ALBERT

Description: Bone marrow (BM) is the accepted source for monitoring post-therapy minimal residual disease (MRD) in APL. PB is easier and less painful to obtain but variable, sometimes contradictory evidence has been presented for its efficacy in MRD monitoring. In this study, PB vs BM monitoring, as well as conventional, qualitative RT-PCR (C-PCR) vs Q-PCR were directly and prospectively compared for their effectiveness as part of an intensive MRD monitoring schedule applied as a safety measure to an investigative Phase II trial (J0422) designed to test the efficacy of minimizing chemotherapy exposure and treatment duration. This trial consisted of one cycle of induction with all-trans retinoic acid (ATRA) and daunorubicin, followed by consolidation with single-agent arsenic trioxide (ATO), followed by a maintenance phase of intermittent ATRA alone or with 6-mercaptopurine and methotrexate for patients (pts) with a presenting white blood cell count (WBC) of 〉10,000 WBC/uL. The MRD monitoring schedule was as follows: BM and PB after the induction and consolidation treatment modules (modules 1 & 2), then, PB every month and BM every 3 months during 2 years of maintenance therapy. C-PCR and Q-PCR were performed according to published procedures for monitoring the APL-specific fusion gene PML-RARα by the BIOMED-1 Concerted Action and the North American Cooperative Oncology Groups, respectively. Criteria for positive assays were: C-PCR, confirmed visualization of an appropriate-sized gel band after conventional, double-nested PCR amplification; Q-PCR, demonstration of a CT value 12 mo, suggesting continued reduction of MRD during first 12 mo of maintenance therapy. No C-PCR assays were positive beyond module-1. In 1 exceptional pt, excluded from the above maintenance analysis, the Q-PCR assays became recurrently positive in BM and/or PB after 6 mo maintenance at a level below the criterion for molecular relapse (normalized quotient relative to the housekeeping gene GAPDH, NQGAPDH, ≥10−5). After 18 mo, the C-PCR became repeatedly positive in PB but not BM with Q-PCRs positive (2 BM & PB, 1 PB-only at shared checkpoints) in the NQGAPDH 4×10−7 to 4×10−6 range, which was associated with relapse in the central nervous system but not the BM. These results indicate that molecular monitoring of PB or BM was equally effective in detecting MRD and that Q-PCR was a more critical measure of MRD than C-PCR on protocol J0422 after single-cycle ATO-based consolidation therapy. The results further suggest that PB monitoring may be more effective in detecting extramedullary relapse, a relatively increasing cause of disease relapse with improved overall therapy for APL.

Description: Current strategies for the treatment of patients with acute promyelocytic leukemia provide event-free survival of 75 – 85%. Most multicenter studies have used large doses of anthracyclines and multiple cycles of treatment. Based on the extremely high efficacy of arsenic trioxide (ATO) as single agent re-induction therapy, we conducted a Phase II study which minimized anthracycline exposure and treatment duration in newly diagnosed APL patients. The study design was modified from a previous trial which successfully used a single cycle of consolidation chemotherapy (Am. J. Heme.2005;79:119–27). All patients received ATRA for 60 days with daunorubicin (DRN, 60 mg/m2/dose IV) on days 4, 6, 8 unless urgent cytoreduction was required. Consolidation, begun between days 60 and 67, consisted of cytarabine 0.667 gm/m2/day IV continuous infusion days 1 – 3, DRN 60 mg/m2/dose IV days 1 – 3, and ATO 0.15 mg/kg IV for 30 doses, administered five days per week beginning on day 8 of consolidation on an outpatient basis. A second module of ATO was planned for patients with a positive qualitative rt-PCR for PML-RARα (sensitivity 1/10000) following recovery from consolidation. Patients whose initial WBC was 〈 10,000 per microliter proceeded to ATRA maintenance given for 15 days every three months for 8 cycles. Patients with WBC counts greater than 10,000 per microliter also received 6-mercaptopurine and methotrexate as part of the maintenance regimen. Forty-five patients received induction therapy. Median age was 50; relapse risk categories (Sanz et al. Blood. 2000;96:1247–1253): Low, 36%; Intermediate, 29%; High, 32%. Four patients expired during induction. Of the 41 remaining patients, 4 patients withdrew consent prior to consolidation due to difficulty traveling to the treatment center. 