Prior Hematopoietic Stem Cell Transplantation Research Articles

Short-term follow-up of the nutritional status of children with Fanconi anemia undergoing hematopoietic stem cell transplant.

The objective of this study was to evaluate the nutritional status of children diagnosed with Fanconi anemia (FA) during hematopoietic stem cell transplant (HSCT), comparing it with healthy children and children with other hematologic diseases. Observational retrospective study was conducted with patients submitted to HSCT in a period of 5years. We assessed anthropometric and biochemical data, food intake, and gastrointestinal complications in 49 FA patients. We compared the anthropometric information with those of transplanted patients with other diagnoses (n=54) in three periods (pre-transplant, 15 and 30days after the HSCT), and with a group of healthy children (n=24). Throughout the post-HSCT period, there was a significant decline in the nutritional status of FA patients: 83.3% presented weight loss equal to or greater than 5%. A progressive decrease in food intake after the transplantation was observed, with weekly deficits reaching 7841.3kcal and 347.6g of protein (both p<0.05). When comparing FA with other diagnoses patients, the former displayed a poorer nutritional status prior to HSCT (p<0.01 for BMI/age z-score), and that difference was maintained during the transplant (p<0.01 for the same parameter), with similar weight loss values for both groups (8.99 vs 7.91%, respectively; p>0.05). When compared to the control group of healthy children, FA patients prior HSCT showed substantially lower z-scores for Ht./age (p<0.01) and BMI/age (p<0.05). Although FA patients demonstrated poorer nutritional status as compared to other diagnosis and healthy children, the decline of anthropometric measures along the treatment is similar to other transplanted patients, imposing a greater risk to FA patients.

Children Receiving Hematopoietic Stem Cell Transplantation are at Increased Risk of Onychocryptosis Requiring Surgical Management

At our institution, a high proportion of children with onychocryptosis (ingrown toenail) requiring surgical intervention were noted to have a history of hematopoietic stem cell transplantation (HSCT). We analyzed the characteristics of patients who underwent surgical intervention for onychocryptosis and examined our institutional HSCT database to determine if an association exists between onychocryptosis and HSCT. Surgical cases for onychocryptosis performed from 2000 to 2012 were identified. Nine demographic, clinical, and perioperative variables for both patients with and without prior HSCT were assessed. In a separate analysis, the institutional HSCT database was then queried to identify the prevalence and clinical characteristics associated with onychocryptosis after HSCT. We identified 17 children who had undergone surgical management of onychocryptosis, of which 8 (47.1%) had previous HSCT. Children who had undergone HSCT had an aggressive form of onychocryptosis with 50.0% having bilateral great toe and nail edge involvement and 37.5% having a recurrence. In HSCT cohort analysis of 1069 children, 91 (8.5%) had onychocryptosis. Male sex, non-black race, acute graft versus host disease, and increasing age at transplantation were independently associated with onychocryptosis. HSCT is strongly associated with onychocryptosis requiring surgical intervention. Children with a history of HSCT may also have more aggressive toenail disease, with higher rates of surgical intervention, bilateral ingrown toenails, recurrence, and need for return to the operating room. Clinicians should perform careful screening and early treatment in these patients.

Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL).

10512 Background: Inotuzumab ozogamicin (InO), a CD22-targeting antibody linked to calicheamicin demonstrated exceptional activity in R/R ALL in adults. InO has been available to pediatric patients with R/R ALL via a compassionate access program. Methods: Participating international pediatric oncology centers received IRB approval to submit retrospective demographic, outcome and toxicity data on pediatric patients who received at least one dose of InO. Results: Thirty-four patients, age 2.3-21.4 yrs (median 11.7) received 1-4 cycles (3 weekly doses) of InO. Patients were heavily pretreated in 1st-5threlapse; 28 were refractory to their preceding regimen. Thirteen patients had prior hematopoietic stem cell transplant (HSCT), 27 received prior CD19 and 8 prior CD22-directed therapy. Pre-InO disease was M3 ( &gt; 25% blasts) in 26 patients, M2 (5-25%) in 3, and MRD only in 5 (1 with extramedullary disease). Of 29 patients with M2/M3 disease at baseline, 18 (62%) achieved a complete remission (CR), 13 of whom were MRD negative. Post-InO, 15 patients proceeded to HSCT and 5 to CAR T-cell therapy. Alterations in CD22 expression at subsequent relapse were noted in two patients with available blasts samples. No deaths were attributed to InO during therapy. The incidence of grade 3/4 infections was 38% and were of the expected types. Grade 1-4 hepatic toxicity was noted in 11/34 (32%) patients, primarily asymptomatic elevations in transaminases/bilirubin. There was no sinusoidal obstruction syndrome (SOS) during InO therapy but 8/15 patients who received HSCT post-InO developed SOS. One patient died from SOS, but the others recovered. The incidence of SOS was higher in patients who had undergone prior HSCT (6/8) versus no prior HSCT (2/7). SIRS (1), neurotoxicity (2) and hemorrhage (3) were infrequent. Three patients had musculoskeletal pain associated with edema. Conclusions: Single agent InO had a CR rate of 62% in heavily pretreated pediatric patients. Toxicities were similar to adults with hepatic and infectious toxicity being the most common. Overall InO was well tolerated, but the incidence of SOS was high in patients who underwent HSCT post-InO, particularly in those who had undergone a prior HSCT.

Retrospective Study Evaluating Hematological Remission Rates and Survival in Chinese Adults with Relapsed or Refractory (r/r) Philadelphia Chromosome Negative (Ph-) B-Precursor Acute Lymphoblastic Leukemia (ALL)

Introduction: Outcomes are poor among Chinese adults with r/r ALL. Current recommendations in China for the treatment of adults with Ph- ALL include induction therapy with vincristine or vindesine, anthracyclines/anthraquinones, and corticosteroids; intensive consolidation therapy following complete remission (CR); and hematopoietic stem cell transplantation (HSCT). Currently, there is a lack of studies assessing treatment status and outcomes in Chinese adults with r/r ALL. The objective of this study was to assess the efficacy of currently available treatments for adults with r/r Ph- ALL in China.Methods: Between January 2009 and December 2014, adults with r/r B-precursor ALL and defined Philadelphia chromosome status were identified and enrolled from 14 hematology centers in China. All patients were ≥ 15 years of age at time of de novo (initial) diagnosis of ALL, had no central nervous system involvement at time of relapse, and had no isolated extramedullary relapse. Clinical data were retrospectively collected by chart review. The primary analysis set included only patients with r/r Ph- ALL, defined as meeting 1 of the following criteria: primary refractory, had relapsed within 12 months of first CR, relapsed after first or later salvage, or relapsed within 12 months of HSCT. The primary endpoint was rate of overall response (CR or CR with partial hematologic recovery [CRh]) after last salvage treatment. Key secondary endpoints included rate of CR with incomplete hematologic recovery (CR/CRh/CRi), duration of CR/CRh, rate of allogeneic hematopoietic stem cell transplantation (alloHSCT) realization after CR/CRh, and overall survival (OS).Results: Of 458 eligible patients, 304 (66%) had Ph- ALL, 270 (89%) of whom were in the primary analysis set (female, 46%; median [range] age at diagnosis, 29 (15-73) years). Of these, 45 (17%) had primary refractory disease, 159 (59%) had relapsed within 12 months of first CR, 49 (18%) had relapsed twice or more, and 17 (6%) had relapsed within 12 months post-HSCT. Baseline characteristics at the time of last salvage therapy among patients without prior HSCT included 195 (72%) with no prior salvage, 45 (17%) with 1 prior salvage, and 6 (2%) with ≥ 2 prior salvage treatments. Prior HSCT (n = 24; 9%) included both autologous (n = 8) and allogeneic (n = 16). Among those with prior HSCT, 18 (7%) had prior salvage, 6 (2%) had 1 prior salvage, and none had ≥ 2 prior salvages.Efficacy data at last salvage are presented in the table. Overall, 31% (84/270; 95% confidence interval [CI], 26%-37%) of patients achieved CR/CRh at last salvage. The median time to CR/CRh was 30 days. Median (range) number of therapies to CR/CRh was 1 (1-3). The occurrence of CR/CRh by line of salvage was 104/254 (41%) for 1st line, 13/55 (24%) for 2nd line, and 1/6 (17%) for 3rd line or later. Median (95% CI) duration of CR/CRh at last salvage was 2.7 (2.0-3.8) months with 57% events among 84 patients who achieved CR/CRh. Among CR/CRh responders, 13 of 16 evaluable patients (81%) achieved a minimal residual disease response. Median (95% CI) OS was 4.4 (3.6-5.1) months, with 54 (20%) deaths among 270 patients. At last salvage, 24/84 (29%) responders subsequently received alloHSCT.Conclusions: In this population of Chinese adults with r/r Ph- ALL treated with currently available salvage chemotherapies, CR/CRh responses were low (31%) and prognosis was poor. The median duration of CR/CRh was short (2.7 months), and the alloHSCT realization rate was low among responders. Thus, new therapies are needed to improve treatment outcomes in Chinese adults with primary refractory or relapsed Ph- ALL. [Display omitted] DisclosuresMeng:Amgen: Employment, Equity Ownership.

Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS): Final Results from a Phase 1/2 Study

Background: Standard chemotherapies for relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) are often unsuccessful. Pre-treatment ("priming") with hypomethylating agents such as decitabine has been shown to sensitize AML cells to chemotherapeutics, prompting a phase 1/2 study (NCT01729845) of MEC preceded by decitabine priming (d/MEC) in relapsed/refractory AML/MDS.Methods: Patients ≥18 years with relapsed/refractory AML or high-risk MDS (>10% blasts) requiring first or subsequent salvage therapy were eligible if they had adequate organ function and a treatment-related mortality (TRM) score of <9.2 (corresponding to an expected TRM of <9.2% with standard induction chemotherapy). Prior treatment with hypomethylating agents or MEC (but not combined) was allowed. Patients with prior hematopoietic stem cell transplant (HCT) were eligible. Excluded were patients with concomitant illness with expected survival <1 year and uncontrolled infection. In phase 1, cohorts of 6-12 patients were assigned to 1 of 3 dose levels of decitabine (20mg/m2 for 5, 7, or 10 days) followed 5 days later by MEC (mitoxantrone 8mg/m2/day x 5 days; etoposide 100 mg/m2/day x 5 days; cytarabine 1 g/m2/day x 5 days). Patients with persistent AML were eligible for re-induction. Patients achieving a CR or CR with incomplete platelet recovery (CRp) could receive 2 more cycles of similarly dosed d/MEC. Dose-limiting toxicity (DLT) was defined as: 1) a grade 3 non-hematologic toxicity lasting >48 hours resulting in a >7-day delay of the subsequent treatment cycle; 2) a grade ≥4 non-hematologic toxicity, if recovery to grade ≤2 within 14 days. Both excluded febrile neutropenia/infection and constitutional symptoms. During phase 2, a Simon minimax 2-stage design was used to monitor whether a response rate of 0.25 was reached, with 80% power and a 1-sided alpha of 7%, assuming a historical CR rate of 10-15%.Results: Fifty-two patients, median age 55 (range: 19-72) years, with primary refractory (n=19) or relapsed disease (n=33; median duration of prior CR: 5 [1-19] months) and a median TRM score of 3.15 (range: 0.07-9.05) were enrolled. They received a median of 2 (1-7) prior therapies; 14 had prior HCT. During dose escalation, 1 DLT occurred at each the 2nd and 3rd dose level, identifying a 10-day course of decitabine with MEC as MTD. Since no differences in response rates were noted between the 7 and 10-day course of decitabine, a 7-day course of decitabine was used in phase 2 for logistical reasons. Overall, 11/51 evaluable patients achieved a CR (21.6%; 95% confidence interval [CI]: 11.3-35.3%) of whom 9 had no measurable residual disease (MRD) by flow cytometry. This CR rate compared favorably to a historic control population with patient matching based on duration of prior remission and number of prior salvage therapies (Estey et al. Blood 1996; 88:756), with an observed/expected CR ratio of 1.77. Seven further patients achieved a CRp, and 2 had a CR with incomplete count recovery (CRi) for an overall response rate (ORR) of 20/51 (39.2%; 95% CI: 25.8-53.9%). Among the 45 evaluable patients treated with a 7 or 10-day course of d/MEC, the ORR was 37.8% (95% CI: 23.8-53.5%). Five patients achieved a morphologic leukemia-free state, 21 had resistant disease, and 5 died before response assessment. Median response duration (CR, CRi or CRp) was 130 (15-1,229) days, with 3 of these responses ongoing. Overall survival of these 20 patients was longer (median of 332 [62-1,000 days]) than that for patients who failed to achieve remission but did not experience TRM (median 119 [45-530] days). Inclusion of 6 eligible patients that were treated with this regimen outside the clinical trial did not change these results. Nine patients died within 28 days of treatment initiation for a TRM rate of 17.6% due to infection/septic shock (5), intracranial hemorrhage (1), respiratory failure (2), and progressive disease (1). Besides grade 3-4 cytopenias, infection/neutropenic fever, nausea, and mucositis were the most common adverse events.Conclusion: D/MEC is feasible and has anti-leukemic activity in heavily pretreated relapsed/refractory AML and high-risk MDS. A comparative analysis of these results with other contemporary intensive salvage regimens is ongoing. A follow-up study is also being done to explore the relative value of pre-treatment vs. concomitant use of decitabine with intensive salvage chemotherapy. DisclosuresOthus:Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multi-Organ Dysfunction: Final Results from a Pivotal, Historically Controlled, Phase 3 Trial

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multi-Organ Dysfunction: Final Results from a Pivotal, Historically Controlled, Phase 3 Trial

Dexamethasone Palmitate for Engraftment Syndrome Is Associated with Favorable Transplant Outcome for Children with Hematological Malignancy

Background: Engraftment syndrome (ES) is an early complication after hematopoietic stem cell transplantation (HSCT) caused by a massive release of pro-inflammatory cytokines, products of degranulation, and oxidative metabolism, in which activated macrophage play a crucial role. Liposome-incorporated dexamethasone, dexamethasone palmitate (DP), is known to suppress activated macrophages by readily taken up via phagocytosis and strongly retained in the cytoplasm. In this retrospective study, we aimed to identify the incidence of ES, assess the efficacy and impact of DP treatment for ES on clinical courses after HSCT.Patients & Methods: This retrospective study included 95 consecutive allogeneic HSCT for children (the median age at HSCT, 9.1 years; range, 0.5 - 18.0 years) with hematological malignancy performed in our institute between April 2006 and December 2014. The underlying diseases consisted of acute lymphoblastic leukemia (n=52), acute myelogenous leukemia (n=30), malignant lymphoma (n=8), and myelodysplastic syndrome (n=5). Sixty patients underwent bone marrow transplantation from human leukocyte antigen (HLA) identical family members (n=26), HLA haplo-identical family members (n=4), or unrelated volunteer donors (n=30), the other 35 patients received unrelated cord blood transplantation. Seventy-three patients were prepared by myeloablative conditioning regimen consisting of total body irradiation based regimen (n=57) and busulfan based regimen (n=16), the other 22 patients were prepared by reduced intensity conditioning. Forty-two patients received HSCT at advanced clinical stage; second remission after prior HSCT, third remission or non-remission. Current cohort contained 22 patients received second or more HSCT. The diagnosis of ES consists of Spitzer's criteria and specific bone marrow aspiration findings; proliferation of activated macrophage or phagocytosis. DP treatment (2.5 mg/m2/day I.V. for 3 consecutive days) indicated for all patients diagnosed as ES, and on demand DP treatment for refractory cases. Univariate analysis of overall survival (OS) was performed using the log-rank test, and Gray's test was used for group comparisons of cumulative incidences. Predictive factors with a p value <0.10 in the univariate analyses were set in the multivariate analysis (Cox hazard proportional model with the time-dependent covariate).Results: Of 95 consecutive patients, 35 patients (38%) developed ES and were treated by DP; defied as ES-group. ES was resolved in 30 of 35 cases by DP treatment, however, 5 patients needed additional methylprednisolone treatment. The cumulative incidence of Cytomegalovirus (CMV) antigenemia in ES-group was significantly higher than that in non ES-group, whereas there was no difference in CMV infection, reactivation of Epstein-Barr virus, and virus associated hemorrhagic cystitis, between two groups. The cumulative incidence of neutrophil recovery at 42 days after HSCT were 94% (95% confidence interval [CI], 78 - 99%) for ES-group and 98% (95% CI, 88 - 100%) for non ES-group; the median time to engraftment was 19 days for ES-group and 17 days for non ES-group, respectively. The median follow-up of survivors was 48.9 months. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) for ES-group was comparable with that for non ES-group (12% versus 12% at 100 days, P=0.97). However, the ES-group was significantly associated with higher incidence of chronic GVHD (25% versus 8% at 4 years, P=0.03, Figure A), lower relapse rate (29% versus 51% at 4 years, P=0.03, Figure B), and higher OS (77% versus 57% at 4 years, P=0.06, Figure C). Moreover, multivariate analyses identified that developing ES as the independent favorable predictor for both relapse (hazard ratio [HR], 0.42; 95% CI, 0.20 - 0.90; P=0.03) and mortality (HR, 0.40; 95% CI, 0.17 - 0.95; P=0.04); simultaneously, advanced clinical stage (HR, 2.74; 95% CI, 1.41 - 5.32; P=0.003) was an independent poor predictor for relapse, and advanced clinical stage (HR, 6.51; 95% CI, 2.59 - 16.4; P<0.001) and age at HSCT >10 years (HR, 2.94; 95% CI, 1.31 - 6.42; P=0.009) were independent poor predictors for OS.Conclusion: Our findings suggested that DP could control early post-transplant immune reaction such as ES without suppressing graft-versus-leukemia effect, which improves the clinical outcome for children with hematological malignancy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia- a Report from the Acute Leukemia Working Party of the EBMT

