Patients Received Donor Lymphocyte Infusions Research Articles

Olverembatinib(HQP1351)-Based Therapy in Adults with Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Advanced Chronic Myeloid Leukemia: Results of the Real-Life Study

Background Relapsed or refractory (R/R) Philadelphia chromosome positive acute lymphoid leukemia (ALL) and advanced chronic myeloid leukemia (CML) including accelerated phase (AP) and blast phase (BP) usually result in treatment failure due to therapeutic resistance, intolerance, T315I mutations, or compound mutations, with a poor prognosis. Olverembatinib (HQP1351) is a novel third generation BCR-ABL tyrosine kinase inhibitor (3G-TKI), exhibiting a high potency of inhibition on wild and almost all mutated BCR-ABL1 kinases, including the T315I mutation and exhibiting preliminary favorable efficacy and safety profile in clinical trials. Methods In this open label, single-arm, single-center study, patients with advanced Ph+ leukemia (including CML-BP, CML-AP and R/R Ph+ ALL) were enrolled. Patients with severe cardiovascular diseases, arterial occlusion, hypertension, and pulmonary arterial hypertension were excluded . Eligible patient received olverembatinib monotherapy, combined chemotherapy, or combined immunotherapy. The primary endpoints was overall response rate (ORR) at 28 days, including complete remission (CR) and complete remission with incomplete hematological recovery (CRi), in patients with advanced Ph+ leukemia. Results Between Dec 8, 2021, to Jun 1, 2023, a total of 56 patients (Ph+ALL (n=40), CML-BP (n=13) and CML-AP(n=3)) assessed were included and received olverembatinib-based therapy. 34(60.7%) patients were men and 22 (39.3%) were women. The median age was 38 years old (IQR 29-48) and the median duration of follow-up was 8.3 months (IQR 4.6-11.9). BCR::ABL1 transcript was of p210 type in 29 (51.8%), p190 in 27 (48.2%). 13 (23.2%) and 11 (19.6%) patients had received 2 and ≥ 3 prior TKIs, respectively. 17 (30.4%) patients were pretreated with third-generation TKI (ponatinib). Genetic testing revealed mutations in 48 (85.7%) patients including compound mutation in 11 (19.6%%) patients, of whom 8 (72.3%) patients had the T315I mutation. 11 (19.6%) patients had central nervous system leukemia (CNSL) and 1 (1.8%) had extramedullary disease. Of 56 evaluable patients, 48 (85.7%) patients reached CR/CRi. After achieving CR/CRi, 13/48 (27.1%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), 3/48 (6.3%) patients received donor lymphocyte infusion (DLI), and 3/48 (6.3%) patients received chimeric antigen receptor T-cell immunotherapy (CAR-T therapy). During further follow-up, 24 (42.9%) patients achieved BCR::ABL1< 0.1% and 29 (49.2%) achieved BCR::ABL1 < 1%. In additional, probabilities of DFS, EFS and OS at 12 months were 80.3% (95%CI 61.0%-90.7%), 80.2% (95%CI 61.0%-90.7%), 93.3% (95%CI 75.8%-98.3%) in R/R Ph+ALL and 55.4% (95%CI 18.4%-81.4%), 38.6% (95%CI 9.8%-67.6%), 80.0% (95%CI 37.4%-95.1%) in advanced CML, respectively (Fig. 1). Common treatment-related adverse events (TRAEs) included skin hyperpigmentation, proteinuria, Elevated liver enzyme and hypertriglyceridemia (Table 1). Most nonhematologic TRAEs were grade 1/2. Only one patient died from pulmonary embolism. As of the data cutoff date, 37 (66.1%) patients continued on treatment and 19(33.9%) discontinued because of disease progression, intolerance, loss to follow-up or death. Conclusion Olverembatinib-based therapy showed strong efficacy and tolerable toxicity in advanced Ph+ leukemia.

Allogeneic Hematopoietic Stem Cell Transplantation for Primary Myelofibrosis: A 20-year Experience in a Single Center

Allogeneic hematopoietic stem cell transplantation is a well-established approach for patients diagnosed with primary myelofibrosis and remains the only potentially curative treatment. To present the overall outcome of patients with myelofibrosis treated with allogeneic hematopoietic stem cell transplantation. A retrospective cross-sectional study. This study is a retrospective analysis of 26 consecutive patients with primary myelofibrosis who underwent transplantation at our center between January 2002 and January 2022. Disease and transplant variables contributing to outcomes were analyzed. The median age at the time of transplantation was 52.5 (range, 32-63) years and the median time from diagnosis to allogeneic hematopoietic stem cell transplantation was 25 (range, 3.1-156.8) months. Myeloablative conditioning and reduced-intensity conditioning regimens were used in 8 (30.8%) and 18 (69.2%) transplantations, respectively. Neutrophil and platelet engraftment was achieved in 23 patients at a median follow-up of 21.2 months (range, 12 days to 234.8 months). Primary graft failure occurred in 1 of 23 patients (4.3%). Neutrophil and platelet engraftment occurred at a median of 16 (range, 12-39) days and 20 (range, 11-78) days, respectively. Acute graft-versus-host disease was seen in 11 of 22 patients engrafted allografts, of which 7 (31.8%) were grade 3-4 acute graft-versus-host disease. Eight patients (36.4%) developed chronic graft-versus-host disease, and three cases were extensive. Four patients (19%) relapsed after a median of 5.5 months, and three patients received donor lymphocyte infusion. The 3-year overall survival rate of the entire study population was 46.2%. The median overall survival was not reached in the myeloablative conditioning group; however, it was 11.9 months in the reduced-intensity conditioning group (p =0.3). According to the donor graft source, the median overall survival was 0.73 months in mismatched unrelated graft recipients, 12 months in matched sibling donors, and not reached in matched unrelated graft recipients (p = 0.03). The 3-year progression-free survival rate of patients who survived > 100 days was 74.7%. The effect of JAK-2 status, graft source, conditioning regimen or dynamic international prognostic scoring system on progression-free survival was not statistically significant. Given the poor prognosis of non-transplant recipients and the lack of non-transplant curative approaches, our results support the consideration of allogeneic hematopoietic stem cell transplantation for eligible patients with primary myelofibrosis.

Impact of Early Post-Transplant 5-Point Deauville Scale (18)F-FDG-PET Status on Survival Outcomes after Allogeneic Transplantation for Lymphoma

