ALBERT

Description: Key Points There is no difference in survival after BMT among children of different BMI.

Description: INTRODUCTION: Allogeneic stem cell transplant (ASCT) is currently the only curative therapy for myelofibrosis (MF). Ruxolitinib, an inhibitor of the JAK-STAT pathway, has been FDA-approved since November 2011 for the treatment of intermediate and high-risk myelofibrosis. Off-label, the medication has been administered prior to ASCT in an effort to reduce spleen size before conditioning and improve subsequent engraftment. In the published literature, there are mixed results for this strategy. Notably, French researchers announced preliminary results of a prospective study of 23 patients in December 2013. They reported several severe adverse events (SAE) following Ruxolitinib discontinuation, including two fatalities. These events included three cases of cardiogenic shock and three cases of tumor lysis syndrome (TLS). Since 2012, all patients with MF receiving ASCT at our institution have been pre-treated with Ruxolitinib until 48 hours prior to the start of conditioning. Herein, we report on outcomes of these patients. METHODS: After receiving approval by the Medical College of Wisconsin Institutional Review Board, we collected data on all patients who received Ruxolitinib prior to an ASCT. Our eligibility criteria included receipt of an HLA-matched sibling or unrelated ASCT for myelofibrosis at the Medical College of Wisconsin between Jan 2012 and March 2014 and treatment prior to transplantation with Ruxolitinib. Patient characteristics, drug-related adverse events including cardiac toxicity, and outcomes including response, relapse, graft-versus-host disease (GvHD), and overall survival were analyzed. RESULTS: Our cohort included ten patients with a median age of 56 years (range: 47-60 years) at the time of transplant. Four patients had de-novo disease and the remaining had myelofibrosis which had evolved from another myeloproliferative neoplasm. Four patients received one or more therapies for myelofibrosis prior to starting Ruxolitinib. One of the ten patients had undergone a splenectomy as part of prior treatment. The majority (6/10) had intermediate II-risk disease by the Dynamic International Prognostic Scoring System (DIPSS). Six of the ten patients received myeloablative conditioning. All ten patients received Ruxolitinib as pre-treatment prior to transplant and a standard taper schedule was employed starting six days prior to conditioning. Patients were slowly transitioned off the medication from a steady-state dose (maximum of 25 mg BID) to 5 mg once a day with the last dose taken 48 hours prior to conditioning. Two patients stopped taking their Ruxolitinib prior to the tapering protocol – one with progressive disease and one due to severe headache. Of the nine patients with splenomegaly, five had reduction of spleen size attributed to the medication. One of nine patients experienced rebound splenomegaly after discontinuation of Ruxolitinib. No patient experienced clinical symptoms of TLS. No patient experienced cardiac toxicity. After ASCT, acute GvHD occurred in two patients but was ≤ grade II in both. Chronic GvHD occurred in four patients, two were graded as mild and two were graded as moderate. After a median follow-up of 14.5 months (range: 5 – 23 months), all ten patients are alive. No patients require transfusions, one patient remains on intermittent granulocyte-colony stimulating factor. By International Working Group for Myelofibrosis Research and Treatment Criteria (IWG-MRT), four patients achieved complete remission, two achieved partial remission, one had clinical improvement and three had stable disease. No patient has experienced treatment-related mortality or graft failure. CONCLUSION: Administration of Ruxolitinib before ASCT has beneficial effects on spleen size and engraftment. We did not observe any serious adverse events with Ruxolitinib pre-treatment and no special safety concerns related to transplant. Table. Variable N=10 % Toxicities to Ruxolitinib Thrombocytopenia 3 30 Anemia 3 30 Headache 2 20 Arthralgia 1 10 Dizziness 1 10 Rebound Splenomegaly following discontinuation 1 10 Toxicities after ASCT Mucositis 2 20 Sinusitis with RSV 1 10 CMV Reactivation 1 10 Acute GvHD 2 20 Grade III/IV 0 Chronic GvHD 4 40 Mild 2 20 Moderate 2 20 Severe 0 Median time to Engraftment in days (range) 17 (13 – 22) Graft Failure 0 0 Disclosures Off Label Use: Ruxolitinib and myelofibrosis prior to transplant.

