Intensity Allogeneic Stem Cell Transplantation Research Articles

Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML

AbstractWe conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT) after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% with prior Ven exposure, and 96% with positive molecular measurable residual disease), 22 received maintenance therapy with Aza 36 mg/m2 intravenously on days 1 to 5, and Ven 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% confidence interval [CI], 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, nonrelapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. Immune monitoring demonstrated no significant impact on T-cell expansion but identified reduced B-cell expansion compared with controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered for patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT03613532.

O-149 - Brentuximab vedotin as a bridging treatment for mycosis fungoides prior to reduced intensity allogeneic stem cell transplant

O-149 - Brentuximab vedotin as a bridging treatment for mycosis fungoides prior to reduced intensity allogeneic stem cell transplant

Renal Impairment Adversely Impacts Melphalan-Induced Severe GvHD- and GI Toxicity- Free Survival (MGTFS) in Patients Undergoing Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation

Renal Impairment Adversely Impacts Melphalan-Induced Severe GvHD- and GI Toxicity- Free Survival (MGTFS) in Patients Undergoing Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation

Reduced Intensity Stem Cell Transplantation for Accelerated-Phase Myelofibrosis

Reduced Intensity Stem Cell Transplantation for Accelerated-Phase Myelofibrosis

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Comparison of Outcomes of Elderly Patients with Acute Myeloid Leukemia (AML) in CR1 Receiving Reduced Intensity Allogeneic Stem Cell Transplantation (RICT) from Matched Sibling (MSD) or Unrelated Donors (URD)

BACKGROUND. Comparative data on the results of RICT from MSD or URD in elderly patients (pts) are scarce. We describe outcomes of AML CR1 pts > 50 years (yrs) allografted from MSDs or URDs as part of a multinational, prospective, controlled study (NCT00342316), which aims to compare RICT vs chemotherapy. The study started in 2004 and completed enrollment (339 pts) in 2016. In this report, we compare the impact of MSD or URD and therefore we focus only on the time period when both MSD and URD transplants were performed within the study (2010-2016).PATIENTS AND PROCEDURES. Included were 136 pts (53 females, 83 males). Median age was 64 (50-70) and 62 (52-70) yrs in URD and MSD groups, respectively. Pts were high (54%) or intermediate (IR) (46%) risk, donors were URD (n=81), and MSD (n=55). Prespecified high risk criteria were: poor risk cytogenetics, secondary or therapy-related AML, blasts >15% after induction #1, or FLT3-ITD+/NPM1-. Eight URDs were <8/8 HLA matched. Reduced intensity conditioning was busulfan/fludarabine based in 92% of transplants (Tx). Anti thymocyte globulin (ATG) pre Tx was used in 93% of URD and 25% of MSD pts. Pts received PBSC (94%) or BM (6%). Distribution of high/intermediate risk pts were: URD 58%/42% and MSD 48%/52% (p=0.29.) STATISTICSOverall survival (OS) and leukemia free survival (LFS) after Tx were estimated by means of the Kaplan-Meier method, whereas cumulative incidence functions were used for non-relapse mortality (NRM) and relapse incidence. The Cox regression model was used to analyze incidence rates.RESULTS. Median time from CR to Tx in URD and MSD groups was 4.0 (range 1.1-8.7), and 3.1 (0.8-10) mo, respectively (p<0.001). URD pts received more chemo pre Tx: ≥3 courses in 85% vs 60% (MSD group) p=0.001. Graft rejection occurred in 1 pt.Median follow-up from Tx for living pts was 23 (4-78) and 25 (3-82) mo for URD and MSD pts, respectively. During follow-up, 36 pts relapsed, 24 URD (30%) and 12 MSD (22%) and 47 pts died, 23 URD (28%) and 24 MSD (44%). Causes of deaths in the URD and MSD groups were AML (n=18,11), GvHD (1,5), infections (2,5) and other (2,3).Estimated 2-year OS for all pts was 64% (95% CI 54-72%). For the subgroups of high and IR risk pts OS at 2 yrs was 49% (36-61%) and 82% (69-90%), respectively. For MSD and URD groups OS were 53% (38-67%) and 72% (60-81%); hazard ratio (HR) 1.66 (0.94-2.95; p=0.08). If adjusting for confounders [risk category (high vs . IR), country (Canada/other vs . Sweden), gender, age] the HR for OS was 1.57 (0.80-3.08; p=0.19). LFS was similar in URD and MSD groups: 53% (38-66%) vs 63% (50-73%); adjusted HR 1.21 (0.65-2.26; p=0.54). The 2-yrs cumulative incidence (CI) of relapse (NRM competing) was 23% (13-35%) in the MSD group and 32% (21-43%) in the URD group; adjusted HR 0.71 (0.32-1.60; p=0.41). The 2-yrs CI of NRM (relapse competing) was 24% (13-37%) in the MSD group and 5% (2-11%) in the URD group, adjusted HR 3.45 (1.03-11.6; p=0.045).Grade III-IV acute GvHD and chronic extensive GvHD were less common in the URD group, 5% vs 21% (p=0.009) and 10% vs 45% (p <0.001), respectively. At 12 mo after CR1, 18% of URD pts and 58% of RD pts were on corticosteroids (p<0.001).CONCLUSION. No significant differences in OS, LFS or relapse rate were found between MSD and URD transplants. However, RICTs from URDs were associated with less acute and chronic GvHD, and less NRM. These findings may be explained by lower donor age, more chemo, longer time from CR to Tx in MUDs and probable contribution of ATG. Our data suggest that URD RICT may be used safely in older patients with AML with satisfactory OS. DisclosuresKiss:Otsuka: Membership on an entity's Board of Directors or advisory committees, Other: meeting attendance support, Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Delage:BMS: Research Funding; Pfizer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ritchie:Amgen Inc.: Honoraria. Sabloff:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brune:Novartis: Other: reimbursement for lecture.

