ALBERT

Description: Background: The discovery that gut microbial dysbiosis correlated with prognosis, immune reconstitution and development of graft-versus-host disease (GVHD) in patients undergoing allogeneic stem cell transplantation (allo-SCT) highlights the clinical relevance of the gut microbiome in shaping anti-tumor immune responses. Treatment of allo-SCT patients with antibiotics has recently been associated with increased GVHD mortality (Routy et al. 2017). Based on these studies and the association of distinct gut bacteria with increased efficacy to PD-1 blockade in patients with solid tumors (Derosa et al. 2018), we performed a retrospective analysis to determine if infection treated with antibiotics affected the outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: A list of all MM patients treated at our institution between January 2012 through December 2015 was obtained and 1095 patients were identified. A comprehensive review of the electronic medical record (EMR) of the first 142 who received ASCT was performed. Information was collected from diagnosis to the date of last contact. Baseline characteristics, treatment history, transplant course, antibiotic treatment, and infection severity using common terminology criteria for adverse event (CTCAE) version 4 were reviewed. Prophylactic antibiotics were excluded. Response was measured and defined using the International Myeloma Working Group Criteria. Progression free survival (PFS) and overall survival (OS) were estimated using log rank tests. Cox hazard stepwise regression model examined for multiple factors affecting PFS and OS using the Akaike information criterion. Results: Of the 142 patients, 93 (65%) were Durie Salmon (DS) III, 20 (14%) were Revised International Staging System (R-ISS) III, 44 (31%) had high-risk cytogenetics, and 76 (54%) were male. The median age at diagnosis was 60. Although there was a similar frequency of DS III (67% vs 61%) and high-risk cytogenetics (35% vs 25%) among patients in the antibiotic and non-antibiotic treated groups, there was an over-representation of R-ISS 3 (19% v 4%) patients in the antibiotic-treated group. Treatment with antibiotics was associated with decreased median PFS (2.38 vs 6.58 years (yrs), p =0.00003) (Figure 1a) and decreased median OS (7.43 vs 17.39 yrs, p =

Description: Abstract 3453 Individuals undergoing allogeneic transplantation receive multiple red blood cell transfusions both as part of the transplant procedure and as part of the pre-transplant care of the underlying disease. Therefore these patients may be at risk for complications of transfusional iron overload. Several studies have noted that individuals entering the transplant with baseline elevated serum ferritin values have decreased overall survival and higher rates of disease relapse. Whether the iron is a direct contributor to inferior outcomes or is a marker of more advanced disease (thereby requiring greater transfusions) is unclear. Little is known about the incidence and consequences of iron overload among long-term survivors of allogeneic transplantation. Methods: Using Kaplan-Meier and Cox regression analyses, we performed a single center, retrospective cohort study of consecutive allogeneic transplants performed at Hackensack University Medical Center from January 2002 through June 30, 2009 to determine the association between serum ferritin (measured approximately 1 yr post allogeneic transplant) and overall survival. Results: During the study time frame, 637 allogeneic transplants (Donor Lymphocyte Infusion procedures excluded) were performed at our center and 342 (54%) survived ≥ one year. Among 1-year survivors 240 (70%) had post-transplant serum ferritin values available for review, including 132 (55%) allogeneic sibling, 68 (28%) matched unrelated, and 40 (17%) mismatched unrelated donor transplants. The median post-transplant ferritin value among 1-year survivors of allogeneic transplant was 628 ng/ml (95% CI 17, 5010), with 93 (39%) above 1000 ng/ml and 40 (17%) above 2500 ng/ml. The median post-transplant ferritin levels varied by underlying hematologic disease (aplastic anemia = 1147, acute leukemia = 1067, MDS = 944, CLL = 297, CML = 219, lymphoma = 123, multiple myeloma = 90). The Kaplan-Meier projected 5-year survival rate was 76% for the cohort that had survived one year and had available ferritin values. Fifty late deaths have occurred; causes of late death were disease relapse (n=37, 74%), GVHD (n=7, 14%), infection (n=4, 8%), cardiac (n=1, 2%) and second malignancy (n=1, 2%). The 1-year post-transplant serum ferritin value was a significant predictor of long term survival. Using a cut-off ferritin value of 1000 ng/ml, the 5-year projected survivals were 85% (95 CI 75%-91%) and 64% (95% CI 52–73%) for the low and high ferritin cohorts respectively (Figure, log-rank p