Description: Background: Light chain (AL) amyloidosis is associated with misfolded, insoluble fibril deposits in vital organs such as the heart, kidneys, liver, and nerves, derived from immunoglobulin light chains made by clonal plasma cells. Plasma cell-directed, standard-of-care chemotherapy has no effect on pre-formed fibrils. Hematologic response is thus insufficient for organ amyloid responses and organ improvement can lag hematologic response by months to years. Fibril-directed therapies are critical to improve early mortality of AL. Doxycycline has been reported to produce fibril disruption, reduce AL deposits and control light chain toxicity. It has been studied in localized AL amyloidosis and other amyloid subtypes. We conducted a phase 2 trial of doxycycline for use in conjunction with chemotherapy in AL. Herein, we report the outcomes of systemic AL patients treated on this study. Patients and Methods: This was an open label, single center, phase 2 pilot trial listed under clinicaltrials.gov (NCT02207556). The study was opened between 12/2014 - 06/2017. The last patient completed end-of-study assessment in 07/2018. Based on predominant symptoms and organ involvement, each patient was labeled to have 1 target amyloid organ involved. Patients were treated with oral doxycycline 100 mg twice daily in conjunction with chemotherapy per physician discretion. Patients were staged using the 2012 staging system. Hematologic and organ responses were categorized based on the consensus guidelines for conduct and reporting of clinical trials in AL amyloidosis published in 2012 for cardiac, renal and hepatic organ involvement and by radiologic measures for soft tissue involvement. The objectives were to study early mortality at 1, 3, 6, and 12 months after enrollment, target amyloid organ response rates at 6 and 12 months, and quality of life (QoL) using the PROMIS Global Health Index at 3-monthly intervals during the study. Results: Of 31 patients enrolled on this study, 25 had systemic AL (6 patients with localized AL syndromes will be described separately). The median age at diagnosis was 61.3 years (range 38.3-77.3), 64% were male, 2012 stage was I in 3 (12%), II in 9 (36%), III in 6 (24%) and IV in 7 (28%). The amyloid clone was lambda in 17 (68%). The median baseline values with range were: hemoglobin 12.3 (9.7-16.5) g/dL, albumin 3.7 (1.1-4.8) g/dL, creatinine 1.07 (0.6-2.42) mg/dL, 24-hour urine protein 0.97 (0.15-16.7) g/day and alkaline phosphatase 77 (42-597) IU/L. The median difference in involved and uninvolved free light chains was 258.6 (26-978.4) mg/L, NT-proBNP was 2564 (65-18333) pg/mL and troponin T was 0.017 (3 organs involved with amyloid, with 60% cardiac, 72% renal, 24% hepatic, 36% soft tissue, 28% gastrointestinal, 20% autonomic nervous system, and 8% peripheral nerve AL involvement. The median follow-up was 21.4 (12.2-40.3) months. All patients received concurrent CyBorD chemotherapy. Early mortality was 0 at 1 month, 2 (8%) at 3 months, 3 (12%) at 6 months and 5 (20%) at 1 year. Target organ involvement and responses at 6 and 12 months are shown in the table. In an intent-to-treat analysis of organ responses, at 6 months 24% had response, 32% had stable disease and 44% had progression (including 3 deaths prior to 6 months). At 12 months, 36% had target organ response, 32% had stable disease and 36% had progression (including 5 deaths). QoL showed improvement in both physical and mental domains at the end of treatment (figure). Overall hematologic response among survivors was 100% at 1-year including 40% complete, 45% very good, and 15% partial responses. The most common adverse event was skin rash and photosensitivity. One patient with end-stage heart failure and multiple hospitalizations, developed Clostridium difficile diarrhea while hospitalized, during the study period. Fifteen patients (60%) underwent melphalan-based autologous stem cell transplantation- 14 within 1 year after diagnosis, and in 1 delayed until relapsed disease 2 years after diagnosis. The 100-day mortality among transplanted patients was 0. Conclusions: In newly diagnosed systemic AL amyloidosis, doxycycline was safe with concurrent chemotherapy. The low 1-year early mortality of 20% and autologous stem cell transplant rate of 60% compares favorably to prior reports. These findings warrant a randomized, multicenter study. Disclosures D'Souza: Prothena: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Dhakal:Celgene: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Amgen: Honoraria. Hari:Janssen: Honoraria; Amgen Inc.: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Description: Key Points Candidate SNP associations with survival outcomes after URD transplant are most likely false-positive findings. Over 85% of candidate SNPs are not linked to a biochemical function; of those that are, about half are not linked to the candidate gene.