Durable Remission of Refractory and Advanced Stage Mycosis Fungoides/Sezary Syndrome (MF/SS) Utilizing an “Outpatient” Alemtuzumab and Fludarabine-Based Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT)

Background:Advanced MF/SS carries a poor prognosis with most therapies failing to provide a long-term benefit. Allogeneic hematopoietic cell transplantation may result in durable remissions or clinically meaningful downstaging in a subset of patients. However, the risk of transplant related mortality has substantially curbed enthusiasm in the use of conventional allogeneic transplantation for this disease. In this study, we describe a novel allogeneic transplant approach in which a G-CSF mobilized, unmanipulated PBSC allograft from HLA-matched siblings was infused after conditioning with a regimen customized to maximally cytoreduce the disease and to provide the necessary immunosuppression to achieve sustained donor immune engraftment needed for the generation of a graft-vs-tumor effect (GVT). We theorized that this outpatient based reduced intensity transplant regimen would provide the essential tumor-debulking and a strategy to achieve sufficient degrees of donor T-cell chimerism necessary to result in the generation of curative GVT effects in patients with the most advanced forms of MF/SS.Patients and Methods:Between January 2004 and May 2014, 5 subjects (median age of 57, range 27-59) with refractory, advanced stage (III and IV) MF/SS who had failed a median 3 prior treatment regimens (range 2-7) underwent PBSCT following mostly outpatient conditioning with alemtuzumab (total of 193 mg), and fludarabine (total of 125 mg/m2). On day 0, subjects received a G-CSF mobilized unmanipulated PBSC allograft from an HLA identical sibling. CSA alone was used as GVHD prophylaxis. Donor lymphocyte infusions (DLI) were given to all patients to convert T-cell chimerism from mixed to full donor and when necessary to boost a GVT effect.Results:All 5 subjects initially had mixed lympho-hematopoietic chimerism but eventually converted to full donor chimeras in both myeloid and T-cell lineages; full donor T-cell chimerism was achieved at a median 7 months post-transplant (Figure 1). 3/5 subjects never became neutropenic and the 2 subjects who developed neutropenia had rapid neutrophil recovery occurring after 5 and 7 days. No patients developed severe anemia or thrombocytopenia and none required RBC or platelet transfusion support.No patients developed acute GVHD prior to DLI and only one (20%) developed acute GVHD (GI, grade IV) following DLI (the 2nd DLI for this patient). Three subjects (60%) developed limited cGVHD which resolved with short course of steroids.At a median follow-up of 3 years, 4 subjects achieved a complete remission, documented by labs, skin biopsy, and imaging. Remissions were delayed in onset, occurring at median 8 months post-transplant (Figure 1). 3 subjects remain alive in remission 13, 11, and 3 years after transplant. One subject with a heavy smoking history died in remission 3 years post-transplant from a secondary head and neck squamous cell carcinoma, and one subject died 7 months post-transplant from grade IV GI GVHD which followed a 2nd DLI given to treat progressive disease (Table 1).Among those at risk, 3 of 4 subjects (75%) developed CMV reactivation. None of the subjects developed CMV disease or PTLD.Conclusions:Our custom designed conditioning regimen 1) resulted in cytoreductive effects against advanced MF 2) proved to be immunosuppressive enough to allow sustained donor engraftment serving as a platform for subsequent DLIs which lead to curative GVT effects 3) could be performed in the outpatient setting avoiding severe neutropenia and its associated opportunistic infections and the need for platelet and RBC transfusion support. These data establish that long-term cures of even the most advanced refractory MF/SS can be achieved utilizing this alemtuzumab and fludarabine-based reduced intensity allogeneic hematopoietic cell transplant approach. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Should patients receive consolidation chemotherapy before reduced intensity allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission?