Background: Conversely to what has been reported for autotransplant,most studies have shown that pre-transplant Fluorine-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) status does not appear to predict survival after allogeneic stem cell transplantation (Allo-SCT) for lymphoma patients. However it is less clear what is the impact of early FDG-PET status on outcomes after Allo-SCT, especially when using Deauville 5-point scale (DS) which has become a standard of care for staging and re-staging of FDG-PET.Methods: This retrospective study included all lymphoma patients who underwent FDG PET before and/or early after Allo-SCT in our institution and who were alive at least 3 months after the graft. The primary objective was to study the impact on OS and LFS of pre-transplant (within 1 month) and early post-transplant (+3 months and within +6-9 months) FDG PET in these patients. All FDG-PET were reviewed by a nuclear medicine expert and restaging was performed according to 5-point DS. Two thresholds of positivity were used: a score of at least 3 (DS3, i.e. scores 3 - 5) and a score of at least 4 (DS4, i.e. score of 4 or 5).Results: Between April 2005 and December 2015, 103 patients fulfilled the inclusion criteria. There were 69 males (66%) and the median age was 51.6 years old (range: 22-67). Forty-seven patients had high-grade non-Hodgkin lymphoma (NHL), 6 low-grade NHL, 34 T-cell lymphoma and 16 Hodgkin lymphoma. Most patients were considered in complete remission at the time of transplant (n=56) and received a reduced-intensity conditioning regimen (n=90). The numbers of patients with available FDG PET before transplant, at 3 months and between 6-9 months post-transplant were 81, 93 and 61, respectively. Deauville FDG PET staging identified 29 DS3 and 20 DS4 patients before transplant, 28 DS3 and 20 DS4 at 3 months, and 25 DS3 and 18 DS4 between 6-9 months post-transplant, respectively.With a median follow-up of 49.5 months (range: 6-140.5) for alive patients, 3-year OS and LFS were 81% (71-87) and 65% (54-74) for the whole cohort, respectively. Twenty-six patients relapsed at a median time of 4.5 months (range: 2.9-15.9) from Allo-SCT.In univariate analysis, only the post-transplant FDG-PET status influenced outcomes. Factors associated with a lower OS were DS3 and DS4 scores at 3 months (HR: 2.25; 95%CI: 0.93-5.44, p=0.07 and HR: 3.00; 95%CI: 1.22-7.36, p=0.01, respectively) and a DS3 score between 6-9 months post-transplant (HR: 4.08; 95%CI: 1.00-16.55, p=0.04). Factors associated with a lower LFS were DS3 and DS4 scores at 3 months (HR: 2.64; 95%CI: 1.30-5.39, p=0.007 and HR: 3.86; 95%CI: 1.86-8.02, p=0.0003, respectively) as well as between 6-9 months (HR: 4.20; 95%CI: 1.26-13.98, p=0.01 and HR: 2.72; 95%CI: 0.86-8.60, p=0.08) post-transplant.In multivariate analysis, DS4 FDG-PET at 3 months was the only independent factor associated with lower OS (HR 2.8; 95%CI: 1.13-6.97), p=0.0269) and LFS (HR 2.44, 95%CI: 0.94-6.33, p=0.06).Total body CTscan evaluation was performed in 16/28 and 14/25 DS3 patients at 3 months and between 6-9 months post-transplant, respectively. At 3 months, all CT-scans were considered normal while 4/14 were considered positive between 6-9 months. Lymph nodes biopsies were performed for 8/25 DS3 patients at 3 months showing 6 lymphoma relapses (75%) and for 7/25 DS3 patients between 6-9 months post-transplant showing 2 lymphoma relapses (29%). Six patients received donor lymphocyte infusion between 3 to 9 months post-transplant, only 2 being guided by FDG-PET.Conclusion: A DS4 FDG-PET status at 3 months is highly predictive of survivals in lymphoma patients receiving an Allo-SCT and may help to guide strategies to prevent relapse. These results have to be validated prospectively. DisclosuresTouzeau:AbbVie: Research Funding. Moreau:Bristol-Myers Squibb: Honoraria; Onyx Pharmaceutical: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria.

The Outcome of Patients with Advanced Phase Chronic Myeloid Leukemia with and without Allogeneic Hemopoietic Stem Cell Transplantation

Introduction: In spite of the widespread use of second- and third-generation tyrosine kinase inhibitors (TKIs) the prognosis of patients with advanced phase CML (accelerated phase (AP) or blast crisis (BC)) is still dismal. The aim of this study was to compare outcomes in advanced phase CML cohorts based on whether or not these patients received allogeneic hemopoietic stem cell transplantation (allo-HSCT). Patients and methods: A total of 162 patients with AP/BC-CML with (allo-HSCT+TKIs, n=20/62,) or without (n=10/70, TKI) history of allo-HSCT were included in this retrospective study. All patients received allo-HSCT with a reduced-intensity conditioning regimen with fludarabine 180 mg/m2 and busulfan 8-12 mg/kg or melphalan 140 mg/m2. Forty-two patients received TKIs for post-transplant relapse prophylaxis. In the majority of cases dasatinib was used (n=36). In the remaining 80 patients alloHSCT was not performed due to refusal for personal reasons or delay in referral to transplant center. They were included in TKI-group and were treated with chemotherapy+TKIs (60) or TKIs only (20). Eighty-one percent received second or third line TKIs. There were no significant differences in age, sex, comorbidity status, disease phase, and additional chromosomal aberrations incidence between allo-HSCT+TKI and TKI groups (Table 1). Overall survival (OS) was defined as the time from the start of treatment (allo-HSCT/TKI, chemotherapy) to death, event-free survival (EFS) - as the time between commencement of treatment and loss of response or post-transplant relapse, death. Response was defined according to European Leukemia Net and National Comprehensive Cancer Network recommendations. All patients signed an informed consent for processing of personal data; the trial was approved by Pavlov University local ethical committee. Results: The median follow-up was 44 months (1-344). The engraftment was documented in 71 (86%) patients. The cumulative incidence of non-relapse mortality at day 100 and 1 year after allo-HSCT were 10% and 18%, respectively. Grade 2-4 acute graft versus host disease (GVHD) was documented in 21 (29%), grade 3-4 acute GVHD - 14 (20%), chronic GVHD - 18 (27%) including mild, moderate and severe form in 6 (9%), 8 (12%) and 4 (6%) patients, respectively. Two-year cumulative incidence of relapse was 39%. Twenty-four patients received donor lymphocyte infusions and TKIs after relapse, in 4 cases chemotherapy was added. In four cases only TKIs were administered to treat relapse. Nine patients achieved sustained complete molecular response (CMR), in 19 cases disease progression was documented. The data on response was available for 71 patients in TKI group. Among patients with BC 36 (59%) patients did not respond to therapy, while complete hematological response (CHR), complete cytogenetic response (CCR) and CMR were achieved in 22 (34%), 1 (2%) and 2 (3%) cases, respectively. Nine patients (90%) without BC history achieved response to therapy (CHR 5, CCR 2, CMR 2), while 1 patient failed to respond. Sixty-nine patients died; all deaths were CML-related. Four-year OS was 58% in allo-HSCT+TKIs versus 33% in TKI group (p=0.032) (Figure 1A). However, there was no significant difference in 4-year EFS between groups: 35% vs. 17% (p=0.5), accordingly. BC at the moment of allo-HSCT significantly worsened 4-year OS: 23% vs. 63% (p=0.007). The 4-year OS in patients transplanted in BC (n=10) was comparable to one in TKI group: 23% vs. 33% (p=0.3) (figure 1B). Conclusions: Allo-HSCT still has an advantage as potentially curative treatment for part of advanced phase CML patients even in the presence of new generation TKIs. Allo-HSCT in BC is associated with worse outcome. An earlier referral of these patients to the transplant center can improve the outcome of allo-HSCT and prognosis.. Disclosures No relevant conflicts of interest to declare.

