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.

Comparison Of Unrelated Cord Blood (CB) and Peripheral Blood Stem Cell (PB) Transplantation In Adults With Myelodysplastic Syndrome (MDS) After Reduced Intensity Conditioning Regimen (RIC): A Collaborative Study From Eurocord and Chronic Malignancies Working Party (CMWP-EBMT)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3334-3334
Author(s):  
Marie Robin ◽  
Annalisa Ruggeri ◽  
Myriam Labopin ◽  
Dietger Niederwieser ◽  
Reza Tabrizzi ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Unrelated Cord Blood ◽  
Reduced Intensity

Abstract Background Outcome of patients with intermediate or high risk IPSS myelodysplastic syndrome (MDS) is poor in the absence of hematopoietic stem cell transplantation (HSCT). Choice of the best stem cell source is debated in this poor risk population. Unrelated cord blood transplantation (UCBT) has been used for patients lacking an HLA identical donor. This is the first study comparing well matched unrelated adult peripheral blood (PB) stem cell transplant to mismatched UCBT for patients with MDS. Method Patients with MDS transplanted from 2005 to 2011 with either unrelated CB or PB receiving a reduced intensity conditioning (RIC) were included. All PB donors were Human Leucocyte Antigens (HLA)-allele matched (10/10) or one allele mismatched (9/10) (-A, -B, -C, DRB1, -DQB1). Overall survival (OS) and disease-free survival (DFS) were estimated by Kaplan-Meier. Relapse incidence (RI), non-relapse mortality (NRM), engraftment, acute and chronic graft-versus-host disease (GVHD) were calculated using cumulative incidence (CInc) methods. Risk factors for outcomes were analyzed by Cox and Fine & Gray models. Results 502 patients transplanted with PB or 129 with CB (80 with double units) were compared. Among the PB recipients, 363 (72%) were 10/10 matched and 123 (25%) 9/10 matched. Most CB (98%) recipients had at least one HLA mismatch on 6 antigens tested (-A, -B antigen level and DRB1 allelic level), 32% had one mismatch and 66% had 2 mismatches. Median follow-up was 12 months for PB and 24 months for CB. MDS was transformed into AML in 416 patients. MDS WHO classification was: RA in 37, RCMD in 31, RAEB1 in 50 and RAEB2 in 87 and unclassified in 10 patients. Considering only patients with MDS, cytogenetic according to IPSS was: good in 96, intermediate in 57 and poor in 65 patients. PB and CB groups were different for age, gender, incidence of secondary AML (CB: 71% vs PB: 64%) and conditioning regimen. CInc of engraftment was lower in CB patients, 78 vs 96% (p<0.0001). Grade II to IV acute GVHD was 29% and 31% for PB and CB. Chronic GVHD was more frequent after PB (42% vs 23%, p=0.001). The unadjusted 2-year OS and DFS were better in patients transplanted with PB (46% vs 30% and 43% vs 28%, p=0.0001). There was no statistical difference for OS and DFS between single and double UCBT. RI was not significantly different (25 vs 30%, p=0.09) whereas NRM was higher in patients transplanted with CB (42 vs 33%, p=0.02). In multivariate analysis, OS (Hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.44-0.80) and DFS (HR: 0.57, 1.89, 0.79) were higher in patients transplanted with PB compared to CB. Furthermore, after adjustment, CB was also a risk factor for higher NRM ((PB, HR: 0.55, 95%CI: 0.37-0.80) and RI ((PB, HR: 0.62, 95%CI: 0.39-0.97). The analyses were performed using 3 groups of patients according to donor HLA type: PB 10/10, PB 9/10 and CB. The unadjusted 2-year OS and DFS were better with PB 10/10 than with PB 9/10 or CB: 49%, 37% and 30% (p=0.0001) and 45%, 36%, 28% (p<0.0001), respectively. NRM was not significantly different between CB and PB 9/10: 42% vs 36%. RI was similar after CB and PB 9/10: 28% vs 30%. Chronic GVHD was significantly lower after CB (PB 9/10: 37% vs CB 23%, p=0.004). The multivariate analysis showed an advantage of OS for PB 10/10 compared to PB 9/10 (HR: 1.45, 95%CI: 1.06-1.97, p=0.02) whereas there was no significant difference between PB 9/10 and CB (HR: 1.24, 95%CI: 0.84-1.83, p=0.29). Likewise, DFS was better after PB 10/10 (HR: 0.57, 95%CI: 0.43-0.77, p=0.05) and it was similar after PB 9/10 or CB (HR: 1.34, 95%CI: 0.92-1.97, p=0.13). In the 9/10 PB no differences in the results were observed according to the specific mismatched locus (A, B, DRB1, vs C, DQB1) Conclusion Despite the limitation of a retrospective registry based study and the short term follow up, our study shows that transplants with PB from matched unrelated donor gives the best outcomes. In the absence of a 10/10 unrelated matched PB donor, a 9/10 PB donor or mismatched CB give similar results. Therefore, for MDS patients without a HLA 10/10 unrelated donor a 9/10 regardless of the specificity of the locus where the mismatch occurs mismatched HLA locus or a HLA mismatched CB are both alternative options for transplantation. Disclosures: Gluckman: Cord use: Honoraria; gamida: Honoraria.