Secondary acute myeloid leukemia (sAML) is a very heterogeneous group of disease derived from myelodysplasia, chronic myeloproliferative disorders or after exposure to chemotherapy and or radiation therapy (therapy related AML) or due to exposure to environmental carcinogens. sAML has traditionally been considered a devastating disease with inferior outcomes compared to de novo AML, affecting a vulnerable population of heavily pretreated, especially older patients. Allogeneic hematopoietic stem cell transplantation (HCT) is the only potential curative therapy and usually considered in patients with low comorbidities and transplant related risk score. However, relapse is the most frequent cause of failure after HCT, occurring in more than 50% of the patients. No systematic large analysis of HCT for sAML is available to study the risk factors and outcome. Therefore, the EBMT Acute Leukemia Working Party has performed a retrospective registry study on patients with sAML (n=4256) undergoing HCT.Patients who underwent HLA-identical sibling (n=2290) or unrelated donor (n=1966) peripheral blood (n=3781) or bone marrow transplantation (n=475) from 2000 to 2013 are included in the study. All unrelated donors were Human Leucocyte Antigens (HLA)-matched (10/10) (n=1532) or one locus mismatched (9/10) (n=434). 1901 (45%) patients received ablative (MAC) and 2355 (55%) reduced-intensity conditioning (RIC) regimen. Median age at transplant was 56 years, IQR 48-63 (MAC 51, IQR 42-58; RIC 60, IQR 54-64). Median time from diagnosis of sAML to HCT was 6.2 months, IQR 4.1-12.0 (MAC 5.6, IQR 3.8-9.7; RIC 7.0, IQR 4.4-14.12; p<0.0001). At time of transplant, 2313 (54%) patients were in CR1, 278 (7%) in ≥CR2 and active diseases in 1665 (39%) patients. 158 (4%) patients had prior autologous HCT (MAC 58 [3%], RIC 100 [4%], p=0.049). Median follow-up of surviving patients was 26 months (IQR 7 -56).Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 33% (95% CI, 32-35%) and 25% (95% CI, 24-27%), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 2 years were 46% (95% CI, 44-48%) and 41% (95% CI, 39-43%), respectively. Acute GVHD (grade II-IV) occurred in 1043 (26%) patients. The 2-year cumulative incidence of chronic GVHD was 54% (95% CI, 51-56). Two year OS, LFS, RI and NRM of MAC and RIC groups were 48% (95% CI, 46-50) vs. 44% (95% CI, 42-47), p=0.06, 44% (95% CI, 41-46) vs. 39% (95% CI, 37-41), p=0.003, 30% (95% CI, 28-32) vs. 36% (95% CI, 34-38), p<0.0001, 26% (95% CI, 24-28) vs. 25% (95% CI, 24-27), p=0.273, respectively. Two year OS of patients in CR1, ≥CR2 and active disease before HCT was 54% (95% CI, 52-56), 45% (95% CI, 39-52) and 35% (95% CI, 33-38), respectively (p<0.0001).In multivariate analysis adjusted for variable with different distribution between groups, the type of conditioning (RIC vs. MAC) had no impact on OS and LFS, however RIC group had higher RI (HR, 1.3, 95% CI 1.12-1.44, p=0.0001) and lower NRM (HR 0.8, 95% CI 0.72-0.96, p=0.01). Older age at HCT was an independent adverse prognostic factor for OS, LFS and NRM. Time from diagnosis to HCT had no impact on transplant outcome. Patients receiving PB grafts had superior OS (HR 0.84, 95% CI 0.73-0.97, p=0.01), LFS (HR 0.85, 95% CI 0.74-0.97, p=0.02) and lower RI (HR 0.83, 95% CI 0.70-0.99, p=0.049) compared with BM. Patients in remission and receiving HCT from HLA-identical siblings were independently associated better outcome.In summary, our registry study in the largest cohort of patients studied so far receiving HCT for secondary AML, demonstrated that about 45% of patients with secondary AML can attain long term survival after HCT. Patients receiving ablative regimens were associated with lower relapse risk and patients in remission had superior survival. Patients receiving PB grafts were associated potent graft-versus leukemia effects with decreased relapse risk and improved survival. Post- transplant pre-emptive therapy to decrease relapse risk might improve outcome further in these high risk populations. DisclosuresNiederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Schmid:Janssen Cilag: Other: Travel grand; Neovii: Consultancy.

Editorial: Improving the safety of cell therapy products by suicide gene transfer.

Editorial: Improving the safety of cell therapy products by suicide gene transfer.

Clinical and In Vitro Studies on Impact of High-Dose Etoposide Pharmacokinetics Prior Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Lymphoblastic Leukemia on the Risk of Post-Transplant Leukemia Relapse

The impact of etoposide (VP-16) plasma concentrations on the day of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on leukemia-free survival in children with acute lymphoblastic leukemia (ALL) was studied. In addition, the in vitro effects of VP-16 on the lymphocytes proliferation, cytotoxic activity and on Th1/Th2 cytokine responses were assessed. In 31 children undergoing allo-HSCT, VP-16 plasma concentrations were determined up to 120 h after the infusion using the HPLC–UV method. For mentioned in vitro studies, VP-16 plasma concentrations observed on allo-HSCT day were used. In 84 % of children, VP-16 plasma concentrations (0.1–1.5 μg/mL) were quantifiable 72 h after the end of the drug infusion, i.e. when allo-HSCT should be performed. In 20 (65 %) children allo-HSCT was performed 4 days after the end of the drug infusion, and VP-16 was still detectable (0.1–0.9 μg/mL) in plasma of 12 (39 %) of them. Post-transplant ALL relapse occurred in four children, in all of them VP-16 was detectable in plasma (0.1–0.8 μg/mL) on allo-HSCT day, while there was no relapse in children with undetectable VP-16. In in vitro studies, VP-16 demonstrated impact on the proliferation activity of stimulated lymphocytes depending on its concentration and exposition time. The presence of VP-16 in plasma on allo-HSCT day may demonstrate an adverse effect on graft-versus-leukemia (GvL) reaction and increase the risk of post-transplant ALL relapse. Therefore, if 72 h after VP-16 administration its plasma concentration is still above 0.1 μg/mL then the postponement of transplantation for next 24 h should be considered to protect GvL effector cells from transplant material.

