Reduced-intensity Conditioning Allogeneic Transplantation Research Articles

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

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

A Novel Dual-Antigen Targeting Approach Enables Off-the-Shelf CAR NK Cells to Effectively Recognize and Eliminate the Heterogenous Population Associated with AML

While acute myeloid leukemia (AML) treatment has improved, relapse is still common, even after reduced intensity conditioning allogeneic transplantation. Natural killer (NK) cells are a promising allogeneic cell immunotherapy without the risk of graft-versus-host disease or cytokine release syndrome. We and others have reported that haploidentical NK cells can safely result in 30-50% complete remissions in advanced AML patients when given with high-dose lymphodepleting chemotherapy and exogenous cytokine support. However, while NK cell natural cytotoxicity has a clinical signal in AML, increased specificity and multi-dosing are likely to enhance the efficacy and durability of this treatment strategy. A number of stress ligands, including the MHC-I polypeptide-related sequence A and B (MICA/B), bind to the NK cell activating receptor NKG2D and initiate NK cell killing of transformed and infected cells, and several groups have shown promising results in clinical trials by developing NK cells that carry a NKG2D chimeric antigen receptor (CAR). However, the distal α1 and α2 domains of MICA/B that are recognized by NKG2D can be proteolytically cleaved from the surface of the tumor by metalloproteases, allowing for escape from NK cell-mediated detection and elimination. Wucherpfennig and colleagues have described that the membrane proximal α3 domain remains on the cell surface and may be a potential target for immunotherapy across many cancers, including AML. However, since AML is heterogenous, we hypothesized that clinical success would require dual-targeting and selected CD33 as the ideal complementary targeting approach since CD33 is a validated marker expressed on greater than 80% of AML blasts. To this end, our lab has developed a Tri-specific Killer Engager (TriKE) capable of agonistically ligating the CD16 Fc receptor to CD33 found on AML along with IL-15 co-stimulation to further activate the NK cell response. Here, we demonstrate the efficacy of a multiplexed-gene edited induced pluripotent stem-cell (iPSC) derived NK cell (iNK) product that expresses a high-affinity, non-cleavable version of CD16 (hnCD16), a membrane-bound IL-15 fusion receptor, CD38 knockout to enhance metabolic fitness, and a CAR against the α3 domain of MICA/B (α3 MICA/B) to drive a potent response against AML alone and when combined with anti-CD33 TriKE. In the initial study, the iNK cell backbone (iNK cells without the α3 MICA/B CAR) induced potent activity against the AML cell line HL60, and displayed further enhancement of activity with the addition of anti-CD33 TriKE (GTB-3650), representing combined effects of natural cytotoxicity and antibody-dependent cellular cytotoxicity. To show specificity for α3 MICA/B targeting, the AML cell line THP-1 was stained for the presence of MICA/B by flow cytometry using the 6D4 clone that recognizes the α1/2 domains of MICA/B or the 7C6 clone that uniquely recognizes the α3 domain +/- proteolytic cleavage with trypsin (Fig. 1A-B). Significant expression of the α3 domain was observed on THP-1 cells using the 7C6 antibody, which was highly expressed even after protease treatment. On the other hand, the α1/2 domains of MICA/B were detectable at lower levels using the 6D4 antibody and were undetectable after protease treatment (Fig. 1A-B). To assess a dual targeting approach, THP-1 cells were used as targets in live imaging functional assays under standard conditions (Effector:Target [E:T] 2:1). The iNK cell backbone had modest natural cytotoxicity at 3 hours that was significantly enhanced by the addition of α3 MICA/B CAR. The effect was further improved with more rapid killing kinetics when combined with the anti-CD33 TriKE (Fig. 1C). To evaluate the efficacy of dual-targeting in a more stringent physiologic manner, we mimicked "stress” conditions by minimizing the E:T ratio to 0.25:1. While all effector conditions induced immediate killing in 4 hours at the low E:T ratio, sustained tumor control was only observed with dual-antigen targeting (Fig. 1D). Studies with primary AML targets, +/- preincubation of decitabine and all-trans retinoic acid, known to upregulate NKG2D ligands in AML, are in progress and will be discussed. In summary, dual-targeting strategies using off-the-shelf CAR NK cells targeting α3 MICA/B in combination with antigen-specific TriKE targeting CD33 represent an ideal clinical strategy to enhance efficacy and durability of treatment in advanced AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Life expectancy and burden of late complications after reduced intensity conditioning allogeneic transplantation.

