducting a multicenter phase II study of 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 in R/R AML pts 18-70 years. The primary objective of this study is to estimate the overall complete remission (CR + CRi) rate. Overall responders can receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (SCT) is permissible before or after maintenance phase.Results: To date, 26 pts are evaluable for safety and response (Table 1). Grade ≥3 immune-related adverse events have been rare and self-limiting. The overall CR rate is 35%. Of the 9 CR pts, 5 (56%) had no evidence of minimal residual disease (MRD) by standard monitoring. Notably, 2/3 primary refractory pts with inv(3) cytogenetics achieved CR and underwent SCT. Additionally, 1 pt with relapsed AML with most recent treatment refractory to HiDAC salvage achieved CR with no evidence of MRD. Five pts received maintenance pembrolizumab: 3 relapsed (median duration of CR = 2.8 months; range: 2-5.7 months), 1 proceeded to SCT after 2 cycles, and 1 initially achieved a partial remission (PR) and had stable disease for 12 cycles of maintenance pembrolizumab before progressing. Four pts received a SCT in CR (n=3) and morphologic leukemia free state (MLFS) (n=1). Grade II acute graft-versus host disease (GVHD) and moderate chronic GVHD was seen in 2/4 (50%) pts, respectively. With a median follow up of 10.8 months to date, median overall survival is 10.5 months (range: 1.8-20.8 months).We performed B cell receptor amplicon sequencing, T cell receptor (TCR) amplicon sequencing from CD8+ T cells, and RNA-seq from enriched blasts and non-blast fractions in bone marrow (BM) from 3 CR and 3 non-responders (NR) prior to HiDAC. From the BM blast enriched fraction, expression of innate immune genes such as NLRP12, C3, S100A9, S100A12 and CD14 correlated with response. Gene Set Enrichment Analysis (GSEA) demonstrated that CR correlated with expression of genes in the Toll Pathway, Lysosome pathway, and adaptive immune system while NRs were associated with expression of the PAR1 and GATA3 pathways. From the non-blast BM population, CR correlated with expression of cell-cycle genes such as CCNE1, CCNB2, E2F2, KIF18B and CDKN3. Not surprisingly, GSEA revealed that expression of cell cycle pathways correlated with response. CR correlated with increased expression of B cell metagenes and the inverse IPRES signature in the non-blast BM fraction. As previously reported, there was a significant increase in peripheral blood (PB) TCR diversity in CR pts. CR was also significantly associated with the abundance and richness of the non-blast BM fraction of the B cell heavy and both light chains suggesting that a broader immune response at baseline may be critical for response to HiDAC and pembrolizumab. Finally, CR correlated with increased expression of CD300E, CCR7, CCR4, CCR8 and CCL7 in PB CD8+ T cells suggesting that migration of monocytes, T and B cells is associated with response.Conclusions: Our findings demonstrate that pembrolizumab is well tolerated after HiDAC in an ongoing study in R/R AML. An encouraging response rate has been seen in a high-risk patient population without apparent additive toxicity post-SCT. Our RNA-seq and amplicon sequencing data indicate that biomarkers of response are present prior to therapy. Increased expression of innate immune genes expressed by leukemic blasts and cell cycle genes by the non-blast fraction correlated with response to therapy. Additionally, CR was associated with increased measures of B and T cell diversity and immune cell migration. Further immunogenomic biomarker correlates are ongoing to determine predictors of response to pembrolizumab after HiDAC in R/R AML. [Display omitted] DisclosuresZeidner:Tolero: Honoraria, Other: Travel Fees, Research Funding; Asystbio Laboratories: Consultancy; Merck: Research Funding; Takeda: Other: Travel fees, Research Funding; Rafael Pharmaceuticals: Other: Travel Fees; Celgene: Honoraria. Vincent:Merck: Research Funding. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Coombs:Incyte: Other: Travel fees; AROG: Other: Travel fees; DAVA Oncology: Honoraria; Abbvie: Consultancy; H3 Biomedicine: Honoraria. Luznik:WIndMIL Therapeutics: Equity Ownership, Patents & Royalties. Gojo:Merck inc: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Serody:Merck: Research Funding.

Assessment of Treatment Effects By Measurable Residual Disease Monitoring in NPM1-Mutated AML Patients Randomized for Gemtuzumab-Ozogamicin (GO) within the AMLSG 09-09 Trial of the German-Austrian AML Study Group (AMLSG)

Assessment of Treatment Effects By Measurable Residual Disease Monitoring in NPM1-Mutated AML Patients Randomized for Gemtuzumab-Ozogamicin (GO) within the AMLSG 09-09 Trial of the German-Austrian AML Study Group (AMLSG)

A Phase II Study of Pegylated Asparaginase, Cyclophosphamide, Rituximab, and Dasatinib Added to the UCSF 8707 (Linker 4-drug) Regimen with Liposomal Cytarabine CNS Prophylaxis for Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL): University of California Hematologic Malignancies Consortium Study (UCHMC) 1401