Description: Since the first report by Nobel laureate, the late E. Donnall Thomas (NEJM, 1957, 257), HSCT has developed from an experimental to an established curative treatment for many congenital or acquired disorders of the hematopoietic system. The key steps of this success story are linked to progress in tissue typing, donor selection, supportive care and immunosuppression and fostered by intensive collaboration of physicians around the world through outcome and donor registries. The WBMT, a federation and official Non-governmental Organization of the World Health Organization, has collected HSCT activity data from its member societies and from national registries not part of an international HSCT society. Data collection did include the first transplants by ED Thomas and the first global report by M. Bortin (Transplantation 1970, 571). European data were derived from the Med A form of the European Group for Blood and Marrow Transplantation-EBMT for the years 1965-1989 and from the annual activity survey since 1990. Non-European data back to 1969 were provided by the Center for International Blood and Marrow Transplant Research-CIBMTR, with additional recent data provided by the Asia-Pacific Blood and Marrow Transplantation Group (APBMT, since 1974), the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR, since 1980), the Eastern Mediterranean Blood and Marrow Transplantation Group (EMBMT, since 1984), the Canadian Blood and Marrow Transplantation Group (CGBMT, since 2002), the Latin American Blood and Marrow Transplantation Group (LABMT, since 2009) and the African Blood and Marrow Transplant Group (AFBMT, since 2010). Double reporting was minimized by crosschecking registries and unrelated donations. Missing data from a few regions in 2012 were extrapolated from previous years assuming a 5% increase. As of December 2012, the 1450 transplant centers from 72 countries over 5 continents had reported 1.000.000 HSCT (58% autologous, 42% allogeneic). The dramatic recent increase in rate of utilization of HSCT is illustrated by the fact that there were 10.000 HSCTs worldwide by 1985, 50.000 by 1990, 100.000 by 1994, 500.000 by 2004 and 1.000.000 by December 2012. The absolute and relative contribution differed significantly with Europe providing 53%, the Americas 31%, Australasia 14% and Eastern-Mediterranean and Africa 2% to the total HSCT number (allogeneic HSCT: 45%, 32%, 20% and 3%; autologous HSCT: 58%, 31%, 10% and 1%). The increase in activity has been almost linear over the past 55 years with two exceptions, a decrease in autologous HSCT for breast cancer from 1999 especially in the Americas and a decrease in allogeneic HSCT for CML after 2000 seen everywhere except in the Eastern-Mediterranean/African region. The rise in HSCT numbers during the last decade was mainly due to an increase in allogeneic HSCT from unrelated donors; the relative increase being highest in Australasia. Recent growth was primarily due to increases in activity in existing transplant centers, rather than in the number of transplant centers. The main indications for autologous HSCT today are lymphoproliferative disorders 87% (myeloma 46% and lymphoma 41%), solid tumors 8.6% and AML 2.75%; for allogeneic HSCT leukemias 73% (AML 34.6%; ALL 16.8%; CML 4%; myelodysplastic and myeloproliferative disorders 13.3%; CLL 2.9% and other leukemias 1%), lymphoproliferative disorders 14.3% and bone marrow failure syndromes 5.5%. In 2010, cord blood was used as stem cell source in 19% of unrelated HSCT. These data were compiled through collaboration of the global HSCT community. Global collaboration has also been essential for the diffusion of HSCT as a therapy and especially for unrelated HSCT. More than 22 million unrelated donors are available today from a global network (World Marrow Donor Association, WMDA) of donor registries and cord blood banks and about 30% of unrelated HSCT involve a donor and recipient in different countries. The success of HSCT serves as a model for organ repair by the use of healthy stem cells and as a model for global cooperation in meeting the needs of an international patient population. These data also illustrate the challenges for the global medical community in providing state of the art care in regions with constrained resources and the need to find ways to make the therapy more available in order to provide better outcomes for patients with life-threatening but potentially curable diseases. Disclosures: Gluckman: Cord use: Honoraria; gamida: Honoraria.