Reduced intensity conditionings (RIC) before after allogeneic hematopoietic stem cell transplantation (HSCT) allow older or unfit patients of being transplanted, but survival expectancy and burden of late complications are poorly described in this setting. All patients (N = 456) who were alive and relapse-free 2 years after HSCT following RIC were included. Cumulative incidences (CI), standardized incidence, or mortality, ratio (SIR or SMR), and competing risk models were used. The 10-year CIs of relapse and non-relapse mortality incidences were 13.9 and 13.4%, respectively. Seventy-eight patients died, late relapse being the most frequent cause of death leading to a SMR of 6.38 (95% CI, 5.1-8.0; p < 0.001). Among non-relapsing patients (n = 412), 30 died (SMR 4.38; 95% CI, 3.3-5.8: p < 0.001). A total of 37 patients developed 41 SM leading to a 10-year cumulative incidence of 12.9%, and a significant SIR relative to the general population (1.4). Finally, we found high CI of cardiovascular (CVC) and venous thromboembolic complications (VTE) (10-year CI; 15.1% and 11.7%, respectively). Older age was the only significant risk factor for CVC and VTE in multivariable analysis. In conclusion, with life expectancy rate of 70%, late survivors after RIC warrants long-term follow-up and active intervention on averting cardiovascular disease and screening cancers.

Test-dose pharmacokinetics guided melphalan dose adjustment in reduced intensity conditioning allogeneic transplant for non-malignant disorders.

We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant disorders (NMD) undergoing allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) containing alemtuzumab, fludarabine and melphalan. Patients received test-dose melphalan (10% of planned full-dose) prior to conditioning. Blood samples for PK were obtained around test and full-dose melphalan (140 mg/m2 or 4.7mg/kg in patients <10kg). Melphalan concentration was measured by liquid chromatography electrospray ionization tandem mass-spectrometry assay and data were analysed using a population-PK model and Bayesian estimation. Test and full-dose melphalan clearance estimates were evaluated by pairwise Wilcoxon test and Bland-Altman plot. Twenty-four patients undergoing 25 transplants were included in the final analysis. Patients received standard full-dose melphalan in 17 transplants, with median area under the concentration-time curve (AUC) of 5.5mg*h/L (range, 3.0-9.5mg*h/L). Patients received test-dose melphalan in 23 transplants with a test-dose PK predicted full-dose AUC range of 2.9-16.8mg*h/L. In seven transplants where patients had baseline organ impairment, test-dose PK predicted higher exposure for standard full-dose (median AUC 13.8mg*h/L). Melphalan full-dose was adjusted in these patients, with achievement of desired target AUC (3.6-5.4mg*h/L) and no excess toxicity. Mean ratio of test-dose clearance to full-dose clearance was 1.03. Twenty of 22 patients (91%) were within the 95% confidence intervals of the clearance ratio. Melphalan test-dose PK reliably predicts full-dose PK and allows for accurate adjustment of full-dose melphalan in RIC-HCT for NMD. This approach can avoid excess toxicity from increased systemic exposure, especially in patients with organ impairment.

Long-term survival of 1338 MM patients treated with tandem autologous vs. autologous-allogeneic transplantation.

Contrary to tandem autologous transplant (auto-auto), autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers graft-versus-myeloma (GVM) effect but with higher toxicity. Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological randomization) and yielded conflicting results. A pooled analysis of multiple trials with extended follow up provides an opportunity to compare these strategies. We obtained individual patient data from participants of four trials comparing auto-auto vs. auto-allo after induction therapy. There were 899 patients in auto-auto and 439 in auto-allo. Median follow up of survivors was 118.5 months. Median overall survival (OS) was 78.0 months in auto-auto and 98.3 months in auto-allo (HR = 0.84, P = 0.02). OS was 36.4% vs. 44.1% at 10 years (P = 0.01) for auto-auto and auto-allo, respectively. Progression-free survival was also improved in auto-allo (HR = 0.84, P = 0.004). Risk of non-relapse mortality was higher in auto-allo (10 year 8.3% vs. 19.7%, P < 0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P < 0.001). Median post relapse survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR = 0.71, P < 0.001). This supports the existence of durable GVM effect enhancing myeloma control with subsequent therapies.