Intensification of therapy for adults with ALL using pediatric regimens with intensive asparagine depletion is feasible. Targeted therapies are improving outcomes. We hypothesized that the UCSF 8707 regimen (Linker et al.JCO 2002;20:2462) could be safely intensified with the addition of pegylated asparaginase (peg asp), cyclophosphamide, rituximab, dasatinib, and intrathecal liposomal cytarabine. Methods: Patients (pts) enrolled at 4 centers. The primary objective was 3-year (yr) EFS (goal >55%). Eligible pts were age 18-60 yrs with untreated ALL or LBL. Treatment consisted of induction Course 1A (C1A): daunorubicin 60 mg/m2 IV d1-3, vincristine (VCR) 1.4 mg/m2 (2 mg if age >50 yrs) IV day 1,8,15,22, prednisone 60 mg/m2 orally (PO) d1-28, peg-asp 2,000 IU/m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d15, cyclophosphamide 750 mg/m2 IV d1,15 (or 500 mg/m2 IV q12h d15,16 if d14 marrow M2 or M3). ALL pts in CR/CRi and LBL pts in CR or PR proceeded to post-remission Course 1B (C1B): methotrexate (MTX) 220 mg/m2 IV bolus then 60 mg/m2/hr CIV for 36 hrs d1,15 with leucovorin rescue, 6-mercaptopurine (6-MP) 60 mg/m2 PO d1-7, 15-21, peg-asp 2,000 IU/ m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d16. Course 1C (C1C) consisted of cytarabine 2,000 mg/m2 IV d1-4 and etoposide 500 mg/m2 IV d1-4. Courses A-C repeated once then a third course B given. Maintenance POMP (6-MP 60 mg/m2 PO daily, VCR 1.4 mg/m2 (2 mg age >50 yrs) IV monthly, MTX 20 mg/m2 PO weekly, prednisone 60 mg/m2 PO d1-5) repeated monthly for 12 months then POMP with every other month VCR and prednisone for 12 months. Peg asp was given d16 of maintenance month 1. If B-ALL (+/- CD20 expression), rituximab 375 mg/m2 IV was given every 2 weeks for 8 doses starting day 1 of C1A. If Ph+ ALL, dasatinib 140 mg PO daily was given but held during high-dose MTX then restarted when serum [MTX] was Results: Between 4/2014 and 2/2017, 31 pts enrolled and 29 were eligible. Median age was 28 yrs (20-54), 62% were male, 52% were Hispanic, and 86% had ALL. The end induction ORR (CR + PR) was 90% (2 ALL with PR, 1 early death). ORR for LBL was 100% (n= 4). The CR rate for ALL was 88%. For Ph- B-ALL (n=16), the CR rate was 86% with MRD 0.1%. Five pts underwent allogeneic HCT in first CR to study therapy. With a median follow up of 32 months (16-44), the 2- and 3-yr EFS were 59%. EFS was similar for B-ALL, T- ALL, LBL, Ph- B-ALL, and Ph+ B-ALL. Five pts relapsed. The 2- and 3-yr RFS were 66%. Concomitant marrow and CNS relapse occurred in 1 pt. No isolated CNS relapses occurred. Transplant-censored 2- and 3-yr OS were 80% and 72%. Uncensored 2- and 3-yr OS were 75% and 70%. Among eligible pts, 8 died: 4 after relapse, 1 in induction from infection, 2 in CR from infection, and 1 from allogeneic HCT complications. Three reversible grade 3-4 events were attributed to liposomal cytarabine, all grade 3: syncope, pseudotumor cerebri, and headache. Grade 3-5 possible peg asp toxicities were transaminitis (58%), hyperbilirubinemia (42%), hyperglycemia (29%), hypertriglyceridemia (26%), elevated GGT/alkaline phosphatase (19%), thrombosis (19%, 1 cerebral venous), hypoalbuminemia (10%), hypersensitivity (6.5%), elevated lipase (6.5%), pancreatitis (3.2%), encephalopathy (3.2%), and avascular necrosis (3.2%). One pt died from encephalopathy. Conclusions: Intensification of UCSF 8707 is feasible and effective. Post-induction remissions were deep with high MRD-negativity rates. EFS, RFS, and OS are favorable with follow up and accrual ongoing (NCT02043587). Strategies to limit peg asp toxicity are needed. Disclosures Wieduwilt:Amgen: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity9s Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership; Leadiant: Research Funding. Schiller:Astellas Pharma: Membership on an entity9s Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Mannis:AbbVie: Membership on an entity9s Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity9s Board of Directors or advisory committees. Curtin:Amgen: Research Funding; Onconova: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Andreadis:Genentech: Consultancy, Employment; Bayer: Consultancy; Astellas: Consultancy; Gilead: Consultancy; Juno: Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Damon:Actelion: Other: spouse9s relationship with company; Boston Scientific: Other: spouse9s relationship with company; Novartis: Other: spouse9s relationship with company; Gilead Sciences Inc: Other: spouse9s relationship with company.

