Reduced-intensity Allogeneic Stem Cell Transplantation Research Articles

Assessment Of The Hematopoietic Cell Transplantation Comorbidity Index In Older Patients Receiving Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy for malignant and nonmalignant hematologic disorders. Reduced-intensity conditioning (RIC) regimens have expanded the use of HSCT to elderly and higher risk patients. However, HSCT still remains associated with a significant mortality and morbidity and the careful assessment of risks and benefits before transplantation is essential. Major factors which influence non-relapse mortality (NRM) and overall survival (OS) after HSCT are diagnosis, type of transplant, remission status and the patient's risk profile, which includes age and presence of comorbidities. The use of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been proposed to predict the probability of NRM and OS following HSCT. However, the HCT-CI usefulness for older patients receiving a reduced intensity allogeneic HSCT remains unclear. MethodsA retrospective medical record review was performed to collect data from patients who underwent an allogeneic HSCT at a large, urban, NCI Comprehensive Cancer Center during a five year period (January 2005 to December 2010). Patients 55 years and older who were transplanted using RIC for a hematologic malignancy were selected to be analyzed. Comorbidities and test results were collected to determine the HCT-CI score and other clinical data collected included disease and remission status at time of transplant. Results85 patients aged >55 years old who received a RIC HSCT for hematologic malignancies between January 2005 to December 2010 were analyzed. The median patient age at the time of transplantation was 63 years (range: 55-75 years). The patient diagnoses included AML (39%), NHL (29%), MM (9%), MDS (11%), CLL (8%), ALL (4%). The median pre-transplantation HSCT-CI score was 2 (range: 0-9). Among 85 patients, OS at 2 years was 44%. The 2 yr OS was 31%, 37% and 44% in the low-, intermediate-, and high-risk HSCT-CI groups (p = 0.61), respectively. The corresponding NRM at 2 years was 25%, 17% and 18% (p = 0.91). We found no predictive value of HSCT-CI for either OS or NRM in older patients having an allogeneic HSCT with reduced-intensity condition. Stratification of age (55-59, 60-64, and 65+) showed no significant impact on 2 yr OS or NRM. However, there was a trend towards a better 2 yr OS for patients who had achieved a CR versus no CR at time of transplant (48% vs 41%). ConclusionOlder patients with hematologic malignancies represent a highly selected cohort, with the prospect of an allogeneic HSCT often considered too high-risk. A method to reliably stratify these older HSCT candidates is greatly needed. However, the HCT-CI score in this retrospective analysis did not help predict their NRM or 2 year OS for patients 55 years and older with hematologic malignancies receiving a reduced intensity HSCT. Further research is warranted into what combination of factors may provide a reliable predictive score for older patients with hematologic malignancies. Disclosures:Mehta:Millennium: Speakers Bureau; Celgene: Speakers Bureau.

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

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

Predictors of increased melphalan exposure correlate with overall survival, nonrelapse mortality, and toxicities in patients undergoing reduced-intensity allogeneic stem cell transplantation with fludarabine and melphalan.

The reduced-intensity conditioning regimen, fludarabine and melphalan 140 mg/m2 (FM140), is widely adopted in practice. Pharmacokinetic studies report 10-fold interpatient variability in melphalan exposure. We identified low hemoglobin (Hb) and/or creatinine clearance (CrCl), determinants of melphalan pharmacokinetic, as strong predictors of outcomes after high-dose melphalan and autologous transplant. We hypothesized that these variables could predict for outcomes after FM140. Overall survival was shorter in patients with a lower Hb (113 vs. 2536 days; p = 0.004), due to an increased rate of nonrelapse mortality (NRM) (p = 0.0005). Overall survival was also worse in patients with lower CrCl (75 vs. 317 days; p = 0.003), with a significantly worse nonrelapse mortality (p = 0.0023). In a multivariate analysis, a higher Hb and CrCl predicted for better overall survival (p = 0.017). In patients with a lower Hb, the median duration of hospitalization (p = 0.02) and the mean duration of diarrhea (p = 0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization (p = 0.06) and the mean duration of diarrhea (p = 0.0009) longer, and the rate of infection was higher (p = 0.02). We show for the first time that Hb and CrCl represent important determinants of outcomes after FM140, suggesting that pharmacokinetic-directed dosing may be beneficial in achieving optimal outcomes.