Tandem Autologous-Autologous Vs. Autologous-Allogeneic Transplantation for Newly Diagnosed Multiple Myeloma: Pooled Analysis of 1,338 Patients from Four Trials with Long-Term Follow up

Introduction: Tandem autologous transplant (auto- auto) has been studied as a method to increase remission rates and reduce relapse in the upfront therapy of MM. The use of autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers the potential of long-term graft-versus-myeloma (GVM) effect, but with the risk of graft versus host disease and potentially higher non-relapse mortality (NRM). Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological "randomization") and have yielded conflicting results, in part due to trial size or limited follow up. A pooled analysis of multiple trials with extended follow up provides the best opportunity to compare these two transplant strategies. Methods: We obtained individual patient data from participants of 4 trials comparing auto-auto vs. auto-allo after brief induction therapy, namely BMT CTN 0102 (N=709), NMAM2000 (N=357), PETHEMA/GEM2000 (N=110), and the Torino consortium trial (N=162). In all 4 trials arm allocation was by biological "randomization". Patients were designated high risk if beta-2 microglobulin ≥ 4.0 mg/L at diagnosis or presence of deletion of chromosome 13 by metaphase karyotyping. Time to event outcomes were analyzed by intention to treat, from the time of first autologous transplant. Main outcomes analyzed were overall survival (OS) and progression free survival (PFS). Secondary outcomes analyzed were NRM and risk of relapse, treated as competing risks, and post relapse survival. Results: There were 1,338 patients included in the analysis, 899 in auto-auto and 439 in auto-allo. Median follow up of survivors is 118.5 months. Characteristics of the two arms are displayed in Table 1. Median OS was 78.0 months in auto-auto and 98.3 months in auto-allo (HR= 0.85, P=0.003, Figure 1). OS was 59.8 % vs. 62.3% at 5-years (P=0.37) and 36.4% vs. 44.1% at 10 years (P=0.01) for auto-auto and auto-allo respectively. PFS was also improved in auto-allo (HR= 0.84, P=0.004) with 5-year PFS of 23.4 vs. 30.1% (P=0.01) and 10-year PFS of 14.4% vs. 18.7% (P=0.06). For the 214 high risk patients (125 auto-auto, 89 auto-allo) there was superior 5-year and 10-year PFS with auto-allo, but no difference in OS. Risk of NRM was higher in auto-allo (10 year 8.3% vs. 19.7%, P&amp;lt;0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P&amp;lt;0.001). There were 685 progressions in auto-auto and 266 in auto-allo. Median post relapse overall survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR= 0.71, P&amp;lt;0.001, Figure 2). Five years post relapse, 37.0% of patients were alive in auto-auto vs. 51.1% in auto-allo (P&amp;lt;0.001). Conclusion: Long-term follow up using a large pooled dataset of 4 trials indicates durable, long-term disease control with an auto-allo strategy. Despite higher NRM, there was a reduction in the risk of relapse and superior post relapse survival in auto-allo. This supports the hypothesis of a durable GVM effect enhancing myeloma control with subsequent therapies. Disclosures Costa: Janssen: Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding. Pasquini:Pfizer: Consultancy; Medigene: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Kite Pharmaceuticals: Research Funding; BMS: Research Funding. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Schonland:Sanofi: Research Funding; Takeda: Honoraria, Research Funding; Prothena: Honoraria; Medac: Other: Travel grant; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Giralt:Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kite: Consultancy; Johnson &amp; Johnson: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding. Patriarca:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Abbvie: Research Funding; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Celgene: Consultancy; Takeda: Consultancy. Krishnan:Celgene, Janssen, Sanofi, BMS: Consultancy; Sutro BioPharma, zPredicta: Consultancy; Amgen, Takeda: Speakers Bureau; Celgene, Z Predicta: Other: Stock Ownership; Takeda: Research Funding.

Allogeneic transplantation of multiple myeloma patients may allow long-term survival in carefully selected patients with acceptable toxicity and preserved quality of life.

