ALBERT

Description: Background: Induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients (pts) with untreated mantle cell lymphoma (uMCL); however, there is no consensus on the optimal induction regimen. The addition of rituximab + high-dose cytarabine (RC) to an RCHOP-like regimen is associated with better outcomes. In addition, two randomized trials have demonstrated superior efficacy and tolerability for rituximab/bendamustine (RB) compared to RCHOP for uMCL. Based on this, we conducted a phase 2 trial of 3 cycles of RB followed by 3 cycles of RC in 23 TE pts with uMCL, with encouraging preliminary results (Armand, BJH 2016). Pts continued to be followed for relapse and survival. Meanwhile, RB/RC became the standard frontline regimen at Dana-Farber Cancer Institute (DFCI). Simultaneously, investigators at Washington University in St. Louis (WUSTL) initiated a similar study of alternating cycles of RB/RC for uMCL. Herein, we report the results of both phase 2 trials as well as the off-trial experience. Methods: In the DFCI trial, TE pts (age 18-69) with uMCL were treated with 3 cycles of RB (R 375 mg/m2 d1, B 90 mg/m2 d1-2) followed by 3 cycles of RC (R 375 mg/m2 d1, C 3gm/m2 BID d1-2 with dose reductions for age, renal dysfunction, or pre-existing neurotoxicity). Off-trial pts treated with RB/RC at DFCI or in consulting community practices were retrospectively identified using clinical and pharmacy databases. In the WUSTL trial, TE pts (age 18-65) received alternating cycles of RB (cycles 1, 3, 5) and RC (cycles 2, 4, 6) (same dosing as above). Response assessments were made using CT scans for the DFCI trial and PET/CT for the WUSTL trial and DFCI off-trial pts. Results: In total, 86 pts (23 DFCI trial, 49 DFCI off-trial, 14 WUSTL trial) were treated with RB/RC. The median age was 57 (range 30-72). Pts in the WUSTL cohort were more likely to be male, have a high MIPI score, and have blastoid variant (Table). 94% of pts completed 6 cycles of RB/RC therapy. Off-trial pts were more likely to receive a lower starting dose (≤ 2gm/m2) of cytarabine (76%) compared to trial pts (38%). At the EOI, the overall response rate and CRR were 98% and 92%, respectively, with similar response rates across cohorts (Table). 73 pts (85%) subsequently underwent ASCT and 4 additional pts (5%) have ASCTs planned. 9 pts did not undergo ASCT because of persistent or PD (n=3), prolonged cytopenias (n=3), an incidentally identified ASXL1 mutation without cytopenias (n=1), pt preference (n=1), and inadequate stem cell collection (n=1). Delayed platelet engraftment after ASCT was seen for pts receiving alternating cycles of RB/RC compared to sequential RB/RC at day 30 (plts

Description: Introduction The effect of CMV reactivation after allo-HCT on relapse and overall survival (OS) in patients with acute myeloid leukemia (AML) and myelodysplatic syndrome (MDS) is controversial (Green et al blood 2013, Elmaagacli et al Blood 2011, and Erard et al Hematologica 2006). Methods We retrospectively analyzed the effect of CMV reactivation on OS and cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) in AML and MDS patients older than 〉 18 years who had received allo-HCT between 2005-2011 and had not died within 30 days of receiving allo-HCT at MD Anderson Cancer Center. The effect of any CMV antigenemia on allo-HCT outcomes was evaluated by comparing any CMV antigenemia with no CMV antigenemia. Because of potential immunomodulatory effect of CMV infection, the effect of prolonged antigenemia (defined as CMV antigenemia with duration more than 12 days, the median duration of antigenemia for the cohort) on transplant outcomes was analyzed by comparing patients with prolonged antigenemia with patients with no CMV antigenemia or CMV antigenemia with ≤ 12 days. All patients underwent surveillance by pp65 antigenemia test. Preemtive therapy was initiated for 〉 3 pp65 Ag cells/million WBC's. Kaplan-Meier survival curves were used to estimate OS and the log-rank test was used to assess group differences. CIR and NRM were determined using the competing risks method; competing risk for CIR was death and for NRM was relapse. Group differences in CIR and NRM were assessed using Gray's test. Results Table 1 shows baseline characteristics. Comparing R+/D+, R-/D-, R-/D+, and R+/D- groups, the incidence of any CMV antigenemia after HCT was 48%, 16.7%, 