Background:For acute myeloid leukemia (AML) patients, the role of bridging consolidation chemotherapy after achieving first complete remission (CR1) in the transplant setting is a frequently debated issue. The lack of data from Asian patients led us to conduct this study.Methods:We retrospectively studied outcomes of 106 patients in CR1 undergoing allogeneic stem cell transplantation (alloSCT) with reduced intensity conditioning (RIC) based on their exposure to pre-transplant consolidation chemotherapy. There were 35 in the no consolidation group versus 71 in the consolidation group.Results:The median relapse free survival (RFS) was 9 months for the no consolidation group and 51 months for consolidation group (p = 0.023). The median overall survival was 32 months for the no consolidation group and not reached for the consolidation group (p = 0.034). Multivariate analysis recognized consolidation and poor cytogenetics as adverse prognostic factors for RFS. Moreover, RFS was better in patients with a shorter time lapse between last chemotherapy and alloSCT in both the no consolidation group and the consolidation group. Consolidation chemotherapy did not negatively affect neutrophil and platelet engraftment, infection rates, or acute graft-versus-host disease (GVHD) incidence. On the other hand, patients undergoing consolidation chemotherapy showed trends towards a more severe degree of chronic GVHD.Conclusion:The exposure to consolidation chemotherapy in CR1 prior to alloSCT with RIC conditioning did not negatively impact the outcomes in Korean AML patients, for whom a suitable donor is rarely immediately available. Therefore, post-remission consolidation chemotherapy is a reasonable option if required.

Hodgkin Variant of Richter's Transformation (HvRT) Among Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Patients in British Columbia (BC), Canada

Hodgkin Variant of Richter's Transformation (HvRT) Among Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Patients in British Columbia (BC), Canada

Tandem autologous-reduced intensity allogeneic stem cell transplantation in high-risk relapsed Hodgkin lymphoma: a retrospective study of the Lymphoma Working Party-EBMT.

Autologous hematopoietic stem cell transplantation (ASCT) is curative for a proportion of patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). However, there is a small group of patients with high-risk of relapse after ASCT that might benefit from other approaches. We conducted a retrospective analysis on 126 patients treated with tandem ASCT-reduced intensity conditioning (RIC)-allogeneic-SCT and reported to the EBMT registry to analyze the efficacy and safety of this approach. Patients were included if they had received an ASCT followed by a planned RIC-SCT in <6 months without relapse between the procedures. The median time between diagnosis and ASCT was 16 months (2-174). The median number of lines prior to ASCT was two (33% of the patients received >3 lines). Forty-one percent were transplanted with active disease. The median follow-up was 44 months (6-130). Three-year-progression-free survival (PFS), overall survival (OS), incidence of relapse (IR), and non-relapse mortality (NRM) after the tandem were 53% (45-64), 73% (65-81), 34% (24-42), and 13% (8-21), respectively. This is the largest series analyzing the efficacy and safety of a tandem approach in R/R HL. The low NRM and IR with promising PFS and OS suggest that this might be an effective procedure for a high-risk population.