Despite significantly improved survival and response rates in patients diagnosed with multiple myeloma, it still remains an incurable disease with a poor outcome, especially in high-risk groups. Allogeneic stem cell transplantation offers a potentially curative option but remains controversial due to considerable treatment-related toxicity. We analyzed 109 consecutive myeloma patients who had received reduced-intensity conditioning allogeneic transplantation at the Freiburg University Medical Center between 2000 and 2016. Although most patients were heavily pre-treated in high-risk constellations, the overall response rate was high with 70%, the median overall survival (OS) 39.2%, and the median progression-free survival (PFS) 14.2 months, with a median follow up of 71.5 months. Survival was significantly better in patients with response to previous therapies than in those with progressive disease (median OS 65 vs. 11.5 months, P=0.003; median PFS 18.4 vs. 5.1 months, P=0.001). Moreover, survival of patients transplanted in first-line was significantly prolonged compared to relapsed/refractory disease (median OS not reached vs. 21.6 months, P<0.001; median PFS 47.7 vs. 9.6 months, P<0.001). The non-relapse mortality was relatively low with a cumulative incidence of 12.4% at ten years. Acute graft-versus-host disease (GvHD) grade II-IV was observed in 25%, and moderate or severe chronic GvHD in 24%. Quality of life (QoL) assessed with the revised Myeloma Comorbidity Index before and after transplantation remained unchanged. Our data suggest that allogeneic transplantation in the context of novel immunotherapeutic approaches may enable long-term survival and even a potential cure in a carefully selected subgroup of high-risk multiple myeloma patients with acceptable toxicity and preserved QoL.

Comparative Analysis of Calcineurin Inhibitor–Based Methotrexate and Mycophenolate Mofetil–Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P < .001) and grade III to IV acute GVHD (RR, 1.93; P = .006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P = .008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results.

Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis

AbstractThe application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.

High CD3+ and CD34+ peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia - an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Inconsistent results have been reported regarding the influence of graft composition on the incidence of graft versus host disease (GVHD), disease control and survival after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplantation (allo-PBSCT). These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning. The current retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose on the outcome of RIC allo-PBSCT in patients with acute myelogenous leukemia (AML) in first complete remission, allografted from HLA-matched unrelated donors (10 of 10 match). We included 203 adults. In univariate analysis, patients transplanted with the highest CD3+ and CD34+ doses (above the third quartile cut-off point values, >347 × 10^6/kg and >8.25 × 10^6 /kg, respectively) had an increased incidence of grade III-IV acute (a) GVHD (20% vs. 6%, P = .003 and 18% vs. 7%, P = .02, respectively). There was no association between cellular composition of grafts and transplant-related mortality, AML relapse, incidence of chronic GVHD and survival. Neither engraftment itself nor the kinetics of engraftment were affected by the cell dose. In multivariate analysis, CD3+ and CD34+ doses were the only adverse predicting factors for grade III-IV aGVHD (HR = 3.6; 95%CI: 1.45-9.96, P = .006 and 2.65 (1.07-6.57), P = .04, respectively). These results suggest that careful assessing the CD3+ and CD34+ graft content and tailoring the cell dose infused may help in reducing severe acute GVHD risk without negative impact on the other transplantation outcomes.

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

Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission - a review from the Acute Leukemia Working Party of the EBMT.

Acute myeloid leukemia is the most common indication for an allogeneic hematopoietic cell transplant. The introduction of reduced intensity conditioning has expanded the recipient pool for transplantation, which has importantly made transplant an option for the more commonly affected older age groups. Reduced intensity conditioning allogeneic transplantation is currently the standard of care for patients with intermediate or high-risk acute myeloid leukemia and is now most often employed in older patients and those with medical comorbidities. Despite being curative for a significant proportion of patients, post-transplant relapse remains a challenge in the reduced intensity conditioning setting. Herein we discuss the studies that demonstrate the feasibility of reduced intensity conditioning allogeneic transplants, compare the outcomes of reduced intensity conditioning versus chemotherapy and conventional myeloablative conditioning regimens, describe the optimal donor and stem cell source, and consider the impact of post-remission consolidation, comorbidities, center experience, and more intensive (reduced toxicity conditioning) regimens on outcomes. Additionally, we discuss the need for further prospective studies to optimize transplant outcomes.

