Reduced Intensity Allogeneic Hematopoietic 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.

Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature

BackgroundBone marrow transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively frequent but under-recognized and under-treated hematopoietic stem cell transplant (HSCT) complication that leads to significant post-transplant morbidity and mortality. Classic TMA-defining laboratory abnormalities appear at different times in the course of TA-TMA development, with schistocytes often appearing later in the disease course. In some severe TMA cases, schistocytes may be absent due to increased endothelial permeability. Unfortunately, many clinicians continue to perceive the presence of schistocytes as an absolute requirement for TA-TMA diagnosis, which leads to delayed recognition and treatment of this potentially fatal transplant complication.MethodsPatient chart review and PubMed literature search using the term, “transplant-associated thrombotic microangiopathy”.Case presentationA 54-year-old male IgG kappa multiple myeloma underwent a reduced intensity allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with fludarabine and melphalan. On day + 27, the patient developed acute kidney injury followed by repeated episodes of diarrhea and gastrointestinal bleeding attributed to graft versus host disease (GVHD) and cytomegalovirus (CMV) colitis. Repeated colonic biopsies suggested CMV infection and GVHD. Despite appropriate treatment with antiviral therapy and immunosuppressants, the patient’s condition continued to deteriorate. He experienced concomitant anemia and thrombocytopenia as well as elevated lactate dehydrogenase and low haptoglobin levels, but a TA-TMA diagnosis was not made due to an absence of schistocytes on peripheral smear. The patient expired secondary to uncontrolled gastrointestinal bleeding. A post-mortem analysis of the resection specimen revealed extensive TMA involving numerous arteries and arterioles in the ileal and colonic submucosa as well as in the muscularis propria and deep lamina propria of the mucosa.ConclusionsTA-TMA can occur in the absence of peripheral blood schistocytes. Our experience underscores the importance of considering the diagnosis of intestinal TA-TMA in patients with refractory post-transplant diarrhea and GI bleeding, even if all classic features are not present.

Addition of R-HMA to R-DA-EPOCH Favourably Changes the Outcome in Patients with Untreated High-Grade Diffuse Large B-Cell Lymphoma: The First Results of Russian Prospective Multicenter Trial

Background: Approximately 50% of diffuse large B-cell lymphomas (DLBCL) are defined as high-grade by IPI. They are characterized by aggressive course and poor response to standard chemotherapy (CT): 5-years overall survival (OS) rate of less than 30%. R-DA-EPOCH has demonstrated very optimistic results (overall and progression-free survival (PFS) were 90%), but high-risk patients (IPI 3-4) showed only 43% of OS and PFS [1]. The addition of high-dose AraC (12 g/m2) to the upfront therapy of high-risk DLBCL has significantly improved the outcome on Hyper-CVAD/HMA and mNHL-BFM-90 protocols [2, 3]. But high toxicity of these protocols restricts their application. We suggested that addition of courses R-HMA in rotation with R-DA-EPOCH could improve the treatment outcome and decrease toxicity.Aim: To evaluate the efficacy and toxicity of R-DA-EPOCH/R-HMA protocol in patients with untreated high-grade diffuse large B-cell lymphoma.Patients and Methods: 33 untreated DLBCL patients from 4 centers were enrolled in a prospective study between August 2013 - July 2015; stage II-IV; ECOG 0-3; median age 55 years (27-76); age ≥60y/<60y 50%/50%; M/F 60%/40%; IPI: 48% high-intermediate and 52% high risk; 15% with bone marrow involvement. All patients underwent 4-8 courses (2-4 cycles) of chemotherapy: R-DA-EPOCH (standard dose and scheme), R-HMA (R 375 mg/m2 d1, MTX 1000 mg/m2 24 hours d 2, AraC 3000 mg/m2 q 12 hrs d 3-4). For patients older than 60 year dose of R-HMA was reduced (R 375 mg/m2 d1, MTX 500 mg/m2 24 hours d 2, AraC 1000 mg/m2 q 12 hrs d 3-4). In 4 cases of DLBCL with bone marrow involvement BEAM conditioning and autologous stem cell transplantation were applied.Results: The median follow-up is 12 months (4-24). There was no mortality associated with toxicity. The main non-hematological toxicities of R-HMA were infections (mucositis, pneumonia, sepsis, enteropathy) grades 1-2 and 3-4 in 90% and 10%, respectively. Hematological toxicity grade 4 for less than 4 days we observed only after courses R-HMA. Complete remission (CR) was achieved in 29 (88%) patients. In 2 patients we observed progression of the disease after first cycle of chemotherapy, in another 2 cases - partial remission after 2-3 cycles and following progression of disease. In patients older than 60 years with doses reduction in R-HMA failures were absent, except one later relapse after 13 month CR.With a median follow 12 months overall and disease-free survival of 33 patients constituted 90,5% and 74% , respectively. In a group of patients older than 60 years results of therapy seemed to be better than in young patients: OS were 100% vs 85,6% (p=0,1), DFS were 80% vs 74,9% (p=0,2), respectively. So the combination of R-DA-EPOCH/R-HMA may be considered as optimal intensive approach in the older patients.Conclusions: TheR-DA-EPOCH/R-HMA protocol demonstrated acceptable toxicity and high efficacy in patients with high-grade DLBCL. This protocol has shown optimistic results in the elderly patients and it could be recommended for further investigation in that group.Ññûëêè:1. Salit RB, Fowler DH, Wilson WH, et al. Dose-adjusted EPOCH-rituximab combined with fludarabine provides an effective bridge to reduced-intensity allogeneic hematopoietic stem-cell transplantation in patients with lymphoid malignancies.J Clin Oncol. 2012. 10;30(8):830-6.2. Oki Y, Westin JR, Vega F, et al. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol 2013; 163(5):611-20.3. Magomedova AU, Kravchenko SK, Kremenetskaia AM, et al. Nine-year experience in the treatment of patients with diffuse large B-cell lymphosarcoma. Ter Arkh. 2011;83(7):5-10. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Alemtuzumab-Cyclosporine Versus Tacrolimus-Methotrexate-Sirolimus for Graft-Versus-Host Disease Prophylaxis in Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Donors: Final Results of a Randomized Trial