Description: Therapy-related myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML) have a poor prognosis with conventional therapy. Encouraging results are reported after allogeneic transplantation. We analyzed outcomes in 868 persons with t-AML (n = 545) or t-MDS (n = 323) receiving allogeneic transplants from 1990 to 2004. A myeloablative regimen was used for conditioning in 77%. Treatment-related mortality (TRM) and relapse were 41% (95% confidence interval [CI], 38-44) and 27% (24-30) at 1 year and 48% (44-51) and 31% (28-34) at 5 years, respectively. Disease-free (DFS) and overall survival (OS) were 32% (95% CI, 29-36) and 37% (34-41) at 1 year and 21% (18-24) and 22% (19-26) at 5 years, respectively. In multivariate analysis, 4 risk factors had adverse impacts on DFS and OS: (1) age older than 35 years; (2) poor-risk cytogenetics; (3) t-AML not in remission or advanced t-MDS; and (4) donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50% (95% CI, 38-61), 26% (20-31), 21% (16-26), 10% (5-15), and 4% (0-16), respectively (P 〈 .001). These data permit a more precise prediction of outcome and identify subjects most likely to benefit from allogeneic transplantation.

Description: Abstract 3506 Recurrent disease is the most important cause of treatment failure after HCT. Total body irradiation (TBI)-containing conditioning regimens are associated with fewer relapses and longer leukemia-free survival (LFS) in children and adolescents with ALL. While TBI

Description: Transplant-related mortality (TRM) is the largest limiting factor to successful URD-BMT as curative therapy. Identification of non-HLA genetic factors in either recipients or donors could improve BMT outcomes through better matching at these loci. We performed a genome-wide association study (GWAS), named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) of 1-year TRM in 3,532 patients treated for AML, ALL or MDS (recipients) reported to CIBMTR from 2000-2011 and their HLA-matched URD (donors); donor DNA was available for 98% of HCT recipients. Cohort 1 includes 2,240 donor-recipient pairs; patients received a 10/10 HLA URD-BMT from 2000-08. Cohort 2 includes 823 donor-recipient pairs; patients received either a 10/10 HLA URD-BMT from 2009-11 or 8/8 (but

Description: Introduction. The definitive management of R/R FL remains controversial due to various treatment options, including chemoimmunotherapy, pathway inhibitors, and autologous stem cell transplantation (auto-SCT). These options can provide prolonged progression-free survival (PFS). Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the sole curative therapy for FL. Herein, we report the long term outcome of the largest sample of allo-SCT for FL ever studied as well as the identification of patient and disease related factors that were significantly associated with treatment failure. Patients. Eligible were adult patients with R/R FL having received a first allo-SCT between 2001 and 2011 from an HLA identical sibling donor (SIB) or a well-matched unrelated donor (MUD). Patients with transformed lymphoma were excluded from the analysis as well as planned second transplants, allotransplants from cord blood, mismatched donors, and transplants with ex vivo T cell depletion (TCD). Results. 1567 patients met the eligibility criteria (EBMT, n = 1115; CIBMTR, n = 452). Demographics separated by data source demonstrate some differences in transplant practices between the two regions. The CIBMTR cohort had a higher proportion of MUD recipients [167 (37%) vs 252 (23%), p 〈 0.001], more cases with chemoresistant disease [113 (25%) vs 145 (13%), p 〈 0.001], less patients having received a prior auto-SCT [53 (12%) vs 403 (36%), p 〈 0.001], more use of myeloablative conditioning (MAC) (145 (32%) vs 220 (20%), p 〈 0.001) and less use of alemtuzumab in-vivo TCD [29 (6%) vs 201 (18%), p 〈 0.001] compared to the EBMT cohort. Median (range) follow up of survivors in months was 58 (3 - 130) and 54 (3 - 160) for CIBMTR and EBMT patients, respectively. Cumulative incidence of acute (grades II-IV) graft versus host disease (GVHD) was 20% (18-22) at 100 days and of chronic GVHD 45% (42-48) and 55% (52-58) at 1 and 3 years, respectively for the whole series; this risk was slightly but significantly reduced in the EBMT cohort. All major outcomes [non-relapse mortality (NRM), relapse/progression (R/P), overall survival (OS) and PFS] were comparable between the CIBMTR and EBMT samples (Table 1). Table 1. Outcomes CIBMTR EBMT p-value NRMN@ 1 y@ 3 y@ 5 y 45021 (17-25)27 (23-32)31 (26-35) 108819 (16-21)24 (21-27)28 (25-31) 0.3630.1720.114 R/PN@ 1 y@ 3 y@ 5 y 45013 (10-16)16 (13-20)17 (13-21) 108813 (11-15)18 (15-20)21 (18-23) 0.8740.4800.114 PFSN@ 1 y@ 3 y@ 5 y 45066 (62-71)56 (52-61)52 (47-57) 108869 (66-72)58 (55-61)52 (48-55) 0.3750.4950.792 OSN@ 1 y@3 y@ 5 y 45274 (70-78)65 (60-69)61 (56-65) 110475 (72-78)67 (64-70)62 (59-65) 0.5890.4550.695 Multivariate analysis indicated that NRM was significantly affected by age (HR 1.04, 1.02-1.05, p 〈 0.0001), chemoresistant disease (HR 1.61, 1.28-2.03, p 〈 0.0001), 〉= 5 lines of prior CT (vs 3-4) (HR 1.62, 1.20-2.19, p=0.0015) and Karnofsky performance score (KPS) 〈 80 (HR 2.05 (1.32-3.19, p=0.0014); R/P was significantly affected by grade 3 histology (HR 1.63, 1.16-2.26, p=0.0049) and chemoresistant disease (HR 1.46 (1.07-1.97), p=0.0156); PFS by grade 3 histology (HR 1.42, 1.15-1.76, p=0.0012), chemoresistant disease (HR 1.54, 1.28-1.86, p= 5 lines of prior CT (vs 3-4) (HR 1.45, 1.13-1.85, p=0.0031), MAC (HR 1.36, 1.14-1.63, p=0.0008) and KPS 〈 80 (HR 1.78, 1.23-2.58, p =0.0022) and OS by age (HR 1.03, 1.02-1.04, p