Strategies for Graft Versus Host Disease Prophylaxis after Reduced-Intensity Conditioning Transplantation: Combination of Sirolimus Plus Tacrolimus Allows to Obtain the Best Outcome

INTRODUCTION AND AIMSDifferent strategies for GVHD prophylaxis have been evaluated in the last decade in different clinical trials in the setting of reduced-intensity conditioning allogeneic transplantation (RIC-AlloSCT) within the Grupo Español de Trasplante Hematopoyetico (GETH). Following multicenter clinical trials, some of these strategies have been adopted as standard practice in some centers. With this background, we analyzed in a multicenter retrospective study the outcomes of the different strategies used as GVHD prophylaxis in the setting of RIC-AlloSCT. MATHERIAL AND METHODSA total of 558 patients from 6 Spanish centers underwent to RIC-AlloSCT from January 2007 to December 2013. Conditioning chemotherapy consisted of fludarabine plus melphalan or busulphan (for lymphoid and myeloid malignancies, respectively). Regarding GHVD prophylaxis, group 1 (n:170) received Sir-TKR, (plus ATG, n: 15); group 2 (n:161) a calcineurin-inhibitor (CNI)+MTX (plus ATG, n:23) and group 3 (n:217) received CNI+Mophetil Micophenolate (MMF), (plus ATG, n:28). Patients who received ATG, regardless the type of associated immunosuppression, were analyzed separately as well as within each subgroup. There were no statistically significant differences regarding transplant characteristics except for a higher frequency of unrelated donor in Sir-TKR subgroup and more frequent non-remission status of basal disease in CNI-MMF subgroup. RESULTSAfter a median follow-up of 31 months, (IC-95%: 27-34), the 3-year cumulative incidence of relapse was significantly higher with CNI-MTX (37.6%) as compared to the other two strategies (24,8% for Sir-TKR and 26,1% for CNI-MMF, p=003) whereas transplant-related mortality (TRM) was significantly higher within patients receiving CNI-MMF (27% at 1 year / 37,9% at 3 years) as compared to Sir-TKR (14,4% at 1 year / 20,2% at 3 years) and CNI-MTX (19,7% at 1 year / 25,6% at 3 years, p=0.01). Overall survival (OS)was higher in Sir-TKR subgroup (78% at 1 year/68% at 3 years) as compared to the other 2 groups (64% at 1 year / 47% at 3 years for patients receiving CNI-MTX and 57% at 1 year / 45% at 3 years for those receiving CNI-MMF, p:0.01). The addition of ATG as prophylaxis did not significantly modified the prognosis for any of the subgroups. In multivariate analysis, significant factors for OS were: chronic GVHD [HR=0,68 (95%CI=0,47-0,98), p=0,03], acute GVHD [HR=2,03 (95%CI=1,54-2,67), p< 0.001), age older than 50 years [HR=1,47 (95%CI=1,07-2), p=0,01], disease status at transplant [HR=1,36 (95% CI=1,02-1,82), p=0,03 in case of non-remission disease) and GVHD prophylaxis other than Sir-TKR [HR=1,85 (95%CI=1,19-2-87),p=0,006 for CNI-MTX and HR=1,94 (95%CI=1,32-2,86),p=0,0006 for CNI-MMF]. CONCLUSIONThe present study shows a favorable impact of Sir-TKR in outcome as compared with other strategies in the setting of RIC-AlloSCT, with OS up to 68% at 3 years. DisclosuresValcarcel:Celgene: Honoraria, Speakers Bureau.

Impact of CD3+ and CD34+ Doses in the Mobilized Peripheral Blood Stem Cell Grafts on the Outcome of Reduced-Intensity Conditioning Allogenic Transplantation from Matched Unrelated Donors for Acute Myeloid Leukemia – an Analysis from the Acute Leukemia Working Party of the EBMT