27/31 patients tested following induction achieved molecular remission at that time point (qualitative rt-PCR). 37 patients received consolidation therapy. No patients expired during consolidation, and no patients required a second module of ATO therapy. Only two events have been recorded in patients who underwent consolidation treatment: one patient with Hemoglobin SC disease expired during maintenance therapy due to intrahepatic sickle crisis, possibly related to methotrexate administration, while one patient developed central nervous system relapse. The table compares overall, event free- and disease-free survival of this series to three recent series, including the ATO-containing arm of C9810. Although median follow-up of the current series is shorter, to date the results are comparable to these three studies which employed more extensive therapy. No cases of secondary MDS or AML have been reported to date. Echocardiographic monitoring pre- and post-induction therapy in 24 patients revealed a decrement in ejection fraction post-induction of ≥ 10% in nine patients, including 〉 20% in three patients to EF values of 20 – 30%, with biopsyproven anthracycline-induced cardiomyopathy documented by biopsy in two patients, indicating possible cardiac sensitization by ATRA to anthracycline. These data suggest that the inclusion of ATO in primary APL management may allow further minimization of conventional cytotoxic chemotherapy without compromising cure rates, and demonstrate the critical need to determine the minimum curative therapy for APL patients. Series Total anthracycline dose administered (mg/m2 DRN equivalent)a Age (median) Sanz Relapse risk: High (percent) Follow- up (years, median) Overall survival Disease- Free Survival Event- Free Survival a Daunorubicin= 1. Mitoxantrone = 2.5. Idarubicin = 5. b nr indicates not reported c Selected based on Sanz risk score 90.5 92.9 83.6 Current 360 50 32 1.8 86 87 77 C9710 ATO arm 500 nrb 24 2.4 82 84 nr PETHEMA LPA99 525 – 625c 37 25 5.4 APL2000 Ara-C arm 495 43 46 5.2 90.5 nr 85.6

Description: Background: Despite recent advances in the therapeutic armamentarium for AML, outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Response rates with high dose cytarabine (HiDAC) salvage chemotherapy are approximately 20%. Multiple immune aberrations in AML lead to immune suppression, exhaustion, and senescence. Programmed Death-1 (PD-1), a co-inhibitory receptor (IR) on immune cells, suppresses immune activation and is exploited by leukemic cells to evade immune surveillance. PD-1 and other IRs are up-regulated during disease progression. We hypothesized that pembrolizumab, a monoclonal antibody targeting PD-1, after HiDAC would stimulate a T-cell mediated anti-leukemic immune response. Methods: Eligibility for this study included R/R AML 18-70 years, ECOG PS 0-1 and adequate organ function. Treatment consisted of HiDAC (60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14. The primary objective of this study was to estimate the overall complete remission (CR + CRi) rate. Secondary objectives included assessment of safety, durability of CR, overall survival (OS) and biomarker correlates of response. Overall responders were eligible to receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (alloSCT) was permissible before or after maintenance phase. Results: Thirty-seven pts were enrolled and evaluable (Table 1). Sixteen (43%) pts had refractory disease and 16 (43%) pts had relapsed AML with CR1 duration 3: n=1), AST elevation (32%; Grade 〉3: n=1), fatigue (27%), alkaline phosphatase elevation (24%), and maculopapular rash (19%; Grade 〉3: n=2). Grade 〉3 immune-related adverse events (iRAE) were rare (maculopapular rash: n=2, AST/ALT increase: n=2, right upper quadrant pain with lymphocytic infiltrate in liver: n=1) and self-limiting. Five (14%) pts required steroid administration for grade 2 hyperbilirubinemia (n=1), grade 3 ALT elevation (n=1), grade 3 AST elevation with liver biopsy revealing no evidence of iRAE (n=1), grade 3 bilirubin subsequently deemed to be a delayed hemolytic transfusion reaction (n=1), and grade 3 systolic dysfunction without evidence of myocarditis by endomyocardial biopsy or cardiac MRI (n=1). Sixty-day mortality was 3% (1/37) due to progressive AML. Median time to full neutrophil (〉1x109/L) and platelet (〉100x109/L) recovery was 32 and 31 days, respectively. The overall response (ORR: CR+CRi+PR+MLFS) and composite CR (CR+CRi) rates were 46% [29%,63%] and 38% [22%,55%], respectively, meeting