13.5%, and 50.9%, respectively (p 0.15) and CIR (p 〉 0.61) in all cohort as well as AML and MDS subgroups. Comparing any antigenemia vs. no antigenemia, CIR at 3 years was 34.6% vs. 35.2% in all cohort, 36.7% vs. 36.6% in AML patients, and 29.5% vs. 30.0% in MDS patients, respectively. In patients with CMV antigenemia, duration of antigenemia ranged from 1 to 535 days (median 12 days). We then investigated the effect of prolonged CMV antigenemia on transplant outcomes. Patients with CMV antigenemia 〉 12 days compared with combined group of ≤ 12 days or no CMV antigenemia had a lower cumulative incidence of relapse and a higher NRM, resulting in a similar OS (Fig. 1). Such a difference was seen in AML but not in MDS subgroup. We then investigated the effect of duration of CMV antigenemia in patients with CMV reactivation. Comparing 1-12 days of antigenemia vs. more than 12 days of antigenemia, CIR at 3 years was 41.9% vs. 26.7% (p = 0.003) in all cohort, 45.8% vs. 26.4% (p = 0.001) in AML patients, and 32.1% vs. 27.4% (p = 0.68) in MDS patients, respectively. Conclusion Prolonged CMV antigenemia is associated with decreased relapse in patients with AML, but not in MDS. Lower relapse is offset by increased NRM resulting in no change in OS. In contrast with published data, lower rate of relapse was not found when any antigenemia was compared with no antigenemia. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: CD34+-selected peripheral blood stem cell infusions without conditioning have recently been utilized for poor graft function (PGF) with promising results. Unfortunately, many patients have been unable to receive the boost infusion as their donors were unwilling or unable to undergo an additional stem cell collection. Therefore, we conducted this pilot trial utilizing either fresh or cryopreserved peripheral blood stem cell products to create CD34+-selected peripheral blood stem cell infusions for the treatment of PGF. Additionally, to explore relationship of CD34+ dose and response we included a cohort of donors mobilized with plerixafor in addition to the standard G-CSF. Methods: Poor graft function (PGF) was defined as ANC 〈 0.5k/μL, platelets 〈 30k/μL, or platelet or RBC transfusion dependence despite full donor chimerism and in the absence of GVHD more than 60 days following allogeneic stem cell transplant (allo-SCT). Three different donor products were used for CD34+ selection: (1) fresh mobilized product using G-CSF only (SC at a dose of 10 μg/kg daily for 5 days), (2) fresh mobilized products using G-CSF (SC at a dose of 10 μg/kg daily for 5 days, days-4 through day 0) and plerixafor (IV at a dose of 320 μg/kg on day 0), and (3) cryopreserved cells mobilized with G-CSF (SC at a dose of 10 μg/kg daily for 5 days). Seventeen donor-recipient pairs were enrolled onto this prospective study. The original allo-SCT donor either underwent an additional peripheral blood stem cell (PBSC) mobilization and collection with G-CSF only (n=5) or G-CSF plus plerixafor (n=9) or a cryopreserved product (n=3) from a previous collection (using G-CSF only) was used to create the CD34+ cells for infusion. CD34+ cell selection was performed using a CliniMACS. The infusion was not preceded by administration of any chemotherapy or conditioning regimen. Neutrophil improvement was defined as neutrophil count 〉 500/μl without growth factor support for 〉7 days; platelet improvement was defined as platelet count ≥ 50,000/µl without platelet transfusion support for 〉 7 days; and RBC improvement was defined as hemoglobin 〉 9 g/dL and transfusion independence. Complete response was defined as improvement of all involved cells lines; partial response was defined as improvement of platelets and/or neutrophils with continuing RBC transfusion dependence. Results: The mean post-selection CD34+ count per kg of recipient weight was 3.7x106, 12x106, and 1.7x106 for G-CSF only, G-CSF plus plerixafor, and cryopreserved products, respectively. Mean CD34+ yields (defined as the number of CD34+ cells after selection/CD34+ cells prior to CD34 selection) was 58%, 67%, and 31% for G-CSF only, G-CSF plus plerixafor, and cryopreserved products, respectively (Table 1 and Figure 1). The mean number of CD3+ T cells/kg infused in each product was 0.004 x 106, 0.032 x 106, and 0.015 x 106 for G-CSF only, G-CSF plus plerixafore and cryopreserved groups respectively (Table 1). Following the CD34+-selected stem cell infusion, 12 of the 17 recipients (71%) had a complete response including all 3 who received cryopreserved products; 3 had a partial response (17%) and 2 patients (12%) did not respond. One year relapse-free and overall survival was 71% and 65%. There was no treatment related toxicity reported other than graft-versus-host-disease (GVHD); three (18%) developed acute GVHD (1 grade I localized to the skin, 2 grade II with gut involvement), 6 chronic GVHD (2 limited and 4 extensive) (Table 1). Conclusion: Cryopreserved products seem to be a viable alternative to create CD34+ -selected peripheral blood stem cell infusions for the treatment of PGF. When collecting fresh products is an option, the addition of plerixafor increases CD34+ yield over G-CSF alone. Disclosures Abboud: Teva Phamaceutical: Research Funding. Uy:Novartis: Research Funding.

Description: Background The negative impact of acute graft-versus-host disease (GvHD) on morbidity and mortality after allogeneic transplant is significant; thus, finding a means to harness the beneficial Graft versus tumor effect (GVT) while reducing or eliminating GvHD is a major goal of transplant trials. Alterations in immune subsets present after transplant can work to suppress allo-reactive T-cell responses by increasing regulatory T-cells and suppressing allo-reactive T-cell proliferation. Azacitidine (AZA) treatment in pre-clincal models resulted in an increase in regulatory T-cells, a decrease in allo-reactive T-cell proliferation and prevention of acute GvHD while preserving GVT effects. (Choi et al. Blood 2010). Based on these results a phase I/II study was designed to test the safety and efficacy of AZA administered shortly after transplant for the prevention/prophylaxis of acute GvHD and relapse in subjects receiving transplants from matched unrelated stem cell donors. We report the results for the Phase I portion of this trial. Methods Patients with hematologic malignancies in remission age 18 - 70 were eligible. Myeloablative or reduced intensity conditioning without antithymocyte globulin was used. All recipients were required to receive at least 2 x 106 CD34/kg and have at least 1 x 106 CD34/kg cryopreserved as back up in case of primary graft failure. AZA was administered intravenously on day +7 for five consecutive days and repeated every 28 days for a total of 4 cycles after allogeneic transplant from a 10/10 HLA matched unrelated donor. Standard GvHD prophylaxis with mini-methotrexate and tacrolimus was given. A Phase I, 3+3 dose escalation design of 4 cohorts (AZA dose levels 15, 30, 37.5, and 45 mg/m2) was used to determine toxicity and recommended phase II dose. The primary outcome for phase II is the rate of grade II - IV acute GvHD at day 180 after transplant. Results We have transplanted 16 subjects on trial, 15 have received study drug. Recipient characteristics include: median age 57, 67% male, and diagnoses of AML in CR (9), ALL in CR (2), or MDS (4). One DLT was observed in the final cohort of 6 subjects. The DLT experienced in the final cohort was primary graft failure. The subject had developed Clostridium difficile colitis during conditioning and fungemia shortly after transplant. A total CD34 dose of 2 x 106/kg was infused after myeloablative conditioning of Busulfan and Cytoxan. The subject received the cryopreserved back up donor leukocyte infusion at day +28 but died at day 29 of sepsis without evidence of neutrophil engraftment. Contributing causes to the DLT were thought to be the CD34 dose infused, sepsis, severe colitis and possibly AZA administration. For the remainder of subjects treated in phase I the median CD34 dose infused was 5 x 106/kg (range 2 - 5), median ANC engraftment was 14 days (range 10 - 22 days). Median platelet engraftment was 22 days (range 14 - 70). No grade III/IV acute GvHD has been observed. Grades 1 and 2 skin and gut GvHD have been observed, and all cases have responded to steroids except one case of steroid refractory GvHD in cohort 1 (15mg/m2 AZA). At the recommended phase 2 dose of 45mg/m2 AZA, 3 cases of skin GvHD were observed occurring just prior to or at the time of cycle 2 of treatment. All responded to steroids. With a median follow up of 233 days (range 29 - 784), only 2 subjects have relapsed and 11 (73%) remain alive. The most common non-hematologic