Description: Allogeneic stem cell transplantation (SCT) using HLA-haploidentical (HAPLO) related donors has been an effective strategy for treating hematologic malignancies in patients who lack a matched donor. In multiple myeloma (MM), allogeneic SCT used in tandem or as salvage therapy can be a potentially curative option, however, there is little data regarding the use of HAPLO donors in this population. We report 10 patients with MM who received HAPLO allografts between 2011-2014. Median age was 53 (range 28-61) and 5 patients were male. All patients, except one, were relapsed or refractory to at least 1 prior autograft. Patients with pre-transplant CD4 counts 〉200/uL received a fludarabine (Flu)-based regimen for in-vivo lymphodepletion to prevent graft rejection. Conditioning regimen for transplantation was Flu 30 mg/m2 daily x5 with cyclophosphamide (Cy) 14.5 mg/kg daily x 2, followed by TBI 200-400 cGY in 1 or 2 fractions. Post-transplant immunosuppression consisted of Cy 50-60 mg/kg on days +3 and +4, followed by tacrolimus and mycophenolate starting on day +5. All patients received filgrastim starting on day +5. Six patients received bone marrow (BM) with a median cell dose of 2.76 x 10e6 CD34cells/kg (range 1.1-4.02) and 4 patients received peripheral blood stem cells (PBSC) with a median cell dose 4.01 x 10e6 CD34 cells/kg (range 1.05-4.04). One patient developed sepsis on day +14 and died on day +31 without hematologic recovery. All other patients achieved engraftment, with median neutrophil engraftment of 18 days (range 14-45) and median platelet engraftment of 21 days (range 14-53). There was no difference between engraftment for BM or PBSC. Median time to neutrophil engraftment was 17 days for BM and 19.5 days for PBSC (p=ns). Median time to platelet engraftment was 29 days for BM and 20.5 days for PBSC(p=ns). Median time to full donor chimerism was 32 days overall (range 27-61); 38 days for BM (range 29-61) and 27.5 days for PBSC (range 27-32). At a median follow up of 10 months (range 1-35), 6 patients are alive. Of those, 2 patients are in CR, 3 in VGPR, and 1 with stable disease (SD). The 2 year overall survival is 46%. The causes of death for 4 patients were sepsis (1), progressive disease (2), and chronic inflammatory demyelinating polyneuropathy (CIDP) (1). Eight patients developed acute graft versus host disease (GVHD), with one having grade III, and 7 with grade I-II. Five patients were treated for chronic GVHD, 3 mild and 2 moderate by NIH criteria. None of the deceased patients developed chronic GHVD and all of the surviving patients had chronic GVHD, except for 1 who is prior to day +100 at the time of this report. Four patients were treated for grade 3 infections, with 1 infection-related death. Five patients relapsed or progressed their disease after HAPLO transplant, with a median time to progression of 7.8 months (range 3.2-11.4). Of these, 1 is in VGPR after salvage therapy, 1 has SD after salvage therapy and donor lymphocyte infusion, 2 died from relapse and 1died from CIDP. KIR typing was available for 8 recipient and donor pairs. There were 2 KIR B/x to A/A transplants, with1 patient deceased and 1 alive. All of the 4 KIR B/x to B/x recipients are alive, and the 2 KIR A/A to B/x recipients are deceased. This small series suggests HAPLO transplantation can be used in patients with advanced MM who are without a suitable matched donor. Our patients achieved timely hematologic engraftment and donor chimerism with BM or PBSC. There was no fatal acute GVHD, and as previously