Outcomes of AML Patients Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation with Adverse Risk Disease By European Leukemianet Classification: A Single Center Retrospective Analysis

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults with a median age at diagnosis of close to 70 years. (Juliusson G, et al. Blood, 2011;119(17):3890-3899) The majority of patients with AML require allogeneic stem cell transplant (Allo-SCT) in order to achieve cure. European LeukemiaNET (ELN) published risk stratifications for AML patients according to cytogenetics in 2010 and then updated risk categories in 2017 to incorporate molecular abnormalities as well. The ELN adverse risk category predicts for a higher risk of relapse and worse overall survival (OS) compared to favorable and intermediate risk patients. (Döhner H, et al. Blood, 2017;129(4):424-447) Older patients are more likely than younger patients to have adverse risk disease. (Mrozek K, et al. JCO, 2012;30(36):4515-4523). In addition, older patients are typically not considered for myeloablative conditioning (MAC) regimens due to the high risk of non-relapse mortality (NRM). Thus, a significant proportion of AML patients who are candidates for Allo-SCT have adverse risk disease by ELN criteria and are only candidates for RIC Allo-SCT, both of which increase the risk of relapse. A recent randomized trial in AML and MDS patients noted a trend toward improved OS and statistically significant improvement in relapse free survival (RFS) favoring MAC over RIC (Scott BL, et al. JCO, 2017; 35(11): 1154-1161). Despite this, studies have shown durable remissions and long term disease free survival with RIC Allo-SCT in AML patients with high risk features. (Tauro S, et al. JCO, 2005; 23(36):9387-9393) However, to our knowledge no study has investigated the use of RIC Allo-SCT exclusively in patients who have adverse risk by 2017 ELN criteria. Thus, we reviewed AML patients with adverse risk disease by 2017 ELN criteria at diagnosis who underwent RIC Allo-SCT at our institution. Methods: We conducted a single center retrospective study of high risk adult AML patients by ELN criteria who underwent RIC Allo-SCT at MUSC from 3/20/2010 to 2/20/2018. Adverse risk disease was defined by the 2017 ELN criteria. Baseline demographic, clinical, laboratory, pathology, and outcomes data were collected by retrospective chart review. Kaplan Meier was utilized for time to event analysis. Results: A total of 42 patients with adverse risk AML received RIC Allo-SCT. The median follow up was 16.6 months. Clinical characteristics were collected for each patient and are included in table 1. The median age was 62 with 16 patients (38%) ≥ 65 years of age. Twenty-three patients had a HCT-CI score ≥ 3 (54%) with 9 patients (21%) having a HCT-CI score ≥ 5. Complete remission (CR) was defined as bone marrow blasts &lt; 5% without known molecular evidence of persistent/relapsed AML. CR and CR with incomplete count recovery (CRi) was not able to be defined. Thirty-one patients (73%) were in CR1 at transplant, 7 patients (16%) were in CR2+ defined as CR necessitating ≥ 2 treatment regimens. Four patients (9%) never achieved a CR and were labelled as primary induction failure (PIF), and one patient (3%) received prior MAC Allo-SCT before receiving RIC Allo-SCT and was labeled as Relapse. Four of the five patients with disease status of PIF or relapse were deceased within 13 months of Allo-SCT. The non-relapse mortality (NRM) at 1 year was 26.2%. Relapse-free survival (RFS) at 1, 2, and 3 years was 57.1%, 45.2%, and 35.7% respectively. The overall survival (OS) at 1, 2, and 3 years was 66.7%, 50.0%, and 40.5% respectively. A subset analysis of the patients in CR1 or CR2+ prior to RIC-Allo SCT noted a NRM at 1 year of 27% along with a RFS at 1, 2, and 3 years of 59.5%, 48.7%, and 40.5% respectively. Cause of death included relapse (33%), infection (29%), acute GVHD (25%), and chronic GVHD (3%). Conclusion: This provides evidence that although adverse risk disease by ELN criteria and reduced intensity conditioning both increase the incidence of relapse in patients with AML, that RIC Allo-SCT for this high risk patient population can provide long term disease free survival. In addition, the favorable outcomes for patients in CR1 and CR2+ prior to RIC-Allo are promising. It would be interesting to investigate a larger multi-center series of patients with adverse risk disease by ELN in CR prior to RIC Allo-SCT. Minimal residual disease by myeloid molecular panel and/or flow in this patient population prior to transplant would be of great interest as well. Disclosures Edwards: Genzyme: Consultancy.

