Lille Scoring System Rather Than DIPSS Is a Better Predictive of Overall Mortality After Allogeneic Hematopoietic Cell Transplantation (HCT) for Primary Myelofibrosis Using Reduced Intensity Conditioning: A Report From the Center for International Blood and Marrow Transplant Research (CIBMTR)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 432-432
Author(s):  
Vikas Gupta ◽  
Kwang W Ahn ◽  
Xiaochun Zhu ◽  
Zhenhuan Hu ◽  
Parameswaran Hari ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Scoring System ◽  
Conditioning Regimen ◽  
Primary Myelofibrosis ◽  
Reduced Intensity Conditioning ◽  
Donor Type ◽  
Conditioning Regimens ◽  
Reduced Intensity ◽  
Overall Mortality

Abstract Abstract 432 The Dynamic International prognostic scoring system (DIPSS) is increasingly being used as a prognostic tool for determining the risk of mortality for primary myelofibrosis (PMF), and has largely replaced Lille scoring system. However, it is unclear whether this scale can predict mortality after reduced intensity conditioning (RIC) allogeneic HCT, a procedure that is increasingly being utilized, as demonstrated by data from the CIBMTR. Using the CIBMTR database, the impact of patient, disease and transplant related factors on outcomes of 222 patients, who underwent HCT for PMF using RIC was analyzed. Median follow-up of survivors was 50 months (range, 3–165). Median age at HCT was 55 years, and 56 (25%) were >60 years. Donors were matched related donor (MRD), well-matched unrelated (MUD), and partially/mismatched unrelated (MMUD) in 85 (38%), 94 (42%), and 43 (19%), respectively. Conditioning regimens were: Fludarabine (Flu) and Melphalan (Mel), 62 (28%); Flu and Busulphan (Bu), 81 (36%), Flu and total body irradiation (TBI), 49 (22%); and others 30 (14%). Disease-risk status at HCT according to Lille scoring system was: low 48 (22%), intermediate (Int) 105 (47%), and high 69 (31%); and according to DIPSS was: low 25 (11%), int-1 110 (50%), int-2 81 (36%), and high, 4 (2%). The cumulative incidences of acute graft versus host disease (GvHD) at 100 days and chronic GvHD at 5-years were 48% (95% confidence intervals [CI] 41–54) and 50% (95% CI 43–57), respectively. The cumulative incidence of relapse/progression and non-relapse mortality (NRM) at 5-years was 28% (95% CI 22–34) and 38% (95% CI 31–44), respectively. The corresponding disease-free and overall survival was 34% (95% CI 28–40), and 37% (95% CI 31–44), respectively. In multivariate analysis, high-risk disease defined by Lille scoring system was associated with two-fold higher mortality compared to low-risk disease (Table). Higher risk disease status as defined by DIPSS was not associated with a significant increase in mortality when compared to lower-risk disease (Table). MUD and MMUD use were associated with higher mortality risk compared to MRD with relative risk (RR) of 1.59 (95% CI 1.00–2.52) and 2.6 (95% CI 1.56–4.35), respectively. A comparison of conditioning regimens demonstrated a trend towards reduced mortality with FluMel when compared to FluBu (RR 0.56, 95% CI 0.33–0.92; overall p=0.11), or other regimens (RR 0.51, 95% CI 0.26–0.99; overall p=0.11). In conclusion, the current study highlights that the DIPSS was limited in predicting the mortality after RIC transplantation for PMF, while the Lille scoring system remained predictive of mortality in high risk patients. These findings underscore the need for transplant-specific scoring system. Compared to other conditioning regimens FluMel appears to be associated with a trend towards better survival, which needs to be confirmed in prospective randomized trials. Table. Multivariate Analysis (MVA) for overall mortality* Model 1. MVA of Lille scoring system Variable Relative Risk (RR) 95% CI Overall p-value Lille-risk score low-risk (n = 48) 1 0.02 Intermediate-risk (n = 105) 1.47 0.84-2.58 High risk (n = 69) 2.22 1.23-4.00 Conditioning regimen Flu TBI 1 0.11 Flu Mel 0.67 0.38-1.19 Flu Bu 1.20 0.73-1.97 Others 1.30 0.68-2.48 Donor type HLA-identical sibling/other related 1 0.001 Well-matched URD 1.60 1.01-2.53 Partially matched/mismatched URD 2.61 1.57-4.36 Contrast Flu Mel vs. Flu Bu 0.56 0.33-0.93 0.03 Flu Mel vs. Others 0.51 0.27-0.99 0.05 Flu Bu vs. Others 0.92 0.52-1.66 0.79 Intermediate vs. High 0.66 0.43-1.01 0.06 Well-matched URD vs. Partially matched/mismatched URD 0.61 0.38-0.98 0.04 Model 2. MVA of DIPSS DIPSS Low/Int-1 (n = 135) 1 0.10 Int-2/high (n = 85) 1.39 0.94-2.043 * Adjusted for age, sex, Karnofsky performance score, platelet count, spleen status, conditioning regimen, donor type, GVHD prophylaxis and year of transplant. Disclosures: No relevant conflicts of interest to declare.