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) can provide a curative therapy for hematological malignancies but may result in complications such as relapse, infection, and acute and chronic graft versus host disease (GVHD). Two divergent approaches to GVHD prophylaxis (post-HSCT depletion of donor lymphocytes vs. suppression of immune activation) in a reduced-intensity, matched-unrelated donor setting were compared in a randomized, open label, phase 2 prospective trial (NCT00520130), powered to assess the incidence of severe cGVHD using NIH criteria.Methods: Hematological malignancy patients received disease-specific induction chemotherapy DA-EPOCH-FR or FLAG (Salit et al, JCO 2012; 30:830) for disease control and host lymphodepletion to CD4+ cell target <100/µl. All patients received identical conditioning with concurrent fludarabine (30 mg/m2/d x4) and cyclophosphamide (1200 mg/m2/d x4), followed by mobilized T-replete peripheral blood allograft from a matched unrelated donor. Patients were randomized to receive alemtuzumab 20 mg/d x5 and cyclosporine (AC) or tacrolimus, sirolimus, and methotrexate (TMS).Results: 81 pts (NHL=25, HL=8, CLL=18, AML/MDS=10, CML=3, CTCL/PTCL=5, ALL=4, MM=2, other=6), median age 50 yrs (range, 21-71) were included in the study (AC=42, TMS=39). The two arms were similar in age, gender, disease, relapse risk (Kahl), HCT-comorbidity index, and donor HLA match (8/8 or 7/8). Median time to neutrophil engraftment was 9 vs. 11 days in AC vs. TMS, respectively (p=0.017). There were no differences in platelet recovery (p=0.96). One case of graft failure occurred in a myeloma patient on the AC arm.D100 mortality probabilities were 12% (95% CI, 5-25) and 10% (95% CI, 4-24) in AC and TMS, respectively (p=0.20). Median survival in AC was 18.8 mo and 41.7 mo in TMS, with a median follow-up of 53 mo in AC and 50.6 mo in TMS. 3yr OS was comparable: AC 42% (95% CI, 28-57) vs. TMS 58% (95% CI, 42-73) (p=0.20). The 3yr malignancy progression rate was higher in the AC arm (AC 51% (95% CI, 34-65) vs. TMS 21% (95% CI, 10-35), p= 0.0062). 3yr relapse related mortality rates were 29% (95% CI, 16-44) vs. 14% (95% CI, 5-29) (p=0.067) and non-relapse mortality 29% (95% CI, 16-43) vs. 28% (95% CI, 14-43) (p=0.75) in AC vs. TMS, respectively. The most common grade ≥3 adverse events (CTCAE 4.03) within 100 d post-transplant were infections (22%) with more viral infections in the AC arm (p=0.0007). Reactivation of CMV occurred earlier in the AC arm, incidence 58% (95% CI, 42-71) vs. 24% (95% CI, 12-38) by D100 (p=0.035).Rates of aGVHD were similar; Gr II-IV at 6 mo in AC 38% (95% CI, 23-53) vs. TMS 41% (95% CI, 26-57) (p=0.59); Gr III-IV at 6 mo AC 21% (95% CI, 11-35) vs. TMS 13% (95% CI, 5-26) (p=0.61). In contrast, significantly lower rates of any grade cGVHD occurred in the AC arm compared to TMS at 36 mo (27% (95% CI, 14-41) vs. 59% (95% CI, 40-74)) (p=0.0076). The incidence of severe cGVHD was strikingly different: AC 5% (95% CI, 1-15) vs. TMS 31% (95% CI, 16-47) (p=0.0007). In the Cox model, the only prognostic factor for severe or any cGVHD was the TMS treatment arm, HR 6.8 (95% CI, 1.5-30.3, p=0.012) and HR 2.3 (95% CI, 1.1-4.8, p=0.026), respectively.Lymphocyte recovery (ALC 500/µL) was markedly delayed in AC, median 76 vs. 16 d (p<0.0001). NK-cell recovery was disparate during the first month (p <0.0001, D28: 31 vs. 270/µl), but similar thereafter. B-cell reconstitution was negligible in both through 6 mo. AC resulted in profound and prolonged deficit in T cells. CD4+ cells were significantly reduced in AC vs. TMS through 1 yr (p <0.0001, D28: 21 vs. 285/µl, 1yr: 131 vs. 447/µl). CD8+ disparity persisted for 6 mo (p<0.0001, D28: 6 vs. 205/µl, 6 mo: 58 vs. 429/µl). Naïve T-cells were significantly reduced in AC through 6 mo (p<0.0001, median naïve cell frequency (AC vs TMS) Treg 2.8 vs 8.4%; nonTreg CD4+ 1.0 vs 23.7%; CD8+ 2.9 vs 20.0%). Assessment of CD4+ and CD8+ TCR Vβ repertoire diversity by spectratyping demonstrated significantly lower diversity in AC at 6 mo (p=0.003).Conclusions: This prospective, randomized trial demonstrates that the use of AC when compared with TMS led to a significant reduction in incidence of severe and overall cGVHD. These two GVHD prophylaxis regimens had similar incidences of aGVHD but very different effects on post-alloHSCT immune reconstitution, infection and relapse. Future strategies for cGVHD prevention will need to further address these issues. DisclosuresOff Label Use: There is currently no FDA approved product for GVHD prevention or therapy. The GVHD prophylaxis regimens described in this study (Alemtuzumab-Cyclosporine and Tacrolimus-Methotrexate-Sirolimus) are used off-label as GVHD prophylaxis regimens in reduced-intensity allogeneic HSCT.