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.

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.

scholarly journals Outcome in Allo- SCT in Patients with Refrectory Acute Lymphoblastic Leukemia with Non TBI Conditioning Regimens

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5947-5947
Author(s):  
Ajay Sharma ◽  
Velu Nair ◽  
Sataya Ranjan Das ◽  
Sanjeevan Sharma ◽  
Jasjit Singh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Remission Induction ◽  
Infection Prophylaxis ◽  
Resource Limited ◽  
Conditioning Regimens

Abstract Background: Despite intensive remission induction chemotherapy, up to 5–10% AYAs with acute lymphoblastic leukemia (ALL) are primarily refractory.1,2 Of those that achieve a remission, as much as 70–80% fail consolidation largely due to relapse or sustained aplasia. Allogeneic stem-cell transplantation (allo-SCT) remains the only salvage option with curative potentials available, but the long-term benefits of the procedure and whether all patients should benefit from it remains controversial. There has always been a discussion about best conditioning regimen for ALL transplants especially in resource limited situation where TBI is not available. We analyzed our data on allo-transplants for ALL, wherein we had used non-TBI protocols for conditioning. Study: This study retrospectively analyzes the outcome in 32 patients ( 19 females & 13 males) who underwent Allo-SCT for refractory acute lymphoblastic leukemia at our center between 2000-2013. The median age was 28 years (range, 7–26). 14 patients had relapse, 8 failed re-induction, 5 in partial remission & 7 patients had high risk disease ( Ph+ disease). All patients were in a state of bone marrow remission at the time of transplantation. All received myeloablative conditioning using busulfan( BU) & cyclophosphamide( CY). The stem cell harvesting was done by peripheral G-mobilized stem cell collection from related donors. All patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporin and methotrexate. Infection prophylaxis & supportive care was provided as per standard protocols. The median cell dose was 5.4 MNCx10 7/Kg (3.8-7.6) & CD34 cells 3.7x105/Kg. 31 patients engrafted successfully by median day 12(7-23) for White cells & median day 38 ( 27-48) for platelets. One patient experienced late graft failure. 21 patients developed Gd-II acute-GVHD, 11 of them progressed to severe form( Gd-III). 5 pateints had severe grade IV Ac GVHD. 3 of them died chronic-GVHD appeared in 14 patients,. 19 patients (58%%) remain alive after a median of 60 months (range, 6–174); with 13 deaths, mostly from relapse (n=10) and infections (n=3). Overall survival (OS) and progression-free survival (PFS) at 5 years was 53% and 48%, respectively. OS and PFS were significantly better with blasts 20% and time to transplant 1 year. Conclusions: We conclude that patients with refractory leukemia can benefit from allogeneic BMT, if they are transplanted in a state of remission, by using non-TBI based protocols. Thus in a resource limited situation, the outcome in refractory ALL can still be improved by improvisation of protocols without using TBI in conditioning regimens. Disclosures No relevant conflicts of interest to declare.

Outcome of Sibling Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantations in Low-Grade B Cell Lymphoproliferative Disorders. A Single Centre Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5059-5059
Author(s):  
Ronan Desmond ◽  
Marianna David ◽  
Eibhlin Conneally ◽  
Paul Browne ◽  
Mairead Ni Conghaile ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Chronic Gvhd ◽  
Autologous Transplantation ◽  
Conditioning Regimen ◽  
Lymphoproliferative Disorders ◽  
Mixed Chimerism ◽  
Low Grade ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity

Abstract Reduced intensity conditioning allogeneic stem cell transplantations (allo-SCT) have been developed to exploit graft-versus-malignancy effect while reducing the toxicity of allo-SCT. We report the outcome of 21 patients with low-grade B cell lymphoproliferative disorders transplanted in a single center. The mean age of the patients was 54 years (range 32–66) with 11 males, 10 females. Follicular lymphoma was the diagnosis in 10 patients, CLL in 5, mantle cell lymphoma in 4, MALT lymphoma in 1 and lymphoplasmocytoid lymphoma in 1 patient. The median number of prior treatment lines was 2. All patients received peripheral blood stem cell transplants from sibling donors and no patients had undergone a prior autologous SCT. 12/21 patients (57%) received a ATG based conditioning regimen while the remainder, 9/21 (42%) received a Campath containing conditioning regimen. Full donor chimerism was confirmed in 17/19 (89%) patients. Acute graft versus host disease (GVHD) developed in 5/21 (23%) of the patients. Chronic GVHD occurred in 7/21 (33%) with 5/21 occuring post donor lymphocyte infusion (DLI). DLI has been administered in 11/21 patients (52%), 2 for progressive disease and 9 for re-emerging mixed chimerism. Non-relapse mortality (NRM) at 100 days and 1 year were 5% and 12.5% respectively. With a median follow up of 21 months (range 3–54) the overall survival rates (OS) at 1 year and 2 years were 72% and 58% respectively. Progression free survival (PFS) at 1 year and 2 years were 66% and 50%. We have shown that reduced intensity conditioning allogeneic stem cell transplantation is associated with a low TRM comparible to that of autologous transplantation and allows long term control of low grade B-cell lymphoproliferative disorders.

Reduced Intensity Conditioning Regimen for Allografting Following Autografting Is Feasible and Has a Strong Anti Multiple Myeloma Activity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5130-5130
Author(s):  
A.M. Carella ◽  
Germana Beltrami ◽  
Maria T. Corsetti ◽  
Potito Scalzulli ◽  
Nicola Cascavilla ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Chronic Gvhd ◽  
Intensive Therapy ◽  
Conditioning Regimen ◽  
Mixed Chimerism ◽  
Reduced Intensity Conditioning ◽  
Conditioning Regimens ◽  
Age Range ◽  
Reduced Intensity

Abstract The development of reduced intensity conditioning regimens (RICT) has renewed interest in allografting for patients with multiple myeloma (MM). Taking advantage of this new approach, we firstly postulated that combining maximal tumor reduction achieved with autografting and the benefits of RICT, we could achieve more cures of multiple myeloma (MM) with acceptable toxicity. Sixteen patients, 51 years of age (range, 36–63) with previously treated stage III MM were given melphalan 140 mg/m2 and autologous peripheral blood progenitor cells (PBPC) reinfusion. The regimen-related toxicities were moderate with a median of 8 and 11 days of neutropenia and thrombocitopenia, respectively. Forty-six to 156 days later (median, 79 days), the patients received fludarabine 30 mg/m2/d x 3 days plus 2 Gy TBI and HLA-identical donor mobilized PBPC. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. Donor lymphocyte infusions were given to eight patients with stable mixed chimerism or progressive disease who did not show signs of aGVHD. Engraftment occurred in 14 patients (87%). Ten patients (62%) are alive with 9 of them in continuous complete remission 11–36 months (median, 30 months) after transplants. All remitters patients achieved full chimerism and developed GVHD. Grade II–III acute GVHD occurred in 7 patients (43%) but no patient died of aGVHD. Three patients (18%) developed extensive chronic GVHD requiring intensive therapy. Six patients died; five of them of progressive disease and one of progressive disease combined with extensive cGVHD and interstitial pneumonitis. In conclusion, this 2-step approach is feasible and demonstrated to have a strong antimyeloma activity with reduced deaths due to acute toxicities.