the primary endpoint of the study. Notably, 13/28 (46%) pts receiving HiDAC + pembrolizumab as their first salvage regimen achieved CR/CRi. Two pts refractory to HiDAC (administered within past 6 months) achieved CR including one pt who was refractory to HiDAC salvage 1 month prior to enrollment and ultimately achieved CR without evidence of minimal residual disease. Nine (24%) pts received an alloSCT. There were no instances of Grade 〉3 acute GVHD or veno-occlusive disease post-alloSCT. Nine (24%) pts received maintenance phase pembrolizumab (median # of cycles = 3; range: 1-12) for CR (n=8) or PR (n=1). Seven out of 9 pts relapsed/progressed after maintenance phase. Median follow-up among survivors, and median OS, event-free survival and disease-free survival was 7.8 months, 8.9 months [6.0,13.1], 6.9 months [4.2,11.5], and 5.7 months [1.9,7.3], respectively. Conclusions: Pembrolizumab can be safely administered after HiDAC salvage in R/R AML. Severe iRAE's were uncommon despite administration after cytotoxic chemotherapy. The addition of pembrolizumab to HiDAC led to an encouraging overall CR rate meeting the primary endpoint of the study. Immunogenomic biomarker analyses consisting of B cell receptor amplicon sequencing, RNA-seq of blasts and CD8+ T cells, CD8+ T cell receptor repertoire, whole exome sequencing and flow cytometry analyses are ongoing to determine predictors of response. These results warrant further investigation of IR blockade and other immunomodulatory therapeutic strategies after intensive cytotoxic chemotherapy in AML. Disclosures Zeidner: Takeda: Research Funding; Merck: Research Funding; AsystBio Laboratories: Consultancy; Pfizer: Honoraria; Tolero: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria; AbbVie: Honoraria. Vincent:Pharmacyclics: Research Funding; Merck: Research Funding. Foster:Bellicum Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Consultancy. Coombs:Dedham Group: Consultancy; Covance: Consultancy; Cowen & Co.: Consultancy; Octopharma: Honoraria; H3 Biomedicine: Honoraria; Loxo: Honoraria; Pharmacyclics: Honoraria; Medscape: Honoraria. Webster:Pfizer: Consultancy; Amgen: Consultancy; Genentech: Research Funding. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Smith:Jazz: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Agios: Consultancy. Levis:Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents & Royalties: Patent holder. Serody:Merck: Research Funding; GlaxoSmithKline: Research Funding. Gojo:Amphivena: Research Funding; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Merck: Research Funding; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. OffLabel Disclosure: Pembrolizumab is investigational for AML.

Description: Background: CD8+ T-cells in AML pts co-express multiple inhibitory receptors (IRs), including PD1, and IR expression increases with disease progression (Knaus et al, JCI Insight 2018). AZA upregulates pathways related to immunity and immune evasion in tumor cells, including PD-L1, (Wrangle et al, Oncotarget 2013) providing rationale for exploring AZA/Pembro combination in AML. Aims: To assess safety and response to AZA/Pembro after minimum 2 cycles of therapy in relapsed/refractory (R/R) (Cohort 1) and newly diagnosed (dx) older AML (Cohort 2). Methods: Cohort 1: Pts must have failed prior AML therapy. The first 6 pts (run in phase) received AZA 75 mg/m2 Days (D) 1-7 with Pembro 200 mg beginning on D8 and every (q)3 weeks (wks) thereafter. AZA cycles were repeated q4wks. No pts experienced dose limiting toxicity after minimum 3 cycles observation. After safety was established with the dosing schedule, patients with prior allogeneic stem cell transplant (alloSCT) were included and Cohort 2 started enrollment. Cohort 2: Pts ≥65 years (yrs) with newly dx AML and not candidates, or unwilling to receive, intensive chemotherapy. Other eligibility criteria (Cohort 1 and 2): ECOG PS 0-2 (changed to PS 0-1), adequate organ function, and no autoimmune processes requiring systemic immunosuppression. Results: Efficacy: Cohort 1 : 37 R/R pts have been enrolled. Baseline characteristics are summarized in Table 1A. 29 (78%) pts completed at least 2 cycles and are evaluable for response: 4 achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi) (2/2) (14%) (Table 1B), 1 partial remission (PR) (4%), 4 hematologic improvement (HI) (14%), and 7 stable disease (SD) for at least 6 cycles (24%). The median # of cycles to response was 4 (range, 2-6). The 4- and 8-week mortality were 8% [all with rapidly progressive disease (PD): 2 received AZA for 3 and 5 days only] and 13%, respectively. With a median follow-up of 14.9 months (mos), the median overall survival (OS) for the whole cohort, responders + SD, and CR/CRi/PR is 10.8 mos (40% 1-yr), 13.9 mos (51% 1-yr), and 17.2 mos (75% 1-yr). The median event-free survival (EFS) is 6 mos, for all responders + SD 8.7 mos versus 2.6 mos for others (P