Immunologic Effects of CCR5 Blockade in Graft-Versus-Host Disease Prophylaxis

▪Background: Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Experimental models and clinical studies suggest that blocking lymphocyte trafficking with the chemokine receptor CCR5 antagonist maraviroc (MVC) ameliorates visceral GVHD. However, the effects of CCR5 blockade on immune reconstitution and activation in allogeneic HSCT recipients remain unknown.Methods: We previously reported a phase I/II study of 38 high-risk patients undergoing reduced-intensity allogeneic HSCT with standard GVHD prophylaxis (tacrolimus, methotrexate) combined with brief (33-day) MVC treatment. We compared the clinical and immunologic outcomes of these patients to a contemporary control cohort of 115 consecutive patients undergoing allogeneic HSCT with standard GVHD prophylaxis alone. Multivariate analysis was used to assess the effect of MVC treatment on the incidence of GVHD. Flow cytometry on day 30 and day 60 PBMC samples was used to monitor immune cell subsets, T cell activation markers and chemokine receptor expression. We also used a multiplex Luminex assay to quantify serum cytokine levels at day 30.Results: Since our initial report, longer follow up (median 37 months) now shows that patients who received MVC have reduced incidence rates of acute grade II-IV GVHD (adjusted hazard ratio [aHR]=0.42, 95% CI 0.21-0.84, p=0.015) and grade III-IV GVHD (aHR=0.43, 95% CI 0.17-1.09, p=0.075) compared to our control cohort (Figure 1). There was no difference in chronic GVHD between the groups. Early lymphocyte recovery was similar between MVC and control cohorts, with no significant difference in absolute lymphocyte, CD4 T cell and CD8 T cell counts at day 30. We observed increased CCR5 expression on CD4 T cells, CD8 T cells and B cells at day 30 in response to MVC treatment (Figure 2A-B). However, CCR5 expression on these cell types equalized between MVC and control patients by day 60. Day 30 MVC samples also demonstrated decreased percentages of CD38+ CD4 T cells and HLA-DR+ CD8 T cells (Figure 2C-D), an effect that also faded by day 60. These data suggest that inhibition of lymphocyte trafficking with CCR5 blockade dampens peripheral T cell activation.Notably, some patients developed acute GVHD despite MVC prophylaxis, and therefore we investigated differences between MVC responders and non-responders. Patients who developed GVHD had a higher percentage of activated CD38+ CD4 T cells in peripheral blood (Figure 3A) and an increased proportion of naive CD4 (36.5% vs 18.1% p=0.005) and CD8 (35.5% vs 11.9% p=0.0008) T cells, which has been associated with the development of GVHD. We also observed higher CCR5 expression on CD8 T cells from MVC non-responders (CCR5 MFI 8800 vs 6595, p=0.02). Intriguingly, while MVC responders and non-responders had similar serum concentrations of CCR5 ligands (MIP-1a, MIP-1b, Rantes), MVC non-responders had elevated levels of CXCR3 ligands (IP-10, MIG) (Figure 3B-C). Taken together, these data suggest that lymphocyte migration via CXCR3 may be a potential escape mechanism for GVHD initiation and T cell activation in the setting of CCR5 blockade.Conclusion: Brief CCR5 blockade in high-risk patients inhibits T cell activation and reduces the incidence of GVHD. MVC does not inhibit early lymphocyte recovery, which was similar in treated and control patients. This supports the hypothesis that MVC treatment would not impair graft-versus-leukemia activity. Our analysis of immunologic outcomes of MVC reveals a distinct immunologic effect for CCR5 blockade in allogeneic HSCT recipients and suggests a novel resistance mechanism. These studies bolster CCR5 antagonism as an effective strategy for GVHD prevention and provide support for extended MVC treatment duration and investigation into CXCR3 as a therapeutic target. [Display omitted] [Display omitted] [Display omitted] DisclosuresOff Label Use: Off label use of CCR5 antagonist maraviroc for the prevention of graft-versus-host disease. Vonderheide:Pfizer: Research Funding. Porter:Pfizer: Research Funding.

Stem-Cell Transplantation for Middle-Aged Patients with Myelofibrosis

Myelofibrosis is a progressive disease that culminates in fatal cytopenias or leukemic transformation. The only curative therapy is allogeneic hematopoietic stem-cell transplantation (AHSCT), but the feasibility of this approach in older patients has been unclear. To examine the safety and effectiveness of reduced-intensity AHSCT in this setting, investigators conducted a prospective, multicenter, phase II study involving 66 patients with primary myelofibrosis (median age, 55; range 30–65; about half …

Reduced Intensity Allogeneic Stem Cell Transplant In Patients With Multiple Myeloma: A Comparison Of Planned Autologous-Reduced Intensity Allogeneic Stem Cell Transplant (Auto-Allo) and Reduced Intensity Allogeneic Stem Cell Transplant (RIC) As Upfront Transplant In Patients With Multiple Myeloma, An EBMT Analysis