Allogeneic Hematopoietic Stem Cell Transplantation Following Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

Introduction: Improvements in the therapeutic options available for adult relapsed/refractory (r/r) B-precursor ALL are required. Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. Based on encouraging clinical data from a small phase 2 study (Topp MS et al. J Clin Oncol. 2014;32(15s): abstract 7005), we conducted a large confirmatory open-label, single-arm, multicenter phase 2 study of blinatumomab in patients with r/r B-precursor ALL. The aim of the present analysis from this phase 2 study was to characterize those patients who proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) after achieving complete remission (CR)/complete remission with partial hematologic recovery (CRh*) with blinatumomab treatment.Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r B-precursor ALL with one of the following negative prognostic factors: primary refractory, 1st relapse within 12 months of 1st remission, relapse within 12 months of HSCT, or ≥2nd salvage. Blinatumomab was given by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was CR/CRh* within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), HSCT realization rate, 100-day mortality following HSCT, and adverse events.Results: 189 patients with a median age (range) of 39 (18‒79) years were enrolled and received blinatumomab for a median (range) of 2 (1‒5) cycles. At enrollment, 74 (39%) patients had received ≥2 prior salvage therapies, 64 (34%) had received prior HSCT, and 105 (56%) had ≥75% bone marrow blasts.43% (81/189) of patients achieved CR/CRh* within 2 cycles, with similar rates of remission observed in both the HSCT-naïve (42%; 52/125) and prior HSCT (45%; 29/64) groups. In total, 32/81 responders (CR, n=28 and CRh*, n=4) underwent HSCT during blinatumomab-induced remission, yielding a transplantation realization rate for blinatumomab responders of 40% (Table 1). 52% (27/52) of the HSCT-naïve patients and 17% (5/29) of patients who had received prior HSCT proceeded to on-study HSCT during blinatumomab-induced remission. These 32 transplants occurred after a median of 2 (1-5) cycles of therapy, with 11 (34%) patients receiving myeloablative conditioning pre-HSCT, 12 (38%) reduced intensity conditioning, and 9 (28%) unknown regimens. Twenty-two (69%) patients used unrelated donors (stem cells derived from blood, n=11; bone marrow, n=6; cord blood, n=5), 7 (22%) used related donors including 6 siblings (blood, n=5; bone marrow, n=1) and 1 haploidentical mother (blood), with 3 (9%) donor types and stem cell sources unknown. Six patients achieving CR/CRh* after 2 cycles of blinatumomab underwent HSCT but were not included in the transplantation realization rate of 40% due to receiving subsequent antineoplastic therapy before HSCT conditioning (Table 1). Among the 43 patients who achieved CR/CRh* within 2 cycles of blinatumomab treatment but never reached HSCT, 20 (47%) had undergone prior HSCT, 7 (16%) were ≥65 years, and 2 (5%) were ≥65 years and had received prior HSCT (Table 1). [Display omitted] At the time of the primary analysis (data cut-off in October 2013), with median follow-up of 9.8 months, median (95% CI) OS for the 189 blinatumomab-treated patients was 6.1 (4.2‒7.5) months. When censoring for HSCT, median OS was 5.1 (4.1‒7.1) months; although the medians are slightly different, the curves with and without HSCT censoring largely overlap. Median RFS was 5.9 months with and without censoring for HSCT. Nine patients died at any time after HSCT, with 5 deaths due to infection, 3 due to disease progression, and 1 due to graft-versus-host disease (GvHD). Three of these deaths (2 infections and 1 GvHD) were within 100 days of HSCT. The 100-day post-HSCT mortality rate was 11%.Summary: This large phase 2 study demonstrated antileukemia activity of single-agent blinatumomab in heavily pretreated or aggressive r/r ALL, irrespective of prior HSCT. The data suggest that blinatumomab enables patients to reach HSCT, with 11% 100-day mortality post-HSCT. Two-thirds of patients who did not reach HSCT after responding to blinatumomab were either ≥65 years old or had received prior HSCT. Longer follow-up is required to assess the role of HSCT in patients achieving CR/CRh* after treatment with blinatumomab. DisclosuresStein:Amgen Inc.: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Topp:Amgen Inc.: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Goekbuget:Amgen Inc.: Consultancy, Honoraria, Research Funding. Bargou:Amgen Inc.: Consultancy, Honoraria. Dombret:Amgen Inc.: Honoraria, Research Funding. Larson:Amgen Inc.: Consultancy, Research Funding. Rambaldi:Amgen Inc.: Consultancy. Zugmaier:Amgen Reseach (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Jia:Amgen Inc.: Employment, Equity Ownership. Maniar:Amgen Inc.: Employment, Equity Ownership. Huber:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment, Equity Ownership, Related to blinatumomab Patents & Royalties. Kantarjian:Amgen Inc.: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

Safety and Efficacy of Ibrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Who Have Undergone Prior Allogeneic Stem Cell Transplant

Introduction: Ibrutinib (Imbruvica®), a first-in-class Bruton’s tyrosine kinase inhibitor is a once-daily single-agent approved by the US FDA for patients with chronic lymphocytic leukemia (CLL) who have received ≥1 prior therapy, and for CLL with a 17p deletion. The phase III trial evaluating the efficacy and safety of ibrutinib in patients with relapsed/refractory CLL or small lymphocytic leukemia has previously been reported (Byrd et al. N Engl J Med, 2014). Allogeneic hematopoietic stem cell transplantation (HSCT) is also used to treat CLL, particularly in those who are at high risk. Patients with CLL who relapse after allogeneic HSCT are extremely difficult to treat with chemotherapy due to impaired hematopoietic reserve and/or infections. Furthermore, both B and T cells are known to play a role in the immunopathophysiology of graft-versus-host disease (GVHD), and in preclinical studies, ibrutinib, which inhibits both ITK and BTK, reversed established chronic GVHD. To evaluate whether ibrutinib is safe and effective in treating patients with CLL with a history of prior allogeneic HSCT, we evaluated the subset of patients enrolled in ibrutinib clinical trials who had undergone prior HSCT.Methods: Data were collected for patients with relapsed/refractory CLL who had undergone allogeneic HSCT and had been treated with ibrutinib, either as a single agent or in combination with ofatumumab, in 1 of 4 clinical trials (PCYC-1102, PCYC-1109, PCYC-1112, and PCYC-1117). Two of the studies (PCYC-1112 and PCYC-1117) allowed only patients who were >6 months post-HSCT and without GVHD to enroll. Efficacy evaluations included assessment of overall response rate (ORR) by iwCLL criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety evaluations included reporting of adverse events (AEs), including serious AEs (SAEs).Results: A total of 16 patients from 4 ibrutinib clinical trials had undergone prior allogeneic HSCT. Median patient age was 54.5 years (range, 43-68); 12.5% were ≥ 65 years of age, 11 were male, and all 16 patients had an ECOG performance status of 0 or 1. Chromosomal abnormalities del17p and del11q were reported in 10 and 3 patients, respectively. More than 4 prior therapies were reported for 12 patients. Of the 16 patients, 13 had received an intervening salvage therapy between allogeneic HSCT and the start of ibrutinib treatment. The median time since the most recent transplant was 27 months (range, 8-115). Baseline neutropenia, anemia, and thrombocytopenia were reported in 31%, 25%, and 38%, respectively. Median time on ibrutinib was 18.1 months (range, 0.4-38.8) including 12 patients who were treated with ibrutinib for >12 months. At the time of data cut-off, 11 patients were continuing treatment. Reasons for discontinuation included disease progression (n=2), AEs (n=2), and withdrawal of consent (n=1). No dose reductions were reported. Investigator-assessed responses included 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis, resulting in a best ORR of 87.5%. Median DOR, median PFS, and median OS were not reached at a median follow-up of 23 months. The 24-month PFS and OS rates were each 77% and 75%, respectively. Treatment-emergent grade ≥3 SAEs were observed in 11 patients and included infections (n=6), with the remaining events occurring in 1 patient each, including febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea. The only AE leading to discontinuation of ibrutinib was pneumonia in 2 patients; both were fatal events (at 0.9 and 2.3 months). Two additional deaths occurred on study due to disease progression at 24 and 28 months.Conclusion: Ibrutinib was well tolerated in patients who had undergone prior allogeneic HSCT, with a safety profile similar to that observed in the overall population of patients with relapsed/refractory CLL. The best ORR of 87.5% in this subgroup was also consistent with the 90% reported for the broader relapsed/refractory population in the PCYC-1102 study of single-agent ibrutinib. These data support use of ibrutinib in CLL patients with previous allogeneic HSCT and exploration of ibrutinib treatment for chronic GVHD (ongoing clinical trial: clinicaltrials.gov NCT 02195869). DisclosuresCoutre:Janssen, Pharmacyclics: Honoraria, Research Funding. O’Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Byrd:Pharmacyclics: Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Miklos:Pharmacyclics: Research Funding. Zhou:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Styles:Pharmacyclics: Employment. Jaglowski:Pharmacyclics: Research Funding.