Reduced intensity allogeneic stem cell transplantation for younger patients with myelofibrosis.

Allogeneic stem cell transplantation (alloSCT) is a curative procedure for myelofibrosis. Elderly people are mainly affected, limiting the feasibility of myeloablative regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible for older patients. Nevertheless, the incidence of myelofibrosis is not negligible in young patients, who are theoretically able to tolerate high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in younger myelofibrosis patients. This study included 56 transplanted patients aged <55years. Only 30% had a human leucocyte antigen (HLA)-matched sibling donor, the others were transplanted from a fully-matched (36%) or partially-matched (34%) unrelated donor. All transplants were conditioned according the European Society for Blood and Marrow Transplantation protocol: busulfan-fludarabine + anti-thymocyte globulin, followed by ciclosporin and mycophenolate. One patient experienced primary graft failure. Incidence of graft-versus-host disease grade II-IV was 44% (grade III/IV 23%). One-year non-relapse mortality was 7% and the 5-year cumulative incidence of relapse was 19%. After a median follow-up of 8·6years, the estimated 5-year progression-free survival and overall survival (OS) was 68% and 82%, respectively. Patients with fully-matched donor had a 5-year OS of 92%, in contrast to 68% for those with a mismatched donor (P=0·03). The most important outcome-determining factor is donor HLA-matching. In conclusion, RIC-alloSCT ensures optimal engraftment and low relapse rate in younger myelofibrosis patients, enabling the possibility of cure in this group.

Reduced Intensity Allogeneic Stem Cell Transplantation for Younger Patients with Myelofibrosis

INTRODUCTION Allogeneic stem cell transplantation (alloSCT) is the only curative procedure for primary and secondary myelofibrosis (PMF, SMF). Elderly people are mainly affected, limiting the feasibility of intensive myeloablative chemotherapy regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible and effective for old patients. Nevertheless, the incidence of PMF and SMF is not negligible in young patients, theoretically able to tolerate also high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in the particular setting of young-aged MF patients.PATIENTS AND METHODS This study includes 56consecutive Myelofibrosis young patients (age <55y) who received alloSCT allogeneic stem cell procedure between 2002 and 2016 at the University Hospital Hamburg/Germany treated in UK-Eppendorf, Hamburg. Only 4 patients were previously splenectomized. Patients mostly fall into intermediate risk groups according to DIPSS model (int-1: 22; int-2: 24; high: 3). Four patients belonged to the high-risk triple-negative category (JAK2/CALR/MPL-). ASXL1 additional mutation was tested in 50 patients (, and positive: in 17) cases. In 96% graft source was peripheral blood stem cells, 2 patients received bone marrow stem cell. Only 30% of patients had a 10/10 HLA-matched sibling donor, the others were transplanted from fully-matched (36%) or partially-matched (34%) unrelated donor. All transplants were conditioned according the EBMT protocol with Busulfan (10 mg/Kg PO or 8 mg/Kg IV), Fludarabine (150 mg/m2), ATLG (Grafalon® Neovii, Germany) administered in 3 days at a dose of 20 mg/Kg die for MUD, 10 mg/Kg die for MRD transplants, followed by Cylosporin A, and Mycophenolate in the first 28 days was added only in MUD/MMUD transplants.RESULTS Engraftment rate was 98%, with a median neutrophil engraftment time of 15 days. Platelet engraftment was reached by 51 patients (91%) in a median time of 19 days. Four patients (7%) developed poor graft function, successfully treated with CD34+ selected PBSC boost. After a median follow up of 8.6 y estimated 5y PFS and OS was 68% and 82% respectively. DIPSS risk and donor HLA-matching resulted the only significant impacting factors on OS. Neither cytogenetic nor molecular abnormalities (included ASXL1) were significantly related to OS. Twenty-five patients (44%) experienced acute GVHD grade >1. Chronic GVHD was observed in 34 patients (65%), mostly (82%) beginning in the first 300 days after transplantation. Cumulative incidence of TRM was 7% at 1 year, with a plateau after the first year (5y TRM = 12%). TRM was observed only in patients with maximal grade (3) of marrow fibrosis (p=0.00). Furthermore, TRM never occurred in previously splenectomized patients (p=0.00), but no significant impact from splenectomy on OS was observed (p=0.32). After transplant, 11 patients (20%) relapsed: 1 died without any treatment because of infection, 9 received DLI with durable recovery of complete remission in 3 cases, 7 patients (6 after DLI) underwent a second alloSCT, with long-term survival in 5 cases.CONCLUSION Reduced intensity conditioning followed by allogeneic SCT is a curative treatment approach for younger patients with myelofibrosis with a low NRM. The most important outcome-determining factor is donor HLA-matching. Interestingly, marrow high grade fibrosis showed to significantly impact TRM. Biological markers such as ASXL1 mutation and cytogenetics, largely known as highly predictive for poor prognosis in the disease natural course, did not show any impact on survival, suggesting that patients harboring these abnormalities could get the greatest benefit from alloSCT. According to these data, RIC-alloSCT ensures optimal engraftment and low relapse rate, being able to lead also younger MF patients to cure. Further data collection, and a prospective randomized trial are needed to confirm our conclusion. DisclosuresNo relevant conflicts of interest to declare.