BackgroundDespite the advances in the treatment of multiple myeloma using new targeted therapies and autologous hematopoietic stem cell transplant (HSCT) the disease remains largely incurable. Recent efforts in using reduced intensity allogeneic HSCT have been hampered by increased allograft-related morbidity and mortality. Several prospective studies comparing single or tandem autologous HSCT with planned tandem autologous-reduced intensity allogeneic HSCT (auto-allo) have shown no overall survival advantage despite improvements in progression-free survival (PFS) and lower relapse rates with reduced intensity allograft, mainly due to increased non-relapse related mortality (NRM) rates. However, two of these prospective studies; the European Group for Blood and Marrow Transplantation NMAM 2000 and the Italian group study with long term follow-up reported PFS and overall survival (OS) benefits in favor of the auto-allo arm. Currently allogeneic HSCT is recommended within the context of clinical trials and only in high risk multiple myeloma patients who continue to have a very poor outcome with autologous HSCT. While such clinical trials are ongoing there remains a need to address the role of autologous HSCT prior to reduced intensity allogeneic HSCT. The objective of this retrospective study is to evaluate the role of upfront cytoreductive autologous HSCT prior to allograft in the outcomes of patients who have undergone allograft following induction therapy. StudyWe performed a retrospective analysis of the EBMT database comparing the outcomes of patients who were planned to receive auto-allograft to those who underwent reduced intensity allograft (early RIC) without a prior autologous HSCT within one year from diagnosis. The data in 504 patients were previously reported at the ASH meeting 2010 (abstract 3512). We subsequently included additional patients and requested more information from the participating EBMT centers and updated the study. From 1996 to 2013 a total of 689 patients were registered as reduced intensity allograft. 517 patients were registered as planned auto-allograft; however, 73 did not receive the planned allograft. A total of 172 patients received reduced intensity allograft after induction treatment without prior auto-HSCT. Median age at first transplant was 53 years (range 20-72) in the auto-allo and 51 years (range 31-77) in the early RIC group. Median time from diagnosis was 6.6 months (range 2-156 months) in the auto-allo and 7.7 months (2.8-12.0) in the early RIC group. The disease status at the time of first transplant for the auto-allo group was CR - 8%, PR - 67%, other or missing - 25%; and for the RIC group was CR - 15%, PR - 62%, other or missing - 23%. Donors were HLA matched siblings in 88% and matched unrelated in 12% for the auto-allo group, and 84% siblings and 16% matched unrelated in the RIC group with no significant differences between the two groups. ResultsWith a median follow-up of 93 months in the auto-allo and 84 months in RIC groups, PFS rates were significantly better at 3 and 5 years in the auto-allo group (45.6% and 34.2%) as compared to the RIC group (33.9% and 22.0%, p<0.001). Overall survival was also significantly improved in favor of the auto-allo (3 yr and 5 yr OS 67.9% and 58.9%) as compared to the RIC group (54.3% and 42.7%, P = 0.001). The non-relapse mortality (NRM) rates were lower in the auto-allo group as compared to RIC: 1 yr and 3 yr NRM were 8.1% and 14.1% in the auto-allo and 20.3% and 27.4% in early RIC group, p<0.001. We examined potential differences in outcomes based on use of novel agents, and used the year 2004 as a surrogate for introduction of novel agents to routine clinical practice. There were no significant differences by multivariate analysis in outcomes for patients transplanted before or after 2004. ConclusionThis large multicenter retrospective study suggests that cytoreductive autologous HSCT prior to allograft is associated with improved PFS and OS. We are in the process of conducting an extended analysis to control for possible confounders. If the results are confirmed, future studies should be conducted to verify the importance of autologous stem cell transplant as part of the allograft treatment strategy. Disclosures:No relevant conflicts of interest to declare.

Long-Term Survival In Patients With Acute Steroid Refractory Graft-Versus-Host-Disease (SR-GVHD) Treated With Infliximab Combined With Daclizumab

Acute SR-GVHD occurs in approximately 15% of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), and is associated with a 70-90% long-term mortality rate. We previously reported that concomitant blockade of TNF-α and IL-2 pathways with infliximab combined with daclizumab have a synergistic therapeutic effect, with a high probability of complete resolution of SR-GVHD. Although various treatment modalities are effective in the treatment of SR-GVHD, minimal long-term follow up data exists for complete responders to second line treatments. Here we report long-term outcomes in a cohort of 23 subjects developing SR-GVHD treated with infliximab/daclizumab. A consecutive series of 141 patients with a variety of hematological and non-hematological malignancies as well as nonmalignant hematological disorders including severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria and pure red cells aplasia, underwent a reduced intensity allogeneic HSCT from an HLA identical or single antigen mismatched relative at a single institution between 2/2001 and 12/2008. Transplant conditioning consisted of cyclophosphamide (60 mg/kg days -7, -6) and fludarabine (25 mg/m2days -5 to -1) with or without equine ATG or 6-12 Gy of total body irradiation. GVHD prophylaxis was with cyclosporine with or without additional MMF or MTX. Twenty three patients (median age 35 years, range 13-65 years) developed SR-GVHD at a median of 28 days post transplant. SR-GVHD was defined as absence of response to at least 6 days of high dose methylprednisolone therapy. Following a diagnosis of SR-GVHD, patients received a combination of daclizumab (1mg/kg given on days 1, 4, 8, 15, 22), infliximab (10mg/kg given on days 1, 8, 15, 22), broad spectrum bacterial and anti-fungal prophylaxis, and had their methylprednisolone tapered to 1mg/kg/day. Combined cytokine blockade was highly active against SR-GVHD, with 21/23 (87.5%) patients achieving a complete response (CR), defined as total resolution of GVHD in all involved organ systems. All complete responders survived to hospital discharge. With a median follow-up of 9 years (range 5-10 years), 9/23 (39%) survive, including 6 patients without chronic GVHD whose immunosuppressive therapy (IST) has been discontinued and 3 patients with chronic GVHD (2 limited and 1 extensive) who continue to be tapered off IST. Fourteen of 21 patients with resolution of SR-GVHD died a median 173 days post transplant (range 67-1039 days), including 1 from complications related to recurrent SR-GVHD, 6 from progression of malignancy (all solid tumors), 2 from bleeding related to peptic ulcer disease and 5 from infectious complications including invasive fungal infection and CMV disease. A subgroup analysis showed 5/6 patients with SAA developing SR-GVHD had a complete response to combined infliximab/daclizimab. Remarkably, at a median 6 years follow up, 67% (4/6) of these SAA patients were long-term survivors. All these survivors have maintained normal blood counts and remained transfusion independent with 100% donor chimerism in myeloid and T-cell lineages. Conclusion Patients with SR-GVHD treated with infliximab combined with daclizumab had a high probability of achieving a complete response with nearly 40% of patients having long-term survival. This is the first report to show that long-term survival can be achieved in a substantial proportion of patients receiving combined IL-2 and TNF blockade for SR-GVHD. Disclosures: Off Label Use: Infliximab is FDA approved for the treatment of psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. Daclizumab gained FDA approval for use in transplant rejection.

Bone Marrow Transplantation (BMT) in Myelodysplastic Syndromes: To BMT or Not to BMT—That Is the Question

Those who treat patients with myelodysplastic syndromes (MDS) have been forced to become comfortable with a rather uncomfortable truth. MDS is a bone marrow failure syndrome that represents the most commonly diagnosed myeloid malignancy and predominantly affects older adults, with a median age at diagnosis of 71 years. The only cure for MDS is hematopoietic stem-cell transplantation (HSCT). For a variety of reasons, including patient comorbidities, availability of related or matched donors, related donor comorbidities, physician and patient preference, and treatment-related adverse events, transplantation is only considered in approximately 5% of patients with MDS. Thus, even when we offer disease-modifying therapies such as azacitidine, decitabine, and lenalidomide, we are ultimately palliating 95% of our patients. Despite this, patients often perceive these drugs to have curative potential in this setting, but cure is unfortunately not possible with these agents. How do we change this paradigm? Although some factors, such as patient comorbidities and availability of donors, are largely immutable, others factors have improved, making HSCT more appealing. One such advance is reduced-intensity conditioning transplantation, which greatly reduces the toxicity of the preparative regimen without compromising efficacy, and in so doing has raised the age for potentially eligible transplantation candidates into the eighth decade. Another modifiable area is in identifying patients for whom the riskbenefit analysis for transplantation is more favorable compared with managing the disease with palliative intent. This, in turn, could affect patient and physician preferences. In the article that accompanies this editorial, Koreth et al report on a Markov decision analysis exploring the role of reduced-intensity allogeneic HSCT in older patients with MDS. This statistical technique relies on assumptions, which themselves are based on best estimates of outcome given in previously published studies, to play out scenarios of what would happen in real life to a given patient if he or she decided to undergo HSCT early, at or near diagnosis, or instead to pursue supportive care, growth factor, or disease-modifying therapy. Although this approach is not perfect, it does allow for sensitivity analyses in which assumptions can be changed to see if the same conclusion holds, and it is the best substitute available in the absence of prospective, randomized studies. This is also not the first time some of these investigators have tackled this question, or this methodology. In 2004, Cutler et al published a decision analysis of patients with MDS treated with myeloablative conditioning transplantation. Given this conditioning regimen, patients were younger (with a median age of 40.4 years), and given the timing at which this analysis was conducted, a paucity of individual patient data were available to appropriately reflect nontransplantation treatment approaches. So, although the results of the study by Cutler et al make clinical sense, namely, that early transplantation provides maximal quality-adjusted survival in higher-risk patients with MDS (those falling into intermediate-2 and high-risk categories of the International Prognostic Scoring System [IPSS]), these conclusions have always given treating doctors pause because the participants did not reflect the full spectrum of patients with MDS who are seen in everyday clinical practice. The analysis by Koreth et al addresses these shortcomings. Now, given the nonmyeloablative preparative regimen, the median age of the 132 patients undergoing transplantation gleaned from the Center for International Blood and Marrow Transplant Research, DanaFarber Cancer Institute, and Fred Hutchinson Cancer Research Center data sets is 64 years—closer to what we see in clinic. Patients who did not undergo transplantation included 132 with lower-risk disease (IPSS low and intermediate-1) receiving best supportive care; 91 anemic or transfusion-dependent patients receiving erythropoiesisstimulating agents; and 164 higher-risk patients with MDS receiving azacitidine or decitabine. Patients being treated with lenalidomide, immunosuppressive approaches, or drug combinations were not included. Primary end points of the model were life expectancy (LE) and quality-adjusted life expectancy, an end point adjusted for quality of life, the values of which were derived from studies in which patients may not reflect those included in the current analysis. The authors tried to keep the assumptions used in an already complicated model to a minimum, and in so doing ignored some real-life scenarios, such as a patient initially in the nontransplantation arm deciding at a later time to undergo transplantation. That being said, the results suggest that for lower-risk patients with MDS, median LE for those avoiding HSCT was approximately double that of those undergoing HSCT, at 77 versus 38 months. For higher-risk patients, a more modest advantage was seen for early HSCT, with a median LE of 36 months, versus 28 months for nontransplantation approaches. Interestingly, in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 21 JULY 2

Blockade of CCR5 to protect the liver graft in HIV/HCV co-infected patients

Background: Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stem-cell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity. We tested whether CCR5 blockade would be safe and limit GVHD in humans. Methods: We tested the in vitro effect of the CCR5 antagonist maraviroc on lymphocyte function and chemotaxis. We then enrolled 38 high-risk patients in a single-group phase 1 and 2 study of reduced-intensity allogeneic HSCT that combined maraviroc with standard GVHD prophylaxis. Results: Maraviroc inhibited CCR5 internalization and lymphocyte chemotaxis in vitro without impairing T-cell function or formation of hematopoietic-cell colonies. In 35 patients who could be evaluated, the cumulative incidence rate (±SE) of grade II to IV acute GVHD was low at 14.7 ± 6.2% on day 100 and 23.6 ± 7.4% on day 180. Acute liver and gut GVHD were not observed before day 100 and remained uncommon before day 180, resulting in a low cumulative incidence of grade III or IV GVHD on day 180 (5.9 ± 4.1%). The 1-year rate of death that was not preceded by disease relapse was 11.7 ± 5.6% without excessive rates of relapse or infection. Serum from patients receiving maraviroc prevented CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro, providing evidence of antichemotactic activity. Journal of Hepatology 20

Feasibility of reduced‐intensity allogeneic stem cell transplantation with imatinib in children with philadelphia chromosome‐positive acute lymphoblastic leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) in children is one of the highest-risk ALL groups. Improved outcome in combination with imatinib has been reported. However, intensive chemotherapy or myeloablative conditioning followed by hematopoietic stem cell transplantation (HSCT) can be associated with significant adverse late effects. We report a case series of five children with Ph + ALL underwent reduced-intensity allogeneic HSCT (RIST) after induction and consolidation in chemotherapy combined with imatinib. Four of the five patients remain first complete remission for a median of 3.1 years after RIST. These results are preliminary, but suggest the feasibility and effectiveness of RIST with imatinib.

Blockade of Lymphocyte Chemotaxis in Visceral Graft-versus-Host Disease

BackgroundGraft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stem-cell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity. We tested whether CCR5 blockade would be safe and limit GVHD in humans.MethodsWe tested the in vitro effect of the CCR5 antagonist maraviroc on lymphocyte function and chemotaxis. We then enrolled 38 high-risk patients in a single-group phase 1 and 2 study of reduced-intensity allogeneic HSCT that combined maraviroc with standard GVHD prophylaxis.ResultsMaraviroc inhibited CCR5 internalization and lymphocyte chemotaxis in vitro without impairing T-cell function or formation of hematopoietic-cell colonies. In 35 patients who could be evaluated, the cumulative incidence rate (±SE) of grade II to IV acute GVHD was low at 14.7±6.2% on day 100 and 23.6±7.4% on day 180. Acute liver and gut GVHD were not observed before day 100 and remained uncommon before day 180, resulting in a low cumulative incidence of grade III or IV GVHD on day 180 (5.9±4.1%). The 1-year rate of death that was not preceded by disease relapse was 11.7±5.6% without excessive rates of relapse or infection. Serum from patients receiving maraviroc prevented CCR5 internalization by CCL5 and blocked T-cell chemotaxis in vitro, providing evidence of antichemotactic activity.ConclusionsIn this study, inhibition of lymphocyte trafficking was a specific and potentially effective new strategy to prevent visceral acute GVHD. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00948753.)

Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies

There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4(+) count < 200/μL) or progressive disease. Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3(+) (P < .001), CD4(+) (P < .001), and CD8(+) (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001). DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.

Results of Phase II Clinical Trial MPD-RC 101: Allogeneic Hematopoietic Stem Cell Transplantation Conditioned with Fludarabine/Melphalan in Patients with Myelofibrosis

Abstract 1750▪▪This icon denotes a clinically relevant abstractThe Myeloproliferative Disorder-Research Consortium (MPD-RC) designed the first US prospective phase II study of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with primary myelofibrosis (PMF) or MF secondary to essential thrombocythemia (ET-MF) or polycythemia vera (PV-MF). Between May 2007 and March 2011, 66 patients were entered into the MPD-RC 101 study. Thirty-two patients received an allogeneic HSCT from a related and 34 patients from an unrelated donor. In the two groups diagnoses were: PMF: 44%, 74%; ET-MF: 47%, 12% and PV-MF: 9%, 15%, respectively. A reduced intensity regimen with fludarabine/melphalan (FluMel) ± ATG was used. Of 66 patients, 63 were at intermediate/high risk according to Lille score system and 3 patients were at low risk but had thrombocytopenia. Recipients of related and unrelated HSCT were comparable with respect to age (median: 54 vs 55 years), gender (M/F 19/13 vs 19/15), Lille score intermediate (63% vs 68%) or high risk (28% vs 32%) and time from diagnosis to transplant (median, range: 16, 1–247 vs 20, 2–341 months). At the time of transplant, 66% and 82% of patients in the related and unrelated cohorts had splenomegaly and 19% and 15% had previous splenectomy. Jak-2 V617F mutation was present in 38% and 50% and an abnormal karyotype was detected in 56% and 59% of patients with known status, respectively. Bone marrow stem cells were utilized in 19% of related and 9% of unrelated transplants, while in the remaining cases patients received peripheral blood stem cell (PBSC) grafts. Donor compatibility was assessed by molecular typing for HLA A, B, C, DRB1 and DQB1 antigens; inclusion criteria allowed enrollment with maximum 1 antigen mismatched donor. Thirty of 32 transplants (94%) in the related cohort and 25/36 (74%) in the unrelated cohort were fully matched. In transplants from related donor, engraftment of neutrophils and platelets occurred in 31/32 patients, One patient in this group experienced a secondary graft failure. In contrast, among patients in the unrelated group only 26/34 (76%) patients engrafted and of these 4 had a secondary graft failure post transplant. Median time to neutrophils > 0.5 × 109/L and platelets >20 × 109/L engraftment was: day 22 and day 28 in the related, and day 18 and day 28 in the unrelated cohort, respectively. Acute GVHD grade II-IV was observed in 37% related (grade III-IV: 12%) and in 42% unrelated transplants (grade III-IV: 21%). Based on the International Working Group criteria, in patients who were followed for at least 6 months there were 7 CR, 8 PR, and 11 CI among the 28 patients in the related group, and 5 CR, 1 PR, and 5 CI among the 16 patients in the unrelated group. After a median follow-up for survivors of 24 months, 25 patients (78%) in the related group are alive, 6 patients (18%) died for causes related to transplant (GVHD n=3, cardiac toxicity n=1, renal failure n=1, secondary cancer n=1) and 1 (3%) for progression of disease. In the unrelated group, 15 patients (44%) are alive at 12 months follow-up for survivors, 18 patients (53%) died for causes related to transplant and 1 patient (3%) due to relapse. Median survival time has not been reached in the related transplant group and is 7 months in the unrelated group (hazard ratio 4.2, 95% CI: 1.7–10.1, p<0.001). Survival in unrelated transplants was not associated with HLA matching, diagnosis, or the presence of Jak-2 mutation. In this prospective study a reduced intensity allogeneic HSCT with Flu/Mel regimen was very effective in patients with myelofibrosis transplanted from related donors. In unrelated transplants, a high rate of primary or secondary graft failure led to a high rate of transplant-related-mortality. For these patients a different conditioning regimen may be required. Disclosures:No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem-Cell Transplantation for Myeloma: It's Time for the Appropriate Studies