Description: Abstract 3143 Hematopoietic cell transplantation (HCT) is the treatment of choice for many patients with malignant and non-malignant disorders. Transplant practices have evolved allowing patients previously not otherwise candidates to receive this procedure. Activity surveys and registries play an essential role in the success of HCT, by tracking activities, identifying areas of need and through clinical research to continue improving patient outcome. Because of the need of matched donors, ethnic characteristics and legal requirements HCT has acquired a global dimension. In the current analysis the Worldwide Blood and Marrow Transplantation network (WBMT) reports the global activities, indications and trends for the years 2006 to 2008. The survey consisted of activities reported to the WBMT from international societies members (EBMT, CIBMTR, APBMT, EMBMT, ABMTRR), national registries (SBTMO) and also directly from transplant centers in regions were no societies are established. Annual transplant center specific activities were from 1327 transplant centers in 71 countries in 2006. The number of participating centers increased to 1382 and 1407 in 2007 and 2008, respectively. Annual number of transplants steadily increased from 46,563 in 2006 to 48,709 and 51,536 in 2007 and 2008. When analyzing the median number of transplants/year performed at each center the corresponding annual activity was 38 (range 3–180), 46 (3–421) and 48 (1–389), suggesting that the increment in transplant activity is not only related to higher number of reporting centers. The highest increase in total HCT over two years was observed in the Asia Pacific region (38.6%) followed by the East Mediterranean region (19.4%), Europe (5.6%) and the U.S. (4.5%). An absolute increase of autologous and allogeneic was observed over the three year period with more autologous (55%) than allogeneic (45%) HCT reported, however the increase was less in autologous (+5.0%) when compared to allogeneic (+17.9%). Among indications for allogeneic HCT, acute leukemias (AML +23%; ALL +27%), myelodysplasia (MDS +26%), chronic lymphocytic leukemia (CLL +24.6%) nonmalignant diseases (NMD +23.6%) and bone marrow failure disorders (BMF +21.2%) significantly increased during the study period. Slower increase was reported for lymphoproliferative disorders (LPD +6%) and a clear decrease for chronic myelogenous leukemia (CML -17%) and solid tumors (−13.3%). Among autologous HCT indications autoimmune diseases (+24.5%), PCD (+9.8%) and LPD (+7.5%) increased during the period. A negative trend was seen in autologous HCT for solid tumors (−2.4%), ALL (−22.0%), AML (−9.0%), CLL (−52.0%) and CML (−57.1%). These data show the trend and activity for autologous and allogeneic HSCT worldwide. There is a clear increase in activity especially in acute and chronic (except CML) leukemias for allogeneic HST and for autoimmune diseases, LPD and PCD in autologous HCT. Monitoring global transplant practices is an important activity for WBMT in order for capacity planning of HCT donor pool worldwide and to promote the field by expanding access to transplantation at regions in need. Disclosures: No relevant conflicts of interest to declare.