Low Pre-Treatment Hemoglobin and Creatinine Clearance Correlate with Worse Overall Survival, Treatment-Related Mortality, and Regimen-Related Toxicities in Patients Undergoing a Reduced-Intensity Allogeneic Stem Cell Transplantation with Fludarabine and Melphalan

The reduced-intensity conditioning (RIC) regimen consisting of fludarabine and melphalan 140 mg/m2 (Flu/Mel140) prior to allogeneic hematopoietic stem cell transplant (HSCT) has been widely adopted in clinical practice. However, pharmacokinetic (PK) studies report up to a 10-fold interpatient variability in melphalan exposure (AUC). Specifically, melphalan binds to proteins in the red blood cell membrane, leading to higher plasma concentrations in patients with lower hemoglobin. Likewise, since renal elimination contributes significantly to melphalan clearance (~ 40%), the presence of renal impairment also leads to higher concentrations. We previously identified lower hemoglobin and/or creatinine clearance as strong predictors of survival and toxicities after high dose melphalan and autologous transplant. Given this, we hypothesized that clinical variables, in particular, pre-treatment hemoglobin, could predict for outcomes after Flu/Mel140 and HSCT. We analyzed 67 consecutive patients who received Flu/Mel140. In addition to standard clinical parameters, hemoglobin (Hgb) and creatinine clearance (CrCl) on day -6 were obtained. Hemoglobin was grouped as low or high relative to the median (<9.5 or ≥ 9.5 g/dL), and CrCl was divided into two groups (< 60 or ≥ 60 ml/min). In the entire cohort, the median age was 57 (21-73) years, with most patients being female (n=37; 55.2%) and white (n=27; 40.3%) or African-American (n=16; 23.9%). Most patients were diagnosed with AML/MDS (n=27; 40.3%) or idiopathic myelofibrosis (n=14; 20.9%), and the median lines of prior therapy was 2 (0-7). Prior to HSCT, 36 (53.7%) patients presented with intermediate disease risk index (DRI) and 19 (28.4%) with high DRI, while 31 (62%) patients had a high hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score. Thirty (45.5%) patients received a matched related donor transplant, while 31 (47%) received a matched unrelated donor transplant. The median time to neutrophil and platelet engraftment was 15 (9-26) and 16 (8-104) days, respectively. The median overall survival (OS) was significantly shorter in patients with a lower Hgb (113 vs. 2536 days; p=0.004). This difference was attributed to an increased rate of transplant-related mortality (TRM) in patients with a lower Hgb (n=26; 81.3%) versus a higher Hgb (n=11; 36.7%) (p=0.0005). Time to relapse between patients with a lower and higher Hgb was not different (p=0.89). The median OS in patients with a lower CrCl was significantly worse (75 vs. 317 days; p=0.003). The rate of TRM was also found to be significantly worse in patients with a lower CrCl (n=10; 90.1%) compared to patients with a higher CrCl (n=27; 52.9%) (p=0.0023). Time to relapse was not different between patients with a lower and higher Cr Cl (p=0.29). Patients with both a low Hgb and CrCl experienced a shorter median OS (75 days vs. not reached; p<0.0001; Figure 1). Multivariate Cox proportional hazards model with adjustment for clinical and prognostic factors found that a higher Hgb strongly predicted for better OS (HR 0.12, 95% CI 0.03-0.52; p=0.004) and less TRM (HR 0.13, 95% CI 0.03-0.53; p=0.004). The combination of a higher Hgb and CrCl ≥ 60 ml/min predicted for better OS (HR 0.08, 95% CI 0.01-0.63; p=0.017) and trended towards a decreased rate of TRM (HR 0.16, 95% CI 0.02-1.43; p=0.102). We then analyzed regimen-related toxicities among patients with a lower and higher Hgb and lower and higher CrCl. In patients with a lower hemoglobin, the median duration of hospitalization (35 vs. 29 days; p=0.02) and the mean duration of diarrhea (14.6 vs. 7.2 days; p=0.008) were significantly longer. In patients with a lower CrCl, the median duration of hospitalization (40 vs. 29 days; p=0.06) and the mean duration of diarrhea (20.9 vs. 8.6 days; p=0.0009) were longer, and the rate of infection was higher (90.9% vs. 49.1%; p=0.02). We show for the first time that pre-treatment Hgb and CrCl represent important determinants of clinical outcomes after Flu/Mel140 and HSCT. A lower hemoglobin in particular was strongly associated with a shorter OS and TRM. This is consistent with PK studies showing increased melphalan exposure in patients with low Hgb and CrCl. We conclude that consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes in patients receiving FluMel140 and HSCT. Figure Disclosures Galvin: Incyte: Consultancy. Patel:Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.