TO THE EDITOR: The International Myeloma Working Group recently published a consensus statement regarding the use of allogeneic hematopoietic stem-cell transplantation (HSCT) in myeloma. 1 They conclude that new strategies are needed to make allogeneic HSCT safer and recommend reduced intensity conditioning in the context of clinical trials only. The group is to be congratulated for taking up the task for such a consensus statement, and the main conclusions are undoubtedly correct. It is essential to render allogeneic HSCT safer, and further clinical studies are urgently warranted. However, the report misses some important aspects. Some results with allogeneic HSCT for patients with myeloma could be looked at from a different point of view. The conclusions to be drawn and the way forward might then look completely different from the way they are presented in the consensus statement. The authors report that non–relapse mortality is excessively high after allogeneic HSCT for myeloma; they give no explanation for why this is the case. A recent analysis of the European Group for Blood and Marrow Transplantation (EBMT) sheds some light on this erroneous observation. Survival and non–relapse mortality of 1,351 patients with myeloma was not different from survival and non–relapse mortality of patients with any other acquired hematologic disease when risk was adjusted for by the EBMT risk score. 2 In contrast, risk distribution was strikingly different. The risk score includes age, disease stage, time interval from diagnosis, donor type (HLA-identical sibling donor v other), and donor-recipient sex combination (female donor for a male recipient v other). Median age of the patients with myeloma was 46 years, and 60% of them had received transplantations with an EBMT score of 4 or higher. Median age of the 16,000 patients with acute myeloid leukemia was 35 years, and only 24% who had received transplantations had a score of 4 or higher. The sense that there is a higher mortality rate with myeloma is correct. The cause is not the disease but the wrong selection. Recommending allogeneic HSCT to patients for whom autologous HSCT and modern drug therapy have failed will only perpetuate the assumption that allogeneic HSCT is associated with high mortality and is not beneficial. There is no need for novel conditioning regimens. There is an urgent need to investigate standard allogeneic HSCT for the few selected high-risk patients with myeloma who have a donor with a low EBMT risk score. Transplantations should be considered early in the disease course, as soon as remission is reached, when an HLA-identical sibling donor or a fully matched unrelated donor is available for a younger patient with a normal Karnofsky score, and a male recipient should not be given a female donor transplant. Risk of non–relapse mortality will not be higher than that for a comparable patient with leukemia. A randomized study comparing such early HSCT with the current conventional approach could rapidly provide the answer. There is no need to precede the allogeneic HSCT with an autologous transplantation. The tandem approach, autologous HSCT followed by a reduced-intensity conditioning allogeneic transplantation is believed to have improved outcome. This study was reported at a time of general improvement in outcome and provided the impression of early low mortality. 3 No study since has ever confirmed in any disease that separation of cytoreduction and allogeneic HSCT is indeed superior to a direct, full-conditioning allogeneic HSCT. It is an attractive theoretical concept but there are no facts. The authors simply present it as such. There is a more important missing aspect. The authors mention several potential approaches, including reduced-intensity allogeneic HSCT combined with maintenance with one of the novel antimyeloma agents. There are no data, and the authors do not mention costs. Long-term treatment with these novel agents will not be affordable for the vast majority of the global population. An early standard allogeneic HSCT for those few selected patients with high-risk disease and a low-risk transplantation score might provide the most cost-effective approach. Such considerations have been made for patients with chronic myeloid leukemia, and they relate as well to patients with myeloma. 4 Consensus statements should consider global aspects. 5 It is the perfect time to perform the appropriate studies evaluating early allogeneic HSCT for those patients with high-risk disease and a lowrisk donor. The International Myeloma Working Group should be challenged to take on this task.

HLA Alloantibody Persistence and De Novo Production of HLA Alloantibodies of Donor Origin Following Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 1109▪ Background:Platelet refractoriness as a consequence of HLA alloimmunization complicates allogeneic hematopoietic stem cell transplantation (HSCT). Little is known regarding the affects of reduced intensity HSCT on the incidence and duration of HLA alloimmune-mediated platelet refractoriness following reduced intensity HSCT. Methods:We retrospectively studied HLA alloimmunization in 16 patients with malignant and non-malignant hematological disorders, who underwent an allogeneic HSCT from an HLA matched relative using reduced intensity, non-myeloablative conditioning. All patients received a G-CSF mobilized, lymphocyte replete, peripheral blood stem cell (PBSC) allograft following cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) based conditioning (+/− equine ATG 40 mg/kg × 4 days) with cyclosporine (CSA; beginning on day −4) and IV methotrexate (5 mg/m2 × 3 days) given as GVHD prophylaxis. Eight patients known to be HLA alloimmunized pre-transplant were compared to 8 control patients who were HLA alloantibody negative pre-transplant. Stored patients' serum samples from pre-transplant (day -30) and post-transplant intervals (days +30, +60, +100, +180, and ≥ 365) were analyzed for the presence of IgG antibodies to HLA class I antigens using a membrane-independent solid phase assay involving color-coded microbeads coated with HLA antigens and analysis with a flow analyzer (LABScan 100; One Lambda, Canoga Park, CA). Panel reactive antibody (PRA) and mean fluorescent intensity (MFI) were analyzed for all samples to measure HLA antibody strength and specificity, respectively. HLA alloantibodies were analyzed and compared with the degree of donor myeloid and T-cell engraftment measured on post-transplant blood samples by PCR of short tandem repeats (STRs). Results:Among the 8 alloimmunized patients who required HLA matched platelets pre-transplant, the median time until HLA antibodies disappeared was 100 days post HSCT. Remarkably, among these patients, 3/8 (37%) had HLA class I antibodies detectable for more than 100 days post-transplant including one patient who continued to show high level alloreactivity greater than 1 year after HSCT. Among the 8 control patients who tested negative for HLA alloantibodies pre-transplant, 3 acquired HLA alloantibodies after HSCT which were first detected at day +30 in all 3 cases. In 2 of the 3 cases, the donors for these patients were found to have pre-existing HLA antibodies of equivalent specificity to those found in the patient post-transplant suggesting patient acquisition of HLA antibodies was mediated by passenger donor lymphocytes that were transplanted in the allograft. Overall, HLA antibodies were detectable for more than 100 days after transplantation in 6/16 (37%) patients analyzed with 3/16 (18%) having alloantibodies detectable for more than 1 year post-transplant despite chimerism being 100% donor in myeloid and T cell lineages. Conclusions:Prolonged production of HLA alloantibodies leading to platelet refractoriness can occur following reduced intensity allogeneic HSCT and may persist even after full donor myeloid and T-cell chimerism have been achieved. Remarkably, we observed that transplantation of passenger donor lymphocytes can result in de novo HLA alloimmunization, complicating post-transplant transfusion management. Screening patients and their donors for HLA antibodies before HSCT would identify the majority of subjects at risk for alloimmune-mediated platelet refractoriness after transplantation. This new screening strategy would not only assist in transfusion support after allogeneic HSCT but could also play a role in the decision analysis for selecting optimal stem cell donors. Disclosures:No relevant conflicts of interest to declare.