First Prospective Data on Impact of Minimal Residual Disease on Long-Term Clinical Outcomes after Venetoclax Plus Rituximab Versus Bendamustine Plus Rituximab: Phase III MURANO Study

First Prospective Data on Impact of Minimal Residual Disease on Long-Term Clinical Outcomes after Venetoclax Plus Rituximab Versus Bendamustine Plus Rituximab: Phase III MURANO Study

Minimal Residual Disease (MRD) at Time of Complete Remission Is Commonly Detected in Acute Myeloid Leukemia (AML) Patients Age ≥60 Years and Significantly Impacts Outcome Based on Post-Remission Treatment Strategies: Prospective Analysis of ECOG-ACRIN (E-A) E2906 Phase III Trial

Minimal Residual Disease (MRD) at Time of Complete Remission Is Commonly Detected in Acute Myeloid Leukemia (AML) Patients Age ≥60 Years and Significantly Impacts Outcome Based on Post-Remission Treatment Strategies: Prospective Analysis of ECOG-ACRIN (E-A) E2906 Phase III Trial

Different Treatment Regimens, Optimal Time Points and Threshold Level While Minimal Residual Disease Evaluation in AML Patients

Introduction. Minimal residual disease (MRD) detection by multicolor flow cytometry (MFC) after early induction or consolidation AML therapy is a well known factor of adverse prognosis, especially in intermediate risk group. New assessment of response in AML is complete remission with MRD-negative status. However, there is still no standardization of MFC method for AML patients (pts). Optimal time point for MRD status and its threshold value vary in different studies.Aim. To study different consolidation treatment regimens in AML pts by measuring of MRD reduction, to determine optimal time point and threshold level for additional risk stratification.Patients and methods. From March 2016 to February 2018 42 pts (younger than 60 y.o.) with newly diagnosed AML were included in prospective MRD study in hematology department of National Research Center for hematology. Initial leukemia-associated immunophenotype was analysed before any treatment, and bone marrow assessment for MRD detection was performed in CR pts after 1st and 2nd chemotherapy courses. The standard antibody panel included CD19, CD7, CD2, CD38, CD65, CD66b, CD99 (FITC); CD56, CD15, CD11b, CD13 (PE); CD33 (APC); HLA-DR, CD14, CD16, CD117 (PerCP-Cy 5.5); CD45 (APC-H7) and CD34(PE-Cy7). For results record BD FACSCanto II (Becton Dickinson) machine was used. The first course for all pts was the standard «7+3». Before March 2017 the second course was also «7+3» and included 25 pts, after March 2017 - 17 pts received intensive «Flarida» regimen (Fludarabine 30mg/m2 1-4, Ara-C 1g/m2 1-4, Idarubicin 8mg/m2 1,3). The 2nd MRD test was compared in these two groups. There was no difference between the two groups by pts in CR after the first «7+3», ELN status and age.Results. By using of special mathematical and statistical method the threshold value of 0,01% was estimated for long-term prognosis. Two years relapse-free survival (RFS) in MRD-positive (MRD+) and MRD-negative (MRD-) groups after the 1st induction was 23% and 87%, respectively (p<0,01). Probability of relapse (PoR) during the first year of observation in these two groups was 72% and 10%, respectively (p<0,01). After the second course 9 more pts in two groups became MRD-negative and 6 of them developed a relapse. RFS in MRD+ and MRD- after the 2nd course was 36% and 65% (p<0,01), and PoR - 71% and 34%, respectively (p<0,01). Multivariate analysis showed MRD factor as the only important in RFS compared to cytogenetic, molecular status, age and initial leukocyte count. OS and RFS in «7+3» and «Flarida» regimens during the first year were 100% vs 80% (p=0,27) and 74% vs 76% (p=0,63), respectively. MRD level reduction after different consolidation regimens («7+3» vs «Flarida») didn't show any variation (p=0,14) and there was no association between MRD status after induction in different ELN groups (p=0,52).Conclusion. MRD threshold value of 0,01% allows to distinguish the two cohorts of AML pts groups: with different prognosis even in any ELN risk subgroups. The RFS was reliably higher in pts with CR and MRD-negative status right after the first induction, which reflected the chemo sensitivity of the tumor. After the consolidation course MRD detection still has a prognostic value. MRD level reduction was not associated with intensification of chemotherapy. There is a great need to achieve MRD negative status in AML pts after the 1st induction course so new therapy approaches are pending. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Phase 2 Study of Lenalidomide Maintenance for Patients with High-Risk Acute Myeloid Leukemia in Remission

Phase 2 Study of Lenalidomide Maintenance for Patients with High-Risk Acute Myeloid Leukemia in Remission