Introduction:The impact of peripheral blood stem cell (PBSC) grafts composition on the outcome of reduced-intensity conditioning (RIC) allogenic transplantations (allo-SCT) is still controversial. Inconsistent results have been reported regarding the influence of CD3+ and CD34+ cells dose on incidence of GVHD, disease control and survival. These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning.Aim and methods:This retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose in PBSC grafts on the outcome of RIC allo-SCT in patients with acute myeloid leukemia (AML) allografted from matched unrelated donors (MUD). Two hundred and three adults with AML in first complete remission (CR1) treated with RIC allo-PBSCT from MUD (10 of 10 match) between 2000 and 2012 (median 2011) were included. Ex-vivo T-cell depletion was an exclusion criterion. Median age was 58 (range, 21-73) years; gender: male-116, female-87; 142 had intermediate, 42 unfavorable, 4 favorable, and 15 unknown cytogenetic features; median time to achieve CR1 was 51 (range, 21-350) days, whereas time from CR1 to allo-SCT was 115 days (15-351). Median donor age was 34 (range, 19-61) years. The preparative regimen was based on chemotherapy in 143 (70%) of the RIC allo-CST (Flu-Bu:110; Flu-Mel:12; Flu-Treosulfan:14, other:7), whereas in 60 (30%) low dose TBI was applied (2 Gy:57; 4 Gy:3). In-vivo T-cell depletion (ATG or Campath) was used in 166 (82%) of the transplants. Median transplanted CD3+ and CD34+ doses were 250 (50-885) x 10^6 and 6.53 (1.34-413) per kg of recipient b.w., respectively. Follow-up was 22 months (3-105).Results:The engraftment rate equaled 99% (202 pts) and was not affected by CD3+ nor CD34+ counts. In univariate analysis, patients transplanted with the highest CD3+ doses (above the third quartile cut-off point value, >347 x 10^6/kg) had an increased incidence of acute (a) GVHD grade >2 (45% vs. 26%, p=0.007) and grade 3-4 (20% vs. 6%, p=0.003), respectively. In the quartile of pts transplanted with the highest CD34+ graft content (>8.25 x 10^6 /kg) increased incidence of grade 3-4 aGVHD (18% vs. 7%, p=0.02) was observed. Other risk factors for aGVHD were transplantation from CMV seropositive donors (grade >2; 44% vs. 24%, p=0.005) and from females to males (grade 3-4; 19% vs. 8%, p=0.04). There was no association between cellular composition of grafts and non-relapse mortality (NRM), AML relapse, incidence of chronic (c) GVHD and survival. There was also no significant correlation between CD3+ and CD34+ cells infused. In multivariate analysis, CD3+ dose was the only adverse predicting factor for aGVHD grade >2 (HR= 2.1; 95%CI: 1.25-3.55, p=0.005) and together with CD34+ dose for aGVHD grade 3-4 (CD3+, HR=3.6; 95%CI: 1.45-9.96, p=0.006; CD34+, HR=2.65; 95%CI: 1.07-6.57, p=0.04). Other factors that independently affected unfavorable outcome were: time from diagnosis to CR1 above median for NRM, transplantation without in-vivo T-cell depletion for cGVHD, time from CR1 to allo-SCT above median and unfavorable karyotype for leukemia-free and overall survival and unfavorable karyotype for relapse incidence.Conclusions:These results suggest that the incidence of severe acute GVHD post RIC allo-SCT, still a major cause of morbidity and mortality, is associated with the composition of the PBSC grafts, specifically higher numbers of infused CD3+ and CD34+ cells. As graft composition can be manipulated, careful assessing the CD3+ and CD34+ graft content and the cell dose infused may help in reducing severe aGVHD risk and improving transplantation outcome. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation Outcomes in Acute Myeloid Leukemia: Similar Outcomes Regardless of Donor Type

The use of alternative donor transplants is increasing as the transplantation-eligible population ages and sibling donors are less available. We evaluated the impact of donor source on transplantation outcomes for adults with acute myeloid leukemia undergoing myeloablative (MA) or reduced-intensity conditioning (RIC) transplantation. Between January 2000 and December 2010, 414 consecutive adult patients with acute myeloid leukemia in remission received MA or RIC allogeneic transplantation from either a matched related donor (n = 187), unrelated donor (n = 76), or umbilical cord blood donor (n = 151) at the University of Minnesota or Hôpital St. Louis in Paris. We noted similar 6-year overall survival across donor types: matched related donor, 47% (95% confidence interval [CI], 39% to 54%); umbilical cord blood, 36% (95% CI, 28% to 44%); matched unrelated donor, 54% (95% CI, 40% to 66%); and mismatched unrelated donor, 51% (95% CI, 28% to 70%) (P < .11). Survival differed based on conditioning intensity and age, with 6-year survival of 57% (95% CI, 47% to 65%), 39% (95% CI, 28% to 49%), 23% (95% CI, 6% to 47%), 47% (95% CI, 36% to 57%), and 28% (95% CI, 17% to 41%) for MA age 18 to 39, MA age 40+, or RIC ages 18 to 39, 40 to 56, and 57 to 74, respectively (P < .01). Relapse was increased with RIC and lowest in younger patients receiving MA conditioning (hazard ratio, 1.0 versus 2.5 or above for all RIC age cohorts), P < .01. Transplantation-related mortality was similar across donor types. In summary, our data support the use of alternative donors as a graft source with MA or RIC for patients with acute myeloid leukemia when a sibling donor is unavailable.

Is Timing Everything?

Is Timing Everything?