EPOCH-FR: A novel salvage regimen for patients with lymphoid malignancies being considered for reduced-intensity allogeneic hematopoietic stem cell transplantation.

6536 Background: There is no standard chemotherapy regimen for patients (pts) with lymphoid malignancies being considered for reduced intensity allogeneic hematopoietic stem cell transplantation (RI-alloHSCT). The ideal regimen would result in disease control and recipient lymphocyte depletion and have limited toxicity. We developed a novel regimen consisting of continuous infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus fludarabine ± rituximab, depending on CD20+ expression (EPOCH-FR). Methods: 147 pts, median age 50 yrs (range 21-71), with high-risk lymphoid malignancies (47% with chemo-resistant disease to last regimen, median 3 prior regimens [range 1-13]) were given EPOCH-FR (74% dose-adjusted) prior to RI-alloHSCT. Pts received 1 (48%), 2 (21%), or 3 (31%) cycles of EPOCH- FR until they were lymphodepleted (CD4+ count < 100/μl) or had progressive disease. Results: Overall response rate (RR) was 41% (16% CR, 25% PR); 39% had SD. RR of FCC/CLL>DLBCL/HL>TCL (p = 0.047). More EPOCH-FR cycles were associated with higher RR (17% vs. 33% vs. 84%) (p < 0.0001). 17% of pts with chemo-resistant disease had CR/PR. EPOCH- FR resulted in significant lymphodepletion (pretreatment median CD3+ = 574/μl, CD4+ = 244/μl, and CD8+ = 249/μl vs. posttreatment CD3+ = 184/μl, CD4+ = 97/μl and CD8+ = 68/μl (p < 0.0001). Pts with greater lymphodepletion of CD3+ (p=0.038) and CD4+ (p=0.017) were more likely to achieve CR/PR. Toxicity in 263 cycles included Grade 4 thrombocytopenia in 25%, neutropenia in 65%, and non-heme toxicity in 6%. Of 147 pts, 143 proceeded to RI-alloHSCT. Pts with greater lymphodepletion of CD3+ (p = 0.0007), CD4+ (p = 0.0004), and CD8+ (p = 0.0019) were more likely to achieve full donor lymphoid chimerism by Day +14 post-transplant. Following transplant, pts with CR/PR vs SD/PD to EPOCH-FR had median EFS = 77.4 vs. 4.8 mos (p < 0.0001) and OS = 98.5 vs. 16.2 mos (p = 0.0006) respectively. Conclusions: EPOCH-FR safely provides disease response and lymphodepletion in pts with lymphoid malignancies being considered for RI-alloHSCT. No significant financial relationships to disclose.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (RI-HCT) For MDS Using Tacrolimus/Sirolimus As GVHD Prophylaxis

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (RI-HCT) For MDS Using Tacrolimus/Sirolimus As GVHD Prophylaxis

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Abstract 2771Poster Board II-747We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures:Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

The Influence of Disease-Specific Prognostic Factors on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Myeloma

Although allogeneic HSCT is potentially curative in myeloma, series reporting encouraging results with submyeloablative regimens suffer from limited follow-up and incomplete information on prognostic factors known to be relevant in myeloma. The outcome of 24 myeloma patients (50–66 years, median 52) undergoing reduced-intensity allogeneic HSCT after 100 mg/m2 melphalan from related (n=21) or unrelated (n=3) donors. The 9 patients who had not relapsed after preceding autotransplantation received 50 mg/kg cyclophosphamide in addition. No patient underwent a planned sequential autograft-allograft procedure.Complete prognostic factor information was available on each patient. High-risk disease (n=16) was defined by one or more of the following: del(13) on conventional karyotyping, t(4;14), del(17p), plasma cell labeling index >1%, elevated LDH, plasmablastic morphology. The disease was refractory to therapy in 16 patients. Three patients (13%) had disease that was neither high-risk nor progressive, 10 had disease that was either high-risk or refractory, and 11 had refractory, high-risk disease.Four patients died of toxicity (3 GVHD, 1 multiorgan failure) and 19 relapsed. 18 of 19 relapsing patients died of progressive disease and 1 is alive in CR after a second allograft. High-risk (RR 0.11, P=0.0007) disease and refractoriness to therapy (RR=0.10, P=0.0006) were associated with poorer event-free survival. High-risk (RR 0.16, P=0.002) disease and refractoriness to therapy (RR=0.23, P=0.007) were associated with poorer event-free survival.The combination of the two factors resulted in the identification of 3 categories of patients with highly disparate outcomes as shown in Figure 2. [Display omitted] [Display omitted] Our data suggest that the outcome of allogeneic HSCT in myeloma is disappointing unless the disease is sensitive to therapy and biologically low-risk. However, such disease responds exceedingly well to autotransplantation–and is associated with prolonged survival that can rival that seen after allogeneic HSCT. Alternative strategies are needed to improve the outcome of patients with refractory or high-risk disease–and may include elective post-allograft maintenance therapy with novel agents such as thalidomide, lenalidomide or bortezomib.