Risk Factors for Primary and Secondary Graft Failure in Allogenic Hematopoietic Cell Transplantation: A Single Center Study

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for high risk hematological diseases and sustained engraftment of the donor stem cells is essential for transplant success. Graft failure (GF) is a rare, but serious complication post allo-HCT. In the presented study we aimed to assess the incidence, risk factors in a single-center population and as well the impact on transplant outcome. Methods: Between 01 January 2015 and 31 December 2018, 557 patients underwent allo-HCT at our center. Data was collected retrospectively and updated in June 2019. Cases were included regardless of the underlying diagnosis, disease status prior to transplant, preparative regimen, or stem cell source. Primary graft failure was defined as failure to achieve an absolute neutrophil count (ANC) of >500/ µL by 28 days after bone marrow (BM) or peripheral blood stem cell (PB) transplantation. In contrast, secondary graft failure was defined as cytopenias after initial engraftment (ANC <500/µL), with (a) donor chimerism of less than 5% or (b) falling donor chimerism with intervention such as second transplant or donor lymphocyte infusion (DLI) or (c) patient death due to cytopenias, and fall in donor chimerism, even if chimerism was >5%. Exclusion criteria for diagnosis of GF were (a) disease relapse (b) graft versus host disease or (c) other causes of cytopenias such as, viral infections, or drug induced. Outcomes examined included overall survival (OS), cumulative incidence of GF, non-relapse mortality (NRM) and cause of death. Results: Baseline characteristics are summarized in (Table 1). GF was seen in 43 (7.7%) patients. Of these 43 patients, 9 (21%) had primary GF, and 34 (79%) had secondary GF. The cumulative incidence of GF overall (primary and secondary) is 1.6% (0.8- 3.0%) at day 100 and 6.5% (4.5-8.8%) at day 800. The median survival of patients following primary GF was 41 days versus 144 days in secondary GF. At one hundred days OS in primary GF was 22% and in secondary GF was 64%. The 1y and 2y OS for secondary GF was 33% and 28% respectively (Figure 1-A). Multivariable analysis demonstrated that the (a) diagnosis/transplant indication (MDS, myelofibrosis, lymphoma or non-malignant diseases) and (b) donor type (HLA-mismatched unrelated or haploidentical) were the only factors significantly associated with increased GF (Table 2). We determined the effect of more than one of these risk factors on the occurrence of graft failure as seen in (Figure 1-B). In the absence of any of the risk factors, the incidence of GF was 3.6%. If one risk factor was present, the incidence of GF was 9.9%, and if 2 risk factors were present, the incidence of GF was 24.5%. In primary GF, 5 patients underwent second allo-HCT. In secondary GF, 15 patients (44%) underwent a second allo-HCT and another 8 patients received donor lymphocyte infusion. All the patients with primary GF died because of graft failure and its associated complications. In secondary GF, 22 patients (51%) died, 30% of causes related to infections. Conclusions: Our study showed an increased risk for graft failure following the use of mismatched unrelated or haploidentical donors for diseases such as lymphoma, myelofibrosis, myelodysplastic syndrome and non-malignant diseases. As well, we found that a presence of two risk factors puts patients at clinically significant increased risk of graft failure. More intense conditioning therapy should be considered for patients with one but in particular two risk factors. Disclosures Michelis: CSL Behring: Other: Financial Support.

Efficacy of Venetoclax Combination Therapy with Hypomethylating Agents in Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Introduction: Venetoclax (VEN), a selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA) has high efficacy in treatment-naïve elderly patients with acute myeloid leukemia (AML). The role for VEN in patients with relapsed/refractory (R/R) AML, myelodysplastic syndrome (MDS), or other myeloproliferative neoplasms remains incompletely defined. In particular, the efficacy of VEN+HMA has not been studied systematically in patients who experience AML relapse following allogeneic hematopoietic cell transplantation (HCT). Method: All patients treated with VEN+HMA (azacitidine or decitabine) for R/R de novo or secondary AML or progressive MDS following allogeneic HCT were identified and reviewed retrospectively. All included AML patients had overt clinical relapse with ≥ 5% bone marrow blasts or extramedullary disease biopsy proven to be AML. Patients were included in this analysis if they received at least 14 days of VEN therapy. Results: Eleven patients with median age 66 (range 25-75) were treated for R/R AML post-allogeneic HCT. Transplant characteristics included use of reduced intensity conditioning in 10/11 (91%), matched sibling donors in 5/11 (45%), matched unrelated donors in 5/11 (45%), and cord blood in 1/11 patients. The median time from HCT to relapse/disease progression was 7 months (range 3-36). Two patients had extramedullary relapse only, and the remainder had marrow involvement. Eight patients (73%) received azacitidine and 3 (27%) received decitabine in combination with VEN. All but two patients (82%) had prior HMA exposure and most received VEN+HMA as initial post-transplant salvage therapy (64%). Only one patient received donor lymphocyte infusion in conjunction with VEN+HMA therapy, and none proceeded to a second allotransplant. Nine patients (82%) experienced an objective response, which included 4 CR/CRi (36%) and 5 PR/SD (45%). In patients with CR/CRi, three patients had adverse risk cytogenetics and one had a favorable risk profile at diagnosis consisting of normal cytogenetics with an isolated NPM1 mutation. All patients who failed to remit with VEN+HMA had intermediate- or high-risk genetic features. The median number of treatment cycles given was 3 (range 1-20). Median survival was 11 months and estimated 6-month and 12-month survival was 82% and 36%, respectively. Three patients remain alive with median 16.5 months follow-up (range 2.5-32). Conclusion: Venetoclax in combination with HMA is a viable salvage option in patients with relapsed AML or progressive MDS after allogeneic HCT, including those with prior exposure to HMA. Although one patient in this cohort sustained long term complete remission, overall prognosis remains dismal in this high-risk patient population and improved treatment options for relapsed/refractory AML following alloHCT remain needed. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; AstraZeneca: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Mirati Therapeutics: Research Funding; Spectrum: Research Funding. Smith:Astellas Pharma: Research Funding; Abbvie: Research Funding; fujiFilm: Research Funding; Revolution Medicines: Research Funding. Logan:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pharmacyclics: Research Funding; Astellas: Research Funding; Jazz: Research Funding; Kite: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; TeneoBio: Consultancy; Kiadis: Consultancy; Kadmon: Research Funding; Abbvie: Consultancy.

Factors Influencing Acute Leukemia Relapse: A Single-Center Look at Post-Transplant Maintenance Therapy