Pediatric-Inspired Chemotherapy Incorporating Pegaspargase Is Safe and Results in High Rates of MRD Negativity in Adults Ages 18-60 with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Introduction: Among adolescents and young adults with (w/) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), treatment using a pediatric (vs. adult) regimen appears to achieve superior event-free (EFS) and overall survival (OS); this observation has driven increased interest in adapting pediatric regimens for middle-aged adults w/ ALL/LBL. However, greater risk of toxicities associated w/ asparaginase complicates administration of pediatric-inspired regimens in adults. We therefore designed a pediatric-inspired chemotherapy regimen w/ doses of pegaspargase (PEG) rationally synchronized to limit overlapping toxicities w/ other chemotherapeutic agents.Methods: We conducted a phase II multi-center trial in adults ages 18-60 w/ newly-diagnosed Philadelphia chromosome-negative (Ph-) ALL/LBL (NCT01920737). Pts w/ Ph+ ALL or Burkitt-type ALL were ineligible. The treatment regimen consisted of 2-phase induction (I-1, I-2), followed by consolidation w/ 2 courses of alternating high-dose methotrexate-based intensification and reinduction, followed by 3 years of maintenance (Figure 1). PEG 2000 IU/m2 was administered in each of the 6 intensive courses of induction/consolidation at intervals of ≥4 weeks. Minimal residual disease (MRD) was assessed in bone marrow (BM) by multiparameter flow cytometry (FACS) on day (d) 15 of I1 and following I-1 and I-2. Any detectable MRD (even <0.01% of BM WBCs) was considered positive. Toxicities were assessed by CTCAE v4.0.Results: 39 pts were enrolled (30M, 9F), w/ B-ALL (n=28), T-ALL (n=7), B-LBL (n=3), and T-LBL (n=5). Median age at start of treatment was 38.3 years (range 20.2-60.4), w/ 18 pts age 40-60.Grade 3-4 toxicities associated w/ PEG are summarized in Table 1. Grade 3-4 hyperbilirubinemia was observed post-PEG in I-1 in 9 pts, but only recurred thereafter in 1/8 pts resuming PEG. Pts completing consolidation on protocol (n=16) received median of 6 doses of PEG (range, 2-6). Four pts developed hypersensitivity to PEG and subsequently received Erwinia asparaginase. PEG was discontinued in 4 additional pts due to hepatotoxicity (n=2), pancreatitis (n=1), and physician preference (n=1).Of pts w/ available response assessments, 35/36 (97%) achieved morphologic complete response (CR) or CR w/ incomplete hematologic recovery (CRi) following I-1 (n=34) or I-2 (n=1). Both pts not achieving CR/CRi after I-I had early T-precursor ALL; one of these pts was withdrawn from study, and the other (w/ M2 marrow after I-1) achieved CR after I-2.Of the pts w/ ALL (excluding LBL) w/ available BM MRD assessments, 11/28 (39%) achieved undetectable MRD by FACS following I-1; 18/22 (82%) achieved undetectable MRD by FACS following I-2. Of the pts w/ LBL w/ available BM MRD assessments, 7/7 (100%) achieved or maintained undetectable MRD by FACS following I-1 and I-2. Ten pts underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1. Seven pts experienced relapse at median 15.2 months from start of treatment (range, 5.4-30.4), of whom 6 subsequently underwent 1st (n=5) or 2nd (n=1) alloHCT. Of the 11 pts w/ ALL w/ undetectable MRD following I-1, only one has relapsed. Five patients have died, including 2 pts in CR1 (from sepsis and multi-organ system failure), and 3 pts in relapse.At median follow-up of 22.3 months among surviving pts (range, 1.0-48.1), median EFS and OS (Figure 2A&B) have not been reached (EFS not censored at alloHCT). 3-year EFS was 62.1% (95% CI: 38.4-78.9%) and 3-year OS was 80.0% (95% CI: 57.5-91.4%).Conclusions: PEG can be incorporated into pediatric-inspired chemotherapy regimens w/ manageable toxicity for appropriately selected adults up to age 60 w/ Ph- ALL/LBL. While PEG-related AEs are common, few pts require permanent discontinuation of asparaginase. Grade 3-4 hyperbilirubinemia was common, particularly post-I-1, but recurred infrequently when PEG was continued. Two induction courses resulted in a high rate of MRD negativity post-I-2 and translated to a low rate of relapse. Though further follow-up is required, 3-year EFS is encouraging. Data regarding asparaginase enzyme activity and silent inactivation w/ neutralizing anti-PEG antibody will be presented. Ongoing and future studies will additionally investigate whether incorporating novel therapies (e.g. blinatumomab, nelarabine) into frontline consolidation therapy may reduce risk of relapse among adults receiving PEG-containing regimens. [Display omitted] DisclosuresGeyer:Dava Oncology: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Rao:Kite, a Gilead Company: Employment. Tallman:Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding. Douer:Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Pfizer: Honoraria; Spectrum: Consultancy. Park:Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy.

Allogeneic Hematopoietic Cell Transplantation (HCT) Vs. Non-HCT Consolidation Therapies in Acute Myeloid Leukemia (AML) Patients 60-75 Years of Age in First Complete Remission (CR1): An Alliance (A151509), SWOG, ECOG-ACRIN and CIBMTR Study