Correction: Allogeneic hematopoietic stem cell transplantation for relapsed acute myeloid leukemia in ETO positive with reduced-intensity conditioning.

[This corrects the article DOI: 10.18632/oncotarget.22612.].

Outcome of reduced-intensity allogeneic stem cell transplantation in Egyptian patients with myelodysplastic syndromes

Outcome of reduced-intensity allogeneic stem cell transplantation in Egyptian patients with myelodysplastic syndromes

598 - Reduced-Intensity Allogeneic Stem Cell Transplant for Sickle Cell Disease in Pediatrics: A Single Institution Experience

598 - Reduced-Intensity Allogeneic Stem Cell Transplant for Sickle Cell Disease in Pediatrics: A Single Institution Experience

Long-term outcome analysis of reduced-intensity allogeneic stem cell transplantation in patients with mantle cell lymphoma: a retrospective study from the EBMT Lymphoma Working Party.

Reduced-intensity allogeneic stem cell transplantation (RIST) is usually reserved for patients with mantle cell lymphoma who relapse after an autoSCT. However, the long-term efficacy of RIST and its curative potential have not been clearly demonstrated. We studied the long-term outcome of patients receiving a RIST for MCL as reported to the EBMT. A total of 324 patients, median age 57 years (range 31-70), underwent a RIST between 2000 and 2008; 43% of the patients had received >3 lines of prior therapy, including an autoSCT in 46%. Non-relapse mortality (NRM) was 10% at 100 days and 24% at 1 year and was lower for patients receiving anti-thymocyte globulin (ATG)/ALG (RR 0.59, p = 0.046). After a median follow-up of 72 months (range 3-159), 118 patients relapsed at a median of 8 months post RIST (range 1-117). The cumulative incidence of relapse was 25% and 40% at 1 and 5 years, respectively, and was associated with chemorefractory disease (HR 0.49, p = 0.01) and the use of CAMPATH (HR 2.59, p = 0.0002). The 4-year progression-free survival rate and overall survival rate was 31 and 40%, respectively. RIST results in long-term disease-free survival in about 30% of the patients, including those patients relapsing after a prior autoSCT.

The long-term outcome of reduced-intensity allogeneic stem cell transplantation from a matched related or unrelated donor, or haploidentical family donor in patients with leukemia: a retrospective analysis of data from the China RIC Cooperative Group.

This study compared 6-year follow-up data from patients undergoing reduced-intensity conditioning (RIC) transplantation with an HLA-matched related donor (MRD), an HLA-matched unrelated donor (MUD), or an HLA-haploidentical donor (HID) for leukemia. Four hundred and twenty-seven patients from the China RIC Cooperative Group were enrolled, including 301 in the MRD, 79 in the HID, and 47 in the MUD groups. The conditioning regimen involved fludarabine combined with anti-lymphocyte globulin and cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis was administered using cyclosporin A (CsA) and mycophenolate mofetil (MMF). Four hundred and nineteen patients achieved stable donor chimerism. The incidence of stage II-IV acute GVHD in the HID group was 44.3%, significantly higher than that in the MRD (23.6%) and MUD (19.1%) groups. The 1-year transplantation-related mortality (TRM) rates were 44.3, 17.6, and 21.3, respectively. Event-free survival (EFS) at 6years in the HID group was 36.7%, significantly lower than that of the MRD and MUD groups (59.1 and 66.0%, P < 0.001 and P = 0.001, respectively). For advanced leukemia, the relapse rate of the HID group was 18.5%, lower than that of the MRD group (37.5%, P = 0.05), but the EFS at 6years was 31.7 and 30.4% (P > 0.05), respectively. RIC transplantation with MRD and MUD had similar outcome in leukemia which is better than that with HID. RIC transplantation with HID had lower relapsed with higher TRM and GVHD rate, particularly in advanced leukemias. RIC transplantation with MRD and MUD had similar outcomes in leukemia and they were better than those with HID. RIC transplantation with HID had a lower relapse rate but higher TRM and GVHD rates, particularly in cases of advanced leukemia.

Sixty as the new forty: considerations on older related stem cell donors.