Favorable Outcomes with Acceptable Toxicity Using a Reduced Intensity Conditioning Regimen for Patients Otherwise Ineligible for Related Donor Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5137-5137
Author(s):  
Peter Westervelt ◽  
Wendy Holmes ◽  
Robert Emmons ◽  
Pamela Becker ◽  
Phil Lowry ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract Allogeneic stem cell transplantation represents a potentially curative treatment modality for patients with advanced hematologic malignancies. However, the toxicity associated with fully myeloablative conditioning regimens has historically limited its use to younger, otherwise healthy patients. To investigate the feasibility of allogeneic stem cell transplantation in older (over 55 years) or otherwise higher risk patients (eg, prior transplant) with fully HLA-matched sibling donors, a reduced intensity conditioning regimen consisting of fludarabine (30 mg/M2 IV qd X 6, day −8 to −3), ATGAM 10 mg/kg IV qod X 4, day −7/−5/−3/−1) and melphalan (100 mg/M2 IV X 1, day −2) was employed in a single institution setting. GVHD prophylaxis consisted of cyclosporine (2 mg/kg IV bid, adjusted, beginning day −1) and methotrexate (10 mg/m2 IV, day +1/+3/+6). RESULTS: 21 patients with a variety of hematologic malignancies (AML=4, MDS=5, NHL=5, CML/MPD=3, HD=2, MM=1, CLL=1) were enrolled. Mean age was 54 years (range 28–66). 7 patients had undergone prior autologous transplants. Median followup among surviving patients was 42 months (range 3–58 months). Peripheral blood chimerism at day +100 was >95% donor in 16/18 patients, 80% (with subsequent conversion to 95%) in one patient, and >95% recipient (with documented relapse) in one patient. Acute GVHD grade 1–2 was seen in 52% and grade 3–4 in 10% of patients. Chronic GVHD was observed in 9/20 evaluable patients (45%). Infectious complications included documented bacteremia (6 cases), candida albicans fungemia (1), aspergillus pneumonitis (3), nocardia pneumonitis (2), CMV viremia (6), CMV colitis (1). Veno-occlusive disease (self-limited, grade 1–2) was observed in 4/21 patients (19%). Relapse was observed in 5/21 patients (24%) at a median 249 days post-transplant (range 97–328 days). Event-free survival was 90% (19/21) at 100 days, 58% (11/19) at 1 year and 47% (8/17) at 3 years. Overall survival was 95% (20/21) at 100 days, 68% (13/19) at 1 year and 47% (8/17) at 3 years. Primary causes of death were relapse (4/9), infection (4/9), and idiopathic pneumonitis/multi-organ failure (1/9). Chronic GVHD was a significant contributing factor in 3/4 fatal infections. PTLD was observed in one patient, who subsequently died of CMV infection/sepsis syndrome. CONCLUSIONS. Allogeneic BM/SCT using a reduced intensity conditioning regimen is feasible among older patients, and those who are otherwise poor candidates for myeloablative BM/SCT regimens; however, GVHD, infection, and relapse remain formidable obstacles to achieving successful outcomes.

Impact of Myeloablative and Reduced Intensity Conditioning On Outcomes After Unrelated Cord Blood Transplantation for Adults with Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3117-3117
Author(s):  
Luciana Tucunduva ◽  
Annalisa Ruggeri ◽  
Guillermo Sanz ◽  
Sabine Furst ◽  
Bernard Rio ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Lymphoblastic Leukemia ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Reduced Intensity Conditioning ◽  
Blood Transplantation ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract Abstract 3117 Allogeneic hematopoietic stem cell transplantation is the only curative option for high risk or relapsed acute lymphoblastic leukemia (ALL) in adults. In the absence of an HLA identical sibling donor, HLA matched adult donor or HLA mismatched cord blood are alternative sources of stem cell to treat those patients. However, very few data on the outcomes after umbilical cord blood transplantation (UCBT) for adult ALL using myeloablative or reduced intensity conditioning regimens have been reported. With this aim, we conducted a retrospective survey on the outcomes after UCBT for adult ALL and a more specific analysis for patients with cytogenetic data transplanted in remission with either a myeloablative (MAC) or reduced intensity conditioning regimen (RIC). From 1996 to 2011, 433 adult patients (pts) received a UCBT for ALL. Overall 2-year LFS was 37% for pts in first complete remission (CR1) (n=199), 32% for CR2 (n=138) and 9% for advanced disease (n=96). Complete cytogenetic information at diagnosis was available for 316 pts, of those 251 pts were transplanted in CR1 (63%, n=157) or in CR2 (37%, n=132). Median age at UCBT was 33 years (18 to 66 years) and 76% of the pts (n=191) had an abnormal karyotype at diagnosis. Pts were analyzed according to the presence of t(9;22) as Ph+ (n=115) and Ph- (n=136). Double CBT was performed in 109 pts (43%) and the median total nucleated cell dose at freezing was 4.02×107/kg. Most pts received CBU with one (30%, n=74) or two (56%, n=136) HLA disparities. A myeloablative (MAC) conditioning was given to 177 pts (70%) and 73 (30%) received a reduced intensity conditioning (RIC). Overall 2-year leukemia- free survival (LFS) was 36±3%; 37% for Ph- and 35% for Ph+ pts (p=0.74). On multivariate analysis, 3 factors were associated with improved LFS: age <44 years (HR: 0.6, p=0.004), CR1 at transplant (HR: 0.6, p=0.005) and use of RIC (HR: 0.6, p=0.015). Since the outcomes were different according to disease status and conditioning intensity, a subgroup analysis was performed. Results are shown in Table 1. In pts transplanted with MAC (n=177), most frequent conditioning regimens were Cy-TBI (27%) and Bu+Flu+Thio (25%). Median follow-up (FU) was 26 and 35 months for those in CR1 (n=107) and CR2 (n=70), respectively. Cumulative incidence (CI) of 60-day neutrophil recovery was 87% for pts in CR1 and 83% for those in CR2; acute GVHD was 43% and 37%, respectively. Two-year CI of NRM was 41% for CR1 and 49% for CR2 and 2-year RI was 24% for CR1 and 22% for CR2. Two-year LFS was 35% for CR1 and 30% for CR2. No factor was found to be associated with LFS, relapse nor NRM. One-hundred and four pts died, 81 of transplant-related causes (79%, n=46 for CR1 and 74% n=35, for CR2), mainly due to infections (53% n=24 for CR1 and 38% n=12 for CR2). In pts transplanted with RIC (n=94), Cy+Flu+TBI regimen was used in 74% (n=54). Median FU was 31 and 34 months and median age was 50 and 39 years for those in CR1 (n=49) and CR2 (n=24), respectively. At 2 years, CI of NRM was 22% for CR1 and 17% for CR2. Two-year RI was 30% and 47%, respectively. Two-year LFS was 49% for CR1 and 36% for CR2. For pts in CR1, univariate analysis showed that younger age (< 50 years) was associated with improved LFS (62% × 36%, p=0.042) and lower NRM. Eighteen patients died, 6 of relapse and 12 of transplant-related causes. All patients who died from NRM were 50 years or older. UCBT is an option to treat high risk and relapsed adult ALL. Pts transplanted with MAC had an LFS comparable with that reported with other stem cell sources, but strategies to reduce toxicity are still needed, especially for pts in CR2. Results with RIC are encouraging and may be considered in younger pts. Importantly, in this large series outcomes after UCBT for Ph+ ALL were not statistically different from those compared to Ph-. Table 1. Outcomes according to disease status at UCBT and conditioning regimen MAC RIC CR1 (n=107) CR2 (n=70) CR1 (n=49) CR2 (n=24) LFS (2y) 35 ± 5% 30 ± 6% 49 ± 7% 36 ± 10% Relapse (2y) 24 ± 4% 22 ± 5% 30 ± 7% 47 ± 11% NRM (2y) 41 ± 5% 49 ± 6% 22 ± 6% 17 ± 8% Disclosures: No relevant conflicts of interest to declare.

Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3829-3836 ◽  
Author(s):  
Naoto T. Ueno ◽  
Yee Chung Cheng ◽  
Gabriela Rondón ◽  
Nizar M. Tannir ◽  
James L. Gajewski ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Solid Tumors ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Donor Chimerism ◽  
Reduced Intensity

AbstractWe evaluated the feasibility and efficacy of a reduced-intensity conditioning (RIC) regimen of fludarabine and melphalan to achieve rapid complete donor chimerism after allogeneic stem cell transplantation (SCT) in patients with metastatic solid tumors. Between January 1999 and January 2003, 8 patients with metastatic breast cancer (BC) and 15 with metastatic renal cell carcinoma (RCC) underwent allogeneic SCT after an RIC regimen of 5 days of fludarabine and 2 days of melphalan. Filgrastim-mobilized stem cells from HLA-identical related or unrelated donors were infused. Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus and methotrexate. All 22 evaluable patients had 100% donor chimerism at day 30 and at all measurement times thereafter. One patient died 19 days after SCT. Nine patients (39%) had grades II to IV acute GVHD and 10 patients (43%) had chronic GVHD. Five patients (22%) died of nonrelapse treatment-related complications. Treatment-related disease response was seen in 10 patients (45%), with 3 complete responses, 2 partial responses, and 5 minor responses. Fludarabine-melphalan is a feasible and effective RIC regimen for allogeneic SCT in metastatic BC and RCC. It induces rapid complete donor chimerism without the need for donor lymphocyte infusion. Tumor regression associated with GVHD is consistent with graft-versus-tumor effect. (Blood. 2003;102:3829-3836)

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