Higher doses of CD34+ progenitors are associated with improved overall survival without increasing GVHD in reduced intensity conditioning allogeneic transplant recipients with clinically advanced disease

The influence of CD34+ cell dose on the outcome of allogeneic peripheral blood stem cell (PBSC) transplantation after reduced intensity conditioning (RIC) remains controversial. The impact of the number of CD34+ hematoprogenitors infused on transplant outcome and on the incidence of graft versus host disease (GVHD) was analyzed. Data of 138 patients with advanced hematological diseases who received an allogeneic PBSC transplant after RIC were analyzed. Donors were mobilized with granulocyte colony-stimulating factor and underwent one to three apheresis procedures. Incidence of acute and chronic GVHD and overall and event-free survival (OS and EFS) was determined. The median number of CD34+ cells infused was 5.57 × 10(6) kg(-1) (range: 1.1-15.6). There was no relationship between CD34+ cell dose and neutrophil or platelet engraftment. Patients receiving ≥5 × 10(6) kg(-1) CD34+ cells had a 63.1% 5-year OS when compared with 48.2% for those receiving a lower number (P = 0.024). At 5-year follow-up, there was no significant difference in EFS between the groups (44% vs. 42.8%, P = 0.426). No relationship between CD34+ cell dose and acute GVHD was found (P = 0.1). Relapse rate was the same in patients with and without acute GVHD (P = 0.117). A nonsignificant improvement on OS and EFS in patients who developed chronic GVHD was found (P = 0.57 and 0.41). A CD34+ cell dose ≥5 × 10(6) kg(-1) was associated with a significantly higher OS, but no improved EFS in high-risk patients. The number of CD34+ progenitors infused had no influence on the incidence of acute or chronic GVHD.

Post-transplant T cell chimerism predicts graft versus host disease but not disease relapse in patients undergoing an alemtuzumab based reduced intensity conditioned allogeneic transplant

In this multicentre retrospective study we have studied the impact of T cell chimerism on the outcome of 133 patients undergoing an alemtuzumab based reduced intensity conditioning allograft (RIC). The median age of the patients was 50 years (range 42–55 years). 77 patients were transplanted using an HLA identical sibling donor while 56 patients received a fully matched volunteer unrelated donor graft. 64 patients had a lymphoid malignancy and 69 were transplanted for a myeloid malignancy. 38 patients (29%) relapsed with no significant difference in risk of relapse between patients developing full donor and mixed donor chimerism in the T-cell compartment on D+90 and D+180 post transplant. Day 90 full donor T cell chimerism correlated with an increased incidence of acute GVHD according to NIH criteria (p=0.0004) and the subsequent development of chronic GVHD. Consistent with previous observations, our results confirmed a correlation between the establishment of T cell full donor chimerism and acute GVHD in T deplete RIC allografts. However our study failed to identify any correlation between T cell chimerism and relapse risk and challenge the use of pre-emptive donor lymphocyte infusions (DLI) in patients with mixed T cell chimerism transplanted using an alemtuzumab based RIC regimen.

Role of 18F-FDG PET-CT for evaluating the response to reduced-intensity conditioning allogeneic transplant in heavily pre-treated patients with chronic lymphocytic leukemia: preliminary results in nine patients

The aim of our preliminary study was to evaluate the potential role of 18F-FDG PET-CT in monitoring response to reduced-intensity conditioning (RIC) transplant in a small series of chronic lymphocytic leukemia (CLL) patients and to compare the results with those obtained by standard criteria. We retrospectively analyzed 9 consecutive refractory/relapsed CLL patients, who underwent RIC transplant from March 2004 until May 2009. PET-CT was planned at 6-8 months after transplant to assess response and at a mean of 6 months during follow-up. The mean long-term follow-up period was 38 months (range 12-74 months, median 29 months). The first PET-CT showed abnormal 18F-FDG uptake in five patients, while by standard criteria eight patients showed persistent disease. At the end of follow-up (mean 38 months), all four patients with previously negative scan were still PET negative and in complete remission by standard criteria. All five patients with previously positive scan were still PET positive: one patient died for disease progression and four are alive with disease. Our preliminary data, although in a small series of CLL patients, suggest that the metabolic findings revealed at first PET-CT after transplant seem to predict the patient outcome and to assess the metabolic disease status earlier than clinical evaluation by standard criteria. PET-CT performed during follow-up may be useful to early detect disease progression.