The era of reduced-intensity allogeneic stem cell transplantation, with its emphasis on older patients, has created new challenges in the management of what is now an older related stem cell donor population. These donors are now on average no less than 10 years older than in the mid-1990s. Donors over 70 years of age are no longer isolated or exceptional cases. They may still be considered eligible for donation but many of them, based on the older age and their medical history, may no longer fully qualify as 'healthy' or 'normal'. The older the donor, the more likely that hematologic abnormalities, comorbidities and treated malignancies will complicate the picture. Assessing the risk-benefit ratio for both donor and recipient can now be more challenging than ever.

Cytomegalovirus Status and the Outcome of T Cell–Replete Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

Cytomegalovirus (CMV) serostatus of donor and recipient are frequently used in algorithms of donor selection, whereas the impact of CMV reactivation on transplantation-related mortality, leukemia control, and overall survival (OS) remains controversial. Therefore, we retrospectively studied the impact of latent or active CMV infections on the outcome and occurrence of graft-versus-host disease (GVHD) after reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (SCT) in 294 patients during the period from 2004 to 2010. CMV viral load was routinely monitored in plasma using a quantitative PCR. Preemptive antiviral therapy was initiated when the viral load in plasma exceeded a predefined threshold. In a proportional hazards model, a seropositive recipient was significantly associated with increased occurrence of acute GVHD. However the CMV serostatus of both recipient and donor and the presence of active CMV infection was not associated with the occurrence of relapses, chronic GVHD, or OS. We conclude that in the presence of viral load monitoring and preemptive treatment, latent or active CMV infection does not substantially affect the OS after T cell–replete RIC allogeneic SCT.

Research progress of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in treatment of myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is likely to be the optimum method to cure international prognostic scoring system (IPSS) intermediate and high-risk patients with myelodysplastic syndrome(MDS). However, patients suffered with MDS are usually too old to undergo myeloablative conditioning allogeneic stem cell transplantation(MAC-HSCT). On account of its advantages of higher efficiency and lower toxicity, reduced intensity conditioning allogeneic stem cell transplantation(RIC-HSCT) is widely applied in the treatment of MDS patients. Currently, fludarabine plus alkylating regimens are widely applied, but the clinical outcomes are different from each regimen. Although RIC-HSCT has unique advantages in treating intermediate and high-risk elder MDS compared with MAC-HSCT and non-HSCT therapy, whether the outcome is influenced by factors such as tumor burden, recipient age, IPSS risk stratification, type of allo-HSCT, and comorbidity before transplantation is still unclear. In this article, we review literatures on RIC-HSCT in treatment of MDS. Key words: Myelodysplastic syndrome; Transplantation conditioning; Hematopoietic stem cell transplantation

Prognostic Impact of Peripheral Blood Count Recovery and Cytogenetic Remission Prior to Reduced Intensity Allogeneic Transplantation in Patients with Acute Myelogenous Leukemia and Myelodysplastic Syndromes