Reduced Intensity Conditioning Regimens Do Not Offer a Survival Advantage to Myeloma Patients Receiving Allogeneic Stem Cell Hematopoietic Transplantation: A Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC) Registry Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4113-4113
Author(s):  
Yvan Beaussant ◽  
Etienne Daguindau ◽  
Aurore Vivot ◽  
Mohamad Mothy ◽  
Herve Avet-Loiseau ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
New Drugs ◽  
Rank Test ◽  
Reduced Intensity Conditioning ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract Abstract 4113 Purpose: Despite the raise of major new drugs in the management of multiple myeloma (MM), it is still an incurable disease and allogeneic stem cell transplantation (alloSCT) is currently the sole potential curative therapy mediated by a graft-versus-myeloma (GVM) effect. For over ten years, reduced intensity conditioning regimens (RIC) in alloSCT has been developed to maintain the GVM effect and to decrease the high transplanted related mortality (TRM) associated with myeloablative conditioning (MAC) in myeloma patients. Yet, as numerous studies have assessed RIC alloSCT versus autologous SCT, only few data provides a comparison between RIC and MAC for MM in large series. Our study aims to compare RIC and MAC alloSCT for MM on a large retrospective French cohort. Methods: We report a retrospective multicenter study based on the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry, evaluating the outcome of patients undergoing alloSCT for MM. Between 1995 and 2009, 811 patients allografted for MM were registered. Data concerning disease characteristics and the allograft procedure were screened using the French Promise® database; computerized discrepancy errors and data verification of every single file ensure data quality, important missing data were directly retrieved in each centre. We assign the type of conditioning regimen for each patient according to the registry's data reported by the local physician and check this information according to the following rules. We consider as myeloablative (MAC) all regimens containing > 8 mg/kg oral busulfan, > 600 cGY TBI, ≥ 200 mg/kg cyclophosphamide or combinations as BEAM like regimens. All other chemotherapy combinations with or without TBI are defined as RIC regimens generally including fludarabine. Patients were excluded when major data or conditioning information were not available; 566 patients (70% of the entire cohort) were finally eligible for analysis, 478 RIC and 88 MAC. Chi-squared test and T-test were used for comparisons. Survival analyses (Overall survival, OS; progression-free survival, PFS) are made using the Kaplan-Meier curve and log rank test. Multivariate analysis is made using the Cox proportional hazards model. Results: The RIC and MAC populations were statistically different regarding age (respectively 53 versus 46 years, p<.0001), number of prior transplant (> 1 prior transplant in 94% RIC versus 77% MAC, p<.0001), time to transplantation (<12 months after diagnosis in 22% RIC versus 38% MAC, p=.001) and stem cell source (peripheral blood 84% RIC versus 52% MAC, p<.0001, and bone marrow 10% RIC versus 45% MAC, p<.0001). The 2-year OS is 69.5% after RIC and 79.9% after MAC (p<.0001); 5-year OS is 49.7% after RIC and 60.2% after MAC (p<.0001, fig.1). The 2 year PFS is 49.3% and 70.1% and 5-year PFS is 29.6% and 40.8% after RIC and MAC respectively (p<.0001, fig.2). Factors associated with better OS and PFS in multivariate analysis are the following in the whole cohort: < 12 months between diagnosis and alloSCT (p=.0078 and p=.0037, respectively); disease status at transplantation (at least partial response, p=.0409 and p=.0026); no or limited acute graft-versus-host disease (GvHD) (p<.0001 and p=.0094) and presence of chronic GvHD (p<.0001 and p<.0001). On multivariate analysis, the intensity of conditioning regimen (RIC vs MAC) do not appear statistically significant for OS (p = 0.64) and PFS (p = 0.17). For patients transplanted between 2006 and 2009, neither high risk-cytogenetic nor bortezomib use before transplantation seems to affect the outcome in multivariate analysis. Conclusions: In the French practice, MAC regimens have had more limited indications due to their higher toxicity. This study suggests that the outcome after MAC-alloSCT is comparable to that after RIC-alloSCT with a trend to a better OS in the late follow-up (after 5 years) after MAC. The aspect of flattening in the survival curves suggests that the anti-tumoral action of the conditioning regimen remains essential on the anti-myeloma effect after alloSCT and that should be considered in the transplantation procedure. Disclosures: No relevant conflicts of interest to declare.

Reduced Intensity Conditioning Regimen in Single Unrelated Cord Blood Transplantation in Adults with Hematological Malignant Disorders. An Eurocord-Netcord and SFGM-TC Survey.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3143-3143 ◽  
Author(s):  
Vanderson Rocha ◽  
Bernard Rio ◽  
Federico Garnier ◽  
Marc Renaud ◽  
Anne Sirvent ◽  
...  
Keyword(s):  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Blood Transplantation ◽  
Reduced Intensity Conditioning Regimen ◽  
Conditioning Regimens ◽  
Unrelated Cord Blood ◽  
One Year ◽  
Reduced Intensity

Abstract Results of reduced intensity conditioning regimen (RIC) in unrelated cord blood transplantation (UCBT) have been reported, however more frequently RIC was performed using double cord blood transplants. In order to study risk factors in single RIC-UCBT we have analyzed 65 patients with hematological malignancies (ALL=10, AML=37, Hodking and NHL=10, MDS=4, CML=3, Myeloma =1) transplanted from 1999–2005 and reported to Eurocord and SFGM-TC. The median follow-up was 8 months (3–26) and the median age was 47 years (16–76). At transplant, 49% of the patients had advanced phase of disease and 39% had received a previous autologous transplants. The conditioning regimen varied according diasease and centers: Fludarabine(FLU)+Endoxan (EDX) +TBI (2Gy) was given to 33 patients, FLU+(EDX or Melphalan) in 11, FLU+BU (<8mg/kg) associated or not to other drugs in 13, FLU+TBI(2GY) in 3 and other regimens in 5 patients. ATG/ALG was added in 26% of the cases. GVHD prophylaxis most commonly (55%) consisted of CsA and MMF; 87% received hematopoietic growth factors (<day 8). The median nucleated cell dose infused was 2.4 x107/kg and the graft was HLA identical (6/6) ( HLA A and B low resolution and DRB1 allelic typing) in 3 cases, 5/6 in 15, 4/6 in 37 and 3/6 in 10. Results: Median time to neutrophil recovery (>500/mm3) was 20 days (0–56) and 35 dyas for platelets recovery (>20.000/mm3). At day 60 probability of neutrophil recovery was 87± 7% of the 33 patients who received the Flu+End+TBI conditioning regimen and was 65±10% for patients receiving other regimens (p<0.01). Chimerism analysis was available in 71% of the patients at 3 months and was full donor in 67%, mixed chimerism in 9% and autologous reconstitution in 24%. Grade II aGVHD was observed in 13%, grade III in 7% and grade IV in 7%; the TRM was 45±7% overall, 50±15% in acute leukemia, 30±15% in lymphomas and 27±16% for other diagnoses. The TRM at one year for those receiving <2.4 x 107 TNC/kg was 53±9% and for those receiving >2.4 x107TNC/kg was 39±10% (p=0.07). For patients receiving Flu+End+TBI the TRM at one year was 24±10% and for those receiving other conditioning regimens was 60±9% (p=0.001). DFS at one year for lymphomas was 50±9%, for leukemias was 27±7% and for other diagnoses was zero. When the HLA compatibility was 6/6 or 5/6, DFS at one year was 42±12%, for 4/6 disparities DFS was 27±9% and for 3/6 disparities DFS was zero. DFS was 43±11% for those receiving Flu+End+TBI, and was 16±7% for patients receiving other conditioning regimens (p=0.005). For patients receiving >2.4 x 107TNC/kg the DFS was 31±12% and for patients receiving <2.4 x 107TNC/kg the DFS was 14±8% (p=0.05). In collusion, results of single RIC-UCBT are encouraging; cell dose and HLA remain important factors in this setting. The type of conditioning (Flu+End+TBI) seems to be associated with decreased TRM and better DFS, but a multivariate analysis with a higher number of patients is needed.

Concurrent Fludarabine and Cyclophosphamide As a Reduced Intensity Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation Ablates Host T-Cells and Results in Rapid Full Donor Chimerism

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1937-1937
Author(s):  
Rachel B. Salit ◽  
Michael R. Bishop ◽  
Steven Z. Pavletic ◽  
Frances T. Hakim ◽  
Seth M. Steinberg ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Donor Chimerism ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract Abstract 1937 Background: Reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) is associated with decreased transplant-related mortality (TRM). However, RIC-HSCT is typically associated with higher rates of mixed chimerism and graft rejection compared to myeloablative conditioning. Host T-cell immunity has been demonstrated to be an important predictor of engraftment and establishment of full donor chimerism in clinical studies. It was previously demonstrated in murine models that concurrent fludarabine (F) and cyclophosphamide (C) ablated host T-cells to the extent of myeloablative total body irradiation with reduced myeloid cell toxicity and prevented rejection of fully MHC-disparate marrow allografts (Petrus et al, BBMT, 2000). While fludarabine and cyclophosphamide are agents commonly used in reduced intensity conditioning regimens, their concurrent use has never been reported. Here, we analyze results from 102 patients who received the reduced intensity conditioning FC regimen in the setting of matched related or unrelated allogeneic stem cell transplantation. Methods: On four consecutive protocols at the National Cancer Institute, hematologic malignancy patients received induction chemotherapy followed by the FC regimen: fludarabine 30 mg/m2/d, days −6 to −3 and cyclophosphamide 1200 mg/m2/d, days −6 to −3. Peripheral blood stem cells were infused on Day 0. GVHD prophylaxis was either a calcineurin inhibitor alone or in combination with other agents. Results: 102 patients (females, 36; males, 66) were enrolled on study. Median age was 50 yrs (range, 21–71). Diagnoses included AML/MDS (n = 2), HL (n = 12), DLBCL (n = 35), CLL (n = 13), FL (n = 12), MCL (n = 10) and TCL (n = 10). Median number of prior regimens = 3 (range, 1 – 9); 25 patients had prior autologous transplant. Transplants were performed using HLA - matched sibling donors (n = 82) or 10/10 matched unrelated donors (n = 20). At the time of study entry, disease status was defined as chemosensitive (n = 53) or chemorefractory (n = 49). Patients were in CR (n = 19), PR (n = 26), SD (n = 37), or PD (n = 19); one patient was not evaluable. 101 of 102 patients (99%) proceeded to transplant. Median CD3+, CD4+, and CD8+ lymphocyte counts after induction chemotherapy (pre-FC conditioning) were: 150 cells/μl (1–1557), 80 cells/μl (0–1332), and 52 cells/μl (52–1195), respectively. Following FC conditioning, median CD3+, CD4+, and CD8+ counts were: 3 cells/μl (0–65), 3 cells/μl (0–93), and 0 cell/μl (0–22) (each p< 0.0001). All patients engrafted. Median time to neutrophil engraftment (ANC > 500) was 10 days and platelet engraftment (plt > 20 48 hours post transfusion) was 11 days. At Day +14, median CD3+ chimerism was 100% (range 30–100%), CD14+/15+ chimerism was 100% (range 6–100%), and whole blood chimerism was 100% (range 11–100%). Patients maintained full donor chimerism as evidenced by median 100% (range 50–100%) whole blood chimerism at Day +100. By Day +28 post-transplant, 41 patients (40%) achieved (n=24) or maintained (n=17) a CR and 38 patients (37%) achieved or maintained a PR for an overall response rate of 77%. Fourteen patients had SD and 4 had PD. Day +100 and one year TRM were 7% and 15% respectively. With a median follow-up of 92.4 months, 1 yr and 2 yr EFS were 52% and 41% and 1 yr and 2 yr OS were 68% and 58% respectively. Both EFS (p = 0.0003) and OS (p = 0.01) were significantly associated with response to FC. Acute GVHD grades II-IV and III-IV occurred in 56% and 23% of patients respectively. The rate of chronic GVHD was 65%. Grade IV non-hematologic toxicities as of Day +28 post-transplant included cardiac (n = 7, n = 1 Grade V), pulmonary (n=9), GI (n=9), and neurologic (n=3). While 62% of patients had at least one Grade III infection, only 2 patients had a Grade IV infection. Conclusion: The concurrent FC conditioning regimen resulted in host T-cell ablation and rapid full donor chimerism characteristic of myeloablative conditioning regimens. Furthermore, RIC-HSCT using concurrent FC achieved a high rate of complete remissions with an acceptable safety profile. Disclosures: No relevant conflicts of interest to declare.

Phase I/I Clinical Trial for the Evaluation of Bortezomib within the Reduced Intensity Conditioning Regimen (RIC) and Post-Allogeneic Transplantation As Gvhd Prophylaxis Among High-Risk Myeloma Patients. EudraCT: 2005–004858-27

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3025-3025
Author(s):  
Jose Antonio Perez-Simón ◽  
Teresa Caballero-Velazquez ◽  
Cristina Encinas ◽  
Cristina Castilla-Llorente ◽  
Rodrigo Martino ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract Abstract 3025 Introduction: Although allogeneic stem cell transplantation (allo-SCT) is the only curative treatment for MM, it is associated to a high morbility and mortality. Moreover, relapses are common after allo-RIC. Accordingly, new strategies are required to reduce both the risk of relapse and the toxicity of the procedure. As we have previously demonstrated, Bz induces a selective depletion of alloreactive T-cells and has immunomodulatory properties which might be of potential benefit for GVHD control. The primary end point of this study was to evaluate the efficacy of allo-RIC in terms of response when Bz was added as part of a reduced intensity conditioning prior to allo-SCT. Secondary end points included incidence of GVHD and analysis of the toxicity of the procedure when Bz is also administered post-infussion as part of the GVHD prophylaxis. Method: Prior to allo-RIC, patients received two cycles of Bz plus dexamethasone. Conditioning consisted of fludarabine (30 mg/m2 intravenously on days -9 to -5) and melphalan (70 mg/m2 intravenously on days -4, -3) plus Bz 1, 3mg/m2 on day - 11 and -2. GVHD prophylaxis included cyclosporine (CsA) and methotrexate for the first 9 patients and CsA plus MTX and Bz on days +3 and +7 for the remaining 7 patients. From day +50 post allo-RIC 7 cycles of Bz (+1, +8, +15) were administered, the first two cycles every 28 days and the rest every 56. Results: 16 patients from the Twenty-one initially enrolled, were evaluable. All 16 patients had received at least 2 lines of therapy including autologous-SCT. Disease status was CR or nCR in 4 patients, 9 had PR and the remaining 3 patients had relapsed / progressive disease. 15 patients maintained or improved status at transplant including all × patients with active disease at transplant. Eight patients (50%) relapsed, four with extramedullary involvement. No patient developed grade 4 aGVHD.Grades 2–3 aGVHD occurred in 6 patients (37%). Interestingly, two out of the nine (29%) patients who received Bz on days +3 and 7 developed grades 2–3 acute GVHD as compared to four of the nine (44%) who did not receive it. In terms of toxicity, one patient did not achieve platelet engraftment and 2 patients developed peripheral neuropathy requiring treatment withdrawal. 8 patients died, four of them due to relapse (MRT: 25%). With a median follow-up of 457 days overall survival was 46%. Conclusions: The current trial is the first evaluating the efficacy and safety of Bz as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Regarding the efficacy of the procedure all but one patient improved disease status post-alloRIC although relapse rate was still high in this heavily pretreated population. In addition, Bz post-alloSCT is well tolerated and may decrease the incidence of GVHD. Disclosures: Perez-Simón: Janssen-Cilag: Patents & Royalties. Off Label Use: This study evaluates the efficacy of Bortezomib as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

A Phase II Trial Combining Radiolabeled Anti-CD45 Antibody with Fludarabine and Low-Dose Total Body Irradiation (TBI) Followed by Related or Unrelated Hematopoietic Cell Transplantation for Patients Under Age 50 with Advanced Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1924-1924
Author(s):  
Raya Mawad ◽  
Ted A. Gooley ◽  
Joseph G Rajendran ◽  
Darrell R. Fisher ◽  
Ajay K. Gopal ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Reduced Intensity Conditioning ◽  
Younger Patients ◽  
Reduced Intensity Conditioning Regimen ◽  
Total Body ◽  
Reduced Intensity

Abstract Abstract 1924 Innovative therapeutic approaches are needed to reduce the morbidity and high relapse rates in patients with advanced AML or high-risk MDS following myeloablative hematopoietic cell transplantation (HCT). Success with stable donor chimerism and low toxicity following infusion of allogeneic peripheral blood stem cells (PBSC) with reduced-intensity regimens affords an opportunity to induce a graft-versus-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burden at the time of HCT. In an attempt to improve outcomes, we previously transplanted 58 patients older than age 50 with advanced AML (beyond first remission) or high-risk MDS (≥5% marrow blasts at the time of HCT) in a Phase I trial using 131I-labeled anti-CD45 antibody (BC8) in conjunction with fludarabine (FLU) and 2Gy total-body irradiation (TBI). Data from this study suggested that 131I-anti-CD45-targeted radiotherapy could be safely integrated into a reduced-intensity conditioning regimen for older, high-risk patients with AML or MDS yielding encouraging survival outcomes. These results prompted us to evaluate a similar strategy in younger patients (ages 16–50) with advanced AML or high-risk MDS who may not be able to receive a high dose HCT conditioning regimen. In this phase I dose–escalation trial 14 patients received a dose of 131I-BC8 that delivered 10–27 Gy of targeted radiation to the healthy organ receiving the highest dose combined with FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 7) or unrelated (n = 7) PBSC grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The 131I radiation dose was escalated until the maximum planned dose of 28 Gy was reached without any appreciable dose limiting toxicity. The median patient age was 39.5 (range, 23.8–49.7) years. Thirteen patients had AML, with 9 patients in second complete remission, 3 with primary refractory disease, and 1 in active relapse. One patient had advanced CMML with >5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in 7 patients (50%), and 11 of the 12 evaluable patients had 100% donor CD3+ and CD33+cell engraftment by day 28 after HCT; an additional patient had 79% CD3 and 82% CD33 positive donor marrow cells at day 28. The absolute neutrophil count surpassed 500/μL at a median of 15 (range, 13–22) days. Self-sustained platelet levels of 20,000/μL were reached at a median of 11 (range, 11–27) days after HCT. Five patients (36%) are surviving relapse-free 46 to 99 months (median 87 months) after HCT. Seven patients (50%) have died, with five patients relapsing 0.9 to 45 months after HCT. No non-relapse mortality occured by day 100; however, two patients died 14 and 18 months after HCT of cardiomyopathy and GVHD complications, respectively. This study demonstrates that, in addition to a standard reduced intensity conditioning regimen, an average of 27 Gy of targeted 131I radiotherapy can be delivered to bone marrow, an average of 20Gy to the liver, and an average of 84 Gy to the spleen without a marked increase in day 100 mortality for younger patients. This strategy may thus provide a reasonable alternative for patients with high-risk AML/MDS who may not be able to tolerate a high dose conditioning HCT. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Transplantation in Elderly Patients with AML and MDS Comparing Reduced-Intensity Conditioning with Flamsa-Busulfan Versus Fludarabine/BCNU/Melphalan

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5839-5839
Author(s):  
Nicole Engel ◽  
Wolfgang Hill ◽  
Susanne Fritsch ◽  
Dusan Prevalsek ◽  
Anna-Katharina Zoellner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Toxicity ◽  
Elderly Patients ◽  
Umbilical Cord Blood ◽  
Peripheral Blood ◽  
Allogeneic Transplantation ◽  
Reduced Intensity Conditioning ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract By reducing treatment intensity allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become feasible for elderly patients. Different reduced-intensity conditioning (RIC) regimens are available, but there is little consensus about the optimal preparative regimen to use, in particular with regard to the outcomes counterbalancing the aim of feasibility and tolerability with higher rates of relapse. Here, we retrospectively evaluate the outcome of sequential therapy employing RIC with fludarabine 30 mg/m2, cytarabine 2g/m2 and amsacrine 100 mg/m2 for 4 days (FLAMSA; Schmid C et al. JCO 2005) followed by busulfan 10 x 0.8 mg/kg (FLAMSA-Bu) compared to RIC utilizing fludarabine 5 x 30 mg/m2, carmustine (BCNU) 2 x 150 mg/m2 and melphalan 110 mg/m2 (FBM; Marks R et al. Blood 2008) in elderly patients treated consecutively at our institution between July 2005 and October 2012. We analyzed the course of 114 patients (pts) with acute myeloid leukemia (AML; n=99) or myelodysplasia (MDS; n=15) aged ≥ 59 years with 59 pts aged ≥ 66 years who were treated with either FLAMSA-Bu (n=66; n=24 ≥ 66 years) or FBM (n=48; n=35 ≥ 66 years). All patients received sero-therapy with anti-thymocyteglobuline (ATG). Median patient age was 66 years for the entire cohort (68 years FBM; 64 years FLAMSA-Bu). 36 patients (75%) of the FBM and 42 patients (63 %) of the FLAMSA-Bu group suffered from high risk disease defined as relapsed or refractory AML or refractory anemia with excess of blasts in transformation (RAEB-T). The hematopoietic cell transplantation comorbidity index (HCT-CI) was higher for the patients of the FBM group than for the FLAMSA-Bu group with 26 (54 %) versus (vs) 24 patients (36 %) scoring ≥ 2 (p 0.085). Graft source after conditioning with FBM/FLAMSA-Bu was bone marrow (1/2), G-CSF mobilized peripheral blood stem cells (40/62) and double-umbilical cord-blood (7/1). In 23 pts (20 %) HLA-matched related and in 91 pts (80 %) HLA-matched unrelated donor transplantation was performed. Engraftment failure was observed in 1 patient after FLAMSA-Bu, while engraftment was achieved in all evaluable patients of the FBM group in a median of 23 days vs 18 days after FLAMSA-Bu (p 0.003), while 7 pts with double-umbilical cord-blood transplantation where included in the FBM group vs 1 pt in the FLAMSA-Bu group. Non-hematological treatment-related acute toxicity ≥ CTC III (gastrointestinal, hepatic, cardiovascular, renal, centralnervous system) occurred in 12/48 pts (25 %) after FBM and in 18/66 pts (27 %) after FLAMSA-Bu. Incidence of severe acute (III-IV) and chronic GvHD was 22.9 %/16.6 % for FBM vs 18.2 %/19.7 % for FLAMSA-Bu, respectively. After conditioning with FBM 2/48 pts vs 9/66 pts after FLAMSA-Bu were diagnosed with a secondary malignancy (p 0.08). Non-relapse mortality (NRM) after 12 months was 26.8 % for FBM versus 25.2 % for the FLAMSA-Bu group. Incidence of relapse after FBM vs FLAMSA-Bu conditioning was 22.9 % vs 15.2 % after 1 year and 31.3 % vs 16.7 % after 2 years. Occurrence of relapse was significantly related to an incomplete or mixed chimerism (donor cells ≤ 95 % in peripheral blood and/or bone marrow) at day +30 (p 0.001). After a median follow up of 31.4 months (range 4.4-97.5) estimated overall survival (OS) and relapse-free survival (RFS) after 2 years was 55.4 % and 51.4 % for the FBM vs 58 % and 56.7 % for the FLAMSA-Bu group, respectively. Analyzing different subgroups, FBM conditioning might be favorable for pts aged ≥ 66 years when suffering from high risk AML (n=26): Within this group 1-year OS after FBM vs FLAMSA-Bu was 71.4 % vs 66.7 % (p 0.58) and 1-year RFS was 71.4 % vs 58.3 % (p 0.59), respectively. Notably, for pts at highest risk (aged ≥ 66 years and suffering from secondary or therapy-related AML; n=24) the benefit of FBM conditioning becomes more pronounced: 1-year OS after FBM vs FLAMSA-Bu was 62.5 % vs 37.5 % (p 0.26) and 1-year RFS 54.2 % vs 37.5 % (p 0.17). Both conditioning regimens are feasible, and provide similar rates of acute toxicity, NRM and GvHD. There might be evidence for a benefit of conditioning with FBM for the subgroup of “the oldest patients at highest risk”. Taking into account that there is an increasing group of ‘medically fit’ elderly patients in the field of allogeneic transplantation, prospective clinical trials are needed to investigate different conditioning regimens considering their special requirements. Disclosures No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation Using Oral Fludarabine as Part of the Conditioning Regimen.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4925-4925
Author(s):  
Julio Delgado ◽  
Ana Marco ◽  
Estela Moreno ◽  
Jose L. Pinana ◽  
David Valcarcel ◽  
...  
Keyword(s):  
Hospital Admission ◽  
Myeloid Leukemia ◽  
Hodgkin’S Lymphoma ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
Hodgkin's Lymphoma ◽  
Mixed Chimerism ◽  
Reduced Intensity Conditioning ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract Since its introduction in 2003, oral fludarabine has gradually replaced the intravenous (IV) formulation as treatment for patients with hematological malignancies. In an attempt to simplify the management of patients undergoing reduced intensity allogeneic transplantation, we have incorporated oral fludarabine to the conditioning regimen. We present a retrospective analysis of 37 patients conditioned with oral fludarabine compared with a historical cohort of 134 patients conditioned with the IV formulation. In addition to fludarabine, the conditioning regimens also included IV melphalan or oral busulfan depending on the underlying disease. Donors were HLA-matched siblings in 76% of cases and unrelated donors in the remaining 24%. Patient characteristics are summarized in Table 1. There were no statistical differences in terms of hospital admission (P = 0.414), time to neutrophil engraftment (P = 0.392), time to platelet engraftment (P = 0.307), acute graft-versus-host disease rate (P = 0.182) or non-relapse mortality at days +30 (P = 1.0) and +100 (P = 0.433). The subgroup of patients conditioned with oral fludarabine plus busulfan had a significantly higher incidence of mixed chimerism by day +100, but this did not translate into a significantly increased relapse rate. Side effects were tolerable and all patients on oral fludarabine were able to commence their conditioning regimen as outpatients. This preliminary analysis confirms that oral fludarabine could replace its IV formulation as part of reduced intensity conditioning regimens with no deleterious effect on any of the early transplantation outcomes. Furthermore, the use of oral fludarabine in combination with oral cyclophosphamide, oral busulfan or low dose total-body irradiation could potentially reduce hospital admission or even allow us to perform reduced-intensity allogeneic transplants as outpatient procedures. Finally, other advantages of oral fludarabine are cheaper costs and a more convenient use for both patients and health care workers. Patient characteristics according to fludarabine administration route Oral fludarabine (n = 37) IV fludarabine (n = 134) P value Age, median (range) 57 (38–69) 52 (18–70) 0.002 Sex, male/female % 60/40 65/35 0.566 Underlying diseases, n (%) 0.129 Acute myeloid leukemia 7 (19) 21 (16) Myelodysplastic syndrome 6 (16) 19 (14) Acute lymphoid leukemia 0 (0) 4 (3) Non-Hodgkin’s lymphoma 10 (27) 26 (18) Hodgkin’s lymphoma 0 (0) 30 (22) Myeloproliferative disorder 1 (3) 2 (2) Multiple myeloma 7 (19) 20 (15) Chronic lymphocytic leukemia 4 (11) 9 (7) Chronic myeloid leukemia 2 (5) 2 (2) Paroxysmal nocturnal hemoglobinuria 0 (0) 1 (1) Stem cell source, PB/BM % 100/0 93/7 0.121 Donor, n (%) 0.821 Matched related 29 (78) 101 (75) Mismatched related 0 (0) 2 (2) Matched unrelated 6 (16) 20 (15) Mismatched unrelated 2 (6) 11 (8) Previous autograft, n (%) 8 (22) 52 (39) 0.055 Conditioning regimen, n (%) 0.333 Fludarabine plus melphalan 21 (57) 89 (66) Fludarabine plus busulfan 16 (43) 45 (34) CD34+ cell dose (x106/kg), median (range) 6.1 (2.9–15) 6.5 (1.29–18.1) 0.787 Follow-up (days), median (range) 298 (83–631) 847 (80–1925) < 0.001

Reduced-Intensity Conditioning of Allogeneic Transplantation for Nodal Peripheral T-Cell Lymphomas

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2585-2585 ◽  
Author(s):  
Kazunari Aoki ◽  
Ritsuro Suzuki ◽  
Dai Chihara ◽  
Tatsuya Suzuki ◽  
Sung-Won Kim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
T Cell ◽  
Elderly Patients ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Younger Patients ◽  
T Cell Lymphomas ◽  
Reduced Intensity

Abstract Introduction The outcome and the role of allogeneic hematopoietic cell transplantation (Allo-HCT) with reduced-intensity conditioning (RIC) in patients with nodal peripheral T-cell lymphomas (PTCLs) remain unclear. Patients and Methods To address this issue, we retrospectively analyzed the outcome of Allo-HCT for patients with nodal PTCLs using the transplant registry data from the Japan Society for Hematopoietic Cell Transplantation (JSHCT). Patients who fulfilled the following criteria were included in this study: aged 16-69 years, diagnosed with PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), or anaplastic large cell lymphoma (ALCL), and received the first Allo-HCT in Japan between January 1, 2001 and December 31, 2011. In this analysis, conditioning regimen intensity was the main variable of interest. The conditioning regimen was classified as myeloablative conditioning (MAC) if it included total body irradiation (TBI) > 8 Gy, oral busulfan (BU) ≥ 9 mg/kg, intravenous BU ≥ 7.2 mg/kg, or melphalan (MEL) > 140 mg/m2. Otherwise, it was classified as RIC. Results A total of 354 patients (200 PTCL-NOS, 77 AITL, and 77 ALCL) were analyzed. Median follow-up duration of surviving patients was 3.8 years. Donor sources consisted of 122 human-leukocyte-antigen (HLA)-matched bone marrow (BM)/peripheral blood (PB), 122 HLA-mismatched BM/PB, and 110 cord blood. Of the 354 patients, 146 (41.2%) received MAC, which consisted of cyclophosphamide (CY)-TBI-based (n = 84), other TBI-based (n = 24), BU-CY-based (n = 11), fludarabine (FLU)-BU-based (n = 10), FLU-MEL-based (n = 15), and other (n = 2) MAC. The remaining 208 (58.8%) patients received RIC, which consisted of FLU-BU-based (n = 62), FLU-MEL-based (n = 108), and other (n = 38) RIC. Comparison of the patients who received MAC and RIC revealed that the RIC patients were significantly older (median age: 40.5 years vs. 50.3 years; P < 0.001) and more likely to have received autologous-HCT prior to Allo-HCT (15.1% vs. 29.3%; P = 0.002). The unadjusted 3-year cumulative incidence of non-relapse mortality were following: younger patients receiving MAC, 22%; younger patients receiving RIC, 14%; elderly patients receiving MAC, 50%; elderly patients receiving RIC, 30% (P < 0.001; Figure 1). The multivariate analysis showed that patients receiving RIC had a significantly lower non-relapse mortality than patents receiving MAC (HR, 0.51; 95% CI, 0.32-0.80; P = 0.004). Figure 1. Unadjusted non-relapse mortality. Figure 1. Unadjusted non-relapse mortality. The unadjusted 3-year cumulative incidence of relapse mortality were following: younger patients receiving MAC, 35%; younger patients receiving RIC, 30%; elderly patients receiving MAC, 32%; elderly patients receiving RIC, 35% (P = 0.692; Figure 2). The multivariate analysis showed that patients receiving MAC and RIC had a comparable relapse mortality (HR, 1.08; 95% CI, 0.73-1.58; P = 0.711). Figure 2. Unadjusted relapse mortality Figure 2. Unadjusted relapse mortality The unadjusted 3-year overall survival rates were following: MAC for younger patients (aged 16-49 years), 43%; RIC for younger patients, 56%; MAC for elderly patients (aged 50-69 years), 18%; RIC for elderly patients, 35% (P < 0.001; Figure 3). The multivariate analysis showed that patients receiving RIC had a significantly superior overall survival than patients receiving MAC (HR, 0.74; 95% CI, 0.54-1.00; P = 0.047; Table I). Figure 3. Unadjusted overall survival Figure 3. Unadjusted overall survival Table I. Multivariate analysis for overall survival Overall Survival HR (95% CI) P value Conditioning Regimen myeloablative 1.00 - reduced-intensity 0.74 (0.54-1.00) 0.047 Patient Age 16 to 34 1.00 - 35 to 49 1.26 (0.83-1.91) 0.270 50 to 59 2.17 (1.46-3.23) < 0.001 60 to 69 2.24 (1.40-3.59) 0.001 Karnofsly Performance Status 90 to 100 1.00 - 10 to 80 2.02 (1.41-2.91) <0.001 missing 1.50 (1.07-2.10) 0.017 Disease Status complete remission 1.00 - partial remission 1.13 (0.71-1.82) 0.607 resistant relapse 2.02 (1.27-3.21) 0.003 primary induction failure 2.09 (1.33-3.27) 0.001 Conclusion We showed a favorable outcome of Allo-HCT with RIC in patients with nodal PTCLs. The efficacy of RIC Allo-HCT for nodal PTCLs needs to be explored in prospective study. Disclosures No relevant conflicts of interest to declare.

Fludarabine Busulfan Compared to Fludarabine Melphalan Is Associated with Increased Relapse Risk in Reduced Intensity Conditioning Transplant Despite Pharmacokinetic Dosing

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 736-736 ◽  
Author(s):  
Moussab Damlaj ◽  
Hassan B Alkhateeb ◽  
Daniel K. Partain ◽  
Jehad Almasri ◽  
Mehrdad Hefazi ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Median Time ◽  
Cumulative Incidence ◽  
Dose Adjustment ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Transplant Outcomes ◽  
Baseline Characteristics ◽  
Reduced Intensity

Abstract Background: Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are two commonly used reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (SCT). A recent analysis showed that both regimens had similar overall survival (OS) but relapse incidence (RI) was significantly higher with FB with a trend towards higher non-relapse mortality (NRM) in FM (Baron et al., Cancer 2015). However, that cohort included patients treated with oral and intravenous busulfan without pharmakokinetic targeting of intravenous which may impact anti-leukemic activity. Aim: Compare transplant related outcomes of FB vs. FM using intravenous (IV) busulfan targeted to the area under the curve (AUC). Methods: After due IRB approval, patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) receiving RIC-SCT from 2008-2014 were identified. All baseline and laboratory features were retrospectively extracted. Busulfan dose in FB was 0.8 mg/kg IV for 10 doses with therapeutic AUC target of 900-1500 mcmol/L (min). All patients received T-cell replete grafts. Categorical and continuous variables were compared using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier method and curves were compared using the log-rank test. Cumulative incidence was computed as competing events using Grey's model. Univariate and multivariate analyses were performed using Cox regression modeling. Results: A. Baseline characteristics and AUC monitoring: 134 pts were identified (47 FB and 87 FM). Median follow up of the entire cohort was 40 months (0-63.3) and at last follow up, 60% and 29% have died or relapsed, respectively. Baseline characteristics stratified according to conditioning regimen are shown in table 1. Younger age (60 yrs FB vs. 61 yrs FM, p = 0.015) and a trend towards a higher CMV R-/D- status (28% FB vs. 14% FM p = 0.064) were the only significant differences identified. All patients in the FB group received intravenous busulfan and 46/47 patients had evaluable AUC data with a range of 732-1354 mcmol/L (min). A total of 19 patients were outside of range, all <900 mcmol/L (min) and required a median dose increase of 28.1% (3.3-50.2%) B. Engraftment and toxicity data: The median time for platelet engraftment was 19 days (0-48) for FB vs. 16 days (14-183) for FM (p = 0.0023) whereas the median time to absolute neutrophil count (ANC) engraftment was 18 days (7-30) for FB and 15 days (11-40) for FM (p = 0.077). Cumulative incidence of grade II-IV, III-IV acute GVHD and chronic GVHD at 2-yr was 57.3%, 11% and 52.8% for FB and 48.6%, 17% and 63.4% for FM (p = 0.73, 0.4 and 0.21, respectively). Two patients in the FM group died of cardiac causes (heart failure and sudden cardiac arrest). No cases of sinusoidal obstructive syndrome were observed in either arm C. Transplant outcomes: A significantly higher 2-yr relapse incidence (RI) was associated with FB vs. FM at 35.6% vs 17.3%, respectively (p = 0.0058). 2-yr progression free survival (PFS) was also significantly lower in the FB vs. FM at 51.2% vs. 65.1%, respectively (p 0.031). However, 2-yr OS and NRM was similar for FB vs. FM (53.1% and 22.9% vs 63.9% and 21.9%, respectively p = 0.26 and 0.89). Necessitating a dose adjustment based on AUC did not increase the risk for relapse or affect NRM. In multivariate analysis, FB was associated with increased RI with hazard ratio (HR) 2.29 (1.07-4.88; p = 0.033). Other factors significantly associated with RI on multivariate analysis were secondary/therapy related disease with HR 2.84 (1.34-6.02; p = 0.0067) and CR1 vs. other with HR 0.39 (0.17-5.32; p = 0.019). The significance of the results remained unchanged after exclusion of MDS patients (data not shown) Conclusion: Despite AUC dose adjustment, FB compared to FM was associated with increased RI with a similar OS and NRM. AUC dose adjustment did not impact transplant outcomes and its routine use in RIC should be further evaluated. Given the wide use of FB as a conditioning regimen, these important observations should be prospectively studied in a randomized fashion. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding. Wolf:Janssen Scientific Affairs, LLC: Consultancy.

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