The Clinical and Therapeutic Drug Monitoring of Oral and Intravenous Busulfan in Patients with Acute Leukemia That Underwent to Stem Cell Transplantation with a Test Dose of Busulfan

▪Introduction: Busulfan (Bu) is used in the conditioning regimen for hematopoietic stem cell transplantation (HSCT). Therapeutic drug monitoring (TDM) of Bu with subsequents adjustments doses based on a “target” therapeutic concentration may reduce toxicity after HSCT.Objectives: To evaluatethe impact of TDM of Bu and clinical outcomes in patients with acute leukemia that underwent to allogeneic matched related donor (MRD) and allogeneic matched unrelated donor (MUD) HSCT.Patients and methods: From January 2009 to January 2014, we prospectively analyzed 42 patients with diagnosis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) who underwent TDM of Bu (IV or oral) before transplantation (test dose) and TDM on 1st day of conditioning regimen. Samples were collected at 0, 30’, 60’ and subsequently every hour until 6 hours after administration of busulfan. The plasma was extracted by HPLC (High Performance Liquid Chromatography). All the patients that were submitted to TDM had a test dose 15 days to 48 hours before transplantion. The dose of Bu was adjusted during the first day of the conditioning regimen based on test dose. At the same time we analyzed 21 patients in the retrospective group who did not underwent TDM (from 2004 to 2010).Results: In the retrospective group (n=21), all of them underwent to MRD transplantation. Six (46.2%) were in first complete remission (CR1), 18(85.7%) patients received Bu and cyclophosphamide (BuCy) and the mean of age was 38 years (18-55 Yo). The median of CD34+ cells was 5.4 x 106/kg. The second group consisted by patients that received oral Bu (n= 21): 7 (33.3%) underwent to MUD transplantation, 14 (66.6%) to MRD transplantation, 8 (44.4%) patients were second complete remission (CR2), 4 (22.2%) had active disease status with a mean age of 32.7 years (14-58 Yo). Fifteen (71.4%) received BuCy and 16 (76.2%) received cells from peripheral blood. The median of CD34+ cells was 5.8 x106/kg. The median area under the curve (AUC) in 24 hours was 4950 μMol.min (3196.6- 8212 μMol.min). The third group was IV Bu (n= 21): 7 (33.3%) patients underwent MRD and 14 (66.6%) MUD transplantation, 7 (33.3%) patients were CR1, 7 (33.3%) had active disease or prior HSCT with a mean of age 52.7 years (20-74 Yo). The majority of patients received fludarabine and Bu (n=18; 85.7%) as conditioning and bone marrow was the main source. Immunosuppression was based on FK-506 and methotrexate (90.5% of patients). The median of AUC in 24 hours was 5690 μMol.min (3539.6- 8881.8 μMol.min). The cumulative incidence (CI) of sinusoidal obstructive syndrome (SOS) in the retrospective group and IV Bu were 9.5% for both, while in the group oral Bu it was at 19% (p = 0.566). The median AUC of Bu received during conditioning for those who died of SOS was lower in oral Bu than IV Bu (4872 uMol.min vs 5732 uMol.min respectively). The CI of acute graft-versus-host disease (aGVHD) at D+100 was 38.1% in the retrospective group, 40.6% in oral Bu and 42.9% in IV Bu. Chronic GVHD was 13.6% in oral Bu, 34% in IV Bu and 42.9% in the retrospective group (p = 0.142). The CI of relapse at D+100 was 19% in IV Bu, 4.8% in the retrospective group and oral Bu did not have this event. The IC of death at D+100 was 34.9% in group oral Bu, 9.5% in IV Bu and 14.3% in the retrospective (p = 0.102). The CI of relapse at 1.5 years was 35.8% in the IV Bu, 34.8% in oral Bu and 14.3% in the retrospective group. The CI of death at 1.5 years was 9.5% in group IV Bu, 53.5% in oral Bu and 34.3% in the retrospective (p = 0.015). Among patients who died until D+100, the median of AUC was 5732 μMol.min (5578.5-6818.5 μMol.min) during the conditioning for IV Bu and 4872 μMol.min (3448-8212 μMol.min) for oral Bu. The range between the AUC was large and there was no correlation with patients who died.Conclusion: In acute leukemia SOS had an impact on mortality at D+100 after HSCT (p <0.005). We observed increased incidence of SOS in oral Bu when compared to IV Bu and the classification of this toxicity was severe in 100% of cases when used oral Bu. We conclude that, regardless formulation, both oral or IV busulfan should be monitored with pharmacokinetics and adjustments of doses. DisclosuresNo relevant conflicts of interest to declare.

A Phase 1 Study of Azacitidine (AZA) in Combination with Fludarabine and Cytarabine in Relapse/Refractory Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study

Background: Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemogenesis, drug resistance, and relapse. It has been shown that pre-treating leukemia cells with AZA or decitabine could partially reverse the aberrant DNA methylation, restore the expression of tumor suppressor genes, and sensitize cells to chemotherapeutic agents.Study design: TACL2011-002 was a phase I study with an expansion cohort, examining the use of AZA in sequence with chemotherapy in pediatric leukemia. The objectives were 1) to evaluate the feasibility and toxicity profile of this combination; 2) to obtain preliminary response data in patients with acute myeloblastic leukemia (AML); 3) to study the extent of hypomethylation pre- and post-AZA therapy. Children 1-21 years of age with relapsed/refractory (R/R) leukemia were eligible for the phase I portion. A rolling six design was employed followed by an expansion to 12 response evaluable AML patients at the selected dose. Patients received AZA at a dose of 75mg/m2/day (dose level 1, DL1) subcutaneously on days 1-5, followed by intravenous (IV) fludarabine (30mg/m2/dose daily) and IV cytarabine (2gm/m2/dose daily) on days 6-10. If < 2 patients experienced dose-limiting toxicity (DLT), then DL1 would be the expansion cohort dose. If ≥ 2 patients experienced DLT, the dose of AZA was to be reduced to 50mg/m2/day (DL0). Patients were to receive up to 2 courses of therapy. DNA methylation was evaluated at days 0, 5 and the end of course 1 using PCR and the Infinium HumanMethylation450 assay.Results: Fifteen patients were enrolled, 13 with AML and 2 with ALL. Fourteen patients were evaluable for toxicity and response. One AML patient was removed from study after day 3 due to central nervous system treatment needs and was replaced. The median number of prior treatment regimens was 2 (range 1-5). 5/12 patients with AML had prior hematopoietic stem cell transplant (HSCT) while none with ALL had prior HSCT. Toxicities were typical of intensive chemotherapy regimens. Non-hematologic toxicities ≥ grade 3 attributed to AZA included: febrile neutropenia (n=6), infections (n=3), AST elevation (n=1), oral hemorrhage (n=1), hypokalemia (n=1). No patients experienced DLT. 7/12 AML patients had complete response (CR) or CRi (CR with incomplete count recovery), including 3/5 that had received prior HSCT. 1/2 ALL patients had partial response (PR). DNA methylation analysis was performed in 4 patients to date. Compared to baseline, all patients had DNA demethylation by G-LINE analysis on day 5. At the end of course 1, DNA demethylation persisted in 2 patients who achieved CR, wheras no demethylation were detected in the other 2 patients who were non-responders.Conclusions: AZA at 75mg/m2/day plus fludarabine and cytarabine is well tolerated in pediatric patients with relapsed leukemia. The favorable toxicity profile and encouraging response rates in AML warrants further testing of AZA in this patient population. Methylation analysis is ongoing to assess the possible correlation between DNA demethylation and response.TableResponseAMLALLOverallPatient evaluable for response12214CR66CRi11PR112SD*112PD#33*SD = Stable Disease; #PD = Progression of DiseaseClinicalTrials.gov Identifier: NCT01861002This study was supported by Gateway for Cancer Research DisclosuresOff Label Use: Azacitidine is not approved by FDA to treat childhood leukemia.