Background:Morphologic complete remission (CR) is the gold standard for assessing response in acute myelogenous leukemia (AML). CR with incomplete count recovery (CRi) and CR with incomplete platelet recovery (CRp) are associated with inferior overall survival post induction therapy (Walter et al, JCO 2010 and Chen et al, JCO 2015). Furthermore, residual cytogenetic disease is associated with a higher relapse compared with patients with cytogenetic CR (CCR; Chen et al, JCO 2011). There is a paucity of literature regarding the impact of CRi, CRp and CCR prior to allogeneic transplantation.Aim:To study the impact of CRi, CRp and CCR and their impact on relapse incidence (RI), non-relapse mortality (NRM) and overall survival (OS) in reduced intensity allogeneic stem cell transplantation (RIC-SCT).Methods:After due IRB approval, patients (pts) with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who received RIC-SCT at our institution between 2008-2014 were identified. All clinical and pathologic data were retrospectively extracted. CR, CRi, CRp and CCR were defined in accordance to the international working group definition. Categorical and continuous variables were analyzed using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the kaplan-meier and log-rank test. RI was estimated on a competing event analysis using Grey's model. Cox proportional regression was used to compute hazard ratios (HR).Results:A. Baseline characteristics: A total of 134 patients were identified. A total of 70 (52%) were in CR, 40 (30%) in CRi and 24 (18%) in CRp. 129 patients had evaluable cytogenetic data pre-SCT; 81 (63%) were in CCR and 48 (37%) had persistent cytogenetic disease. Baseline patient, disease and transplant characteristics stratified by peripheral count recovery pre-SCT are shown (Table 1). Significantly more patients in CR had higher KPS, higher proportion AML diagnosis, more likely to be in first complete remission (CR1), higher rate of cytogenetic CR and a higher proportion of minor ABO mismatched donor. No other significant variables were identified between the three cohorts.B. Transplant outcomes: Median follow up of the entire cohort was 41.9 months and the 2-yr OS, RI and NRM were 61.7%, 25.7% and 21.9%. Patients in CR, CRi and CRp had a similar 2-year rates of RI (26.3%, 18.4% and 28.9%, respectively; p = 0.66), 2-year NRM (20.5%, 38.8% and 22.1%, respectively; p = 0.18) and 2-year OS (61.8%, 55.1% and 58.6%, respectively; p = 0.82). RI was significantly lower for patients in CCR pre-SCT with HR 0.25 (95% CI 0.11-0.51 p = 0.0001) without a difference in overall survival HR 0.68 (0.41-1.15; p = 0.14). However, we observed a similar RI in CR, CRi and CRp patients who had persistent cytogenetic disease pre-SCT (p = 0.55). The outcome remained similar between strata after excluding MDS patients (data not shown).Conclusion: We observed equivalent post-transplant outcomes between CR, CRi and CRp despite the presence of persistent cytogenetic disease. This suggests that RIC SCT had a role in mitigating the negative prognosis associated incomplete hematologic recovery. These findings have implications as physicians may not need to postpone SCT to await count recovery. This important question should be further validated in a larger cohort of patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresAl-Kali:Novartis: Research Funding.

Outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma.

We retrospectively evaluated single-institute outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a reduced-intensity conditioning regimen consisting of fludarabine (125 mg/m²) and melphalan (140 mg/m²) for multiple myeloma. Twenty-three patients (median age: 46 years) were evaluated. Stem cell sources were bone marrow or peripheral blood stem cells from siblings (n = 4) and bone marrow from unrelated donors (n = 19). For graft-versus-host disease prophylaxis, cyclosporine A or tacrolimus with short-term methotrexate was given. Disease status at time of transplant was complete response in four patients, very good partial or partial response in 13, and stable or progressive disease in six. The median follow-up period of 7 survivors at analysis was 73.2 months (range 46.0-158.9 months). During the follow-up, disease recurrence or progression was observed in 21 patients, and was primary causes of death in 88% of the patients. The 5-year overall survival and progression-free survival rates were 38.6% (95% CI 19.3-57.7%) and 5.4% (95% CI 0.4-21.6%), respectively. Although allo-HSCT with this conditioning could be safely performed, further refinement of this approach aiming at more effective eradication of myeloma cells is clearly warranted.

Phase II Trial of Tandem High-Dose Chemotherapy with Autologous Stem Cell Transplantation Followed by Reduced-Intensity Allogeneic Stem Cell Transplantation for Patients with High-Risk Lymphoma

Many patients with lymphoma relapse after autologous stem cell transplantation (AutoSCT). These patients are often considered for allogeneic stem cell transplantation (AlloSCT) if remission can be achieved. If a tandem approach was organized, some cases of relapse might be prevented. We conducted a phase II trial of tandem AutoSCT followed by reduced-intensity conditioning (RIC) AlloSCT for patients with high-risk lymphoma. High-dose chemotherapy was given with busulfan, cyclophosphamide, and etoposide. AlloSCT was composed of RIC with busulfan/fludarabine and tacrolimus, sirolimus, and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Donors were fully matched related or unrelated donors. AlloSCT was performed any time between 40 days and 6 months after AutoSCT. Forty-two patients were enrolled, and all patients underwent AutoSCT. RIC AlloSCT was performed in 29 patients. In the 29 patients who underwent tandem transplant, median time from AutoSCT to AlloSCT was 96 days (range, 48 to 169). The 6-month cumulative incidence of grades II to IV acute GVHD was 13.8% (90% confidence interval [CI], 5.3% to 26.3%). Cumulative incidence of chronic GVHD at 1 year was 37.9% (90% CI, 23.1% to 52.7%). Nonrelapse mortality at 2 years after AlloSCT was 11.1% (90% CI, 3.5% to 23.6%). At a median follow-up of 30 months (range, 17.1 to 51.5) for the entire group, the 2-year progression-free survival rate was 64% (90% CI, 50% to 75%) and the 2-year overall survival rate was 69% (90% CI, 43% to 85%). For the 29 patients who underwent tandem SCT, the 2-year progression-free survival rate was 72% (90% CI, 55% to 83%) and the 2-year OS rate was 89% (90% CI, 74% to 96%). Tandem AutoSCT–RIC AlloSCT appears to be safe and effective in patients with high-risk lymphoma. Prospective trials using such an approach in specific lymphoma subtypes are warranted.