Description: 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 (

Description: Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Description: Introduction: Salvage chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia (AML) are associated with complete response rates of 30 - 60%. Determining the superiority of one treatment over another is difficult due to the lack of comparative data. There are no data comparing treatments with cladribine and clofarabine based salvage regimens to each other. Therefore, we conducted a retrospective study of GCLAC (clofarabine 25 mg/m2 IV days 1-5, cytarabine 2 gm/m2 IV days 1-5, and G-CSF) and CLAG (cladribine 5 mg/m2 IV days 1-5, cytarabine 2 gm/m2 IV days 1-5, and G-CSF). Methods: We identified 41 consecutive patients with pathologically diagnosed relapsed or refractory AML who received either GCLAC or CLAG between 2011 and 2014. The primary outcome was the complete response rate (CRp or CR) as defined by the International Working Group. Secondary outcomes included the percentage of patients who underwent allogenic stem cell transplant, relapse free survival (RFS), and overall survival (OS). Fisher's exact and Wilcoxon Rank Sum tests were used to compare patient characteristics and response rates. The Kaplan Meier method and Log Rank tests were used to evaluate RFS and OS. Results: We found no significant differences in the baseline characteristics of patients treated with GCLAC (n=22) or CLAG (n=19) including age, race, gender, organ function, or cytogenetic risk group (table 1). There were also no significant differences in the percentage of relapsed patients (36% vs. 21%), the average duration of the previous remission (28.6 vs. 19.4 months) or in their previous therapy. An anthracycline-based "7+3" regimen was given to 82% of the GCLAC patients and to 90% of the CLAG patients. The outcomes with these two regimens were also not significantly different. Patients treated with GCLAC had a 64% CR/CRp rate compared with 47% for CLAG patients (p= 0.36). 45% GCLAC patients underwent allogeneic stem cell transplant compared with 26% of CLAG patients (p= 0.32). The median RFS on GCLAC and CLAG respectively was 1.59 years [0.41, non-estimable (NE)] and 1.03 years [0.49, 1.03], (p= 0.75). The median OS was 1.03 years [0.52, NE] and 0.70 years [0.28, 1.11], (p= 0.08). Given the similarities of these regimens, we combined the data sets to compare the OS for patients with refractory AML to relapsed AML. The OS for patients with refractory AML was not significantly worse than patients with relapsed AML (0.94 years [0.36, 1.3] vs.1.11 years [0.46, not evaluable]; p=0.49). Conclusion: We find no significant differences in outcomes using GCLAC or CLAG for relapsed/refractory AML patients. The trends in outcome that favored GCLAC are likely explained by trends in patient populations (e.g. longer first remission for GCLAC patients). Since our results are similar to the published reports describing these regimens, we feel the choice of regimen can be based on other considerations such as cost. We do find the efficacy of both regimens in refractory AML to be encouraging. However, we recognize that overall survival of one year is not acceptable and that most relapsed/refractory patients should be entered into clinical trials. Table 1.Baseline CharacteristicsGCLAC (n=22)CLAG (n=19)p ValueAge (years)54.75 ± 11.552.9 ± 12.50.69Race (C vs Non C)18 (82%)12 (63%)0.21Gender (M)11 (50%)11 (58%)0.76Risk group Favorable4 (19%)2 (11%)0.48  Int-12 (10%)4 (22%)  Int-27 (33%)3 (17%)  Adverse8 (38%)9 (50%)Salvage attempt  120 (91%)15 (79%)0.39  〉12 (9%)4 (21%)Relapse vs Refractory  Relapse8 (36%)4 (21%)0.32Primary Refractory14 (64%)15 (79%)OutcomesGCLAC (n=22)CLAG (n=19)p ValueCRp or CR14 (64%)9 (47%)0.36Transplant9 (45%)5 (26%)0.32Median RFS (years)1.59 (0.41,NE)1.03 (0.49, 1.03)0.75Median OS (years)1.03 (0.52, NE )0.70 (0.28, 1.11)0.083RelapseRefractoryp ValueOS (years) of relapse vs refractory patients*1.11 (0.46, NE)0.94 (0.36, 1.34)0.49*All GCLAC and CLAG patients combined Disclosures Foster: Celgene: Research Funding.