Reduced intensity allogeneic stem cell transplantation for advanced stage mycosis fungoides and Sezary syndrome. A series of 53 patients from the UK.

Reduced intensity allogeneic stem cell transplantation for advanced stage mycosis fungoides and Sezary syndrome. A series of 53 patients from the UK.

Abstract 1785: Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using Cross-Over-Dual-Variable-Domain (CODV) format for the treatment of acute myeloid leukemia (AML)

Abstract Acute myeloid leukemia (AML) is characterized by the accumulation of abnormal blast cells in the bone marrow and blood. While high intensity chemotherapy and allogeneic stem cell transplantation cure a subset of patients with AML, many patients are ineligible or do not respond sufficiently to these therapies. One potential reason for treatment failure in a particular patient may be the inability to reach and eliminate residual leukemic stem cells (LSCs) located in the bone marrow. T-cell mediated cytotoxicity, targeting LSCs with high expression of certain leukemic antigens, represents an attractive therapeutic strategy for relapsed and refractory AML. In this study, the proprietary Cross-Over-Dual-Variable-Domain (CODV) format was applied to a fully humanized IgG1 backbone with reduced Fc functionality, resulting in a bispecific T-cell engager (TCE), CD123-CODV-TCE, that binds to both CD3 on T cells and CD123 (α-chain of the interleukin-3 receptor) on AML blasts and LSCs. CD123-CODV-TCE displayed high affinity for human CD123 and medium affinity for human CD3 proteins. As expected, CD123-CODV-TCE activated CD4-positive and CD8-positive T cells only in the presence of cells expressing the CD123 target, such as THP1 (an AML tumor cell line), and induced killing of these cells with an EC50 in a picomolar range. Potential cytotoxic activity of CD123-CODV-TCE was also evaluated on CD123-expressing normal blood cells such as plasmacytoid dendritic cells (pDC) and monocytes. CD123-CODV-TCE was shown to deplete pDC and monocyte from human Healthy Donor (HD) Peripheral Blood Mononuclear Cells (PBMC) with an EC50 in the picomolar range. This efficacy correlated with the release of numerous cytokines, thus highlighting the potential risk of cytokine release syndrome as described for other TCE's. In an in vivo disseminated AML model using CD123+ Molm13-luc human AML cell line, treatment of the mice with CD123-CODV-TCE suppressed AML tumor growth in the bone marrow compartment following co-injection of primary human T cells. In this murine pre-clinical model, CD123-CODV-TCE displayed favorable pharmacokinetic properties with a terminal half-life of 3 days. To investigate CD123-CODV-TCE activity on myeloid blast cells and LSC, in vivo efficacy studies were performed in NSG mice injected with primary human AML cells obtained from patients. In this model, CD123-CODV-TCE induced the killing of primary AML cells by activating human autologous T cells. Taken together, these results indicate that CD123-CODV-TCE can potently and specifically kill CD123+ leukemic cancer cells in vitro and in vivo. CD123-CODV-TCE therefore represents a potential candidate for future clinical development in relapsed and refractory AML. Citation Format: Helene Bonnevaux, Stephane Guerif, Jana Albrecht, Erwan Jouannot, Laurent Bassinet, Agnès Vergezac, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Anne Caron, Celine Amara, Cedric Barriere, Justine Siavellis, Valerie Bardet, Ernesto Luna, Donald Drake, Ercole Rao, Corina Oprea, Peter Wonerow, Chantal Carrez, Veronique Blanc, Karl Hsu, Dmitri Wiederschain, Paula G. Fraenkel. Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using Cross-Over-Dual-Variable-Domain (CODV) format for the treatment of acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1785.