Intent-to-Treat Results of a Phase I Trial of CD19 Chimeric Antigen Receptor Engineered T Cells Using a Consistent Treatment Regimen Reveals a 67% Complete Response Rate in Relapsed, Refractory Acute Lymphoblastic Leukemia

Relapsed or refractory acute lymphoblastic leukemia (ALL) remains a difficult therapeutic challenge. We developed a platform where T cells are collected, transduced via retrovirus with a chimeric antigen receptor (CAR) targeting CD19 and incorporating CD3ζ and CD28 domains and reinfused in 11 days. Our recently completed Phase I clinical trial (NCT01593696) in patients age 1-30 years with pre-B ALL or B-cell non-Hodgkin lymphoma (NHL) established a maximally tolerated dose (MTD), revealed cytokine release syndrome (CRS) as the dose-limiting toxicity, demonstrated clearance of CNS leukemia without intrathecal (IT) chemotherapy, and resulted in an intent-to-treat complete response (CR) rate of 67%.CAR T cells were administered after fludarabine (25 mg/m2/day Days -4, -3, -2) and cyclophosphamide (900 mg/m2/day Day -2). All patients received either 1 x 106 CAR+ T cells/kg (dose level 1), 3 x 106CAR+ T cells/kg (dose level 2), or the maximum number of cells generated if the total available dose fell below the assigned dose level. In the latter case, patients were not evaluable for toxicity but remained evaluable for all other aspects.We enrolled and treated 20 ALL patients (2 CNS2 leukemia, 6 primary refractory) and 1 NHL. Two of 21 CAR T cell products did not reach the dose level assigned (90% feasibility), but these were still infused.We determined the MTD to be 1 x 106CAR+ T cells/kg as 2/4 patients at dose level 2 had grade (Gr) 3 or 4 CRS. Dose level 1 was then expanded (n=15) to gain more experience and Gr 3 (n=2; 13%) and Gr 4 (n=2; 13%) CRS occurred. In total, 4 patients received the anti-IL6 receptor antibody, tocilizumab, for severe CRS, 2 of whom also required steroids. Neurotoxicities occurred even in patients without CNS disease and consisted of Gr 1 visual hallucinations (5/21; 24%) and transient Gr 3 dysphasia. No seizures occurred. All CRS and neurotoxicities resolved to baseline. No graft-versus-host disease was seen despite collecting donor-derived T cells directly from patients with prior hematopoietic stem cell transplant (HSCT). B cell aplasia occurred in 12/14 responding patients (86%) but was transient.Using intent-to-treat analysis, the CR rate was 67% with overall survival of 51.6% (median f/u 10 mths). In the 20 ALL patients, the CR rate was 70% with 12/20 (60%) achieving minimal residual disease negative (MRD−) CR. Of these 12, the leukemia free survival is 78.8% beginning at 4.8 months. Ten had subsequent HSCT since this is standard of care for refractory, relapsed ALL in MRD− remission. The 2 patients who did not have a second HSCT relapsed with CD19− disease. In 2 patients with CNS2 leukemia CSF blasts cleared without IT chemotherapy coincident with rise in CSF CAR T cells. 61% of patients had CAR T cells in the CSF, and absolute CSF CAR T cells correlated with neurotoxicity (p=0.0039).Peak CAR T cell expansion occurred in blood (PB) at Day 14 and was not detected beyond Day 68, though 10 patients underwent subsequent HSCT complicating interpretation of this data. Expansion of PB CAR T cells correlated with response (p=0.0042). Gr 3 or 4 CRS correlated with disease burden (p=0.0039), total CAR T cell expansion (p=0.0011), total CD8+ CAR T cells (p=0.0087), and effector memory CD8+ (p=0.0087) and CD4+ (p=0.026) CAR T cells in vivo. Maximum fold change in IL-6 and INFγ correlated with Gr 3/4 CRS (p=0.0002 for both) as did peak C-reactive protein (p=0.0015). Three responding patients received second infusions without additional benefit. No evidence of human anti-mouse antibodies were found. But, T cells in 6/11 patients tested proliferated in response to the infused CAR product >3 times that to autologous non-transduced cells (p=0.030). Importantly, all of these patients had complete responses, hence the significance of this finding remains unclear.Our results demonstrate for the first time a high intent-to-treat feasibility and response rate in a uniformly treated patient population and also provide biomarkers for response, CRS and neurologic toxicities. We conclude that this CD19 CAR platform provides an effective bridge to transplant for patients with refractory and relapsed ALL and is highly active in primary chemorefractory ALL, inducing MRD− remission in 6/6 such patients. Future studies will expand eligibility for patients with CNS leukemia and incorporate a reinduction regimen for patients with high disease burden in an attempt to increase response rates and diminish severity of CRS. DisclosuresOff Label Use: CD19 CAR T cell therapy is not FDA approved and will be discussed for the treatment of ALL and NHL. Wayne:MedImmune: Honoraria, Research Funding, Travel support Other; NIH: Patents & Royalties.

Subsequent Hematopoietic Stem Cell Transplantation in Belinostat-Treated Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (R/R PTCL)

Background: PTCL is a heterogeneous group of hematologic malignancies associated with a poor prognosis for most subtypes. In the relapsed setting, hematopoietic stem cell transplantation (HSCT) is the only potentially curative option for patients with PTCL. However, many patients are not able to achieve an adequate response to allow for HSCT.Belinostat (Beleodaq) is a potent pan-histone deacetylase inhibitor that was recently approved in the US for the treatment of patients with R/R PTCL. Approval was based on data from the pivotal Phase 2 BELIEF study that enrolled 129 patients with R/R PTCL (N = 120 evaluable), and demonstrated durable clinical benefit and tolerability. This analysis presents data for 12 of the enrolled patients (9 evaluable) who proceeded to HSCT following belinostat treatment.Methods: Patients with R/R PTCL received belinostat as a 1000 mg/m2IV infusion on Days 1-5 of a 21-day cycle. The primary endpoint of the study was Objective Response Rate (ORR; Complete Response [CR] + Partial Response [PR]) determined by an Independent Review Committee (IRC). We present efficacy and safety data for the subset of 12 patients who subsequently went on to HSCT.Results: Among 12 patients who subsequently proceeded to HSCT, 4 went on to receive an autologous HSCT and 8 received an allogeneic HSCT; 8 patients (67%) were female and 4 (33%) were male, and the median age was 54.5 (range 31-71) years. The median number of prior anticancer therapies was 2 (range 1-8), including 3 patients with prior autologous HSCT. The median number of belinostat treatment cycles was 2.5 (range 1-14) compared to the median of 2.0 (range 1-8) in the overall study population. Most patients in this subgroup had PTCL-Not Otherwise Specified (58.3%), angioimmunoblastic T-cell lymphoma (16.7%), or anaplastic large cell lymphoma (16.7%); 41.7% of patients had Stage IV disease.Three of the 12 patients were not evaluable for response due to insufficient histological material for confirmation by central pathologic analysis. The IRC-confirmed ORR for the 9 evaluable patients was 33.3% vs 25.8% in the study overall, and included 2 CRs, 1 PR, 2 patients with stable disease (SD) and 3 patients with progressive disease (PD). Duration of Response after transplant ranged from 41-261 days for the 3 belinostat responders. At last study contact, 2 patients had died from cardiac events (unrelated to belinostat) and 10 remained alive, with Overall Survival (OS) ranging from 8-23+ months. Most adverse events (AEs) were Grade 1-2, with two treatment-related Grade ≥3 AEs (neutropenia and prolonged QT interval); 3 serious AEs (arthralgia, lower limb fracture, and pyrexia) were reported in this subgroup.Conclusions: Belinostat was well tolerated in previously treated patients with R/R PTCL and enabled some patients to proceed to HSCT. Three patients responded and went on to HSCT following belinostat; the remaining patients had HSCT following SD (2), PD (4) or were not evaluable (3). OS was prolonged when compared to historical controls.Summary of Patients Treated with Belinostat Who Subsequently Went on to Hematopoietic Stem Cell Transplantation Sorted by Subtype and Response Table 1PatientSubtype(Stage)Prior RegimensECOGPSBelinostat CyclesIRC ResponseOS(months)DoR(days)Evaluable Patients931-003^PTCL-NOS (IIIB)3114CR11.56261907-006PTCL-NOS (IIA)5 + auto SCT02SD13.93-907-007^PTCL-NOS (IVA)402SD12.09-907-005^PTCL-NOS (IIIA)202PD13.63-140-002PTCL-NOS (IVA)817PD17.64-914-006PTCL-NOS (IIIA)4 + auto SCT02NE13.73-245-001AITL (UNK)106PR19.9141221-003ALCL ALK– (IA)2 + auto SCT011CR20.4173907-001ALCL ALK– (IVA)204PD22.87-Non-Evaluable Patients*914-002PTCL-NOS (IVB)102PD7.75-147-002^AITL (IIIB)221NE9.43-147-001Hepatosplenic TCL (IVA)103NE10.22-AITL = angioimmunoblastic T-cell lymphoma; ALCL = anaplastic large cell lymphoma; ALK = alkaline phosphatase; auto = autologous; CR = complete response; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; IRC = independent review committee; NE = not evaluable; NOS = not otherwise specified; OS = overall survival; PD = progressive disease; PR = partial response; PS = performance status; PTCL = peripheral T-cell lymphoma; SCT = stem cell transplantation; SD = stable disease; TCL = T-cell lymphoma*Lack of central pathologic confirmation resulted in exclusion from the evaluable population^Autologous hematopoietic SCT DisclosuresAl-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Hsu:Spectrum Pharmaceuticals: Employment. Choi:Spectrum Pharmaceuticals: Employment. Allen:Spectrum Pharmaceuticals: Employment. Visser:Sanofi: Membership on an entity’s Board of Directors or advisory committees. Horwitz:Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jannsen: Consultancy.