Description: Introduction: AML pts have a poor prognosis with conventional chemotherapy regimens. Early lymphocyte recovery (ELR) following intensive timed sequential therapy (TST) induction is characterized by a dysfunctional immunosuppressive state. Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), has direct effects on T cell co-stimulation by promoting the ubiquitination of Aiolos, an IL-2 transcriptional repressor. We hypothesized that the administration of Pom at the time of ELR after induction TST may influence T cell differentiation and enhance an anti-leukemia immune effect. Methods: A multicenter phase 1 dose escalation study was conducted to determine the safety and tolerability of Pom after intensive induction TST in newly diagnosed AML and HR-MDS pts 18-65 years. Core-binding factor AML was excluded. All pts received induction chemotherapy with AcDVP16: cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2/day IV days 1-3, etoposide 400 mg/m2/day IV days 8-10. Pom was administered at the assigned dose and schedule after day 14 and within 3 days of the total white blood cell count (WBC) reaching 〉0.2x109/L above nadir, defined as ELR. Three dose levels were planned (2 mg, 4 mg and 8 mg) within 2 cohorts: 10 days of Pom and 21 days of Pom, in a traditional 3+3 dose escalation design. Results: 25 pts were enrolled on this study January 2014-June 2016 across 3 institutions (Table 1). Pom administration occurred at a median of 21 days after AcDVP16 induction. There were no dose-limiting toxicities (DLTs) in the first cohort of Pom x 10 days within each dose level- 2 mg (n=3), 4 mg (n=3) and 8 mg (n=7). There were no DLTs seen at 4 mg x 21 days (n=7). Two DLTs were seen at Pom 8 mg x 21 days (Grade 3 ALT increase and Grade 3 hypoxia, respectively). Thus, Pom 4 mg x 21 days will be further expanded. Nine (36%) pts discontinued Pom early (median duration = 5 days) due to: grade 3 rash (n=3), physician discretion (decreased WBC: n=1, fever and increased creatinine: n=1), grade 3 ALT increase (n=1), grade 3 hypoxia (n=1), disease progression (n=1), and pt preference (n=1). Adverse events (AEs) possibly associated with Pom that were seen in 〉1 pt included fever (n=8), rash (n=7), AST/ALT increase (grade 1: n=4, grade 3: n=1), mucositis (n=2), and fatigue (n=2). All of these AEs were self-limiting with supportive care and/or discontinuation of Pom. 60-day mortality was 0%. A complete remission (CR) was achieved in 18 pts and 1 achieved CR with incomplete platelet recovery (CRp) with a combined CR + CRp = 19/25 (76%). Among pts with adverse-risk AML, 5/6 (83%) achieved CR. One pt achieved a partial remission and 5 pts were refractory to treatment. Of the 19 CRs, 15 had no evidence of minimal residual disease by cytogenetics, FISH, or flow cytometry. Among pts who completed a course of Pom (10 days or 21 days), 14/16 (88%) achieved CR. As previously reported, a dramatic decrease of Aiolos expression via flow cytometry in T cell subsets was observed in vivo for the duration of POM treatment with doses 〉 2 mg, but the effect was lost after Pom was stopped. Figure 1 displays the pattern of cytokine production of CD4+ T cells visualized with pie charts, and shows a significantly different subset composition at ELR in Pom-treated pts compared to the same pts at full recovery (p=0.02), and compared to control AML pts at the same time point (p=0.004). Furthermore, there was a significant increase in TNF-α production (p=0.009) and the combination of TNF-α and IL-2 production (p=0.03) in stimulated CD4+ T cells during Pom treatment, which was reduced to baseline values after Pom was discontinued at full recovery (Figure 1: data analysis performed with the SPICE software). Conclusions: Pom can be safely administered at the time of ELR after intensive induction TST. Fever and rash are the most common AEs seen after Pom administration. Inhibition of Aiolos and consequent increase in both IL-2 and TNF-α expression, as measured by flow cytometry, appear to be reliable markers of Pom-induced T cell modulation in vivo. Planned expansion of the cohort of 4 mgx 21 days will allow further evaluation of safety and activity of Pom in AML. Expression of Cytokines in CD4+ T Cells Expression of Cytokines in CD4+ T Cells Disclosures Zeidner: Takeda: Research Funding; Merck: Research Funding; Agios: Honoraria; Otsuka: Consultancy; Tolero: Research Funding. Zeidan:Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Smith:Celgene: Consultancy, Other: member of DSMB. Levis:Millennium: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Foster:Celgene: Research Funding.

Description: Background: Relapsed or refractory acute lymphoblastic leukemia (ALL) remains challenging to treat with an extremely poor prognosis. Salvage chemotherapy regimens can achieve complete remission (CR) rates of 30-50%, but CRs are not durable without hematopoietic stem cell transplant (HSCT). Outcomes in untreated adolescents and young adults have improved with the use of pediatric chemotherapy regimens, but data on the use of pediatric chemotherapy regimens in relapsed/refractory adult ALL is lacking. We chose to retrospectively examine the outcomes of adult patients with relapsed ALL at our institution treated with the CCG-1941 pediatric salvage protocol (Gaynon PS, et al. J Clin Oncol 2006). Methods: We conducted a single-center retrospective cohort study of patients aged 18 and older with relapsed/refractory ALL who were treated with the CCG-1941 protocol. Patients received induction with vincristine, dexamethasone, ifosfamide, etoposide, PEG-asparaginase, and methotrexate, as well as intrathecal methotrexate, cytarabine, and hydrocortisone prophylaxis, followed by intensification and continuation phases. This regimen was offered to relapsed/refractory patients who, in the judgement of treating physician, were likely to tolerate multiagent chemotherapy. All adult patients who received this regimen between 2006 and 2015 were included in the analysis. Outcomes of interest were: the CR rate, duration of remission (DOR), toxicity, 30-day mortality, and the rate of patients undergoing HSCT. Results: Between January 2006 and April 2015, 15 patients aged 20-54 (median 31) with first relapse (n=12) or refractory (n=3) ALL were treated with the CCG-1941 regimen. Baseline patient characteristics are described in the Table 1. Seven patients (47%) had alterations to the induction protocol. The majority of these modifications were reduction or omission of PEG-asparaginase or vincristine. All patients experienced infectious complications, most commonly neutropenic fever (n= 12, 80%, 95% CI 52-96). There was one death due to infection, which occurred during an intensification phase. Two patients had grade 3 pancreatitis and two patients had hemorrhage (one grade 2, and one grade 5). 30-day mortality was 7% (95% CI 0-32) due to one fatal intracranial hemorrhage. Median length of hospitalization for induction was 28 days (range 10-61). Twelve patients (80%, 95% CI 52-96) achieved CR, and six of these patients received 1-2 cycles of intensification or continuation. Among the remaining 6 CR patients, one proceeded immediately to HSCT, two received other consolidation, two had early relapse, and one was lost to follow up. Six patients proceeded directly to HSCT, and one more underwent HSCT after receiving subsequent therapies for relapsed disease. The DOR was 81% at 6 months, 54% at 12 months, 36% at 18+ months and 18% at 24 months. One patient has been followed for 63 months and has not recurred. Median follow-up for survivors was 16 months (range 3.6-63). Conclusions: The CCG-1941 regimen appears to be tolerable and efficacious in adult patients with relapsed/refractory ALL. This regimen has been previously reported only in children. Despite the regimen's toxicities, a substantial proportion of patients underwent subsequent stem cell transplantation. Such salvage therapies remain important options for patients with T-ALL and for those B-ALL patients who are not candidates for, or who have failed phenotype-specific immunotherapies. Further prospective, multicenter study is warranted for use of pediatric salvage regimens in the adult patient population. Disclosures Foster: Celgene: Research Funding.

Description: INTRODUCTION: Peak oxygen consumption (VO2peak) and 6-minute walk distance (6MWD) measure overall fitness and functionality. Higher values have been shown to be directly related to lower mortality following allogeneic hematopoietic cell transplant (alloHCT) [Wood WA, et. al. Bone Marrow Transplant 2013;48:1342-1349. Kelsey CR, et. al. Cardiopulmonary exercise testing prior to myeloablative allo-SCT: a feasibility study. Bone Marrow Transplant (e-pub ahead of print 28 July 2014; doi:10.1038/bmt.2014.159.]. These parameters may represent targets for pre-HCT exercise interventions to ultimately improve post-HCT outcomes. Interval exercise training (IET), a type of exercise intervention that utilizes intermittent bouts of individualized high intensity exercise, has demonstrated the ability to induce rapid mitochondrial and enzymatic changes and to improve cardiorespiratory fitness in short periods of time. Thus, IET represents an attractive potential intervention for the time-limited pre-HCT setting. The purpose of this study was to evaluate the feasibility, safety and efficacy of 6 weeks of IET upon cardiorespiratory fitness (VO2peak) and 6MWD prior to HCT. We hypothesized that IET prior to HCT would be feasible and safe in the HCT population. Further, we hypothesized that IET prior to HCT would improve pre-HCT VO2peak and 6MWD. Because of the association of pre-HCT fitness with post-HCT mortality in the alloHCT patient population, this finding could support the use of IET in preparing this high-risk patient population to withstand the physiologic stress of transplantation. METHODS: We planned to recruit 40 adult participants with planned auto (N=20) or allo (N=20) HCT for a study of a 6-week personalized, home-based IET intervention prior to HCT. IET consisted of a 2-week lead-in period followed by 4 weeks of thrice weekly sessions of five 3-minute intervals at 65-85% maximal heart rate (MHR). Each interval was followed by 2 minutes of rest. The mode of home-based exercise was decided in consultation with the participant and the exercise physiologist. A total of 18 sessions were prescribed for each participant. Intensity and compliance were assessed with heart rate monitors and accelerometers that were recorded weekly. Before and after the 6-week intervention 6MWD and exercise testing for the assessment of VO2peak conducted. Accelerometer data was used to assess total daily activity (steps per day) throughout the duration of the study. RESULTS: Twenty-three participants (10 auto, 13 allo) are available for analysis at this time with recruitment ongoing (65% male; median age 53 years [range 27-75]; median BMI 27.6 kg/m2 [range 19.5-35.2]). For these participants, a median of 5 of the 6 prescribed weeks of exercise were completed, with a median of 10 interval exercise sessions performed during this time. Participants achieved target MHR for a median of 9 exercise sessions. Participants achieved a mean of 85% (SD±9) of MHR during exercise sessions. Subjects took an average of 5445 steps per day (SD±1738) throughout the intervention period. One patient reported dizziness, nausea, and shortness of breath during exercise, which resolved without complication; there were no other adverse events noted. For patients planning to undergo alloHCT, median VO2peak before the intervention was 18.8 ml/kg/min (IQR 17.1-26.4), and the median VO2peak improvement following the intervention was 3.7 ml/kg/min (IQR 2.6-5.0, p=0.002). For the entire population including planned autoHCT, these values were pre-intervention VO2peak 18.5 ml/kg/min (IQR 16.0-25.4) and VO2peak change 2.2 ml/kg/min (IQR 0.8-4.1, p=0.01). 6MWD also improved for those with planned alloHCT (median 37m, IQR 18-68, p=0.007) and for the overall group (median 40m, IQR 4-69, p=0.002). CONCLUSIONS: Our findings demonstrate that patients planning to undergo auto or alloHCT are motivated and able to participate in a 6-week intensive, home-based interval exercise training intervention in the immediate pre-transplantation period. Participants were able to safely achieve high-intensity heart rates in the target range. Some participants could not complete the planned 6 weeks because of the timing of transplantation, while others completed the entire duration of the intervention. Preliminarily, the intervention appears to show efficacy in improving pre-HCT cardiorespiratory fitness as measured by VO2peak and 6MWD. Disclosures No relevant conflicts of interest to declare.