Interview with Dr Philip McCarthy.

Philip McCarthy speaks to Roshaine Wijayatunga, Senior Editor: Oncology Philip McCarthy completed his MD at Tufts University School of Medicine, Boston, MA, USA and his Internal Medicine Residency at Yale, New Haven Hospital, New Haven, CT, USA. His Fellowship was completed at Brigham and Women’s Hospital and the Dana Farber Cancer Insitute, Harvard University, Boston, MA, USA. His research interests are devoted to developing novel intensive and reduced intensity allogeneic (allo) and autologous (auto) hematopoietic stem cell transplant (HSCT) approaches for the treatment of hematologic disorders, leading to improved patient outcomes and decreased toxicity. He has over 20 years of experience treating HSCT patients and directing clinical and translational HSCT research studies. He has served as chair or co-chair of several clinical trials including CALGB 100104, a Phase III clinical trial evaluating lenalidomide maintenance after auto-HSCT for multiple myeloma (MM). This study demonstrated an improved progression-free and overall survival for MM patients receiving lenalidomide maintenance therapy after auto-HSCT. The Roswell Park Comprehensive Cancer Center Blood and Marrow Transplant team has developed a systematic approach to the evaluation and treatment of HSCT patients with a specific focus on predicting and minimizing treatment-related mortality. The team participates with a core group of basic science and clinical researchers who are committed to the investigation of the complications of auto- and allo-HSCT and to the developing novel approaches to improve outcomes.

Emerging therapeutic modalities for acute myeloid leukemia (AML) in older adults.

Treatment for the older adult with acute myeloid leukemia (AML) is challenging, due to both more aggressive disease biology as well as patient-related risk factors that limit tolerance of intensive chemotherapy. The use of prognostic models and comprehensive geriatric assessments can help hematologists evaluate the suitability of intensive chemotherapy for individual patients. For older patients considered fit for intensive chemotherapy, standard induction therapy should be given, followed by consideration of reduced intensity allogeneic stem cell transplantation. Patients considered unfit for intensive therapy are standardly treated with hypomethylating agents. Several new therapeutic agents have shown promising results either by improving intensive chemotherapy (CPX-351), by improving upon lower intensity therapy (venetoclax, antibody drug conjugates), or by targeting somatic mutations (FLT3 inhibitors and others).

269 - Prognostic Factors of CLL Patients Undergoing Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in the Immunochemotherapy Era

269 - Prognostic Factors of CLL Patients Undergoing Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in the Immunochemotherapy Era

Prognostic Factors of CLL Patients Undergoing Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in the Immunochemotherapy Era