Introduction: The preferred post-remission therapy for older patients (pts) with AML remains uncertain. We compared outcomes for older AML pts in CR1 receiving HCT reported to the CIBMTR to older AML pts achieving CR1 on National Clinical Trials Network induction and non-HCT consolidation therapy (CT) trials.Methods: This study focused on pts 60-75 years of age treated between 2004 to 2013. CT pts (n=211) underwent induction and consolidation on Alliance for Clinical Trials in Oncology, ECOG-ACRIN or SWOG clinical trials for initial therapy for newly diagnosed AML; the CIBMTR provided data for HCT pts (n=431). CT patients received at least one cycle of CT on study and were excluded if HCT occurred at any time. Time to event started at CR1 and pts entered at CT or HCT, respectively, using left-truncation to account for differential entry times.Results: For the CT cohort, first consolidation included standard therapy (e.g., cytarabine or a hypomethylating agent) and additional study drug (e.g., bortezomib, dasatinib, sorafenib, and Zosuquidar, gemtuzumab) or tipifarnib alone. Among HCT pts, the donor was a HLA-matched sibling or unrelated donor (URD) in 66% and the others were partially HLA-matched/mismatched URD (10%) or cord blood (24%). HCT pts were younger and more frequently had high-risk AML (high WBC, secondary AML and unfavorable cytogenetics) (Table). The median time from CR1 to HCT and CT was 3.2 and 0.5 months, respectively.Allogeneic HCT showed worse overall survival (OS) (HR=1.52, p=0.02) prior to 9 months and better OS thereafter (HR= 0.53, p <0.0001) relative to CT (figure 1A). Treatment-related mortality (TRM) was worse after HCT in the first 9 months (HR=2.8, CI: 1.5 -5.2, p=.0009), while relapse was less frequent beyond 9 months after treatment (HR = 0.42, CI: 0.29 to 0.61, p<.0001). Despite higher early TRM, HCT recipients went on to manifest superior OS [5 year OS: HCT 29% (24-34%), CT 13.8% (9 -22%)] (Figure 1A). The benefit of HCT for survival after 9 months was more prominent in those with unfavorable cytogenetics (Figure 1B). Multivariate analysis for OS showed no statistically significant effect of age or performance status, while unfavorable cytogenetics were detrimental (HR=1.74, p<.0001).Conclusions. Allogeneic HCT led to heightened early risks from TRM, but resulted in superior long-term survival in older AML pts receiving HCT relative to CT by reducing relapse. Efforts to attenuate early TRM after allogeneic HCT may further improve HCT outcomes for older pts. [Display omitted] DisclosuresUstun:novartis: Speakers Bureau. Attar:Agios: Employment, Equity Ownership. Larson:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding. Roboz:Roche/Genentech: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; AbbVie: Consultancy. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Stone:Fujifilm: Consultancy; Ono: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Weisdorf:Seattle Genetics: Consultancy; Equillium: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy.

Phase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

Phase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

The Lysine-Specific Demethylase 1 (LSD1) Inhibitor Tranylcypromine (TCP) in Combination with ATRA Is Tolerable and Has Anti-Leukemic Activity in Adult Patients with Relapsed/Refractory AML and MDS

▪Introduction:Tranylcypromine (TCP) is an irreversible monoamine oxidase inhibitor, a potent antidepressant that has been in use since the 1960s. Additionally, TCP has been demonstrated to inhibit lysine-specific histone demethylase 1A (LSD1), which is highly expressed in AML (Lee 2006; Berglund 2008). Preclinical studies combining TCP and ATRA induced differentiation and impaired clonogenic survival in non-APL AML cell lines and primary patient samples. These findings were supported by mouse xenograft models (Schenk 2011). Based on this preclinical work, we pursued an investigator-initiated Phase 1 study of this combination at the University of Miami Sylvester Comprehensive Cancer Center (NCT02273102).Methods:A Phase 1 study was initiated to evaluate the safety, PK/PD, and preliminary clinical activity of TCP in combination with ATRA in patients (pts) with relapsed/refractory AML and high-grade MDS. The study followed a traditional 3+3 dose escalation design. Safety for all pts and efficacy for all evaluable pts to date are reported. All adverse events were recorded per NCI CTCAE v4.03. All pts received continuous daily dosing of both ATRA (45 mg/m2 in divided doses) and TCP (3 escalating dose levels: 10mg BID, 20mg BID and 30mg BID), with a 3-day lead-in of TCP only during cycle 1. Cycles were 21 days and pts were allowed to remain on study until progression or unacceptable toxicity.Results:At the time of data cutoff, 15 pts had received therapy with combination TCP/ATRA (8 AML and 7 MDS). Median age was 74 years, 40% were female and 67% white/27% Hispanic/7% black. Overall, the combination was well tolerated, with the majority of treatment emergent adverse effects (TEAEs) Grade 1 and 2. The most common TEAEs (all grades, ≥20%) included dry mouth (33%), dry skin (27%), febrile neutropenia (27%), dizziness (27%), fatigue (27%), headache (27%), rash (27%), increase in creatinine (27%); and vomiting, nausea, diarrhea, infection, urinary frequency and thrombocytopenia all with a frequency of 20%. The most common Grade 3/4 TEAEs included febrile neutropenia (27%), thrombocytopenia (20%), sepsis (13%), lung infection (13%) and anemia (13%). There was 1 DLT of dizziness at the TCP 20mg BID dose level (out of 8 pts) and 2 DLTs of generalized weakness and nausea/vomiting, respectively, at 30mg BID (out of 3 pts). All DLTs were grade 2, but persistent and poorly tolerated. Therefore, TCP 20mg BID was determined to be the MTD and selected as the RP2D. Best evaluable responses per modified IWG/ELN criteria included 5 pts with prolonged stable disease (all 3 months or more) (2 AML, 1 CMML, 2 MDS), 1 marrow CR (MDS) and 1 MLFS (AML). Three of the 4 MDS/CMML responders had hematologic improvement (HI) (2 HI-P and 1 HI-P and HI-E). One AML pt also recovered neutrophils (0.62 to 14.75) with a decrease in blasts but did not meet response criteria. The 2 pts with best response of marrow CR and MLFS continued on study for 7 and 10 months, respectively. Importantly, these 2 pts and a third pt who had prolonged SD (5 months) plus HI-P/HI-E were all taken off study for cumulative skin toxicity (not progression), and the marrow CR and MLFS pts are both still alive.Conclusions:TCP/ATRA combination therapy has demonstrated an acceptable safety profile in pts with R/R AML and MDS, and additionally has demonstrated clinical activity. TCP 20mg BID is the RP2D, and a phase 1 dose expansion at this dose level is ongoing. In responders, skin toxicity may be treatment duration-limiting due to continuous exposure to ATRA, and an intermittent ATRA schedule after cycle 4 may be pursued for the phase 2 study. Additional data will be presented at the meeting, including myeloid mutational analysis, RNA-seq and ATAC-seq, in order to delineate pre- and post-treatment molecular profiles and chromatin accessibility in these pts. Preliminary data (not shown) suggest that a baseline gene expression pattern may predict sensitivity or resistance to TCP/ATRA. DisclosuresWatts:Takeda: Research Funding; Jazz Pharma: Consultancy, Speakers Bureau. Swords:AbbVie: Employment.

