Low Rates Of Non-relapse Mortality Research Articles

Allogeneic Stem Cell Transplantation for Relapsed and/or Refractory Hodgkin Lymphoma: A Multicenter Real World Experience

Allogeneic Stem Cell Transplantation for Relapsed and/or Refractory Hodgkin Lymphoma: A Multicenter Real World Experience Introduction Relapsed and/or refractory (R/R) Hodgkin Lymphoma (HL) after autologous stem cell transplant (SCT) is associated with poor outcomes and nearly 50% of patients will ultimately relapse. Novel therapeutic agents such as checkpoint inhibitors (CPIs) (nivolumab, pembrolizumab) and brentuximab vedotin (BV) have both shown considerable activity in this patient population, but allogeneic SCT (alloSCT) maintains its curative potential also in the era of new drugs. Herein we report on our multicenter experience with alloSCT for R/R HL. Methods Seventy patients with R/R classic HL who underwent alloSCT between 2004 and 2021 in three transplant centers were included. Patients were included between 2004-2010 (era1) in one centre, 2011-2021 (era2) in all centers. Disease response was evaluated according to Lugano classification. Primary end point was post transplant (tx) overall response rate (ORR). Secondary endpoints were overall survival (OS), progression free survival (PFS), non relapse mortality (NRM) and response rates according to parameters especially tx years, and pre/post tx CPIs and/or BV usage. Results Patient characteristics are summarized in the Table. Median follow up time after alloSCT was 64 months (range, 40.7-87.3). Post tx disease relapse or progression occurred in 23 patients (33%). The median time to disease relapse was 6.3 months (range, 1-24.5). Twenty nine patients were alive at the analytic date (41%); 23 in complete response (CR) (79%), 4 partial response (PR) (14%), 2 stabl disease (SD) (7%). The 3-year OS, PFS were 39% (95% CI 27.2-50.8) and 28% (95% CI 16.2-39.8), respectively; the day 100 and 1-year NRM rates were 26% (95% 16.2-35.8) and 37% (95% CI 25.2- 48.8), respectively. According to the tx year, the pre tx response rates were not statistically different between the two eras (p=0.46) but post tx CR rates were significantly higher in era2 (p=0.01). The survival (OS, PFS) analysis and NRM rates demonstrated no difference between both eras, but the PFS was significantly longer in 2016 and after (p=0.03). Patients who received alloSCT between era 1 and era 2 in one and only centre; the survival rates, and NRM were similar across the two eras. The patients with chemosensitive disease (CR, PR) at the time of alloSCT had more common pre tx BV usage (p=0.03), RIC conditioning regimen (p=0.002), and were with high HCT CI score (p=0.02), while the low proportion of ATG usage (p=0.02). Achievement of a CR at pre tx associated with better OS, PFS, and NRM. Patients in CR at the time of the post tx was associated with significantly improved OS and PFS (p<0.05). Patients who received BV and CPIs at any point pre and post tx had better OS, PFS and the NRM was low, but not statistically significant. There was a lower NRM rates in the post tx BV (p=0.06) and CPIs (p=0.08) usage. Regarding to post tx cyclophosphamide (cy) versus ATG usage; patients who received ATG had signicantly shorter OS (p=0.04), an increase in NRM (p=0.01), but similar PFS (p=0.28) compared with those who did not. Patients who received post tx cy had signicantly better OS (p=0.04) and PFS (p=0.05) but similar NRM (p=0.19) compared with those who did not. There was no statistically significant difference in OS, PFS and NRM with regard to the conditioning regimens (RIC and MAC) (p>0.05). Regarding donor type; the use of pre tx CPIs, TBI in conditioning regimen, and post cy were common for haploidentical (haplo) tx (p<0.05). ATG was used more commonly for matched/mismatched unrelated donor (MUD/MMUD) when compared with matched related donor (MRD) (p<0.001). The incidence of acute graft versus host disease (GVHD) (p=0.09) and chronic GVHD (p=0.002) were higher in patients who received MRD grafts when compared with MUD/MMUD and haplo. Haplo donors had significant better OS (p=0.015) and PFS (p=0.03) compared with MUD/MMUD and MRD. There was a significantly higher NRM in the MUD/MMUD compared with others (p<0.05). Conclusions Our results suggest that alloSCT continues to play an important therapeutic role for patients with R/R cHL. The improved outcomes of alloSCT in HL over time, probably due to general improvements in supportive care, a better selection of patients and the arrival of novel therapeutic therapies. The efficacy of alloSCT can be determined by multicenter prospective studies in selected patient groups.

Allogeneic Blood or Marrow Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Age ≥55 Years

Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of ∼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval [CI], 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio [HR], 4.65; P=.001), whereas transplantation in CR1 (HR, .30; P=.004) and transplantation for Philadelphia chromosome-positive (Ph+) ALL versus T-ALL (HR, .29; P=.03) were associated with improved RFS. Of the 54 patients who underwent RIC alloBMT in CR1 for B-ALL, the 5-year RFS and OS were 62% (95% CI, 47% to 74%) and 65% (95% CI, 51% to 77%), respectively, with a 5-year relapse incidence of 16% (95% CI, 7% to 27%) and an NRM of 24% (95% CI, 13% to 36%). RIC alloBMT with PTCy in CR1 represents a promising consolidation strategy for B-ALL patients age ≥55 years.

Allogeneic Blood or Marrow Transplantation (AlloBMT) with High-Dose Post-Transplantation Cyclophosphamide (PTCy) for Acute Lymphoblastic Leukemia (ALL) in Patients Aged ≥ 55: Best Results in B ALL in First Remission (CR1) with Reduced-Intensity Conditioning (RIC)

Background: Older patients with ALL fare poorly with conventional chemotherapy. Patients aged 55-65 on E2993 and ≥ 60 treated with Hyper-CVAD have 5-year overall survival (OS) of just 21% and 20%, respectively (Sive. BJH. 2012 and O'Brien. Cancer. 2008). Recently, HyperCVD with inotuzumab +/- blinatumomab in patients ≥ 60 years old with Ph- B ALL demonstrated an improved 5-year OS of 47% with 38% of patients dying in remission (Short. Blood. 2021). AlloBMT provides an alternative consolidation strategy. Registry studies in ALL patients ≥ 60 years old and B ALL patients ≥ 55 years old who underwent alloBMT with RIC in CR1 demonstrated 5 and 3-year OS of 42% and 45%, respectively (Roth-Guepin. Oncotarget. 2017 and Rosko. Am J Hematol. 2017). These studies utilized heterogenous conditioning and graft-versus-host disease (GVHD) prophylaxis regimens. The use of high-dose post-transplantation cyclophosphamide as GVHD prophylaxis facilitates transplants in older adults with low rates of non-relapse mortality, GVHD, and the use of HLA haploidentical donors (Kasamon. JCO. 2015). Methods: The bone marrow transplant database at Johns Hopkins was queried for patients ≥ 55 years old who received a first alloBMT using PTCy from January 2008-January 2021. Characteristics of patients were summarized and compared using Fisher's exact test for categorical variables. Estimators of OS and relapse-free survival (RFS) were reported using the Kaplan-Meier method. Differences in time-to-event outcomes were estimated using Cox proportional hazards model, or Fine and Gray's model for cumulative incidence of relapse (CIR)/nonrelapse mortality (NRM) considering competing risks. Results: A total of 77 patients aged ≥ 55 underwent a first alloBMT with PTCy for ALL. The vast majority were performed in CR1 (85.7%), utilized RIC (88.3%), and were performed for B ALL (90.9%). Demographics and transplant characteristics are presented in Table 1. RIC consisted of fludarabine, cyclophosphamide and total body irradiation followed by PTCy-based GVHD prophylaxis as previously described (Kasamon. BBMT. 2008). Relapse-free survival (RFS) and OS at 5 years for the entire cohort were 46% (95% CI 34-57) and 49% (95% CI 37-60), respectively, with a 5-year CIR of 27% (95% CI 18-38) and NRM of 28% (95% CI 18-39). The cumulative incidences of grade 3-4 acute GVHD at 1 year and chronic GVHD at 3 years were 3% (95% CI, 0% to 9%) and 13% (95% CI 5% to 21%), respectively. In univariate analysis, the use of myeloablative conditioning led to worse RFS (HR 0.25, p=0.0004); while the absence of MRD (HR 2.93, p=0.008), transplant in CR1 (HR 3.81, p=0.0004), and transplant for Ph+ ALL vs. T ALL (HR 3.15, p=0.03) led to improved RFS. Subsequent analysis focusing on the 54 patients receiving RIC alloBMT in CR1 for B ALL demonstrated RFS and OS at 5 years of 61% (95% CI 46-73) and 64% (95% CI 49-76), respectively, (see Figure 1) with a 5-year CIR of 16% (95% CI 7-27) and NRM 24% (95% CI 13-36), although just 7% at 1 year. For B ALL patients transplanted with RIC in CR1, 3-year NRM was higher among patients who received a peripheral blood stem cell transplant (55%, 95% CI 18% to 81%), those treated with rituximab pre-transplant (36%, 95% CI 16% to 57%), and those who received ≥100 mg/m2 of doxorubicin equivalent for ALL (67%, 95% CI 19% to 90%). Outcomes did not differ among the 20% of patients who received pre-transplant blinatumomab compared to those who did not. Among the 23 Ph+ B ALL patients transplanted with RIC in CR1 following treatment with a 2nd or 3rd generation tyrosine kinase inhibitor (TKI), the 5-year CIR was 5% (95% CI, 0% to 22%). Conclusions: RIC AlloBMT with PTCy in CR1 represents a promising consolidation strategy for B ALL patients ≥ 55 years old. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics of Graft-Versus-Host Disease (GvHD) After Post-Transplantation Cyclophosphamide Versus Conventional GvHD Prophylaxis

Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P=.001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P=.01), and chronic GI GvHD (21% versus 31%, P=.006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGvHD rate after Haplo/PTCY was also lower (hazard ratio [HR]=.4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR=.6, P=.01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR=.6, P=.04). Mortality rate was higher (HR=1.6, P=.03) during, but not after (HR=.9, P=.6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.

Rabbit Anti-Thymocyte Globulin Exposure (rATG) in CD34+ Selected Hematopoietic Cell Transplantation and Its Impact on Immune Reconstitution and Outcomes in Children and Adults

Rabbit Anti-Thymocyte Globulin Exposure (rATG) in CD34+ Selected Hematopoietic Cell Transplantation and Its Impact on Immune Reconstitution and Outcomes in Children and Adults

Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients

Allogeneic hematopoietic stem cell transplant (HSCT) for relapsed pediatric non-Hodgkin lymphoma (NHL) is often reserved for patients with certain NHL subtypes or high-risk disease whereas the remainder receive autologous HSCT. Given the aggressive nature of pediatric NHL, we performed allogeneic HSCTs for all patients regardless of disease risk. We report overall survival (OS) and prognostic variables in 36 pediatric patients who underwent allogeneic HSCT between 1998 and 2016. OS at 3 years was 67%. The 3-year OS varied based on NHL subtype: 100% for anaplastic large cell lymphoma (n = 14), 63% for diffuse large B-cell lymphoma (n = 8), 17% for lymphoblastic lymphoma (LL; n = 9) and 80% for other subtypes combined (n = 5). Disease status influenced outcome with 3-year OS of 100% for patients in complete remission (n = 15), 59% with partial remission (PR; n = 17), and 0% with progressive/stable disease (n = 3) (P = .004). Of the 17 patients in PR, all 6 with LL died of relapsed disease, whereas the other 11 attained remission after HSCT and remained disease-free. The cumulative incidence of relapse after HSCT for LL was 78% compared with 15% for all other NHL subtypes combined (P < .0001). Cumulative incidence of nonrelapse mortality (NRM) was low in our cohort at 6%. Hence, allogeneic HSCT is a well-tolerated and useful therapeutic option with low rates of NRM and relapse for all NHL subtypes except LL with active disease at HSCT.

Fludarabine and Total-Body Irradiation Conditioning before Ablative Haploidentical Transplantation: Long-Term Safety and Efficacy

Although myeloablative conditioning (MAC) before haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is being increasingly used, the optimal preparative regimen remains unclear. In our initial trial, the feasibility of HIDT following a MAC preparative regimen using fludarabine and 12 Gy of total-body irradiation was demonstrated in 30 patients. We now present long-term outcome results, including an additional 52 patients, now with 47 months (16 to 96) median follow-up. Median patient age was 42 (19 to 61) years. The most common diagnoses were acute myelogenous leukemia (51%) and acute lymphoblastic leukemia (33%), and 39% had a high/very high disease risk index (DRI). Engraftment was universal with no cases of primary or secondary graft failure. Grade 3 to 4 acute graft-versus-host disease (GVHD) and moderate to severe chronic GVHD occurred in 17% and 23%, respectively. Nonrelapse mortality (NRM) was 7% at 1 year and 13% at 4 years. Estimated 4-year overall survival (OS), disease-free survival, and cumulative incidence of relapse (CIR) were 67%, 60%, and 27%, respectively. CIR was significantly higher in patients with high/very high- versus low/intermediate-risk DRI (38% versus 20%, P= .032), which led to inferior 4-year OS (50% versus 77%, P = .001). Median time to systemic immunosuppressive therapy (IST) discontinuation was 7.8 months, with 84% of patients off IST at 2 years post-transplant. Current GHVD-free, relapse-free survival (CGRFS) at 2, 3, and 4 years was 60%, 57%, and 60%, respectively. This approach to MAC HIDT results in universal engraftment; low rates of NRM, infection, and clinically significant GVHD; and relatively rapid IST discontinuation, resulting in high rates of CGRFS and survival.

Higher Graft T Cell and CD34 Cell Content Is Associated with Earlier Complete Chimerism, Lower Relapse Rates, and Improved Overall Survival (OS) in Recipients Undergoing Matched Related (MR) Myeloablative Hematopoietic Stem Cell Transplant (HSCT) on the 2 Step Approach

To reduce non-relapse mortality (NRM) due to graft versus host disease (GVHD) in matched related HSCT, we used cyclophosphamide (CY) T cell tolerization within the framework of a 2 step myeloablative approach in recipients with hematological malignancies. Patients were treated on our institution's 2 step approach in which after 12 Gy conditioning, a fixed dose of 2 × 108/kg unmanipulated T cells (DLI) was administered (step 1) followed 2 days later by CY 60 mg/kg/d x 2 days. One day later, a CD34-selected graft was infused (step 2). MMF and tacrolimus were initiated on d-1, the former discontinued on d+28 and a taper of the latter by day +42 in the absence of GVHD. All donors began G-CSF after DLI collection to obtain a mobilized stem cell product (PBSC). To examine the impact of cell doses on outcomes, T cell chimerism at d+28, relapse, grades 2-4 acute and chronic GVHD, OS, and NRM were analyzed based on whether patients received above or below the median CD34 cell dose (CD34HI v LO), or above or below the median residual T cell dose (T HI v LO) in the PBSC products for the whole group. 46 consecutive patients, median age 50 with AML (18), MDS (7), ph+ (5) and B cell (5) ALL, CMML (3), NHL (6), MPD (2) were treated from 2008-2018 on this recently completed study. Median follow-up is 49.3 months (range 2-122 months), revised disease risk index was intermediate (31), high (14) and very high (1). In the PBSC products, median CD34 cell dose was 4.90 × 106/kg (range 1.64-10 × 106/kg) and median residual non-tolerized T cell dose was 3.0 × 103/kg (range 0.96-17 × 103/kg). One patient rejected, alive after a 2nd transplant, but leaving 45 for full analysis. At 3 years, cumulative incidence (CI) of relapse for recipients in the CD34HI v CD34LO group was 24% v 55% (p=0.123). CI of relapse for recipients in the T HI v T LO group was 21% v 59% (p=0.029). NRM, cGVHD, and aGVHD rates were virtually identical in all cell groups and low at 5%, 11%, and 9% for the total group respectively. Higher CD34 and residual T cell graft content correlated with ≥98% T cell chimerism at d+28, CD34HI v LO p=0.09 and T HI v T LO p=0.047-Chi square. Recipients with T cell chimerism of ≥98% at d+28 had a CI relapse of 27% v 55% in those with The 2 Step regimen was associated with very low rates of NRM, aGVHD and cGVHD even in patients with higher graft content of non-tolerized T cells. The major barrier to success was relapse, improved with higher CD34 and T cells doses in the PBSC product. OS and T cell chimerism were improved in patients receiving higher amounts of CD34 and T cells, with

Expression of Serum microRNAs is Altered During Acute Graft-versus-Host Disease.

Acute graft-versus-host disease (aGvHD) is the most frequent and serious complication following hematopoietic stem cell transplantation (HSCT), with a high mortality rate. A clearer understanding of the molecular pathogenesis may allow for improved therapeutic options or guide personalized prophylactic protocols. Circulating microRNAs are expressed in body fluids and have recently been associated with the etiology of aGvHD, but global expression profiling in a HSCT setting is lacking. This study profiled expression of n = 799 mature microRNAs in patient serum, using the NanoString platform, to identify microRNAs that showed altered expression at aGvHD diagnosis. Selected microRNAs (n = 10) were replicated in independent cohorts of serum samples taken at aGvHD diagnosis (n = 42) and prior to disease onset (day 14 post-HSCT, n = 47) to assess their prognostic potential. Sera from patients without aGvHD were used as controls. Differential microRNAs were investigated in silico for predicted networks and mRNA targets. Expression analysis identified 61 microRNAs that were differentially expressed at aGvHD diagnosis. miR-146a (p = 0.03), miR-30b-5p (p = 0.007), miR-374-5p (p = 0.02), miR-181a (p = 0.03), miR-20a (p = 0.03), and miR-15a (p = 0.03) were significantly verified in an independent cohort (n = 42). miR-146a (p = 0.01), miR-20a (p = 0.03), miR-18 (p = 0.03), miR-19a (p = 0.03), miR-19b (p = 0.01), and miR-451 (p = 0.01) were differentially expressed 14 days post-HSCT in patients who later developed aGvHD (n = 47). High miR-19b expression was associated with improved overall survival (OS) (p = 0.008), whereas high miR-20a and miR-30b-5p were associated with lower rates of non-relapse mortality (p = 0.05 and p = 0.008) and improved OS (p = 0.016 and p = 0.021). Pathway analysis associated the candidate microRNAs with hematological and inflammatory disease. Circulating biofluid microRNAs show altered expression at aGvHD onset and have the capacity to act as prognostic and diagnostic biomarkers. Their differential expression in serum suggests a role for circulatory microRNAs in aGvHD pathology, which warrants further investigation.

Myeloablative Allogeneic Hematopoietic Cell Transplantation Performed without Routine Inpatient Admission: A Single Center Experience of 462 Consecutive Patients

Patients undergoing allogeneic hematopoietic cell transplants (Allo-HCT) using myeloablative preparative regimens are usually admitted to an inpatient transplant unit from the start of the conditioning regimen until hematopoietic recovery (on average 25-35 days). Historically, the rationale for routine inpatient care during this period has been the facilitation of administration of parenteral medications, prevention of mold infections and the monitoring and management of acute toxicities. However, advances in supportive care and other technologies may allow outpatient management during this period. We analyzed outcomes of all consecutive patients who underwent myeloablative allo-HCT as defined by the CIBMTR (Giralt 2009, BBMT) with planned total outpatient management at our center. Patient characteristics and outcome data were prospectively entered into our institutional database from which they were extracted for this analysis. Patients were scheduled to receive their conditioning regimen and post-transplant care in our purpose-built outpatient clinic. Patients received their stem cell infusion on the inpatient unit and were planned to be discharged home the same day except patients receiving haploidentical transplants who were planned to be discharged on day +5 to accommodate the early cytokine release syndrome commonly seen in such patients (Solomon BBMT 2012). Subsequent admissions were for significant complications necessitating inpatient management only. Our technical approach to total outpatient management of myeloablative allo-HCT was as previously described (Solomon BMT 2010, 45: 468-475). Patients (n=462) were transplanted consecutively between 4/08 and 12/15. Patient characteristics were: median age 46; male (53%); race - white 79%, black 18%, Asian 2%; diagnosis- AML 42%, ALL 21%, MDS/MPS 21%, NHL/HL/CLL 13%, other 3%; donor type - MRD 48%, MUD 35%, Haplo 17%, CBT <1%; graft source- PBSC 87%, BM 12%, BM+PBSC 1%; regimen-busulfan based 60%, TBI based 39%, other 1%; DRI -low 16%, intermediate 48%, high 26%, v. high 10%; HCT-CI- 0-2 (64%), ≥3(36%). The conditioning regimen was entirely delivered in the outpatient clinic as planned in 377 patients (82%). Of 85 (18%) patients who received some of their conditioning regimen in the inpatient setting, in 42(49%) this was to receive drugs not administrable or reimbursed in the outpatient setting, and in 43(51%) it was for management of toxicity. The majority of patients were discharged within 24 hours of stem cell infusion (311 -67%) with the median day of discharge for the remaining patients being d+13 (range d+2 to d+75). Following discharge after stem cell infusion, 82 patients (18%) were never readmitted, days to readmission for the remainder were 0-5 (40%), 6-9 (24%), > 10 (18%). For readmitted patients, most frequent reasons were - febrile neutropenia 33%, mucositis 29%, and lower GI toxicity 4.5%. Median total length of inpatient stay through d+100 was 16 d (range 1-98). Fungal infections were documented in only 3 patients (1%) through d +100. With a median follow-up for surviving patients of 52 months (6-218 months), K-M estimates of survival and DFS at 1 yr are 70% and 61% and at 4 years are 52% and 47% respectively. Cumulative incidences (CI) of non-relapse mortality (NRM) and relapse at 1 yr are 17% and 21% and at 4 yrs are 24% and 29% (Fig.1). CI of acute GVHD grade 2-4 and 3-4 at 6 months were 28% and 10%. CI of moderate to severe, and severe chronic GVHD at 4 years were 30% and 12%. On multivariate analysis, receipt of any part of the conditioning regimen as inpatient was a significant negative factor for survival (HR 1.99, p<0.001), DFS (HR 1.74, p =0.001) and NRM (HR 2.06, p=0.004). These data show that myeloablative allo-HCT performed without routine inpatient admission from conditioning through neutrophil recovery is feasible with low rates of NRM and fungal infection. Median total inpatient stay through d +100 can be reduced to 16 days and nearly 20% of patients can avoid any inpatient stay through d +100. With mature follow-up outcomes appear similar or superior to those commonly reported using a traditional inpatient approach. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prophylactic Natural Killer Cell Immunotherapy Following HLA-Haploidentical Hematopoietic Cell Transplantation Prevents Relapse and Improves Survival in Patients with High-Risk Hematological Malignancies

Background: Regimens using post-transplant cyclophosphamide (CY) have been developed to provide potent in vivo T cell depletion for patients undergoing human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplantation (HCT). Luznik, O'Donnell and colleagues (BBMT 2008) reported that when this immune suppression strategy is coupled with non-myeloablative conditioning (fludarabine 150 mg/m2, CY 29 mg/kg, 2 Gy total body irradiation) followed by marrow transplantation, it was well-tolerated with low rates of non-relapse mortality (NRM; 15% at 1 year). However, the 2 year overall survival (OS) and event-free survival were low at 36% and 26%, respectively, due to high relapse rates (51% at 1 year). One explanation could be that while post-HCT CY promoted low rates of acute graft-versus-host disease (GVHD), it also eliminated early T and natural killer (NK) cell clones important for disease surveillance. Based on this hypothesis, we developed a next-generation Phase I/II clinical trial incorporating a boost of donor NK cells on day +7 as an attempt to prevent relapse after transplant. In this study, CY 50 mg/kg as a single dose on day +3 was used for T cell depletion.Methods: Forty patients (pediatric, n=14; adult, n=26) with median age of 45 (range 8-75) years having ALL (n=11), AML (n=9), MDS (n=6), HL (n=6), MM (n=4), NHL (n=3), and CLL (n=1) underwent non-myeloablative transplantation using related, HLA-haploidentical marrow donors on this prospective clinical trial. Patients were high risk due to underlying disease, potential for relapse, and/or risk for transplant-related mortality (TRM). Most patients were heavily pre-treated, with median time from cancer diagnosis to transplant being 2 (0.3 - 12.1) years, including 18 patients having 26 prior HCTs (auto, n=14; allo, n=12). Twenty-five patients (63%) had HCT-CI scores ≥ 3 indicating high risk for TRM.In order to obtain NK cells, non-mobilized peripheral blood mononuclear cells were collected from donors on day +6 using apheresis and stored overnight. NK cells were isolated on day +7 using the Miltenyi CliniMACS system (CD3 depletion followed by CD56 selection) and were administered as a single, fresh infusion that same day without prior culturing or expansion. The Phase I dose-finding study (n=11) enrolled at 2 NK doses [2.5 or 5 x 106/kg +/- 20%, respectively], with extended enrollment at the 2nd dose level for Phase II (n=29) with 83% of patients meeting NK dose parameters. NK cell products had a median log T cell depletion of 5.4 (4.1-7.1), median NK recovery of 54% (33-68%), and median NK purity of 92% (74-99%). Excellent viability (>95%) was seen in all NK products.Results: One patient developed chest pain associated with NK cell infusion; otherwise all other patients tolerated their NK cell infusions well without fevers or other adverse reactions. Full donor chimerism (>95% CD3) was seen in 83% of patients at last follow-up, while 18% and 10% experienced graft rejection or graft failure, respectively. Cumulative incidence of grades 2-3 and grade 3 (no grade 4 seen) acute GVHD occurred in 36% and 8% of patients, respectively, at day +100. Of the 39 evaluable patients, 16% developed chronic extensive GVHD at 1 year. Relapse or progression occurred in 31% of patients by 1 year after HCT. With a median follow-up of 1.5 years (range, 0.1 - 4.9 years), 14 patients have died from relapse/progression (n=11) or infection/VOD (n=3), giving a probability of OS, relapse/progression-free survival (PFS), and NRM at 1 year of 73%, 62%, and 8%, respectively, and 2 year OS and relapse/PFS of 63% and 46%, respectively (Fig 1).Summary: We have demonstrated the safety of infusing donor NK cells early after HCT in a group of heavily-treated patients with high-risk hematological malignancies. In many patients, disease-free survival was possible with the aid of this prophylactic infusion of donor NK cells in combination with allogeneic HCT. These results provide a promising platform to further augment NK cell alloreactivity in the post-HCT setting to prevent relapse and disease progression. [Display omitted] DisclosuresHari:Merck: Research Funding; BMS: Honoraria.

Combination Therapy for Graft-versus-Host Disease Prophylaxis with Etanercept and Extracorporeal Photopheresis: Results of a Phase II Clinical Trial

Reduced-intensity conditioning (RIC) regimens minimize early toxicity after allogeneic hematopoietic cell transplantation (HCT) by placing greater reliance on establishing a graft-versus-leukemia effect (GVL). Because graft-versus-host disease (GVHD) and GVL are tightly linked, inhibition of T cell populations that cause GVHD may lead to an unintended increased risk of relapse in the RIC setting. Although not completely understood, etanercept and extracorporeal photopheresis (ECP) are thought to ameliorate GVHD without direct T cell inhibition. We hypothesized that adding these 2 agents to a standard GVHD prophylaxis regimen of tacrolimus and mycophenolate mofetil (MMF) would improve survival by reducing GVHD-related mortality without increasing relapse rates. Therefore, we conducted a prospective phase II clinical trial that incorporated tacrolimus, MMF, etanercept, and ECP as GVHD prophylaxis in 48 patients undergoing RIC unrelated donor transplantation. The preferred RIC was fludarabine 160 mg/m2 + busulfan 6.4 mg/kg to 12.8 mg/kg ± total body irradiation 200 cGy. Etanercept .4 mg/kg (maximum dose, 25 mg) was given subcutaneously twice weekly for 8 weeks after HCT and ECP was given for 12 treatments, starting weekly on day 28 weekly and tapering off by day 180. The median age of the study patients was 60 (range, 18 to 71) years. Donors were 7/8 (n = 14, 29%) or 8/8 (n = 34, 71%) HLA matched. All patients engrafted neutrophils at a median of 12 days. The cumulative incidence of grades II to IV acute GVHD at day 100 was 46%, but it was typically sensitive to initial steroid treatment (84% day 56 complete response/partial response rate). Overall survival at 1 year in this older, frequently mismatched unrelated donor setting was excellent (73%) because of low rates of nonrelapse mortality (21%) and relapse (19%). However, this strategy was not effective at preventing a high incidence of chronic GVHD and late deaths led to a drop in 2-year survival, declining to 56%, reflecting a high incidence of chronic GVHD.

Social Economic Status Is Associated with a Lower Non-Relapse Mortality Rate and an Increased Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation

Studies suggest that among cancer patients undergoing hematopoietic stem cell transplantation (HSCT), low socioeconomic status (SES) is associated with worse outcomes and higher mortality. Assessment of SES in these studies has generally been limited to a single dimension such as household income. We examined outcome after HSCT as a function of financial resources at the household and community level, and explored whether their association with survival reflected educational disparities. 383 patients underwent allogeneic HSCT (57% male; 82% White; mean age 50 y; 66% leukemia, 21% lymphoma). Pre-transplant, a social worker documented patients’ financial resources and educational background. Via census data, we derived median household income and high-school graduation rates at the census-block level. HSCT outcomes over six years were obtained from medical records. Controlling for demographics (age, gender, race, marital status) and medical factors (disease, pre-transplant chemotherapy, remission status, cell dose, donor-recipient CMV status, donor sex), greater pre-transplant financial resources were associated with longer survival (HR 1.55; p=0.007), as was higher median neighborhood income (HR 1.52; p=0.02). When entered simultaneously, higher financial resources (HR 1.45; p=0.03) and neighborhood income (HR 1.54, p=0.06) continued to predict longer survival. Adding educational attainment did not change the magnitude of these associations (financial resources HR 1.60; neighborhood income HR 1.90). Also, greater pre-transplant financial resources were associated with lower non-relapse mortality (NRM) than lower resources (HR 0.45; p=0.03). Greater financial resources are associated with lower non-relapse mortality and higher 2-year overall survival post-HSCT. This association is independent of educational attainment, suggesting that it reflects the influence of resources as opposed to knowledge or health literacy.

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

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

Haploidentical Peripheral Blood Stem Cell Transplantation Using Non-Myeloablative Conditioning With Post-Transplant Cyclophosphamide Regimen Is Safe and Is Associated With Very Encouraging Post-Transplant Outcomes

Introduction The availability of HLA matched donors remains a major obstacle for successful allogeneic hematotopoietic cell transplantation. The use of HLA-mismatched alternate donors such as cord blood and haploidentical donor stem cell sources have allowed for greater access for those patients who need an allo-HSCT but lack a suitable matched sibling or unrelated donor. Introduction of high dose cytoxan in the early post-transplant period has significantly improved the outcomes of patients undergoing haploidentical transplantation and has eliminated the need for expensive and labor-intensive ex-vivo T cell depletion. Encouraging results have been reported using this platform with bone marrow as the source of stem cells. However, there have been only limited reports using this transplant platform with G-CSF mobilized peripheral blood stem cells (PBSC) as a source of stem cells for haloidentical transplantation. Here we report the outcomes of 18 patients who underwent haploidentical transplant for hematological malignancies from single institution treated on the Hopkins non-meloablative conditioning regimen but with G-CSF mobilized PBSC as a source of stem cells from a haplo-identical family donor. Patients and Methods A total of 18 patients (median age 41 years, range 22-73 years, 11 males and 7 females) between July 2009 and June 2013 underwent haploidentical transplant at Washington University School of Medicine in St Louis using the Hopkins non-myeloablative conditioning regimen with post transplant cytoxan (fludarabine (30 mg/m2/day on days -6 to -2), cytoxan (14.5 mg/kg/day on days -6 and -5) and TBI (single dose at 200cGy on day -1) and all these patients received two doses of post-transplant cytoxan (50mg/kg on D+3 and D+4). G-CSF mobilized PBSC from parents (n=9) or siblings (9) were used as a graft source with median CD34+ cell dose of 5.0 x 106/kg and median CD3+ T cell dose of 19.7 x 107/kg. GVHD prophylaxis regimen included MMF plus tacrolimus (16/18 patients) or MTX plus tacrolimus (2/18 patients). Median follow-up of all patients was 251 (range 17-1174) days. Diagnoses included AML (n=12), ALL (n=2), NHL (n=2), CLL (n=1) and aplastic anemia (n=1). 7 out of 12 AML patients underwent transplant with active disease (not in remission) and 4/18 of these patients had prior history of allogeneic HCT. Results 16 patients (89%) engrafted (&gt; 95% donor chimerism), median time to neutrophil engraftment was 15 days (range: 12-28 days) and median time to platelet engraftment was 18 days (range: 11-40 days). None of these patients had secondary graft failure. 1-year overall survival (OS) for all patients was 62% and 100-day and 1-year non-relapse mortality (NRM) rates were 11% and 17% respectively. Both 1-year and 2-year relapse free survival (RFS) rates were 53%. Despite very high CD3+ T cell doses, cumulative incidence of grade II-IV aGVHD was 40.7% while grade III-IV aGvHD occurred in only 3 patients (17%). Cumulative incidence of cGVHD at 1 and 2 years were both at 8% (extensive in only 1 patient). CMV reactivation occurred in 11 patients (61%) but did not significantly impact their survival or relapse rates and none of these patients developed CMV disease. Conclusions Here we report the outcomes of 18 patients with hematologic malignancies or marrow failure states undergoing haploidentical transplant using the published Hopkins NMA conditioning platform with post-transplant high dose cytoxan and with G-CSF mobilized PBSC as a source of donor stem cells. In spite of the limited numbers of patients transplanted, our results suggest that this approach is both safe and effective and associated with rapid multilineage engraftment, low rates of both aGvHD and cGvHD and encouraging overall and disease-free survival rates and low rates of NRM. Based on these results, 1) G-CSF mobilized PBSC from haploidentical donors should be considered as an alternative source of haploidentical stem cells to BM and 2) future randomized trials using this platform to test the role of haploidential G-CSF mobilized PBSC with other unrelated donor stem cell sources (cord blood and matched unrelated could also be considered in the future. Disclosures: Abboud: Alexion: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Teva: Speakers Bureau.