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for chronic lymphocytic leukemia (CLL). With this analysis we intended to identify prognostic factors in patients undergoing reduced-intensity conditioning (RIC) or non-myeloablative (NMA) HCT at our center in the immunochemotherapy era.Methods: This retrospective chart review included all CLL patients who underwent RIC or NMA conditioned HCT at Memorial Sloan Kettering Cancer Center (MSKCC) in the immunochemotherapy era between 09/2006 and 10/2014. We then analyzed whether pre-HCT factors including age, disease response status at the time of HCT, presence of Richter's transformation, 17p deletion or TP53 mutation, use of anti-thymocyte globulin (ATG), number of prior lines of treatment, and time from diagnosis to HCT, were associated with overall survival (OS), progression-free survival (PFS), non-progression mortality, and grade 2-4 acute graft versus host disease (aGVHD). Univariate factors were evaluated via log-rank or Gray's test as appropriate, while Cox regression models were used to explore the adjusted effect of multiple factors.Results: Thirty-five patients undergoing RIC or NMA HCT with a median age of 53 years (range 36.3-69.0) were analyzed. The patients had a median of 4 prior lines of therapy (range 1-10) and a median time from diagnosis to HCT of 65.8 months (range 7.5-159.0). With a median follow-up for survivors of 58.8 months (95% CI 17.0-NA), the 5-year PFS and OS were 32.4% (95% CI 17.4-48.4) and 49.4% (95% CI 31.2-65.2), respectively (Figure 1). Treatment-related mortality was 20.0% (95% CI 8.7-34.7) and 31.8% (95% CI 17.0-47.6) at 1 and 2 years, respectively. Chemosensitive disease, defined by complete or partial remission per contemporary International Workshop CLL (iwCLL) response criteria at the time of HCT, was associated with improved 3-year OS of 68.0% (95% CI 46.1-82.5) compared to patients with chemorefractory disease to last line of therapy (stable or progressive disease) with a 3-year OS of 15.0% (95% CI: 1.0-45.7, p = 0.002, Figure 2). Additionally, patients with ≤4 lines of therapy prior to HCT experienced superior 5-year OS of 61.2% (95% CI 37.5-78.2) contrasted to 20.0% (95% CI: 3.1-47.5) in patients with >4 prior lines of therapy (p = 0.008, Figure 3). This difference approached statistical significance in multivariate analysis (HR 2.43, 95% CI 0.91-6.50; p = 0.076) adjusted for chemosensitivity. Furthermore, when adjusted for the number of prior lines of therapy, chemorefractory patients remained at greater risk of death in multivariate analysis (HR 3.29, 95% CI: 1.14-9.48, p = 0.027). Other factors including: age, history of transformed disease, the presence of 17p or TP53 deletion/mutation, time from diagnosis to HCT, or use of ATG with NMA/RIC did not impact PFS or OS.Conclusion: This is the first study to report independent prognostic impact of the number of lines of therapy prior to NMA/RIC HCT on OS for CLL patients in the post-immunochemotherapy era. We confer findings from other groups including: the prognostic significance of chemosensitivity at the time of HCT as well as HCT overcoming poor-risk cytogenetics associated with 17p chromosomal aberrations. Our data is limited by lack of patients previously exposed to recently FDA approved novel kinase or BCL2 inhibitors. Nevertheless, given our reported data, HCT should still be considered as the only therapy with curative potential for poor-risk patients earlier in their disease course, while chemosensitivity is maintained and prior to the accumulation of multiple lines of therapies. [Display omitted] [Display omitted] [Display omitted] DisclosuresPerales:Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Myeloablative versus reduced intensity allogeneic stem cell transplantation for relapsed/refractory Hodgkin's lymphoma in recent years: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

To evaluate long-term outcome of myeloablative allogeneic stem cell transplantation (allo-SCT) (MAC) versus reduced-intensity allo-SCT (RIC) in patients with relapsed/refractory Hodgkin's lymphoma (HL) in recent years. A total of 312 patients (63 MAC and 249 RIC) with relapsed/refractory HL who received allo-SCT between 2006 and 2010 and were reported to the EBMT Database were included in the study. With a median follow-up for alive patients of 56 (26-73) months, there were no significant differences in non-relapse mortality (NRM) between MAC and RIC. Relapse rate (RR) was somewhat lower in the MAC group (41% versus 52% at 24 months, P = 0.16). This lower RR translated into a marginal improvement in event-free survival (EFS) for the MAC group (48% versus 36% at 24 months, P = 0.09) with no significant differences in overall survival (73% for MAC and 62% for RIC at 24 months, P = 0.13). Multivariate analysis after adjusting for disease status at the time of allo-SCT showed that the use of MAC was of borderline statistical significance for predicting a lower RR and EFS [HR 0.7, 95% CI (0.5-1.0), P = 0.1] and [HR 0.7, 95% CI (0.5-1.0), P = 0.07], respectively, after allo-SCT. With modern transplant practices, the NRM associated with MAC for HL has strongly decreased, resulting into non-significant improvement of EFS because of a somewhat better disease control compared with RIC transplants. The intensity of conditioning regimens should be considered when designing individual allo-SCT strategies or clinical trials in patients with relapsed/refractory HL.