reported, chronic GVHD may be protective against relapse. Further studies need to be done to further elucidate the impact of KIR typing on transplant outcomes. Overall Survival Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: In recent years, engraftment syndrome (ES) has been more clearly defined in the autologous transplant setting. It represents a group of symptoms that includes fever, diarrhea, rash, pulmonary infiltrates and hepatic dysfunction, and has been associated with increased morbidity and longer hospitalization. It has also been proposed that ES may be protective against relapse. This study cohort includes 146 patients who received 181 autologous peripheral blood stem cell transplants (PBSCT) for multiple myeloma between January 2010 and December 2014. Thirty five patients received tandem PBSCT, including 1 patient who had 3 PBSCT. Of the patients in the cohort, 63% were male, median age was 59.7 years (range 53.8 - 66.9 years) and median follow-up was 24.1 months (range 0.5 - 64.5 months). Standard definition for ES was used: at least 2 symptoms not attributed to other causes including non-infectious fever 〉100.4, diarrhea, skin rash, pulmonary infiltrates or hepatic dysfunction, occurring from 3 days prior to 10 days post engraftment. There were 63 occurrences of ES by defined criteria. Seven patients did not require treatment, 56 patients were treated with corticosteroids, and 2 patients required the addition of tacrolimus. Potential risk factors for the development of ES were analyzed including age, stage of disease, high-risk cytogenetics or FISH, number and type of prior regimens, mobilization regimen, number of CD34 positive cells infused, and the disease status at the time of PBSCT. Patients above the age of 60 had a 66.7% incidence of ES whereas patientsunder the age of 60 had a 49.1% incidence. By univariate analysis, significant factors included age 〉 60 (p=0.037), lower number of CD34 positive cells infused (p=0.0031), and greater than 3 prior regimens excluding mobilization (p=0.0174). Two separate multivariate analyses revealed that developing ES was significantly associated with age 〉 60 (p=0.0372) and lower number of CD34 positive cells infused (p=0.0076). There was a trend (p=0.11) for increased incidence of ES in patients who did not receive cyclophosphamide for stem cell mobilization. For patients who developed ES, the OS at 5 years was 51.2% versus 73.1% for patients without ES (p=0.0194). Patients under the age of 60 with ES had a significant decrease in overall survival (p=0.0095) .The median progression free survival (PFS) in the overall cohort was 32.5 months, with no significant difference between the two groups. Advanced age and lower number of CD34 positive cells infused were associated with an increased risk for the development of ES, and there was a trend for the use of cyclophosphamide for mobilization as being protective against ES. Development of ES was significantly associated with an increase in all-cause mortality. There appears to be no protective benefit of ES against relapse. Awareness that the elderly population of myeloma patients receiving autologous stem cell transplantation is more susceptible to the development of ES may help in early diagnosis and treatment. Preventative measures such as cell dose and the use of cyclophosphamide warrant further evaluation. Figure 1. Overall Survival of patients post PBSCT for multiple myeloma Figure 1. Overall Survival of patients post PBSCT for multiple myeloma Figure 2. Overall Survival of patients