Higher Tacrolimus Concentrations Early Post-Transplant Reduce the Risk of Acute Graft-Versus-Host Disease in Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

s / Biol Blood Marrow Transplant 21 (2015) S355eS373 S369 be more economically responsible in a small group of patients will have a large impact on drug expenditures. As the price of thiotepa continues to rise and alternative regimens are utilized more frequently, there remains a responsibility for the practitioner to report and determine the most effective, safe, and economically responsible pediatric hematopoietic stem cell transplant conditioning regimen.

Impact of Serotherapy on Immune Reconstitution and Survival Outcomes after Stem Cell Transplantations in Children: Thymoglobulin Versus Alemtuzumab

Abstract The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is strongly affected by the kinetics of reconstitution of the immune system. This study compared the effects of antithymocyte globulin (ATG) and alemtuzumab on various outcome parameters after HSCT. The study cohort consisted of 148 children, with a median age of 9.6 years (range, .4 to 19.0), who underwent HSCT for malignant and benign hematological disorders in a single HSCT unit. Conditioning included ATG (n = 110) or alemtuzumab (n = 38). Cox proportional hazard regression analysis showed that alemtuzumab significantly delayed the recovery of CD3+ T cells and CD4+as well as CD8+ T cell subsets (P ≤ .001) and natural killer (NK) cells (P = .008) compared with ATG. In both ATG- and alemtuzumab-treated patients, shorter drug exposure lead to significantly faster recovery of T cells. Alemtuzumab was associated with lower donor chimerism 3 and 6 months after transplantation and a higher risk of disease relapse (P = .001). The overall survival and event-free survival risks were significantly lower for alemtuzumab-treated patients (P = .020 and P

Efficacy of Reduced-Intensity Allogeneic Stem Cell Transplant after Brentuximab Vedotin in Patients with Hodgkin Lymphoma Relapsed after Autologous Transplant

Purpose: The prognosis of patients with Hodgkin lymphoma (HL) who relapse following autologous stem cell transplantation (ASCT) is generally poor, because salvage chemo-radiotherapy is able to produce only short-lasting remissions. In a previous study on a large patients’ population (Sarina B et al, Blood 2010) was clearly demonstrated that the availability of a donor could significantly improve survival outcomes after allogeneic transplant, in particular for the subset of patients who reach a status of pre-transplant complete remission; however the application of this procedure is actually limited by a difficulty to obtain an objective response before alloSCT. It was recently shown that Brentuximab vedotin, a new generation antibody-drug conjugate, is able to induce nearly 30% of complete remission in HL patients relapsing after autologous transplant; therefore this agent could effectively work in relapses after ASCT as a platform to allow a better disease control in order to improve the outcome of the allografting procedure.Aims: Aim of this study was to retrospectively investigate if brentuximab vedotin administered as a salvage therapy in HL patients relapsing after ASCT could improve the efficacy of a subsequent reduced-intensity allogeneic transplant.Methods: Between August 2011 and September 2013, 11 patients underwent to allo-SCT at four hematologic Divisions of Northern Italy for HL relapse after ASCT, after brentuximab vedotin administered as a bridge to the allografting procedure. Median age was 32 years (range 21-61) and median number of prior regimens was 5, including ASCT. Patients received a median of 6 cycles (range 4-7) of brentuximab vedotin administered every 3 weeks as a 30-minute outpatient IV infusion; median time between the last dose of brentuximab vedotin and the allo-SCT was 1 month (range 1-5 months). No patient experienced progression during treatment with brentuximab vedotin (4 complete remissions and 7 partial remission/stable disease). All but one patients did not have a HLA identical sibling, so they required a matched unrelated (6 patients), haploidentical donor (3 patients) or cord blood (1 patient); peripheral stem cells were the source in patients with HLA identical sibling or unrelated, whereas bone marrow was used in the haplo setting. Reduced-intensity was the conditioning regimen performed in all patients. Post transplant cyclophosphamide plus mycophenolate mofetil/tacrolimus was the graft-versus-host disease (GVHD) prophylaxis of the haplo setting, while Metotrexate/cyclosporine was administered in the other patients. Patients were monitored for engraftment and infectious complications per institutional standards; survival outcomes were defined according to the European Blood and Marrow Transplantation (EBMT) criteria for survival analysis.Results: One patient had primary graft failure with autologous reconstitution; she was a patient with a high body-mass index, in whom the drug’s doses of the conditioning regimen were underestimated in order to avoid excessive toxicity. All the other patients engrafted; median time to neutrophil recovery was 20 days (range 15-26). At a median follow-up of 12 months, the 2-year progression free survival was 51%, 2-year Overall Survival was 61%. There were 2 toxic deaths, one for EBV reactivation and one for leuko-encefalopathy disease, resulting in a 2-year non-relapse mortality of 18%.Conclusions: These data suggest that brentuximab vedotin represents a promising salvage therapy in HL patients relapsed after ASCT. Despite the bias concerning the differences in source of stem cells and pre-transplant conditioning regimens, we showed that brentuximab could be administered in patients who are candidates to a RIC allo-SCT, with encouraging survival outcomes. Further clinical trials with larger number of patients and longer follow-up are recommended to confirm the promising role of brentuximab as a bridge to alloSCT. DisclosuresNo relevant conflicts of interest to declare.