Background Relapse after allogenic hematopoietic stem cell transplant (alloSCT) remains a leading cause of mortality in patients with acute leukemia. Recently, post-transplant maintenance strategies with tyrosine kinase inhibitors, immunomodulators, or hypomethylating agents, either beginning immediately after alloSCT or pre-emptively at the earliest detection of minimal residual disease (MRD) have been described. Post-transplant maintenance therapy may reduce relapse risk. Methods As part of a performance improvement initiative to best assess areas for improvement or intervention, we performed a retrospective chart review of patients who underwent alloSCT for acute myeloid (AML) and lymphoblastic leukemia (ALL) from 7/2011 to 12/2017 at San Antonio Military Medical Center. Evaluation included pre-transplant disease status, use of MRD testing, presence of targetable molecular mutations, pre-transplant conditioning regimen, choice and duration of immunosuppression, use of post-transplant maintenance therapy, relapse, and death. Results A total of 46 alloSCTs were performed for high-risk AML or ALL. There were 18 relapses and 23 deaths. Of those who relapsed, 9 (50%) died from relapse and 2 (11%) died from non-relapse. Five people received a second salvage alloSCT, 3 of which were successful. There was no statistically significant difference in relapse rates with type of transplant or conditioning regimen or type/duration of graft versus host disease prophylaxis. Persistent pre-transplant MRD was associated with a higher risk of relapse (p=0.05). Among patients who relapsed, 17 (94%) underwent pre-transplant MRD testing, 7 (41%) of these had pre-transplant persistent disease. Post-transplant MRD testing was highly variable. Overall, utilization of post-transplant maintenance therapy was 26%. Ten patients had mutations for which a targetable drug exists, 7 of which received post-transplant targeted therapy. Only two patients received a post-transplant hypomethylating agent. Three patients received donor lymphocyte infusions. Although not statistically significant, use of post-transplant maintenance therapy resulted in numerically fewer disease relapses (33 vs. 41%, p=0.63). Conclusion Post-alloSCT maintenance strategies are highly variable among institutions. Our transplant center has no standard protocol for post-transplant maintenance therapy or utilization of post-transplant MRD monitoring as a way to guide pre-emptive treatment. There are several limitations with our review, but with the identification of new molecular targets, a more aggressive approach to maintenance therapy should be investigated on a large, multi-center scale and considered as a way to reduce relapse rates, particularly in those with pre- or post-transplant MRD positivity.

Haploidentical hematopoietic stem cell transplantation using reduced-intensity conditioning for pediatric patients with familial hemophagocytic lymphohistiocytosis.

ABSTRACTImportanceAllogeneic hematopoietic stem cell transplantation (HSCT) is considered to be the only curative treatment for familial hemophagocytic lymphohistiocytosis (FHLH). Treatment of pediatric FHLH with reduced‐intensity conditioning (RIC)‐based haploidentical donor (HID) HSCT has been rarely reported.ObjectiveTo investigate outcomes and adverse events in patients with FHLH who received HID‐HSCT.MethodsWe conducted a retrospective study of five patients, including three with mutations in PRF1 and two with XIAP deficiency. Four of the five donors were heterozygous for these mutations. The conditioning regimen included fludarabine, cyclophosphamide, and antithymocyte globulin, with or without low‐dose irradiation. Unmanipulated mobilized bone marrow and peripheral blood stem cells were used as the grafts.ResultsAll five patients were successfully engrafted. Four patients survived, and one patient died. All exhibited complete response (CR) after HSCT. All of the patients who survived exhibited CR to FHLH without severe regimen‐related complications at a median of 29.5 months (range: 23–34 months) after HSCT. Four of the five patients had mixed donor chimerism. Three patients had 17% to 87% mixed donor chimerism but remained free of disease. Four patients received donor lymphocyte infusion (DLI), which improved the level of mixed donor chimerism. One patient experienced a decrease in donor chimerism to 1% and relapsed; Four patients developed acute graft‐versus‐host disease (GvHD) (grade I or II), and one patient developed grade IV GvHD.Interpretation HID‐HSCT with RIC can be considered for treatment for patients with FHLH, but the conditions and DLI regimens need to be optimized for long‐term use, and more prospective studies should be conducted.

Blinatumomab + Ponatinib for Relapsed Ph1-Positive Acute Lymphoblastic Leukemia: The French Experience

Prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1+ ALL) has been considerably improved since the beginning of the BCR-ABL1 tyrosine kinase inhibitors (TKI) era 20 years ago. However, the prognosis of patients with a refractory/relapsed (including molecular relapse) disease is still very dismal. New drugs or combination of new drugs may improve outcomes of these patients. For example, ponatinib, a 3rd-generation oral TKI, known to have activity against BCR-ABL1 T315I mutations, has shown some efficacy in this context. Similarly, a recent study has reported very encouraging results of the bispecific anti-CD3/CD19 monoclonal antibody blinatumomab as single-agent in refractory/relapsed Ph1+ ALL. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce.This was a retrospective study with the aim to report outcomes of patients receiving a combination of blina/pona for refractory/relapsed Ph1+ ALL in France. Fifteen adults from 8 French centers were identified and data were collected by physicians of each centers, then gathered for the purpose of this study.There were 9 males and 6 females, with a median age of 53 years (range:17-72). All patients, but 2 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Four cases had BCR-ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n=8) or a second (n=7) cytologic relapse. There was no refractory patient in theses series. Previous allograft and autograft has been performed in 7 and 2 patients, respectively. The majority of patients (n=12) had previously received 2 or more lines of TKI. The median time between the first cycle of blina/pona and diagnosis was 14 months (range: 8-40). The median number of blinatumomab cycle (28 mg/day by continuous infusion for 28 days every 6 weeks) administered per patient was 3 (range: 1-6) while ponatinib was concomittantly administered continuously at an initial dose of 45 mg once daily in 11 pts (73%) and 30 mg in 4 pts (27%). Median duration of ponatinib administration was 4 months (range: 1.1-10.9) from first blinatumomab cycle. The toxicity profile was safe: all patients received a complete first cycle without grade 3-4 adverse events. After cycle 1, blinatumomab was stopped in 47% of cases because of neurologic events in 4 and infections in 3; ponatinib was stopped in 33% of cases because of neurologic events in 3, fluid retention in 1 and severe arteriopathy in 1 patient with other vascular disease risk factors. All neurologic events resolved after stopping blinatumomab or ponatinib.The majority of patients were evaluated after one cycle (n=11, after cycle 2 n=3, after cycle 3 n=1). All but one patients (93%) obtained a cytologic complete remission (CR), of whom 12/14 (86%) achieved a complete molecular response. However, 2 patients were documented with CNS relapse at the time of blina/pona evaluation although in bone marrow molecular remission. Both obtained clearance of leukemic blasts after intrathecal infusion of chemotherapy. Then, 5 patients underwent allogeneic transplant (including 2 patients already allotransplanted before blina/pona) and 1 patient received donor lymphocyte infusion. Seven cases pursued maintenance therapy with ponatinib as single agent after stopping blinatumomab. With a median follow-up of 8 months (range: 2.6-30.2) for alive patients, median overall and leukemia-free survivals from first cycle of blina/pona were 8.5 months (range: 1.7-30.2) and 8 months (range: 1.3-30.2), respectively.At last follow-up (July 2018), only 4 relapses had occurred at a median of 3.3 months (range: 1.3-8.3) from first blina/pona cycle and 6 patients had died (3 bacterial infections, 1 fungal infection, 1 secondary cancer and 1 ALL relapse). All alive patients (n=9) but one (cytologic CR but detectable minimal residual disease) are in complete molecular response. Four patients are still under ponatinib medication at last follow-up.The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients and may replace chemotherapy salvage regimens. The combination should be tested in first-line therapy in the future. Our results have also to be confirmed prospectively on a larger cohort of patients. DisclosuresNo relevant conflicts of interest to declare.

Bone lesions in type 1 Gaucher disease after improving dose and compliance with imiglucerase

Relapse of primary hematologic disease constitutes an important reason for failure of allogeneic hematopoietic stem cell transplantation (alloHSCT). There are very few treatment modalities for this indications. Therefore, there is a need for novel effective therapies and even more for the prevention of relapse. There are scarce data that azacitidine can be used for these purposes.At the Polish Adult Leukemia Group, we retrospectively analyzed the results of azacitidine treatment after alloHSCT. Relapsing patients, patients with minimal residual disease/mixed chimerism, and patients in complete remission with high risk of relapse were analyzed separately. There were 17 patients, 6 with myelodysplastic syndrome, 11 with acute myeloid leukemia, 8 male, and overall median age of 56 years (range, 15–78); 7 patients received donor lymphocyte infusion (DLI).Patients treated because of relapse received a median of 3 (range, 1–6) cycles of azacitidine, patients receiving preemptive treatment received a median of 4 cycles (range, 2–6), and those on maintenance received a median of 5 cycles (range, 3–5). Toxicity was considerable, especially in relapse—neutropenia (67%), anemia (67%), thrombocytopenia (100%), serious infections (78%)—and preemptive settings. Median overall survival of patients treated for relapse reached 6.8 months (95% confidence interval [CI], 0.7–∞), with better survival observed in patients with temporary disease control (7.7 vs 4.7 mo) and without previous exposure to azacitidine (7.7 vs 3.4 mo). One-year overall survival reached 75% (95% CI, 13%–96%) for preemptive and 50% (95% CI, 0%–91%) for maintenance treatment. DLI did not aggravate graft-versus-host disease.Effectiveness of azacitidine in relapsing patients is disappointing. Azacitidine seems to be promising in preemptive and maintenance settings. Toxicity is considerable. Further research is needed.

Outcomes with Extracorporeal Photopheresis in the Management of Chronic Gvhd: A Multi-Centre Experience

Introduction: Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and non-relapse mortality in allogeneic haematopoietic stem cell transplant patients (Allo-HSCT). Extracorporeal Photopheresis (ECP) is now an established second-line treatment for steroid-refractory cGVHD. Here we report a large, multi-centre case series of 115 patients treated with ECP for cGVHD. To the best of our knowledge, this is the largest reported series of patients receiving fortnightly ECP for cGVHD.Method:A retrospective case note audit identified 115 consecutive Allo-HSCT patients who commenced fortnightly ECP for cGVHD between 2007 and 2016 at The Christie and Central Manchester NHS Foundation Trusts. cGVHD was classified and graded using the National Institutes of Health (NIH) consensus response criteria.Results: Median age when starting ECP was 49 years (range 18-75). 61% patients were male (n=70) and 39% Female (n=45). Underlying disease groups undergoing Allo-HSCT included Acute Leukaemia/Myelodysplastic Syndrome (n=69; 60%), Lymphoma (10%; n=12), Chronic leukaemia (13%; n=15) Myeloma (14%; n=16) and Aplastic Anaemia (3%; n=3). 24% of patients had myeloablative conditioning (n=27) and 76% had reduced-intensity conditioning (n=88). 61% (n=70) received stem cells from Voluntary Unrelated Donors (VUD) and 39% (n=45) Siblings (Sib). Patients received post Allo-HSCT GvHD prophylaxis with Calcineurin inhibitors, either alone, or in combination with Methotrexate and/or Mycophenolate Mofetil. Median time to stopping Calcineurin inhibitor post Allo-HSCT was 12 months (range 0-88). 14 patients received Donor Lymphocyte Infusions (DLI).Median time to development of GvHD post Allo-HSCT was 5 months (range 0-33). 94% developed cutaneous cGVHD (n=108), 32% oral cGVHD (n=37), 23% gut cGVHD(n=27), 24% liver cGVHD (n=28), 11% lung cGVHD (n=13) and 26% ocular cGVHD (n=30). 49% (n=57) patients had sclerodermoid disease. 37% (n=43) had one, 31% (n=36) two, 21% (n=24) three, 9% (n=10) four and 2% (n=2) five organ involvement. All 115 patients had been previously treated with immunosuppressive drugs - 109 Prednisolone; 73 Calcineurin Inhibitors; 60 Mycophenolate mofetil and other (ATG, n=1; Basiliximab, n=1; Methotrexate, n=6; Rituximab, n=10; and Thalidomide, n=18). Median duration of ECP treatment was 12 months (range 1-27 months).Response to ECP was assessed using NIH Criteria - 29% (n=33) Complete Response (CR), 19% (n=22) Partial Response (PR), 16% (n=18) Stable Disease (SD), 11% (n=13) Progressive Disease (PD), 17% (n=19) Death and 9% (n=10) Other. As a result of ECP treatment 26% (n=30) were able to stop steroid treatment while the remaining 74% were able to reduce their steroid dose. There was no overall difference in response between the two centres. Patients with cutaneous and oral cGVHD were more likely to achieve a PR or better (cutaneous p=0.03; oral p=0.05) but there was no difference with other organ involvement. The chance of response was not influenced by the number of organs involved.Median Overall Survival (OS) from the date of Allo-HSCT was 110 months (range 8-221). OS was not influenced by age, donor type, diagnostic group (Acute Leukaemia/Myelodysplastic Syndrome, Lymphoma, Chronic Leukaemia, Myeloma and Aplastic Anaemia), gender or the number and type of organs involved. The only exception was oral cGVHD which was associated with a lower OS (p=0.03). Patients with cGVHD achieving a CR/PR with ECP treatment, had a significantly better OS (40 months vs. median not reached, p<0.0001).Conclusion: ECP is an effective second line treatment for steroid-refractory and steroid-dependent cGVHD with a 50% response rate. This is not affected by the underlying diagnostic group or pattern of organ involvement, however patients with cutaneous and oral cGVHD seem to respond better. As response to ECP translates into better OS, this most likely reflects the reduction in immunosuppressive related complications. Therefore it is worth considering the use ECP treatment early in the management of cGVHD. DisclosuresRoutledge:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Gilead: Honoraria. Dignan:Jazz: Honoraria; Adienne: Speakers Bureau; Therakos/Mallinckrodt: Honoraria, Research Funding, Speakers Bureau; Gilead: Other: Cl for GvHD Study. Bloor:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria; GSK: Consultancy, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. Tholouli:Johnson and Johnson: Speakers Bureau; MSD: Speakers Bureau; Celgene: Honoraria; Giles: Speakers Bureau; Amgen: Honoraria, Speakers Bureau.

Azacitidine Use After Allogeneic Stem Cell Transplantation—Results From the Polish Adult Leukemia Group

BackgroundRelapse of primary hematologic disease constitutes an important reason for failure of allogeneic hematopoietic stem cell transplantation (alloHSCT). There are very few treatment modalities for this indications. Therefore, there is a need for novel effective therapies and even more for the prevention of relapse. There are scarce data that azacitidine can be used for these purposes. MethodsAt the Polish Adult Leukemia Group, we retrospectively analyzed the results of azacitidine treatment after alloHSCT. Relapsing patients, patients with minimal residual disease/mixed chimerism, and patients in complete remission with high risk of relapse were analyzed separately. There were 17 patients, 6 with myelodysplastic syndrome, 11 with acute myeloid leukemia, 8 male, and overall median age of 56 years (range, 15–78); 7 patients received donor lymphocyte infusion (DLI). ResultsPatients treated because of relapse received a median of 3 (range, 1–6) cycles of azacitidine, patients receiving preemptive treatment received a median of 4 cycles (range, 2–6), and those on maintenance received a median of 5 cycles (range, 3–5). Toxicity was considerable, especially in relapse—neutropenia (67%), anemia (67%), thrombocytopenia (100%), serious infections (78%)—and preemptive settings. Median overall survival of patients treated for relapse reached 6.8 months (95% confidence interval [CI], 0.7–∞), with better survival observed in patients with temporary disease control (7.7 vs 4.7 mo) and without previous exposure to azacitidine (7.7 vs 3.4 mo). One-year overall survival reached 75% (95% CI, 13%–96%) for preemptive and 50% (95% CI, 0%–91%) for maintenance treatment. DLI did not aggravate graft-versus-host disease. ConclusionsEffectiveness of azacitidine in relapsing patients is disappointing. Azacitidine seems to be promising in preemptive and maintenance settings. Toxicity is considerable. Further research is needed.

Outcome of Patients with Myelofibrosis Relapsing after Allogeneic Stem Cell Transplant: A Retrospective Study By the Chronic Malignancies Working Party of EBMT

▪Background: Over the last decade, there has been a significant increase in the number of patients with Myelofibrosis (MF) undergoing allogeneic stem cell transplantation (SCT). However, scarce information exists on the outcome and management of those patients who relapse following SCT. Moreover, the management of relapse occurring post-SCT is often heterogeneous and ranges from palliation to intensive salvage approaches. We therefore conducted a retrospective EBMT registry analysis of adult MF patients who relapsed following first SCT episode.Results: A total of 1216 adult patients (997 (82%) with Primary MF (PMF) and 219 (18%) with secondary MF (sMF)) underwent 1st allogeneic SCT between 2000 and 2010. A total of 251 patients from this cohort (206 with PMF and 45 with sMF) had conformed relapse ≥ day 30 after HSCT and were included in the analysis. Within this relapse cohort, there were 163 males and 88 females; median age was 55 years old (range 21.5-70 years). A total of 84 patients (33%) had received Myeloablative Conditioning (MAC) and 167 patients (67%) Reduced Intensity Conditioning (RIC). Regarding donor type, there were 123 matched siblings (49%) and 128 unrelated donors (51%). Acute GVHD (aGVHD) status was available for 243/251 (97%) patients; no aGVHD was evident in 143 patients, Grade I-II aGVHD 76 patients, Grade III-IV aGVHD 22 patients and 2 patients with aGVHD ungraded.The median time to relapse after SCT was 7.1 months (range 1-111 months). The median Overall Survival (OS) from the time of relapse was 17.7 months (95% Confidence Intervals 11-24). Collectively, there was a significant difference in survival outcome for those relapsing > 7.1 months post-SCT (median survival 30.3 months post relapse) compared to those relapsing within 7.1 months following the initial SCT episode (median survival 7.9 months post relapse; p<0.001). Absence of aGVHD or grade I aGVHD only was associated with a trend towards improved survival following relapse compared to those with Grade II-IV aGVHD (p=0.12). For PMF, disease duration prior to SCT did not significantly affect outcome post relapse. Heterogeneous practice existed as regards management of the relapse episode, with considerable variation in median survival (MS) estimates. 47 patients received Donor Lymphocyte Infusions (DLI) alone (MS 76 months); 21 had chemotherapy alone (MS 23 months) whereas 14 patients had DLI combined with chemotherapy (MS 13.6 months). As regards 2nd allografts: 53 patients underwent 2nd allograft alone (MS 23.6 months) and 26 underwent DLI and 2nd SCT (MS 53.9). In 90 patients active management -if any- was not documented (most likely many were palliative) but represented a very poor risk group with a MS of only 4.8 months. Overall, there was a significant improvement in OS post relapse for those undergoing 2nd SCT (n=79) versus those who did not have a 2nd SCT (n=172; p=0.019).Conclusions: This analysis represents the first study to define the outcome of MF patients who undergo relapse following allogeneic SCT. Treatment of relapse presents huge challenges and the heterogeneous management strategies highlighted above reflects current practice where approaches range from palliation through to intensive chemotherapy and 2nd SCT. It is clear from this analysis that early relapse has a much worse prognosis than those who relapse later than 7.1 months post-SCT. There is a definite survival advantage for those who undergo DLI and/or a 2nd SCT procedure, although we acknowledge that those patients undergoing a 2nd SCT represent a highly selected group who are fit enough to undergo such intervention. Moreover, how relapse management practice will change in the era of novel therapies such as JAK inhibitors to bridge towards 2nd SCT is currently unclear and requires evaluation in prospective studies. DisclosuresMcLornan:Novartis: Research Funding, Speakers Bureau. Finke:Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Craddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Clofarabine Based Chemotherapy in Adult Relapsed/Refractory Acute Lymphoblastic Leukemia/Lymphoma-a Single Institution Experience

Background: Adult relapsed/refractory acute lymphoblastic leukemia/lymphoma (rALL) carries a very poor prognosis with limited options for effective salvage therapy. To date, there has been only a single retrospective report on the use of clofarabine in adult rALL demonstrating CR rate of 31% in this setting (Barba P et al. 2012).Aim: To evaluate the efficacy and toxicity of clofarabine based therapy in a relatively large cohort of adult rALL patients.Method: After IRB approval, a retrospective single institution study of all patients (pts) diagnosed with rALL treated with a clofarabine based regimen at Mayo Clinic between 2000 - 2014 was performed. Categorical variables were analyzed using Pearson's chi-squared test while continuous variables were analyzed using the Wilcoxon / Kruskal-Wallis test with P < 0.05 considered statistically significant. Survival estimates were calculated using Kaplan-Meier method and means were compared using log ranks.Results:Presenting features: We identified a total of 22 pts with a diagnosis of rALL who received clofarabine based therapy. 20 patients were evaluable and 2 were excluded (one received clofarabine as salvage for positive MRD and the other as systemic maintenance with CNS directed therapy for an isolated CNS relapse).Among evaluable pts, median age at time of Clofarabine based chemotherapy was 39 years (range 19-65) and 50% were males. Thirteen had B-ALL while 7 had T-ALL. Median leukocyte count was 6 x109 (0.2-28.7), hemoglobin 9.8 g/dL (7-12.9), platelet 65 x109 (12-493), peripheral blood blast 4% (0-88) and bone marrow blasts 80% (0-95) while five pts had extramedullary disease. Median number of prior regimens was 2 (1-7).. 8 (40%) pts were post allogeneic transplantTreatment and Response: 10 pts (50%) received clofarabine monotherapy, 7(35%) clofarabine and cytarabine, and 3 (15%) had clofarabine, etoposide and cyclophosphamide. Overall response rate (CR/CRi + PR) was 35%. Five (25%) achieved CR/CRi, and 2 achieved PR. Among those who achieved CR, 4 out 5 proceeded to further therapy; 2 to allogeneic stem cell transplant and two additional patients received donor lymphocyte infusion (DLI). One pt with PR also proceeded to allogeneic stem cell transplant. In comparative analysis, there were more males 6 (86%) vs 1(14%) in the responding arm (P = 0.014), otherwise the number of regimens prior to clofarabine, type of clofarabine regimen, transplant status, T vs B cell ALL, did not impact response. Median overall survival was 2.4 months (1.3-2.9) in non-responders vs. 12.8 months (3-27.4) in responders (P =0.0007) (Figure 1). All pts who proceeded to transplant or DLI relapsed with a median time to relapse of 6.4 (4.8-13.7) months.Toxicity: Rash/Hand Foot syndrome was observed in 3 pts (19%), Grade III-IV liver toxicity occurred in 4 (26%) with no permanent sequela. Opportunistic infection occurred in 3 pt (17%).Conclusion: Clofarabine based chemotherapy was a well-tolerated salvage regimen in heavily pretreated patients and was an effective bridge to definitive therapy in a significant proportion of cases. Prospective evaluation of these findings is warranted. [Display omitted] DisclosuresAl-Kali:Celgene: Research Funding.

Effectiveness of Fludarabine- and Busulfan-Based Conditioning Regimens in Patients With Acute Myeloblastic Leukemia: 8-Year Experience in a Single Center

ObjectiveAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for acute myeloblastic leukemia (AML). Because the conditioning regimen of busulfan plus cyclophosphamide carries significant risks of toxicity, we evaluated the factors affecting survival after fludarabine replacement instead of cyclophosphamide. MethodsThe study included 55 patients who underwent allo-HSCT for AML and received busulfan, fludarabine, and antithymocyte globulin (ATG). ResultsForty-eight patients received a myeloablative regimen; 7 patients received a reduced-intensity conditioning regimen. The neutrophil and platelet engraftment times were 12 days (range 9 to 20) and 12 days (range 7 to 19), respectively. Graft-vs-host disease (GvHD) developed in 10% and 50% of the patients, respectively. Seven patients received donor lymphocyte infusion. Of them, 5 patients developed grade I or II GvHD, one grade IV GvHD. The median follow-up period was 20.6 months. The predicted progression-free survival (PFS) at 1 and 3 years after transplantation was 78% and 74%, respectively. The overall survival (OS) at 1, 3, and 5 years was 76%, 74%, and 62%, respectively. Treatment-related mortality (infection in 1 patient, GvHD in 2 patients) occurred in 3 patients (5.5%). Multivariate analysis revealed that OS and PFS were not influenced by age, dose of busulfan or ATG, or presence of cytomegalovirus antigenemia. Acute GvHD and pretransplantation minimal residual disease positivity negatively affected the transplant outcome. The presence of active disease at the time of transplantation was found as an independent risk factor for AML. ConclusionsBusulfan- and fludarabine-based conditioning regimens are effective for AML, and have acceptable toxicity, morbidity, and mortality.

In adults with t(8;21)AML, posttransplant RUNX1/RUNX1T1-based MRD monitoring, rather than c-KIT mutations, allows further risk stratification

AbstractWe asked whether minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels could identify allogeneic hematopoietic stem cell transplantation (allo-HSCT) t(8;21) (q22;q22) acute myeloid leukemia patients who are at high risk for relapse, together with the impact of c-KIT mutations. Ninety-two consecutive adult t(8;21) patients who received allo-HSCT in complete remission were enrolled. MRD status at 1, 2, and 3 months after HSCT identified relapse patients (P = .05, P < .001, P = .0001, respectively). The 2-year cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) was 32% vs 9% (P = .01) and 55% vs 70% (P = .12) for patients with and without c-KIT mutations, respectively. In multivariate analysis, MRD at the first 3 months after HSCT, rather than c-KIT mutations, was an independent factor for CIR (P = .001) and LFS (P = .001). In addition, 17 patients received donor lymphocyte infusion (DLI) as interventional therapy for MRD, and the 2-year CIR and LFS for patients with or without DLI was 24% vs 87% (P = .001) and 64% vs 0% (P < .001), respectively. In conclusion, MRD monitoring early after transplant allows further rapid identification of t(8;21) patients at high risk of relapse and was more predictive of relapse risk than c-KIT mutations.

Calcineurin Inhibitor-Free GVHD Prophylaxis with Post-Transplant Cyclophosphamide and Brief-Course Sirolimus Results in Low Rates of Non-Relapse Mortality and Chronic GVHD Following Matched Related and Unrelated Donor Peripheral Blood Stem Cell Transplantation (PBSCT)

Calcineurin inhibitors (CNIs) form the foundation of current GVHD prophylaxis regimens. Although advances in immunosuppressive regimens have had a significant impact on the incidence and severity of acute GVHD, it is noteworthy that CNIs have had little impact on chronic GVHD. We hypothesized that a CNI-free regimen consisting of post-transplant cyclophosphamide (Cy) and brief-course sirolimus would decrease the risk of chronic GVHD and non-relapse mortality and improve outcomes following reduced intensity allogeneic PBSCT. Twenty-seven patients with high risk hematologic malignancies were enrolled in the study: median age 61 years (25-73). All patients had a 10/10 locus matched donor; MRD=18, MUD=9. Conditioning consisted of fludarabine 30mg/m2 on days -9 to -6, IV busulfan 130 mg/m2 on days -5 to -4, and Cy 14.5 mg/kg on days -3 and -2 followed by unmanipulated PBSCT. Post-grafting immunosuppression consisted of Cy 50 mg/kg/day on days 3 and 4 and sirolimus starting day +5 and completing day+90 in the absence of GVHD. Donor engraftment occurred in all patients with a median time to neutrophil and platelet recovery of 15 and 30 days, respectively. The median day +90 donor T cell and myeloid chimerism was 94% (40-100%) and 100% (11-100%) respectively. Three patients received donor lymphocyte infusions for incomplete donor T cell chimerism. The cumulative incidence of grade II-IV acute GVHD, grade III-IV acute GVHD, all chronic GVHD, and severe chronic GVHD was 41%, 15%, and 32%, and 12% respectively. Non-relapse mortality (NRM) and relapse incidence at 2 years was 4% and 17% respectively. With a median follow-up of 18 months, the estimated 2 year overall and disease-free survival was 71% and 80% respectively for the whole cohort, while it was 87% and 89%, respectively in the subgroup of 18 patients receiving MRD transplants. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rates, occurring in only 4 of 19 at-risk patients (21%). Transplant-related toxicity included BK virus-associated cystitis in 33% of patients and a non-fatal hepatotoxicity syndrome in three patients consisting of transaminase elevation and ascites, with resolution following discontinuation of sirolimus. CNI-free GVHD prophylaxis with post-transplant Cy and brief-course sirolimus achieves consistent donor engraftment, low rates of GVHD and NRM, and excellent outcomes in recipients of HLA-identical donor allogeneic PBSCT.▪ Disclosures:Off Label Use:fludarabine, cyclophosphamide, and sirolimus are not FDA-labeled for stem cell transplantation.