grade 3 or 4 AEs were gastrointestinal toxicity (mucositis, nausea and diarrhea), electrolyte abnormalities, and infections. In conclusion, AZA can be given safely starting at day +7 after MUD transplant up to a dose of 45mg/m2 tested. Phase II is currently enrolling subjects. Because of the DLT experienced in phase I, the infused CD34 dose will be increased to a minimum of 4 x 106 CD34/kg with 1 x 106 CD34/kg cryopreserved in backup. Correlative studies from banked Phase I biospecimens evaluating dynamics of regulatory T-cells, T-cell subsets and methylation before and after treatment are being analyzed and will be reported. Disclosures Schroeder: Incyte: Consultancy; Celgene: Other: Azacitidine provided for this trial by Celgene. Off Label Use: Azacitidine for GVHD prophylaxis. Abboud:Gerson Lehman Group: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Teva Pharmaceuticals: Research Funding. Vij:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy.

Description: Background: The use of post-transplantation cyclophosphamide (PTCy) as a single agent for graft-versus-host disease (GVHD) prophylaxis in HLA matched transplant patients has had varied results. Two recent studies at Johns Hopkins University noted favorable incidences of both GVHD and non-relapse mortality (NRM) in both matched related and unrelated donor allogeneic hematopoietic cell transplant (allo-HCT) recipients (Kanakry CG, et al, JCO, 2013 and Kanakry CG et al, Blood, 2014). In contrast to this data, a phase II study at MD Anderson reported higher rates of grade II-IV acute GVHD and NRM, with worse overall survival in patients receiving PTCy as the sole GVHD prophylaxis compared to their matched cohort receiving a calcineurin-inhibitor (CNI) and methotrexate (MTX) as immunosuppression (Alousi AM et al, BBMT, 2015). Another study in Australia had to be stopped for safety reasons due to high GVHD and NRM when using PTCy as sole GVHD prophylaxis (Bradstock KF, BBMT, 2015). There is no published data on the use of MMF plus tacrolimus in combination with PTCy in HLA matched allo-HCT recipients. We hypothesized that addition of MMF and Tacrolimus to PTCy in HLA matched allo-HCT recipients will lead to significantly improved transplant outcomes. To answer this question we retrospectively analyzed data from patients who received this regimen at a single institution. Methods. We performed a retrospective analysis of 31 HLA matched allo-HCT patients who received PTCy at 50 mg/m2 on days +3 and +4 in addition to MMF and tacrolimus immunosuppression from December 2012 till June 2015 at Washington University School of Medicine in Saint Louis. All of these patients received G-CSF mobilized peripheral blood grafts. Patients included AML (n=13), ALL (n=5), MDS (n=5), CML (n=2), aplastic anemia (n=2) and NHL (n=1), myelofibrosis (n=1). Twelve of the patients underwent a matched related donor (MRD) transplant and 19 underwent a matched unrelated donor (MUD) transplant. Two of the MUD transplants had a HLA match grade of 8 of 10 and the other 17 were a 10 out of 10 match. Twenty-eight of the patients received a graft collected via peripheral blood stem cell mobilization and the other three had a donor graft collected via bone marrow harvest. Cumulative incidence of aGVHD was estimated using Gray's sub-distribution method to account for death without aGVHD as a competing event, and the cumulative incidences of non-relapse mortality (NRM) and relapse were estimated treating each other as competing event, while OS was estimated using Kaplan-Meier limit method. Results: This regimen was associated with acceptable GVHD in our patients. Incidence of grade II-IV acute GVHD was 28% (21.3% for MRD; 31.5% for MUD) at day 100 and 28% at 1 year. Incidence of Grade III-IV acute GVHD was 13.5% at both 100 days and 1 year. Limited chronic GVHD was 25.9% and extensive GVHD was 14.8% at 1 year. Similarly we found acceptable NRM and relapse in these patients, NRM was 10.2% and 19.7% at 100 days and 1 year respectively and cumulative incidence of relapse at 100 days and 1 year were 17.8% and 29.0% respectively. Overall survival at 1 year for all patients was 52%. Summary: Here we report favorable results from a regimen combining MMF and Tacrolimus on PTCy platform in HLA matched MRD and MUD transplant recipients. Relatively low GVHD and NRM results are particularly encouraging in view of almost exclusive use of G-CSF mobilized T cell replete grafts with much higher T cell content. Though limited by the relatively small number of patients, our results suggest combining MMF plus Tacrolimus with PTCy platform in HLA matched allogeneic transplant patients is safe and associated with acceptable transplant outcomes. Disclosures Vij: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

Description: This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program® Introduction: A single institution study conducted at the National Cancer Institute (NCI) using anti-CD19 CAR T cells with CD28 and CD3-zeta signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL) (Kochenderfer et al. Blood 2012, J Clin Onc 2014, ASH 2014). KTE-C19 utilizes the same anti-CD19 CAR construct as investigated in the NCI study in a 6-8 day manufacturing process (Better et al. ASCO 2014). The ZUMA-1 trial is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in subjects with refractory aggressive B-cell NHL. Preliminary phase 1 results presented. Methods: Subjects received KTE-C19 at a target dose of 2 x 106 (minimum 1 x 106) anti-CD19 CAR T cells/kg after a fixed dose conditioning chemotherapy regimen of cyclophosphamide and fludarabine. The primary objective of phase 1 is to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Cytokine release syndrome (CRS) was graded per revised criteria (Lee et al. Blood 2014). Key secondary objectives include evaluating the overall response rate (ORR=CR+PR) per Cheson 2007, duration of response, levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria include ≥ 18 years old, ECOG 0-1, and chemotherapy-refractory disease defined as stable disease or progressive disease as best response to last line of therapy, or disease progression ≤ 12 months after autologous stem cell transplant (ASCT). Subjects must have received at least prior anti-CD20 therapy and an anthracycline containing regimen. Results: As of 28 July 2015, 6 subjects were dosed in the phase 1 portion of the study. All subjects are evaluable for safety with a median follow up time of 4.8 weeks post KTE-C19 infusion and 3 subjects have had 1 month tumor assessments. Two subjects experienced only grade (gr) 1-2 KTE-C19 related events. Three subjects had gr 3 KTE-C19 related events as highest gr toxicities; all these events were reversible within 3 days. CRS and neurotoxicity were managed with supportive care, tocilizumab and systemic steroids. One subject experienced a DLT of gr 4 encephalopathy and gr 4 CRS. This subject died within 30 days of KTE-C19 cell infusion; the death was due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. Of the 3 subjects assessed for response at one month, 2 achieved a complete response and one achieved a partial response. Key safety and efficacy findings are summarized in the table. Biomarker and translational endpoints are included in a separate abstract. Enrollment is ongoing and updated trial results will be presented. Conclusions: Preliminary phase I results ofthe ZUMA-1 study demonstrate that KTE-C19 can be centrally manufactured and administered in a multicenter trial. The predominant toxicities include CRS and neurotoxicity which are generally reversible. Complete and partial responses have been observed in subjects with refractory disease at 1 month after KTE-C19 administration. This potentially pivotal study is the first enrolling multicenter anti-CD19 CAR T cell trial in refractory aggressive NHL. Clinical trial: NCT02348216. Table 1. Subject Sex/Age/ECOG Disease Type Treatment History Gr 3 or Higher KTE-C19-Related Adverse Events Response at 1 Month 101-002-001 M/59/0 DLBCL Relapse ≤ 12 mo after ASCT Gr 3 encephalopathy (resolved) Partial Response 101-002-003 M/69/1 DLBCL Refractory to 2nd line chemotherapy Gr 3 tremor (resolved) Gr 3 delirium (resolved) Gr 3 agitation (resolved) Gr 3 restlessness (resolved) Gr 3 somnolence (resolved) Complete Response 101-009-001 F/29/1 PMBCL Refractory to 1st, 2nd, 3rd line chemotherapy Gr 4 CRS Gr 4 encephalopathy N/A 101-003-001 M/67/1 DLBCL Relapse ≤ 12 mo after ASCT None Complete Response 101-002-004 M/69/0 DLBCL Refractory to 4th line chemotherapy Gr 3 encephalopathy (resolved) Assessment not yet reached 101-003-002 F/34/0 DLBCL Relapse ≤ 12 mo after ASCT None Assessment not yet reached mo - months M - male, F - female N/A - not applicable Disclosures Locke: Kite Pharma: Other: Scientific Advisory Boards. Off Label Use: Tocilizumab for CRS per Blood et al. 2014. Bartlett:Kite: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Colgene: Research Funding; Millennium: Research Funding; MERC: Research Funding; Gilead: Consultancy, Research Funding; Insight: Research Funding; Medimmune: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Kite pharma: Other: attended advisory board meeting; Pharmacyclics/Jannsen: Speakers Bureau. Navale:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Go:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership.

Description: Introduction: The BEAM conditioning regimen (carmustine [BCNU], etoposide, cytarabine, melphalan) is widely used as the high dose chemotherapy given to patients with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) who are undergoing autologous stem cell transplant (ASCT). The lyophilized formulation of melphalan (Alkeran) commonly included in the BEAM regimen has several limitation based on its marginal solubility and the requirement to reconstitute it in propylene glycol (PG), which itself is associated with toxicities. PG-free melphalan (Evomela) overcomes these limitations by using the solubilizing agent Captisol, an inactive excipient used in 6 FDA-approved parenteral drug formulations, to improve the stability of the reconstituted melphalan. PG-free melphalan is stable for 8-10 hours after reconstitution, it can be refrigerated (unlike Alkeran), and it avoids the potential toxicities of PG. PG-free melphalan has demonstrated bioequivalence to Alkeran, and it was safe and effective when used as the conditioning regimen for multiple myeloma patients undergoing ASCT. This Phase II study investigated the safety and efficacy of high-dose PG-free melphalan when included in the BEAM regimen. Methods: Adult patients with NHL or HL who were eligible for ASCT and gave informed consent were prospectively enrolled after collection of an adequate peripheral blood stem cell product. Carmustine, etoposide, and cytarabine were given at standard doses on Day -6 thru Day -3. PG-free melphalan, 140 mg/m2, was diluted with normal saline to a concentration of ≤ 0.45 mg/ml and infused over 30 minutes on Day -2. Autologous stem cells were infused on Day 0. Supportive care was per institutional standards. The primary endpoint was toxicity, and patients were followed post-transplant for toxicity, engraftment, and disease response. Results: Forty-five patients were enrolled from April 2014 thru June 2015 (mean age 52, range 18-73; 31 males/14 females; 32 NHL [15 diffuse large B-cell, 8 mantle cell, 9 other]/13 HL). Response prior to transplant was complete remission (CR, n=21), partial remission (PR, n=22), or progressive disease (PD, n=2). All patients completed BEAM with PG-free melphalan and stem cell infusion (median 5.1 CD34+ cells/kg), and 40 patients had sufficient follow-up for toxicity and engraftment assessments. The most common Grade 3-4 non-hematologic toxicities were neutropenic fever, (n= 26, 67%), infections (n=16, 41%), and electrolyte abnormalities (hypokalemia and hypophosphatemia in 8 and 23 patients, respectively). Twenty-four patients (60%) had oral mucositis, which was mostly Grade 2 (21 with Grade 2; 3 with Grade 3). Moderate or severe gastrointestinal toxicities were uncommon; 5 patients (12.5%) had Grade 3 diarrhea and 3 (7.5%) had Grade 3 nausea/vomiting. There were no treatment-related deaths. Thirty-nine patients (98%) had neutrophil and platelet engraftment at mean 10 and 21 days, respectively. One patient did not have platelet engraftment by Day +100. Among 36 patients who had response assessment at 60-100 days post-ASCT, 29 (81%) were in CR, 2 in PR, and 6 had PD. There have been three deaths, at 6-12 months post ASCT, all due to progressive disease. Conclusions: PG-free melphalan can be used in place of the standard, lyophilized formulation of melphalan in the BEAM regimen for lymphoma patients undergoing ASCT. It was shown to have a safety profile that compares favorably with Alkeran, and it avoids potential PG-associated toxicities. Of note, Grade 3-4 mucositis, diarrhea, and nausea/vomiting each occurred in fewer than 15% of patients, the engraftment rate was high (98%), and response rates were consistent with expectations. Disclosures No relevant conflicts of interest to declare.