Abstract CT068: Phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)

Abstract Introduction: TP53 mutant (mTP53) MDS and AML represent a distinct molecular cohort with poor outcomes. Hypomethylating agents (HMA) have emerged as preferred treatment for these patients with CR rate of 20-30% and median OS of 6-12 months. APR-246 is a mutant p53 activator with single agent activity in mTP53 AML. We report initial phase 1b results of APR-246 + AZA in mTP53 MDS/AML. Methods: Eligible pts included HMA naïve mTP53 MDS and oligoblastic AML (≤ 30% blasts) ≥ 18 years of age. Pts received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight) IV daily over 4 days in a lead-in phase (days -14 to -10) followed by the same dose of APR-246 (days 1-4) + AZA 75 mg/m2 SC/IV over 7 days (days 4-10 or 4-5 and 8-12) in 28 day cycles. Primary objective was safety with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks. Secondary endpoints included response by IWG 2006 criteria as well as serial next generation sequencing (NGS) and p53 IHC for evaluation of clonal suppression and remission depth. Results: As of Jan 1, 2017, 9 pts (33% male; median age 65 years (39-73)) have enrolled with 3 pts per cohort. Three pts had AML-MRC and 6 had MDS; all pts had poor risk cytogenetics (11% poor, 89% very poor) and higher risk disease by IPSS-R (22% high, 78% very high). Median BM blasts were 18% (4-30). Seven pts (78%) remain on study: 2 pts in the 50mg/kg cohort discontinued treatment (Tx), 1 pt due to infection during C2 who later died of sepsis unrelated to Tx, and 1 pt electively discontinued in durable marrow CR (mCR) after 5 cycles of therapy. Median time on study is 106 days (14-221). Tx related AEs during the lead-in phase (all G1) included ataxia (n=1), dizziness (n=1), and facial numbness (n=1). AEs occurring in &amp;gt; 1 pt included dizziness (n=3), nausea (n=3), neutropenia (n=3), thrombocytopenia (n=3), infection (n=3), headache (n=2), pain (n=2), weakness (n=2), falls (n=2), facial numbness (n=2), and ataxia (n=2); all G1/G2 except neutropenia/thrombocytopenia (G4). No Tx-related SAEs or DLTs have occurred to date. Five of six pts were response evaluable with 1 pt discontinuing tx prior to 1st disease assessment. ORR by IWG was 100% with 4 CR (80%, 3/3 in DL2) and 1 mCR. All CR patients achieved complete cytogenetic response. One CR patient achieved a mCR and partial cytogenetic response after APR-246 lead-in prior to combination therapy. All CR pts had high p53 positivity by IHC at baseline (55-70%) which normalized on serial assessment (&amp;lt;5%). Serial NGS with a variant allele frequency (VAF) cutoff of 2% was negative in 80% of patients (4/5). The remaining 3 pts entered the study in Dec 17/Jan 18 with no response data available at data cutoff. Conclusions: APR-246 + AZA combination is well tolerated in mTP53 MDS/AML. Responses have been achieved in all pts (80% CR) accompanied by deep molecular remissions. The maximum tolerated dose has not been reached and dose escalation is ongoing. Citation Format: David A. Sallman, Amy DeZern, Kendra Sweet, David P. Steensma, Thomas Cluzeau, Mikkael Sekeres, Guillermo Garcia-Manero, Gail Roboz, Amy McLemore, Kathy McGraw, John Puskas, Ling Zhang, Chirag Bhagat, Armin Graber, Najla H. Al Ali, Eric Padron, Roger Tell, Jeffrey E. Lancet, Pierre Fenaux, Alan F. List, Rami S. Komrokji. Phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT068.

Myeloablative Conditioning for First Allogeneic Hematopoietic Stem Cell Transplantation in Children with ALL: Total Body Irradiation or Chemotherapy? - a Multicenter EBMT-PDWP Study