Description: Background: Autologous stem cell transplantation (ASCT) is increasingly offered to older patients with multiple myeloma (MM) based on clinical trials demonstrating improved outcome. Inherently, successful mobilization and collection of peripheral blood stem cells (PBSC) is necessary for ASCT. A direct comparison of the efficacy of mobilization between elderly and younger patients has not been reported. Retrospective studies demonstrated that older patients had lower CD34+ cell yield and a higher incidence of mobilization failure (Lee et al 2014, Muchtar et al 2016). In this retrospective study, we compared two age groups (〉/=70 years and /= 70 years and 315 patients

Description: BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is now standard of care for newly diagnosed patients with multiple myeloma (MM) and is used for some forms of non-Hodgkin lymphoma, providing improved outcomes. ASCT has been associated with a high incidence of engraftment syndrome (ES), which clinically presents as skin rashes, diarrhea, non-infectious fevers, and capillary leak syndrome in the peri-engraftment period. ES can be a severe and potentially lethal complication in patients who do not respond to corticosteroid therapy. RATIONALE: Prior to stem cell collection, MM and lymphoma patients are typically exposed to chemotherapy and immunomodulatory agents in order to reduce the cancer cell burden and other drugs to mobilize stem cells. It has been hypothesized that these agents may be involved with ES development in that they can disrupt the balance of immune regulatory and effector cell subsets. OBJECTIVE: To analyze T cell activation/memory and Treg cell compartments as well as classical, intermediate, and non-classical monocytes in the autologous apheresis product of MM and lymphoma patients undergoing ASCT. STUDY DESIGN: Samples were collected under IRB approval from 28 patients undergoing ASCT for the treatment of MM (n=21) or lymphoma (n=7) at the time of peripheral blood stem cell collection (the apheresis product); Peripheral blood mononuclear cells (PBMC) were isolated by sucrose gradient centrifugation and frozen until needed for phenotyping by multi-parametric flow cytometry. MM patients were conditioned for ASCT with melphalan alone (n=14) or in combination with bortezomib (n=7); lymphoma patients received conditioning with BEAM (carmustine, etoposide, cytarabine, and melphalan) chemotherapy. RESULTS: Of the 28 patients undergoing ASCT, 10 (35.7%) developed ES within the first four weeks post-transplantation. We analyzed by flow cytometric phenotyping the following immune cell subsets: overall CD4/CD8 T cells, CD4/CD8 naïve and memory cells, HLA-DR expression on memory T Cells, memory CD4 Tregs, as well as overall classical, intermediate, and non-classical monocytes. The absolute numbers (PBMC conc. (cell/ml of blood) x (% of cells in PBMC/100) and percentage population (# of events in population gate/# of total PBMC events x 100) data were transformed with log and square root functions, respectively. All data were tested for normality with a Shapiro-Wilks online test and p-values were obtained by performing an unpaired Student T-test. From our analysis of the apheresis product, the main cell compartments that were significantly increased in the ES+ group were the % CD8+ T cells [5.41 mean ± 0.51 s.e. vs. 3.34 ± 0.36 (ES-), p=0.003] and naïve CD8+ T cells [3.76 ± 0.56 vs. 1.61 ± 0.18 (ES-), p

Description: Abstract 3120 Introduction: Chemo-immunotherapy (i.e. rituximab combinations) has clearly had a significant impact on the outcome of all B-cell NHL both in terms of PFS and OS. However in the relapse/refractory setting a large proportion of pts still do very poorly especially in aggressive subtypes including DLBCL and MCL. Salvage therapy followed by HDT-ASCT in relapsed DLBCL remains the standard, though pts with early failures (

Description: Haploidentical (HAPLO) and unrelated donors (URD) are established cell sources for patients (pts) who lack HLA-matched siblings. Limited data are available comparing transplant (TP) outcomes using cells from HAPLO vs URD donors. We performed a retrospective analysis of sequential pts (n=54) undergoing HAPLO transplants with post-transplant cyclophosphamide (Cy). A control group of HLA 7/8 or 8/8 matched URD recipients (n=59) matched by diagnosis, transplant date, and cell source (PBSC or marrow) was identified (Table). Most HAPLO pts received cycles of pre-TP fludarabine (Flu) for lymphodepletion to achieve CD4