Photopheresis As Part of Conditioning Reduces Incidence of Severe Graft Versus Host Disease: Fourteen Year Follow-up of a Novel Reduced Intensity Regimen for Allogeneic Hematopoietic Stem Cell Transplantation

Background: Reduced intensity conditioning (RIC) regimens have allowed the use of allogeneic hematopoietic stem cell transplantation (HSCT) in older and high risk individuals, though Graft versus Host Disease (GVHD) remains an issue. Host antigen presenting cells have been implicated in the pathogenesis of GVHD. Extracorporeal photopheresis (ECP) has been shown to modulate host antigen presenting cell function. Tufts Medical Center developed a novel RIC regimen incorporating ECP, pentostatin and reduced dose total body irradiation (PPT). We now report our 14 year experience with this regimen in 206 consecutive patients not eligible for a myeloablative HSCT.Methods: The Tufts BMT database, the Center for International Bone Marrow Transplantation Registry (CIBMTR) database, and chart review were used to gather data. All patients received a conditioning regimen consisting of ECP administered on days -6 and -5, pentostatin 4mg/m2 by continuous infusion over 48 hours on days -4 and -3, a total dose of 600 cGy TBI administered in 3 fractions on days -2 and -1. No antithymocyte globulin was given. All patients received GVHD prophylaxis with cyclosporine and 2 doses of methotrexate. Supportive care was provided per institutional guidelines.Overall survival (OS) was calculated from day 0 using the Kaplan Meier method. Cumulative incidence of non-relapse mortality (NRM) was calculated treating death due to primary hematologic malignancy or relapse as competing risks. Univariate associations between patient characteristics and outcomes were estimated using logistic regression or Cox proportional hazards models as appropriate.Results: 206 patients (56% males) underwent allogeneic HSCT with the PPT regimen between October 1999 and December 2013. Median age at transplant was 53 years (19-70 years) with 45% being older than 55 years. 31% had a prior autologous HSCT. Median time from diagnosis to transplant was 17 months (range 1-180 months). 59% of the transplants were from matched siblings and 41% were from unrelated donors. Marrow was utilized as the source of stem cells in 72% of the transplants. 92% transplants were HLA matched with 8% mismatched at one antigen. The most common indications for transplant were Acute Myelogenous Leukemia (AML) (35%), Myelodysplastic Syndrome (MDS) (16%) and Non-Hodgkin Lymphoma (NHL) (12%). Of the 73 patients with AML 33% were in first complete remission (CR1), 18% were in a second or greater complete remission (CR ≥2) and 49% had active disease at the time of transplant.Median times to neutrophil and platelet engraftment were 17 and 19 days, respectively. 17% of the patients never dropped their platelet counts below 20,000/mm3.The estimated 5 year overall survival (OS) for the entire cohort was 29% [95% CI (23%-36%)]. The estimates of OS by diagnosis are shown in Figure 1. The estimated non-relapse mortality (NRM) at 100 days was 17% [95% CI (13%-23%)]. The incidence of grade 3-4 acute GVHD was 20%. 54% of the patients developed chronic GVHD, of which only 17% were extensive stage.On univariate analysis for the entire cohort, the variables significant for a higher risk of death were 1-antigen mismatch [HR 1.96, p-value=0.01] and KPS <80 [HR 10.66, p-value <0.001]. Age, stem cell source and having an unrelated donor were not found to be significant. On multivariate analysis in the AML cohort, advanced age [aHR 1.37, p-value=0.02] and active disease [aHR 3.02, p-value=0.002] were significant factors for death. OS by remission status in the AML cohort is shown in Figure 2.Conclusions: PPT was well tolerated with low NRM and survival outcomes comparable to other RIC regimens. OS was independent of graft type (related versus unrelated) or stem cell source. Rates of severe acute and extensive chronic GVHD were low, possibly due to the use of ECP and its modulation of the host antigen presenting cells. OS in patients with AML was comparable to other RIC regimens despite almost half of the patients having active disease at the time of transplant. Our long term follow-up data of 14 years shows that PPT remains a novel regimen for patients not eligible for full intensity conditioning. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Incidence and Risk Factors of Invasive Fungal Infection in Adult Patients Receiving Allogeneic Hematopoietic SCT Recipients