CD8 Cell Dose in Peripheral Blood Stem-Cell Grafts Correlates with Relapse and Survival after Reduced Intensity Allogeneic Stem-Cell Transplantation

Background: The most common cause of treatment failure after reduced intensity conditioned allogeneic stem-cell transplantation (RIC alloSCT) is disease relapse. The curative potential of RIC transplants relies primarily on the immunologic graft-versus-tumor (GvT) effect. We hypothesized that graft T-cell doses correlate with relapse and survival outcomes, and that the graft T-cell content could be predicted according to donor characteristics.Methods: We retrospectively studied 218 consecutive patients (pts) who underwent a first peripheral blood alloSCT after fludarabine (120 mg/m2) and busulfan (6.4 mg/kg) conditioning between 2006 and 2014, of whom 190 pts had available graft T-cell content data. CD3, CD4, CD8 and CD34 doses were analyzed. Cox regression was used to evaluate correlations between cell doses and time-to-relapse, relapse-free survival (RFS), overall survival (OS), and acute and chronic graft-versus-host disease (GvHD). Standard variables and the Disease Risk Index (DRI) were used for adjustment in multivariate models. A Classification and Regression Tree (CART) procedure was used to identify optimal cutoffs for continuous variables that correlated with outcome. Finally, we studied 23 alloHSCT donor blood samples to identify clinical and immunophenotypic characteristics that correlate with graft T cell content.ResultsThe median follow-up was 29.6 mo. (range 0.4 – 81.5). The median age was 62 (range 21-76) and diseases included AML (79), MDS (42), NHL (31), CLL (8), ALL (10) and others (20). Pts were allografted from HLA-matched (86%) or mismatched (14%), sibling (43%) or unrelated (57%) donors. There was significant variability in T-cell doses: CD3 - mean 2.3x108/kg (range 0.2 – 8.1), CD8 - mean 0.5x108/kg (range 0.03 – 2.2), CD4 - mean 1.3x108/kg (range 0.1 – 5.4).Relapse and survival: A high CD8 cell dose correlated with a decreased risk of relapse and improved RFS and OS. The univariate hazard ratios (HR) per 1 x 108/kg CD8 cells were: relapse 0.44 (95% CI [0.24 – 0.83]), p = 0.01; RFS 0.50 (95% CI [0.30 – 0.83]), p = 0.008; OS 0.63 (95% CI [0.37 – 1.08]), p = 0.09. After adjustment for DRI, GvHD prophylaxis and age, the CD8 cell dose remained significantly correlated with relapse, RFS and OS (Table 1). There were no significant correlations between the CD34, CD3 or CD4 doses and these outcomes.Using CART, we identified a cutoff of 0.72 x 108/kg CD8 cells that predicted OS. We found that pts who received a CD8hi graft had improved OS (adjusted HR = 0.53, 95% CI [0.33 – 0.84], p = 0.007; Fig. 1).Engraftment: Donor T-cell engraftment correlated with higher CD8 but not CD4 cell doses. Donor T-cell chimerism levels were higher in pts who received a higher CD8 cell dose (day 30: r = 0.27, p = 0.002; day 60: r = 0.28, p = 0.005; day 100: r = 0.22, p = 0.01). Time to neutrophil or platelet engraftment was not affected by CD3, CD4 or CD8 doses although a high CD34 dose predicted faster neutrophil recovery (r = -0.19, p = 0.01).GvHD: There were no significant correlations between T cell doses and GvHD. A trend was observed between acute GvHD and high CD4 but not CD8 cell doses (adjusted HR = 1.29, 95% CI [0.97 - 1.71], p = 0.08). A trend was also observed between moderate-severe chronic GvHD and high CD8 cell doses (adjusted HR = 1.93, 95% CI [0.90 - 4.10], p = 0.09).Donors: We investigated whether a high CD8 cell content could be predicted during donor screening. Not surprisingly, we found that donors whose grafts contained a high CD8 cell dose could be identified in a screening blood sample by having higher %CD8 cells (r = 0.69, p = 0.0004; Fig. 2), lower CD4/8 ratio (r = -0.55, p = 0.008) and higher %CD3 cells (r = 0.37, p = 0.09). There were no correlations between the graft content and other immunophenotypic parameters or clinical variables such as donor age, weight, gender or viral serologies.Conclusion: A high CD8 cell dose correlates with improved RFS and OS after RIC alloSCT through a reduction in relapse without a significant increase in GvHD. Donor screening can potentially be optimized by selecting donors from whom a CD8-high graft can be collected. Targeting CD8 cell doses should be considered in prospective trials of RIC alloSCT.Table 1:Adjusted HRs of graft T-cell doses and outcomesRelapseRFSOSVariableHRpHRpHRpCD8 dose0.430.0110.490.0060.570.046CD4 dose0.910.530.930.571.050.68CD3 dose0.850.150.870.120.940.49 [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Encouraging Outcomes of Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Patients with Acute Lymphoblastic Leukemia in Second Complete Remission