Pentostatin, Alemtuzumab, and Low Dose Rituximab Is Effective Therapy for Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL)

Abstract 1790CLL is incurable with conventional therapies and prognosis is poor in patients with relapsed or treatment refractory disease. Patients with purine analogue refractory disease and defective TP53 function have limited therapeutic options. Based on: 1) The ability of purine analogues to decrease tumor burden; 2) Higher response rates in patients treated with alemtuzumab and rituximab vs. alemtuzumab alone; and 3) Data showing that more frequent lower doses of rituximab could be more effective than standard therapy, we hypothesized that combination therapy with pentostatin, alemtuzumab and low dose rituximab (PAR) would be effective and tolerable therapy for patients with relapsed/refractory CLL and those with previously untreated progressive CLL who had 17p13-.This two stage phase II University of Iowa/Mayo Clinic Lymphoma SPORE clinical trial (NCT00669318) was approved by Mayo Clinic and the University of Iowa IRBs according to the principles of the Declaration of Helsinki. The aims are to assess: 1) Complete (CR) and overall responses; and 2) Progression-free survival (PFS), duration of response, and time to next treatment (TTT). Patients with progressive CLL (including the SLL variant) defined by standard criteria are eligible for this study if they had either previously treated CLL or previously untreated CLL with 17p13-. Cycle 1 of therapy is 5 weeks with rituximab 20 mg/m2/d IV Mon-Wed-Fri starting day 1, subQ alemtuzumab beginning days 3–5 with a dose escalation (3 mg–10 mg– 30 mg/d) and then 30 mg/d Mon-Wed-Fri, and pentostatin 2mg/m2/dose/IV days 8 & 22. Cycles 2–3 are each of 4 weeks duration and are the same as weeks 2–5 of cycle 1. Patients who achieve CR after cycle 2 with a negative CT scan and bone marrow study with no evidence of residual CLL cells after immunohistochemical staining, do not receive cycle 3 of therapy. All patients receive granulocyte growth factor support after pentostatin therapy as well as PCP and herpes virus prophylaxis. Patients are tested for CMV reactivation by PCR weekly during therapy and treated with valganciclovir if reactivation is detected.We report the results of the planned interim analysis performed after completion of therapy for the first 19 patients (July 2008 - October 2010). The median patient age was 63 years (range 47–78) with 74% males. Two patients with 17p13- were previously untreated. Of the 17 previously treated patients (median 2 prior regimens, range 1–6), 8 (47%) had purine analogue refractory CLL (disease progression < 6 months of treatment). Nine (47%) patients had advanced clinical stage (Rai III-IV). Adverse molecular prognostic factors were 17p13- (n=8, 42%, 2 also had 11q22-), 11q22- (n=1), unmutated IGHV (12/17, 71%), ZAP70+ (≥20%, 12/17, 71%) and CD38+ (≥30%, 6/18, 33%). The median beta-2-microglobulin level was 4.3 (range 2.4 – 12.6).Grade 3–4 treatment related toxicities were 9 non-hematological and 20 hematological events. Grade 3–4 infections occurred in 3 patients including one patient requiring hospitalization for CMV re-activation. Fourteen (74%) patients responded to treatment with 6 (32%) CR (includes 2 CRi) and 8 (42%) partial responses (PR). Five (26%) patients had stable disease (SD). Eleven (58%) patients completed 3 cycles of therapy. One patient achieved a CR with no residual disease after 2 cycles of therapy and received no further treatment per protocol. Median duration of response is 7 months (95% CI: 4–not reached (NR)). Among the 8 patients with 17p13- there were 3 CR/CRi, 4 PR, and 1 SD. Four patients proceeded to allogeneic transplant with reduced intensity conditioning (RIC) and were censored for TTT at the initiation of transplant related therapy. With a median of 16 (range 6 – 35) months of follow up, median PFS is 7 months (95% CI: 5–NR), median TTT is 27 months (95% CI: 5-NR) and the calculated median overall survival is 23 months (95% CI: 14–NR).We report that PAR is effective and tolerable therapy in this population of relapsed refractory patients with high to very-high risk CLL. In addition, the responses in patients with 17p13- were similar to that of the patients who did not have 17p13-. The treatment regimen was useful for disease control in 3 patients who proceeded to reduced intensity conditioning allogeneic transplantation. This study shows that PAR could play an important role in the treatment of recurrent and high risk CLL.Supported by the University of Iowa/Mayo Clinic Lymphoma SPORE CA097274 Disclosures:Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding.