Fifty-one consecutive patients with Hodgkin's disease (HD) have been treated with high-dose chemotherapy (HDT) and transplantation of autologous bone marrow (BM) (n = 44), autologous BM plus peripheral blood stem cells (PBSC) (n = 2), PBSC (n = 1), syngeneic (n = 1), or allogeneic BM (n = 3). All patients had received standard salvage chemotherapy prior to HDT and were classified as sensitive (n = 33) or resistant (n = 17) to this treatment; one patient was in untreated relapse prior to BMT. The preparative regimens for patients receiving autologous BM and/or PBSC consisted of cyclophosphamide, VP 16, and BCNU (CVB) (n = 44) or BCNU, etoposide, ara-C, and melphalan (BEAM) (n = 3). The patients receiving allogeneic transplants were treated with the CVB regimen (n = 2) or busulfan (16 mg/kg body wt.) and cyclophosphamide (200 mg/kg body wt.). With a median follow-up of 12 months, overall survival for 44 patients grafted with autologous BM is 61% +/- 9%, progression-free survival for patients with sensitive disease is 44% +/- 11%; no patient with resistant relapse survived beyond 1 year post transplant. Two of three patients grafted with allogeneic BM still survive 15 and 24 months after BMT with Karnofsky performance scores of 70% and 100%, respectively. The main toxicity encountered with the CVB regimen was interstitial pneumonia (IP), seen in four of 15 patients (27%) receiving > or = 600 mg/m2 of BCNU. Three of these patients have died. The results show that HDT followed by hematopoietic stem cell rescue may effectively salvage an important fraction of patients with relapsed HD who respond to standard chemotherapy. The same approach is largely unsuccessful in patients with proven refractoriness to standard chemotherapy. Whether HDT followed by BMT or PBSC support is superior to intensive chemotherapy without stem cell support can be answered only by a prospectively randomized trial.
Introduction and Methods: Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is standard care for relapsed/refractory DLBCL. In the CORAL study, 477 patients were assigned to one of two salvage regimens (R-DHAP or R-ICE). Only the 240 responding patients underwent per protocol ASCT and were randomly assigned to rituximab or observation. The four-year event-free survival (EFS) post ASCT were 52 and 53% for the rituximab and observation groups, respectively (p=.7). Secondary IPI (sIPI) independently predicted EFS, PFS and OS after ASCT (Gisselbrecht et al, JCO 2010 & 2012). Outcome data are limited in DLBCL patients who relapse after ASCT, with reported overall survival (OS) of 9.9 months in rituximab-pretreated patients (Nagle et al, AJH 2013). To shed more light on outcome and prognostic factor in this population, 75 patients included in the CORAL study who relapsed after scheduled BEAM/ASCT were reviewed. Results: Median time between ASCT scheduled in CORAL and relapse was 7.1 months (range 3.1-61.9) with 32.9% relapsing > 12 months. Median age was 56.1y (range 20.9-67.7), M/F ratio 51/24, sIPI 0-2 in 71.6%, >2 in 28.4%. 49.3% were in the rituximab and 45.3% in the observation arm of the CORAL. All patients had previously received rituximab. Third-line therapy consisted of ICE-type (17.3%), DHAP-type (24%), gemcitabine-containing (28%), CHOP-like (13.3%), and miscellaneous regimens (17.3%). Overall response rate to third-line chemotherapy was 44%, with 32% complete response (CR)/CR unconfirmed (CRu), and 12% PR. Among the 75 patients, 16 (21.6%) could eventually be transplanted 3 ASCT and 13 allogeneic SCT with conditioning regimens including fludarabine. Median OS, calculated from time of relapse until death, was 10.0 months (95% CI 6.6-12.6; min: 0.9-max: 55.2 months; median follow-up: 32.8 months) with an estimated 1-y OS of 39.1%. Median OS was statistically different (p=.0007) according to sIPI at CORAL failure: sIPI 0-2: 12.6 months (1-y OS 51.3%), sIPI > 2: 5.3 months (1-y OS 21.6%, HR 2.805). Median OS in patients achieving CR/CRu, PR, or no response after third-line regimen was 37.7 m (1-y OS 90.5%, p<.0001, HR 0.132), 10.0 m (1-y OS 44.4%, p=.03, HR 0.375), and 6.3 months (1-y OS 13.4%), respectively. Median OS of patients who could eventually be transplanted was 17.4 months (1-y OS 68.2%), as compared to a median OS of 8.0 months in those who were not transplanted (1-y OS 31.2%) with a HR of 0.575 (p=.11). Median OS was particularly dismal among patients who relapsed < 6 months after CORAL-scheduled ASCT (5.7 months, n=28), as compared to those relapsing either > 6 and < 12 months (11.3 months, n=21) or > 12 months after ASCT (12.6 months, p=0.01, fig. 1)). In multivariate Cox analysis (with the following variables entered: age, sex, sIPI, response to third line and time between CORAL ASCT and relapse), sIPI >2 (HR 2.464, p=0.01), achievement of CR (HR 0.1, p<.0001) or PR (HR 0.242, p=0.02), and post-ASCT remission lasting < 6 months (HR 2.270, p=0.05) independently predicted for OS. Conclusions: Overall, the outcome of DLBCL patients relapsing after second-line R-DHAP/R-ICE followed by ASCT is poor. However, prognostic factors predicting better outcome in this group are late (> 6 months) relapse, lower sIPI and achieving at least PR after third-line salvage followed by transplantation. In the transplanted patients (allo SCT or second ASCT) a 2-year OS of 50% was observed. Thus, new salvage regimens can be a bridge to transplantation in patients with late relapse and/or low sIPI,. New drugs improving salvage efficacy are urgently needed, especially for patients relapsing < 6 months following ASCT. Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse (<6 months, 6-12 months, > 12 months) Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse (<6 months, 6-12 months, > 12 months) Disclosures Schmitz: Roche, Takeda, Gillead, Riemser und ctilifesciences: Other: Advisory board, Speakers Bureau. Gill:Sanofi Aventis: Research Funding; Roche: Honoraria; AbbVie: Honoraria; Roche: Research Funding. Milpied:Celgene: Honoraria, Research Funding. Briere:St. Louis Hospital, Paris, France: Employment. Thieblemont:St. Louis Hospital, Paris, France: Employment. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Gisselbrecht:roche: Research Funding, Speakers Bureau.
patients receiving Treo [34% vs. 8% (p¼0.03)] while no differences were observed in patients receiving high-dose TBI [29% vs. 12% (p¼0.10)]. Incidence of non-relapse mortality was 15% (95% CI: 4-34) and 19% (95%CI: 10-31) for MRD pos and MRD neg patients, respectively (p¼0.81). Conclusion: Herein we demonstrate that the presence of pre-transplant MRD after myeloablative CBT is associated overall with adverse outcomes. However, the presence of pre-transplant MRD impacted outcomes less if the patient received a high-dose TBI-based preparative regimen. Our study suggests furthering extending the use of CBT with high-dose TBI in AML MRD pos patients.Background: RIC regimens are reported to be associated with equivalent outcome compared to ablative regimens (MAC) but it is unknown if there are any outcome differences after mismatched (MM) unrelated donor (URD) allo-SCT. We hypothesized that, the historically higher relapse rate after RIC compared to MAC can be abrogated by potent GVL effect using MM URD. Methods: Patients (pts) who underwent MAC or RIC MM URD transplant from 2000-12 were included in the study. All had donors with available information on HLA MM at one or two loci (9/10 or 8/10). Regimens were classified as MAC or RIC based on EBMT criteria. The Kaplan-Meier estimator, the cumulative incidence function and Cox proportional hazards regression models were used where appropriate. Results: 1041 pts receiving MAC compared with 883 RIC after MM-URD allo-SCT. Among the MAC, 872 (83.8%) were 9/10 and 169 (16.2%) 8/10 matched and in RIC cohort 754 (85.4%) were 9/10 and 129 (14.6%) were 8/10 matched. Median follow up for MAC and RIC group was 27 and 23 months respectively. MAC recipients were significantly younger (median age 43 vs 57 year), 70% pts were <50 year age in MAC vs only 30% in RIC group (p¼0.0001). Significantly higher numbers of pts had sAML (13 vs 10%, p¼0.04) and KPS<90% (30 vs 25%, p¼0.02) in the RIC group. There were no significant differences in distributions of advanced disease and poor risk cytogenetic among regimens. Commonly used MAC regimens were TBI based (n¼369), BuCy (354) and FluBu (143); and in the RIC group regimens were low dose TBI based (n¼275), BuFlu (312) and FluMel (178). The MAC group had more frequently marrow as the stem cell source (20 vs 9%; p<0.0001). Percentages of engraftment and grade II-IV aGVHD were not different between the groups. The incidence of cGVHD was higher
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