[Background] We have been performing reduced-intensity stem cell transplantation (RIST) to avoid preconditioning-related complications. However, the effectiveness of RIST in pediatric patients with acute lymphoblastic leukemia (ALL) remains to be clarified.[Methods] We retrospectively reviewed 37 pediatric patients with ALL in second complete remission (CR2) who underwent first allogeneic hematopoietic stem cell transplantation (allo-SCT) between 1993 and 2012 in our institute. We compared the outcomes of RIST with those of myeloablative stem cell transplantation (MAST).[Results] The median age at allo-SCT was 9 years (range, 1 to 18 years). There were 33 B-lineage ALL, 3 T-lineage ALL, 1 lineage unknown ALL, and none of Philadelphia chromosome-positive ALL. Sixteen patients received HLA-matched bone marrow (7 related; 9 unrelated), 12 HLA-mismatched bone marrow (11 unrelated; 1 HLA haploidentical related), 4 cord blood, and 5 CD34 positive peripheral blood stem cells (HLA haploidentical related). In all patients, the 5-year overall survival (5y-OS) rate and the 5-year event free survival (5y-EFS) rate were 75.1% and 56.5%, respectively.Seven patients underwent RIST and 30 patients underwent MAST. The median follow-up durations of RIST and MAST groups were 3.3 years (range, 0.9 to 8.2 years) and 11.3 years (range, 0 to 21.2 years), respectively. The 5y-OS rates in RIST and MAST groups were 85.7% and 59.8%, and the 5y-EFS rates were 71.4% and 53.3%, respectively. The 5-year cumulative transplant-related mortality (TRM) rates in RIST and MAST groups were 0% and 31.0%, and the 5-year cumulative relapse rates were 28.6% and 24.3%, respectively.[Discussion] In our series, the cumulative relapse rate in RIST group was similar with that in MAST group, and the cumulative TRM rate in RIST group was lower than that of MAST group. Therefore, both of the 5y-OS and the 5y-EFS rates in RIST group seem to be better than those in MAST group. The outcomes of RIST in our series do not seem to be poorer. Although further studies are needed because of the small size of patients and short follow-up duration, RIST can be considered as the first transplantation for pediatric patients with ALL in CR2. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.