Description: Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

Description: Background: Advances in the treatment for multiple myeloma (MM) have dramatically improved outcomes for younger patients. Older adults, particularly those 80 years of age or older at diagnosis, have seen more modest gains. MM incidence increases with age, and as more of the population is living later into life, the segment of the MM population over 80 will continue to grow. In this study, we sought to better understand the characteristics, treatment, and outcomes of older patients with MM. Methods: We identified all patients diagnosed with MM at age 80 or older in the Surveillance, Epidemiology, and End Results Program (SEER) database from 2007-2013 to determine incidence and outcomes. Subset analysis was then performed on patients included in the SEER-Medicare linked database who were enrolled in Medicare Parts A, B, and D to further explore patient characteristics and treatment patterns. Results: The incidence of MM increases over age, peaking after age 80. The annual incidence for those aged 65-69, 70-74, 75-79, 80-84 and 85+ was 24.4, 32.7, 39.5, 42.8 and 36.4 per 100,000, respectively. Based on 2010 US population estimates, approximately 4,500 new cases of MM were diagnosed annually 2007-2013 in patients age 80 or older. In that period, 8,093 cases, approximately 1,150 per year, were reported to SEER. The estimated median overall survival (OS) of these patients was 14 months (95% CI 13.2-14.8). The estimated relative 12 month survival was 58.9% (95% CI 57.4-60.4) compared to their peers without cancer. Of the 8,093 cases of MM reported to SEER during the study period, 2,385 were present in the SEER-Medicare linked dataset. Of these, 225 were identified as smoldering MM using a previously established algorithm (Fiala, et al, JCOCCI, 2018) and excluded leaving 2,160 for the analyses. The median age was 84 (range 80-100) and 55% were female. 81% were white, 13% black or African-American, and 6% another race. At disease presentation, 22% had claims indicating hypercalcemia, 61% renal failure or chronic kidney disease, 59% anemia, and 34% MM bone involvement. The estimated median OS was 13.4 months (95% CI 12.2-15.1). Only 52% of patients had claims indicating they received systemic MM treatment within 6 months post-diagnosis. Nearly all that did received novel agents; 38% received bortezomib-based treatment, 41% immunomodulatory drug (IMID)-based, and 14% both. The others received antineoplastic chemotherapies such as melphalan or cyclophosphamide. Interestingly, bortezomib utilization increased incrementally from 25% of patients treated in 2007 to 62% in 2013 while IMID utilization declined from 67% to 49%. The median OS of those receiving treatment was 21 months (95% CI 18.5-23.1) compared to 6.3 months (95% CI 5.3-7.3) for those who did not (p

Description: The persistence of leukemic mutation(s) in AML patients who have achieved a morphologic complete remission (CR) after intensive induction chemotherapy is a strong predictor of early relapse and reduced overall survival (OS) (Klco JAMA, 2015; Morita, J Clin Oncol 2018; Jongen-Lavrencic, NEJM, 2018). There is no clinical consensus as to the optimal consolidation therapy for the ~50% of patients with intermediate-risk AML. The median relapse-free survival (RFS) for patients ≤60 years with ELN intermediate-risk disease is 0.8 years to 1.2 years, with a median OS of 1.2-2.1 years (Mrozek, J Clin Oncol, 2012). We have shown that intermediate-risk patients who clear all leukemia-associated mutations (LAMs) to a variant allele fraction (VAF) of