Novel conditioning regimens for bone marrow transplantation

Novel conditioning regimens for bone marrow transplantation Ming Shi, Ming Li, Susumu IkeharaDepartment of Stem Cell Disorders, Kansai Medical University, Moriguchi City, Osaka, JapanAbstract: Bone marrow transplantation (BMT) has evolved into an effective strategy for the treatment of hematological and oncological disorders. Radiotherapy and chemotherapy are used as conditioning regimens prior to BMT to suppress host immunity and reduce tumor burden. High doses of total body irradiation are conventionally administered along with alkylating agents, ie, the myeloablative regimen, to help ensure rapid engraftment of donor cells and to prevent relapse. However, the toxicity of the myeloablative conditioning regimen and unacceptable nonrelapse mortality rules out this approach for older patients by whom less intense preparative regimens are likely to be better tolerated. The reduced-intensity and nonmyeloablative conditioning regimens have been demonstrated by many investigators to be novel approaches resulting in a lower nonrelapse mortality rate and lower incidence of severe acute graft versus host disease. Here, we review the conditioning regimens employed as a pretreatment for BMT, and focus on the novel conditioning regimens and cutting edge developments.Keywords: myeloablative conditioning regimen, reduced-intensity conditioning, nonmyeloablative conditioning regimen, relapse, nonrelapse mortality, graft versus host disease

Favorable Immune Reconstitution After Nonmyeloablative, T-Cell Replete, HLA-Haploidentical BMT with Post-Transplant Cyclophosphamide

Abstract 1009Delayed immune reconstitution with increased risk of opportunistic infection is a major complication of HLA-haploidentical stem cell transplantation, especially in protocols employing extensive T cell depletion of the graft. Previous studies at our institution with high-dose, post-transplantation Cy (PT/Cy) have reported low rates of non-relapse mortality and serious opportunistic infections. Here we characterize immune reconstitution in fifty-three consecutive hematologic malignancies patients receiving nonmyeloablative conditioning, T cell-replete, HLA-haploidentical bone marrow transplantation (BMT), and graft versus host disease prophylaxis including PT/Cy. Patients with advanced hematologic malignancies (median age 51, range 14–71; 5 AML, 2 ALL, 4 MDS, 2 CML, 4 CLL, 1 CMML, 25 NHL, 7 Hodgkins, 3 mantle cell) received Cy 14.5 mg/kg/day IV on days −6 and −5, fludarabine 30 mg/m2/day IV on days −6 to −2, 200 cGy of TBI on day -1 and T cell replete bone marrow from donors with a median age of 44 (range 14–68). GVHD prophylaxis consisted of Cy (50 mg/kg/day) on days 3 and 4, mycophenolate mofetil for 30 days, and tacrolimus for 6 months. Grafts contained an infused median TNC/kg of 4.1 e8 (range 2.6–6.6 e8), CD3+/kg 3.6 e7 (range 1.7–6.7e7) and a CD34+/kg of 3.5e6 (range 1.4–7.0e6). Sustained engraftment of donor cells occurred in 86% of evaluable patients (44/51).The median times to neutrophil (>500/μL) and platelet recovery (>20,000/μL) were 17 days (range, 13–92 days) and 28 days (range, 13–580 days), respectively. Post-transplantation recovery of lymphocyte subsets is shown in Table 1 and Figure 1 and is notable for the following: 1) The median lymphocyte count at day 30 after transplantation is >180/ml and recovers to over 800/ml by day 60; 2) CD4+ T cell counts recover to a median >120/ml by day 60 and >220/ml by day 180 after transplantation; and 3) recovery of CD31+ recent thymic emigrants and CD45RA+ naïve T cells is delayed compared to recovery of memory T cells. T cell receptor spectratyping analysis on a subset of 10 patient/donor pairs chosen specifically for having no relapse/no GVHD (n=4), GVHD and no relapse (n=3), or late relapse (n=3) revealed that patients without relapse, GVHD, or recent viral infection had excellent reconstitution of the T cell repertoire to the level of the pre-transplant donor, as early as 6 months post-transplant (Figure 2). CMV specific T cell response using ELISPOT measured on a subset of 17 patients whose donors were reactive to CMV, revealed that donor-derived immunity to CMV returns by Day 60 in about 70% of patients (12/17) (Figure 3). In conclusion, immune reconstitution after non-myeloablative haploidentical T cell replete BMT with PT/Cy compares favorably with other reduced intensity conditioning alternative donor regimens and suggests that PT/Cy selectively preserves pathogen-specific memory T cells necessary to protect against infection. Further correlations of immune reconstitution with specific infectious and overall outcomes are being analyzed. [Display omitted] [Display omitted] [Display omitted] Table 1Post-transplantation Lymphocyte Subset RecoveryMedian (cells/μL) (N)Interquartile range (cells/μL)ALCDonor1765 (46)1480–2100Recipient pre-BMT840 (45)425–1295Day 30184 (49)54–402Day 60820 (38)470–1260Day 180915 (34)670–1560Day 3653060 (22)820–2030CD3+CD4+CD45RA+ (naïve)Donor119 (33)82–189Recipient pre-BMT22 (34)4–38Day 300.33 (35)0.07–1Day 603 (29)1–9Day 18011 (23)5–31Day 36523 (13)13–92CD3+CD4+CD45RA−CCR7+ (central memory)Donor135 (33)95–158Recipient pre-BMT54 (34)11–79Day 302 (35)0.5–11Day 6034 (29)10–79Day 18061 (23)35–117Day 36589 (13)60–122CD3+CD4+CD45RA−CCR7− (effector memory)Donor187 (33)130–245Recipient pre-BMT87 (34)14–134Day 303 (35)1–18Day 6059 (29)14–122Day 180102 (23)43–179Day 365142 (12)64–204CD3+CD4+CD45RA+CD31+ (recent thymic emigrants)Donor61 (33)30–97Recipient pre-BMT6 (34)1–16Day 300.9 (35)0.03–0.4Day 601 (29)0.5–2Day 1804 (23)1–11Day 3657 (13)2–12CD3+CD4+Foxp3+Donor28 (33)23–35Recipient pre-BMT13 (34)6–24Day 301 (35)0.1–5Day 608 (29)4–16Day 18013 (23)7–25Day 36514 (13)7–17ALC, absolute lymphocyte count; WBC, white blood cell count; Treg, regulatory T cell Disclosures:Jones:Aldagen: Patents & Royalties.

Clinical Significance of Platelet Count at day +60 After Allogeneic Peripheral Blood Stem Cell Transplantation

Thrombocytopenia (TP) is a frequent complication after allogeneic stem cell transplantation (SCT) and regarded as a poor prognostic factor, especially in patients with chronic graft-versus-host disease (GVHD), although various factors were related to the development of TP after allogeneic SCT. Sixty-three patients receiving allogeneic peripheral blood stem cell transplantation (PBSCT) were stratified according to platelet count (PC) at day +60 and analyzed in terms of overall survival (OS) and the incidence of non-relapse mortality (NRM). Ten patients (15.9%) were stratified in group 1 (PC ≤29×109/L), 23 patients (36.5%) in group 2 (PC 30-79×109/L), and 30 patients in group 3 (PC ≥80×109/L). Group 3 was associated with lower incidence of extensive chronic GVHD (p=0.013), better 3-yr OS (p=0.0030), and lower NRM rate (p<0.0001). In multivariate analyses, the PC at day +60 was identified as an independent prognostic factor (p=0.003) together with CD34+ cell dose (p<0.001), disease risk (p=0.004), and acute GVHD (p=0.033) in terms of NRM, and the PC (p=0.047) and CD34+ cell dose (p=0.026) in terms of incidence of infectious events. Measuring the platelet count at day +60 is a simple method for predicting the risk of chronic GVHD development and prognosis after allogeneic PBSCT.

Targeted Busulfan and Cyclophosphamide as Compared to Busulfan and TBI as Preparative Regimens for Transplantation in Patients with Advanced MDS or Transformation to AML

Hematopoietic cell transplantation is the only curative therapy for patients with myelodysplasia (MDS). However, treatment-related toxicity and, in patients with advanced MDS (RAEB, RAEB-T) and those who have transformed to AML (tAML), post-transplant relapse continues to be problematic. We reviewed results in 128 patients with advanced MDS and tAML transplanted from HLA-identical related or unrelated donors after preparation with myeloablative conditioning regimens. Seventy-eight patients were conditioned with busulfan (Bu), prescribed dose 16 mg/kg, adjusted to achieve plasma concentrations of 800 - 900 ng/ml, plus cyclophosphamide (Cy), 2 × 60 mg/kg [tBuCy], and 50 patients were conditioned with Bu 7 mg/kg (without dose adjustment) and total body irradiation (TBI) 6 × 200 cGy given over 3 days [BuTBI]. There was no statistically significant difference in regards to overall survival, relapse-free survival (RFS), or non-relapse mortality (NRM) between the 2 regimens regardless of donor status. However, there was a trend towards higher rates of relapse (HR 1.33, P = 0.38) and lower rates of NRM (HR 0.61, P = 0.09) in patients conditioned with tBuCy. The increased rate of relapse seen with tBuCy was significant when restricted to only those patients with a diagnosis of RAEB (HR 4.50, P = 0.02). Patients given BuTBI had a higher incidence of GvHD; however, the incidence of GvHD regardless of grade did not differ significantly between patients who relapsed and those who did not. Thus, in patients with advanced MDS/tAML, the use of a less toxic conditioning regimen resulted in a non-significant overall gain in RFS largely due to lower rates of NRM. New concepts of conditioning regimens are needed which reduce toxicity without increasing the risk of relapse.

Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin's disease: the 21-year Seattle experience.

To analyze results of 127 patients undergoing myeloablative therapy followed by marrow transplantation for relapsed or refractory Hodgkin's disease. Twenty-three patients had primary refractory disease, 34 were in early first relapse or second complete remission (CR), and 70 had refractory first relapse or disease beyond second CR. Preparative regimens included total-body irradiation (TBI) and chemotherapy (n = 61) or chemotherapy only (n = 66). Sixty-eight patients received autologous marrow, six syngeneic marrow, and 53 allogeneic marrow. The 5-year actuarial probabilities of survival, event-free survival (EFS), relapse, and nonrelapse mortality for the entire group were 21%, 18%, 65%, and 49%, respectively. HLA-identical allogeneic marrow recipients had a statistically lower relapse rate compared with recipients of autologous marrow, but survival, EFS, and nonrelapse mortality rates were not significantly different. In the multivariate analysis, higher performance status and absence of bulky disease predicted for improved EFS and lower relapse rates, while fewer prior treatment regimens predicted for improved EFS and lower nonrelapse mortality rates. Additionally, the univariate analysis showed that patients who underwent transplantation with disease refractory to chemotherapy or beyond second CR had a worse outcome compared with those who had less advanced disease. Outcome with transplantation for patients with Hodgkin's disease is improved if transplantation is performed early after relapse when disease burden is less, tumor chemosensitivity is greater, and the patient is likely to have a better performance status. The use of HLA-matched sibling marrow results in a lower relapse rate and, thus, for some individuals, may be preferable to the use of autologous marrow.