▪Introduction: Most pediatric patients (pts) with ALL receive total body irradiation (TBI) for myeloablative conditioning of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unproven whether TBI can be replaced by chemotherapy (CHT).Methods: To compare the outcomes of TBI- versus (vs.) CHT-based conditioning, we performed a retrospective EBMT-registry based study. Children between 2 and 18 years of age (y.) after myeloablative conditioning for first allo-HSCT of bone marrow (BM) or peripheral blood SC (PBSC) from matched sibling (MSD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to consider the covariate “distribution of TBI recipients” for pts who did not receive TBI.Results: In total 3071 pts (CR1: 1504 (49%), CR2: 1567 (51%)) were included. CR1: 1045 pts (69%) received BM and 459 pts (31%) PBSC from MSD (760 (51%)) or UD (744 (49%)). CR2: 1067 pts (68%) received BM and 500 pts (32%) PBSC from MSD (675 (43%)) or UD (892 (57%)). Overall, conditioning was TBI- in 2647 (86%) and CHT-based in 424 pts (14%). Busulfan/Cyclophosphamide (Bu/Cy) and Bu/Cy/Etoposide (Bu/Cy/Eto) were the two most frequently applied CHT combinations in CR1 (68 (32%), 66 (31%)) and CR2 (68 (32%), 52 (25%)). The remaining conditionings included 5 different combinations of chemotherapeutics (other chemo).1504 pts in CR1 were conditioned with TBI (1291), Bu/Cy/Eto (66) or other chemo (147) with a median follow-up of 4.4, 3.4 and 2.4 y. In weighted univariate analysis no significant differences were detected for LFS (5-y.-LFS, range: 62.4 to 67.5%) and relapse incidence (5-y.-RI, range: 24.0 to 29.0%). In pairwise testing, OS after Bu/Cy/Eto was significantly better compared with TBI (5-y.-OS, 78.7 vs. 66.8%, P=.006). Non-relapse mortality was significantly higher after other chemo (5-y.-NRM, 12.7%, P <.001) and TBI (12.5%, P <.001) compared with Bu/Cy/Eto (3.5%).Other significant influencing factors on LFS were age (5-y.-LFS, 2-11 y. 65.8 vs. 12-18 y. 58.0%, P=.009), y. of HSCT (2008-2012 65.9 vs. 2000-2007 59.6%, P=.035) and donor type (MSD 64.9 vs. UD 59.5%, P=.007). RI was influenced by y. of HSCT (5-y.-RI, 2008-2012 21.7 vs. 2000-2007 26.8%. P=.026). OS was influenced by age (5-y.-OS, 2-11 y. 72.7 vs. 12-18 y. 61.7%, P <.001) and donor type (MSD 70.1 vs. UD 65.0%, P=.002). NRM was influenced by age (5-y.-NRM, 2-11 y. 9.0 vs. 12-18 y. 18.0%, P <.001), donor sex (male 10.9 vs. female 16.6%, P=.007) and donor type (MSD 8.5 vs. UD 17.8%, P <.001).In weighted multivariable Cox model clustered on EBMT centers, TBI-based conditioning in CR1 was associated with lower RI (HR 0.70, P=.047), lower OS (HR 1.54, P=.017) and higher NRM (HR 3.97, P <.001).1567 pts in CR2 were conditioned with TBI (1356), Bu/Cy (68) or other chemo (143) with a median follow-up of 3.9, 3.2 and 3.1 y. In weighted univariate analysis highly significant differences of survival were detected. TBI-based conditioning resulted in highest 5-y.-LFS of 52.2% (Bu/Cy 41.0%, other chemo 18.4%, P <.001), lowest 5-y.-RI of 33.2% (Bu/Cy 38.3%, other chemo 55.3%, P <.001), highest 5-y.-OS of 56.1% (Bu/Cy 43.6%, other chemo 23.6%, P <.001) and lowest 5-y.-NRM of 14.6% (Bu/Cy 20.8%, other chemo 26.2%, P <.001).Other significant influencing factors on LFS were age (5-y.-LFS, 2-11 y. 53.5 vs. 12-18 y. 43.0%, P <.001), y. of HSCT (2008-2012 53.3 vs. 2000-2007 47.3%, P=.009) and SC source (BM 53.3 vs. PBSC 42.5%, P <.001). RI was influenced by SC source (5-y.-RI, BM 33.1 vs. PBSC 36.6%, P=.024). OS was influenced by age (5-y.-OS, 2-11 y. 59.3 vs. 12-18 y. 46.8%, P <.001), y. of HSCT (2008-2012 58.6 vs. 2000-2007 52.0%, P=.005), donor type (MSD 58.5 vs. UD 52.6%, P <.024) and SC source (BM 58.4 vs. PBSC 47.5%, P <.001). NRM was influenced by age (5-y.-NRM, 2-11 y. 12.5 vs. 12-18 y. 22.3%, P <.001), donor type (MSD 10.2 vs. UD 19.8%, P <.001) and SC source (BM 13.6 vs. PBSC 20.8%, P <.001).In weighted multivariable Cox model clustered on EBMT centers, TBI-based conditioning in CR2 was associated with higher LFS (HR 0.48, P <.001), lower RI (HR 0.48, P <.001) and higher OS (HR 0.51, P <.001).Conclusion: Conditioning by TBI demonstrated clear superiority in comparison to CHT for children with ALL undergoing HSCT in CR2. For pts in CR1, TBI- and CHT-based conditioning showed similar results. This retrospective data is currently re-evaluated in a prospective, randomized, international trial (ALL SCTped 2012 FORUM). DisclosuresBüchner:Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Consultancy. Veys:Bellicum: Research Funding; Servier: Research Funding. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

Haploidentical T-Repleted Stem Cell Transplantation (SCT) Has Comparable Survival to 10/10 and 9/10 Unrelated SCT in Poor-Cytogenetics Risk Acute Myeloid Leukemia in First Complete Remission: A Study on Behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Allogeneic stem cell transplantation (SCT) is the most powerful therapy to prevent relapse in poor-cytogenetics risk acute myeloid leukemia (poorAML) patients (pts) in first complete remission (CR1). For pts who lack a matched related donor (MRD), SCT from an unrelated (UD) or alternative donor is indicated. Pts with poorAML and thus at high risk of relapse can theoretically benefit the most from SCT from haploidentical donors (HaploSCT), which is an attractive option as the time required to find a well-matched UD could be inacceptable. Several recent reports show comparable outcomes between HaploSCT and transplants from UD (Piemontese S, JHO 2017; Versluis J, Blood Advances 2017). Comparative studies able to include sufficient numbers of pts with poorAML in CR1 are limited; this prompted us to compare the outcomes of HaploSCT to those of 10/10 and 9/10 HLA-matched UD in this disease category.Methods: We retrospectively selected denovo poorAML pts in CR1 receiving T-repleted haplo (n=74), 10/10 UD (n=433) and 9/10 UD SCT (n=123) from 2007 to 2015 who were reported to the ALWP of EBMT Registry. PoorAML was defined as the presence of: complex karyotype (at least 3 structural abnormalities per clone); monosomal karyotype (1 autosomal monosomy plus 1 monosomy or structural abnormality); inv(3)/t(3;3); -5 or del(5q); -7 or abn(7q); t(v;11)(v;q23); abn(17p); t(6;9); t(9;22). Primary endpoints were leukemia-free survival (LFS) and overall survival (OS). Secondary endpoints were acute and chronic GVHD (aGVHD and cGVHD), relapse and nonrelapse mortality (NRM).Results: Main population characteristics are depicted in Table 1. Recipients of haplo-, 10/10 UD- and 9/10 UD-SCT were comparable concerning time from diagnosis to SCT and time from CR1 to SCT. HaploSCT more likely received bone marrow as stem cell source. In-vivo T cell depletion (TCD) with ATG was most likely adopted in UD-SCT, with a conversely increased use of high-dose post-transplant Cyclophosphamide as GvHD prophylaxis backbone in HaploSCT (65% Vs 3% for 10/10 UD and 2% for 9/10 UD, p<10¯³).LFS and OS at 2 years were not significantly different between haploSCT, 10/10 UD SCT and 9/10 UD SCT (53±12% and 59±12%, 43±5% and 50±6%, 44±9% and 50±9%, respectively, p=0.5 and p=0.5, respectively).In Haplo-SCT, the 100-day cumulative incidence (CI) of grade≥2 aGvHD was in line with the one reported for 10/10 and 9/10 UD (33±11% for haplo, 30±4% for 10/10 UD and 34±9% for 9/10 UD, p=0.6). Likewise, the 2-y CI of cGvHD (35±12%) of HaploSCT was similar to those of 10/10 UD (36±4%) and 9/10 UD (36±9%), p=0.8. The 2-y CI of NRM was 19±8% after haploSCT, 18±4% after 10/10 UD SCT and 18±6% after 9/10 UD SCT (p=0.9). Relapse incidence was not significantly affected by donor source, with a 2-y CI of 27±9% for haploSCT, 39±5% for 10/10 UD SCT and 37±9% for 9/10 UD SCT (p=0.3).After adjustment for centre effect, pts age, time from diagnosis to SCT, conditioning intensity, in-vivo TCD, donor/pts gender and CMV serostatus, the multivariable model showed that haploSCT recipients didn't experience worse outcomes compared to 10/10 and 9/10 UD. Indeed, compared to haploSCT (reference) the hazard ratio (HR) for LFS was 1.2 for 10/10 UD (p=0.3) and 1.2 for 9/10 UD (p=0.4). The hazards for OS in 10/10 and 9/10 UD did not differ from haplo-SCT (1.3, p 0.3 and 1.2, p 0.4, respectively). Moreover, compared to haplo, SCT from 10/10 and 9/10 UD was not associated with lower hazards for relapse (HR: 1.4, p=0.2 and 1.4, p=0.3, respectively), NRM (HR: 1, p=0.9 and 1, p=0.9, respectively), grade≥2 aGvHD (HR: 1.2, p=0.6 and 1.4, p=0.3, respectively) and cGvHD (HR: 1.2, p=0.5 and 1.3, p=0.4, respectively). The only factor associated with worse LFS and OS was pts age (for each 10-year interval: HR 1.1, p=0.02 and 1.2, p=0.001, respectively).Conclusions: In the present series of poorAML pts transplanted in CR1, haploSCT recipients experienced comparable outcomes with respect to 10/10 and 9/10 HLA-matched UDs. This suggests that the immunotherapeutic effect of allogeneic SCT is exerted similarly across these different donor sources in this peculiar population. Therefore, in the absence of a MRD, pts with poor risk cytogenetics who have a very high risk of relapse could be allocated to haploSCT in their first remission, especially in the context of the recent improvements, which fostered an abatement of GvHD and NRM rates, historically the main detrimental factors for Haploidentical transplants. [Display omitted] DisclosuresCiceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty:Sanofi: Honoraria, Speakers Bureau.

The Relationship of Response on Time to Next Treatment Based on Evidence from Two RCTs in Newly Diagnosed Stem Cell Transplantation Ineligible Multiple Myeloma Patients

The Relationship of Response on Time to Next Treatment Based on Evidence from Two RCTs in Newly Diagnosed Stem Cell Transplantation Ineligible Multiple Myeloma Patients