▪To investigate the incidence and risk factors for the occurrence of proven or probable invasive fungal infection (IFI) in adult patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), 421 patients undergoing HSCT between 2002 and 2013 in our hospital were retrospectively analyzed. Thirty-one patients with the median age of 42 years (range: 19-60) developed IFI after HSCT. The post-HSCT IFI incidence was 7.4% and median time from HSCT to the diagnosis of IFI was 139 days (range: 2-1809). The risk factors for the occurrence of IFI were analyzed using Cox regression models.Of the pretransplant factors, European Group for Blood and Marrow Transplantation (EMBT) risk>2 (P=0.001) and prior history of IFI (P=0.006) or DM (P=0.042) were the significant predictors for post-HSCT IFI by univariate analyses. In multivariate analysis, EMBT risk>2 (P=0.015) and prior history of IFI (P=0.006) retained significance. Of the post-transplant factors, acute graft-versus-disease (aGVHD) overall grade III-IV (P<0.001), extensive chronic GVHD (cGVHD) (P=0.002), post-transplant lymphoproliferative disorders (PTLD) (P=0.005) and the use of high-dose steroids (P<0.001) were statistically significant in univariate analyses. After multivariate analysis, high-dose steroids (P<0.001) and aGVHD overall grade III-IV (P=0.045) retained significance. These results suggest that risk group stratification prior HSCT and monitoring of IFI in patients with severe GVHD and receiving high-dose steroids is mandatory to decrease the risk of post-HSCT IFI, especially in those with prior history of IFI. Abstract 2476. Table 1Possible factors for the occurrence of invasive fungal infection (IFI) after adult allogeneic HSCTIFIUnivariate analysisMultivariate analysisFactorsNo. of patientsN%HR95%CIP-valueHR95%CIP-valueEMBT risk=<216952.9>22522610.35.0381.930-13.1510.0013.3901.273-9.0290.015Prior history IFINo406276.6Yes15426.64.4571.551-12.8060.0065.8071.675-20.1290.006Prior history DMNo402286.9Yes19315.73.4901.045-11.6530.042aGVHDNo or Overall Gr. I-II379236.0Gr. III-IV42819.06.9363.046-15.796<0.0012.6271.023-6.7480.045High steroids*No367123.2Yes541935.111.1485.401-23.008<0.00111.1853.875-32.289<0.001cGVHDNo or limited364195.2Extensive571221.03.1311.518-6.4590.002PTLDNo405276.6Yes164254.6271.607-13.3200.005Abbreviations: CI = confidence interval; HR = hazard ratio; EBMT = European Group for Blood and Marrow Transplantation; HSCT = hematopoietic stem cell transplantation; GVHD = graft-versus-host disease; aGVHD = acute GVHD; cGVHD = chronic GVHD; Gr.= grade; PTLD = Post-transplant lymphoproliferative disorders. DM = Diabetes mellitus. High steroids* = post-HSCT high-dose steroid; Significant values (P<0.05) are given in bold. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Follow-up of Patients With Multiple Myeloma Who Received Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic transplantation for multiple myeloma (mm), although seen as potentially curative, has inherent treatment-related mortality and long-term implications. Important questions remain such as the expectation for long-term survival and the role, if any, of the graft versus tumor effect.The study cohort included 56 consecutive patients (pts) with mm who received an allogeneic hematopoietic stem cell transplant (HSCT) between November 9, 2004 and June 1st 2011. Only pts who had received at least one prior autologous transplant were included in this retrospective analysis. Patients received either a non-myeloablative (NMA), a reduced intensity (RIC) or an ablative (MA) regimen. The NMA regimen consisted of low dose TBI for siblings and low dose TBI with fludarabine for unrelated donors. The RIC regimen was fludarabine melphalan, with the addition of low dose thymoglobulin for unrelated donors. The MA regimen was busulfan and melphalan, with thymoglobulin for unrelated donors. A favorable group of 26 pts received their allogeneic transplantation for consolidation after demonstrating a response (PR, VGPR, CR) to their prior autograft and without evidence of progression, leaving 30 pts in the salvage transplant group defined as pts unresponsive (less than PR) or with relapse after their prior autograft. The median age was 52.4 years (SD = 6.9 years). Twenty six (46%) pts were female. The hematopoietic cell donors were 35 siblings and 21 unrelated (URD). In the URD group, 10 (47.6%) pts had a mismatched donor. In our cohort 10 (17.9%) pts received a MA, 22 (39.3%) received a RIC and 24 (42.9%) received a NMA regimen. The median follow-up was 52 months. The related and unrelated donor cohorts were similar except for age (53.9 years versus 49.8 years p = 0.03).Overall, 32 (57.1%) pts achieved a CR. Seven (12.5%) pts had a VGPR, 13 (23.2%) had a PR and 2 (3.6%) had stable disease. At the time of analysis, 49.2% of pts were in CR. Twenty one (37.5%) pts relapsed post transplantation of whom 16 received donor lymphocytes (DLI 15 pts) or immune suppression withdrawal (1 pt), with 10 (62.5%) pts responding to this intervention. The cumulative incidence of acute GVHD (aGVHD) grade II-IV was 35.4%, 28.6% for related donors and 47.6% for URD (p = 0.16). The cumulative incidence of chronic GVHD (cGVHD) was 50%, 52% for related donors and 43% for URD (p=NS). The number of non-relapse deaths (NRM) was 13 (23.2%). The cumulative incidence of NRM at 1 year was 18.2%, and 25.5% at 5 years. In the multivariate model, number of prior autologous HSCT (1 vs >1) and grade III-IV aGVHD were significantly associated with an increased NRM. The overall survival (OS) for all 56 pts was 59% at 5 years. The OS at 5 years for the 30 pts who received transplantation as salvage (refractory to the prior autograft or relapsed after the prior autograft), was 38% compared to 82% for the consolidation group. The univariate analysis indicates that pts receiving their allogeneic transplantation as salvage, disease status prior to allogeneic HSCT, number of prior auto HSCT, aGVHD, response post allo HSCT and cGVHD were significantly associated with the risk of all cause mortality, with cGVHD being protective. Donor type (URD versus related), adverse cytogenetics, preparative regimen and age were not significant predictors of risk for all cause mortality by univariate analysis. [Display omitted] [Display omitted] Multivariate analysis shows OS significance for being in the salvage group (HR 4.05, p=0.0196), a GVHD (HR 2.99, p=0.034) and cGVHD (HR 0.26, p=0.012), the latter being protective. The PFS for all 56 pts was 38% at 5 years, 57% for the consolidation group and 21% for the salvage group.In conclusion, patients with multiple myeloma can have an excellent overall survival following allogeneic transplantation even in the setting of relapsed or refractory disease to a prior auto HSCT. Unrelated donors performed just as well as matched siblings. Acute GVHD was deleterious to OS, whereas chronic GVHD was significantly associated with improvement in OS supporting the role of a graft versus tumor effect in multiple myeloma. Disclosures:No relevant conflicts of interest to declare.

Successful Salvage Treatment With Clofarabine and Cytarabine In Relapsed/Refractory Acute Myeloid Leukemia

ObjectivesRelapsed/refractory AML patients have a poor prognosis; allogeneic hematopoietic stem cell transplantation (HSCT) is the only chance in this setting to achieve long-term disease-free survival (1). It was previously established the activity of clofarabine plus cytarabine in AML relapse (clofarabine dosed once daily for 5 days with 40 mg/m2 followed 4 hours later by ara-C at 1 g/m2 per day)(2).However, modifications of this combination in AML therapy of relapsed/refractory patients warrant further evaluation. Therefore, our goal was to determine the efficacy and safety of clofarabine at lower dosage followed by cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and to evaluate the capacity of this regimen as a bridge for HSCT. MethodsPatients aged 18-65 years with refractory/relapsed AML were treated at the dose of clofarabine 30 mg/mq on days 1-5 and cytarabine 1000 mg/mq gg on days 1-5. We evaluated the complete remission rate (CRR), duration of remission (DOR) and overall survival (OS). Minimal residual disease (MRD) by molecular targeting was considered in all patients. ResultsTwenty-five (25) patients aged 29-64 years (median 47), who were fit for allogenetic HCT, received one cycle of 30 minutes infusion of clofarabine 30 mg/mq, followed 4 hours later by 3 hours infusion of intermediate dose cytarabine 1000 mg/mq days 1-5. Only in the first three patients this schedule was followed by gentuzumab. Nine (36%) patients had refractory disease (seven after one induction regimen, one after two previous regimes, one after a prior hematopoietic stem cell transplant (HSCT); 16 (64%) patients were in their first (12 patients) or second relapse (4 patients); among the 12 patients in first relapse, 5 were from an allogeneic stem cell transplant. Fourteen patients (56%) achieved a complete remission (CR), seven (28%) was refractory and 4 (16%) died of treatment related mortality. Eleven (44%) patients underwent (9 in CR) to allogeneic transplants or DLI infusion (3 patients refractory, and 8 patients relapsed), only one patient underwent to autologous transplant. One patient, who was relapsed after prior HSCT, obtained a CR but he developed acute graft vs host disease after therapy and died in molecular CR*. Among all patients underwent HSCT after Clofa/Ara-c salvage, six patients (50%) are still alive and in complete remission, six patients (50%) died because of HSCT complications or AML relapse. The complete remission rate (CRR) was (56,00 %), the median Overall Survival was 5 months for all patients (range 1-38 M), 11 Months for those underwent to tranplantation and 1,5 Months for non transplanted group. Treatment was complicated by neutropenic fever (n=17), grade III-IV mucositis (n=2) , skin rush (n=4) grade II- III, hepatic transaminase elevations (n=2). Two (n=5) patient died before their disease status could be evaluated. ConclusionsThese preliminary results suggest that combination treatment with clofarabine 30 mg/mq and ARA-C 1000 mg/mq is effective in this particularly poor prognosis category of patients, resulting in an ORR very favorably, representing a potential “bridge” toward bone marrow transplant procedures (among the 14 patients who achieved a CR, twelve (85%) proceeded to HSCT, and six are still alive). The safety profile is acceptable in this relapsed/refractory population, and our results are very similar to previous regimes using higher clofarabine dosages. More studies with this combination in adults are warranted. References1 Estey E. Treatment of relapsed and refractory acute myeloid leukemia. Leukemia. 2000;14:476-479. 2. Faderl S et al, “Results of a pase 1-2 study of clofarabine in combination with cytarabine (ara-C)”Blood 2005 [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.