Description: Background: Allogeneic stem cell transplantation (SCT) remains the only curative option for CLL, in part due to allogeneic graft-vs-leukemia effect (GVL), which can lead to complete suppression of the CLL clone (Schetelig et al, JCO 2003). Management of post-SCT relapse remains challenging, and DLI has been successfully used as salvage, due to its potential to induce GVL (Delgado et al, Blood 2009). We evaluated outcomes of SCT for patients (pts) with a diagnosis of CLL transplanted at our center. Methods: 36 consecutive pts transplanted between 2004 and 2015 were reviewed. Kaplan Meier survival curves were produced to examine overall survival (OS), time to progression (TTP) and post-DLI survival. Univariate Cox Proportionate hazard models were also estimated to assess the impact of pt characteristics on the risk of survival and progression. Bivariate frequencies with Fisher exact tests, correlation analysis, and independent samples t-tests were performed to test associations across outcomes. Results: Sample was 72% male. Median age at time of SCT was 57 yo (range 42-74). Pts had a median time of 70 months (mos) between diagnosis (Dx) of CLL and SCT. Median follow-up post-SCT was 32 mos (range 1-118). Of the 30 pts with known disease status at the time of SCT, 16.7% were in complete remission (CR), 20% had stable disease (SD), 50% were in partial remission (PR) and 13.3% had progressive disease (PD). Median number of lines of therapy pre-SCT was 3 (range 1-8). Thirteen pts (36%) were refractory to their first line of therapy. 10 pts (27.8%) had del(17p), 11 pts (30.6%) had del(11q) and 8 pts (22.2%) had complex cytogenetics. Most patients (72%) received pre-SCT conditioning with FCR (Khouri et al, Exp Hematol 2004). 16 pts (44.4%) received rATG as part of their conditioning regimen. Graft-vs-host disease (GVHD) prophylaxis consisted of methotrexate and tacrolimus. 20 (55.6%) pts had acute GVHD and 19 (52.8%) had chronic GVHD. 5 (13.8%) pts had grade 3/4 acute GVHD and 1 (2.7%) had extensive chronic GVHD. When comparing pts who received SCT from unrelated donors (MUD, 24 pts) vs sibling donors (sib, 10 pts) there were no differences in rates of GVHD, disease progression or overall survival. Twenty-seven pts (75%) were in CR at first disease evaluation after SCT (CR conversion rate of 58.3%) and 2 pts (5.5%) had PD. On follow-up, another 15 pts (41.7%) presented PD. Median TTP was 14 months, with only 3 pts relapsing after 2 years from SCT. Eight pts who had PD and one patient who had a PR post-SCT received short-term anti-CLL therapy for disease debulking, followed by DLI. Six (66.6%) out of the 9 pts who received DLI achieved CR and are currently alive and in CR. Median follow-up post-DLI was 43 months and median duration of response to DLI was 47 mos (range 6-85 mos). Ultimately, 13 (36.1%) pts died, 8 (22.2%) were lost to follow-up, and 15 (41.7%) were alive at last contact. Disease progression was the most common cause of death (5 pts, 13.9%). Transplant-related mortality (TRM) was 13.9% (3 deaths due to infection, 2 deaths due to chronic GVHD). Only 2 deaths (5.5%) occurred during the first 100 days post-SCT, both due to infection. No deaths occurred due to acute GVHD. Median OS was 84 months. PFS (not accounting for pts who relapsed post-SCT but achieved CR with DLI) was 58% in the first year and 25% at five years. The median PFS was 19 months. Univariate and multivariate analysis of pre-SCT pt characteristics (age, time from Dx to SCT, number of therapies, stage, presence of adenopathy, MUD vs sib donor, cytogenetic abnormalities, ABO mismatch, disease status at SCT) did not show any statistically significant correlation with OS, PFS or GVHD rates. Conclusion: SCT remains the only curative option for CLL. Our experience shows that pts may achieve long-term survival with this approach. TRM was low (13.8%) and rates of acute and chronic GVHD were compatible with previous reports (Sorror et al, JCO 2005; Dreger et al, Blood 2010). Type of donor (MUD vs sib) did not impact outcomes, suggesting that patients without a matched sibling should not be denied transplantation if a MUD is available. Although 47% of the patients eventually progressed after transplantation, 66% of patients who received DLI for salvage were able to achieve CR and remain progression-free for a prolonged period of time, underlining the importance of the GVL effect. Most relapses occurred within the first 2 years post SCT and late relapses were rare. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Skarbnik: Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Vesole:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau.

Description: Background: Allogeneic transplantation (alloHSCT) is a potentially curative treatment option for patients (pts) with multiple myeloma (MM). Questions such as optimal donor source, role of graft versus host disease (GvHD), treatment-related mortality and patient selection still remain. Methods: We report on 118 consecutive pts with MM who received an alloHSCT between November 2004 and September 2015 at the John Theurer Cancer Center. Pts received either a non-myeloablative (NMA), a reduced intensity (RIC) or a myeloablative (MA) regimen. The NMA regimens consisted of combinations of fludarabine (flu)/cyclophosphamide and low dose TBI. The RIC regimens consisted of flu/melphalan (mel) or flu/mel/bortezomib with the addition of low dose thymoglobulin (ATG) for unrelated donors (URD). The MA regimen was busulfan/mel, also with ATG for unrelated donors. All pts received at least one prior autograft. The consolidation group was defined as pts entering their allogeneic HSCT for consolidation after demonstrating a response (〉/= PR) to their first autograft and without evidence of progression. The salvage group was defined as pts with 〈 PR or with relapse after their first autograft. Results: The median age was 54 years (range 35-66) and 48 (41%) pts were female. Seventy-five pts were in the consolidation group and 43 pts were in the salvage group. The hematopoietic cell donors were 67 related donors (RD) including 9 (8%) haplo-identical, and 51 URD including 17 (14%) mismatched donors. In our cohort, 10 (8%) pts received a MA, 72 (61%) received a RIC and 36 (30%) received a NMA regimen. The median follow-up for all surviving pts (n = 65) was 49.2 months (6.9-134.3). There were no significant differences between the RD and the URD cohorts except for lower age of unrelated donors (p