Salvage Allogeneic Hematopoietic Cell Transplantation for Relapsed or Progressive Multiple Myeloma After Autologous Hematopoietic Cell Transplantation

AbstractAbstract 2043▪▪This icon denotes a clinically relevant abstract Introduction:Limited data exist about allogeneic hematopoietic cell transplantation (HCT) as salvage treatment of relapsed or progressive multiple myeloma (MM) after autologous HCT in the era of proteasome inhibitors and next-generation immunomodulatory drugs. Methods:Retrospective analysis of 27 consecutive adult patients (median age 52 years, range 38–67, f=7, m=20) with relapsed (n=7) or progressive (n=20) MM after single (n=11) or tandem (n=16) autologous HCT treated at our institution from 2001 to 2012 with allogeneic HCT as salvage treatment. Conditioning regimens consisted of busulfan/cyclophosphamide (CY)/total marrow irradiation (n=8), fludarabine(FLU)/CY/2 Gy total body irradiation (n=8), FLU/melphalan (n=5), FLU/thiotepa/melphalan (n=2) or FLU/treosulfan (n=4). Antithymocyte globuline, calcineurin inhibitor combined with mycophenolate mofetil or methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results:Genetics were available in 14 patients resulting in a high-risk group (+1q21, t(4;14), del17; n=3), del13q14 (n=3), +11 (n=1) and a normal karyotype (n=7). Allogeneic HCT was performed 29 months (median, range 12–107) after autologous HCT. Grafts either from matched related (n=8), haploidentical (n=2), matched unrelated (n=14) or mismatched unrelated (n=3) donors were used. All grafts consisted of G-CSF mobilized peripheral blood stem cells (median CD34+ cells 5.9×106/kg, range 2.6–12.4×106/kg). Median time to neutrophil (>500/μl) and thrombocyte (>20,000/μl) engraftment was 13 days (range 9–22) and 14 days (8–23), respectively. Complete chimerism in peripheral blood was detected after a median of 27 days (range 11–149). No graft rejections occurred. In case of mixed chimerism, relapse and disease progression after allogeneic HCT, 9 patients received donor lymphocyte infusions (median 25.0×106/kg, range 0.2–110.0×106/kg) after a median of 353 days (range 72–1104) in the absence of GVHD. Median follow-up was 1426 days (range 184–3512) of all patients alive resulting in a Kaplan-Meier estimated 4-year event-free survival (EFS) and overall survival (OS) of 15% and 37%, respectively. Although not statistically significant, the use of a related donor (n=10) was associated with an improved outcome compared to an unrelated donor (n=17) (4-year OS 50% vs. 29%, p=0.16). Cumulative incidence of non-relapse mortality (NRM) adjusted for relapse/progression as competing risk was 22% at 4 years. Causes of death were disease progression (n=9), GVHD (n=4), infections (n=2) and multiple organ failure (n=2). Cumulative incidence of relapse/progression at 4 years with death due to NRM as competing risk was 63%. Autologous HCT (n=11, 2001–2005) for induction treatment prior to allogeneic HCT showed a trend towards an adverse outcome compared to alternative induction regimens containing thalidomide (n=2), lenalidomide (n=7) or bortezomib (n=6) (2004–2012): 4-year OS 27% vs. 44% (p=0.16). NRM adjusted for relapse/progression was lower in the latter group (36% vs. 13% at 4 years, p=0.18), whereas relapse/progression adjusted for NRM was lower in the first group (45% vs. 75% at 4 years, p=0.24). In total, 18 patients relapsed or progressed after salvage allogeneic HCT after a median of 177 days (range 33–1823). 11 of these patients were treated with thalidomide (n=1), lenalidomide (n=4), bortezomib (n=2) or a combination of these drugs (n=4) resulting in a median survival post relapse/progression of 1048 days compared to 200 days of patients who were not treated with these compounds upon relapse or progressive disease (n=7) (p=0.20). Acute GVHD≥2 (n=6) was associated with a reduced 4-year OS of 17% compared to 43% (p=0.07). Chronic GVHD (limited n=3, extensive n=8) was not associated with an adverse outcome (4-year OS 36% vs. 38%, p=0.82). Conclusion:Allogeneic HCT is a potential salvage treatment option for relapsed or progressive MM after single or tandem autologous HCT with an acceptable NRM, although EFS is considerably short. The introduction of proteasome inhibitors and next-generation immunomodulatory drugs for induction treatment might improve outcome after allogeneic HCT due to a decreased NRM. In case of relapse or progression after salvage allogeneic HCT, the use of these agents may lead to prolonged survival. Disclosures:Off Label Use: Off-label use of conditioning regimens and immunomodulatory drugs/proteasome inhibitors.

Tissue-specific regulatory T cells: biomarker for acute graft-vs-host disease and survival

Regulatory T cells (Tregs) are a subset of CD4(+) T cells that are characterized by the expression of CD25 and Foxp3 and are capable of suppressing alloimmune responses. We assessed whether high frequencies of circulating skin or gut tissue-specific Tregs at engraftment could predict acute graft-vs-host disease (aGVHD) incidence and survival in a cohort of hematopoietic cell transplant (HCT) recipients. Tregs were analyzed at engraftment in 74 patients receiving HCT. Treg skin-homing (CLA(+)) or gut-homing (α(4)β(7)(+)) subsets were identified by flow cytometry, and patients were divided into high CLA(+) Tregs or high α(4)β(7)(+) Tregs groups, using the 75(th) percentile of tissue-specific Treg percentages as a threshold. At day +100 post-HCT, the cumulative incidence of any stage skin or gut aGVHD was significantly lower in those patients with high CLA(+) Tregs or high α(4)β(7)(+) Tregs at engraftment, respectively (high CLA(+) Tregs, 24.0% vs low CLA(+) Tregs, 55.1%; p = 0.011 for skin aGVHD or high α(4)β(7)(+) Tregs, 47.3% vs low α(4)β(7)(+) Tregs, 74.5%; p = 0.029 for gut aGVHD). The 2-year probabilities of overall survival and nonrelapse mortality were 73.4% and 7.5% among patients with high frequencies of tissue-specific Tregs vs 49.4% and 36.1% for those with both low CLA(+) Tregs and low α(4)β(7)(+) Tregs (p = 0.039, p = 0.010). These results suggest that a threshold value forCLA(+) or α(4)β(7)(+) Tregs could be used to predict important HCT outcomes, and to direct the rationale use of tissue-specific pre-emptive therapies to decrease clinical aGVHD and improveHCT survival.

Allogeneic Hematopoietic Stem Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm

Abstract 4938 BackgroundBlastic plasmacytoid dendritic cell neoplasm is a rare malignancy that typically follows a highly aggressive clinical course,formerly known as blastic natural killer (NK)-cell lymphoma and CD4+/CD56+ hematodermic neoplasm. Here we report 2 cases of blastic plasmacytoid dendritic cell neoplasm that underwent allogeneic stem cell transplantation. Patients and MethodsCase one was recognized as acute lymphocyte leukemia and then was revised to BPDC at recurrence, and another initially presented with typical cutaneous involvement and was promptly diagnosed by biopsy. After induction/re-induction and subsequent consolidation chemotherapy, 2 cases of BPDC received HLA identical-sibling donor allogeneic stem cell transplantation (Allo-HSCT) after BU/Cy, TBI/Cy+VP-16 conditioning regimen, respectively. Both achieved rapid hematopietic recovery in 2 weeks. Multi-color labeling flow cytometry was performed to monitor minimal residual disease (MRD) and the patient received donor lymphocyte infusion (DLI) to control primary malignancy as MRD-triggered or preventive strategy. ResultsCase 1 survived refractory acyclovir-resistant Epstein-Barr virus viremia after rituximab treatment, but failed in DLI-related grade IV graft versus host disease (GVHD) mixed with thrombotic microangiopathy (TMA) on 1 year post-transplantation. Case 2 died from relapse. Conclusion:Allo-HSCT seems to be a promising treatment for aggressive BPDC aided with MRD monitoring and MRD-triggered DLI. GVHD mixed with TMA deserves more attention for treatment of refractory GVHD. Disclosures:No relevant conflicts of interest to declare.