Non–myeloablative Allogeneic Hematopoietic Stem Cell Transplantation with Low-Dose Total Body Irradiation and Peri-Transplant Rituximab for B Cell Non-Hodgkin Lymphoma: Favorable Disease Control in Chemosensitive Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4160-4160
Author(s):  
Craig S Sauter ◽  
Esperanza B Papadopoulos ◽  
Miguel-Angel Perales ◽  
Ann A Jakubowski ◽  
Jenna D Goldberg ◽  
...  
Keyword(s):  
Stem Cell ◽  
Disease Control ◽  
B Cell ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Total Body ◽  
Grade 3 ◽  
Related Mortality

Abstract Abstract 4160 Background: Allogeneic stem cell transplantation (allo-SCT) remains the only curative therapy for patients with indolent B cell Non-Hodgkin's Lymphoma (B-NHL) as well as patients with aggressive B-NHL that have failed prior autologous stem cell transplants (ASCT). Myeloablative conditioning is associated with a high incidence of early transplant related mortality (TRM) particularly in patients with extensive prior therapy and advanced age. Non-myeloablative conditioning (NMA) provides less TRM and the opportunity to exploit graft-versus-lymphoma (GVL) effects at the expense of conditioning intensity for disease control. The addition of rituximab to these regimens provides both anti-lymphoma and potential immunomodulatory benefit in terms of decreasing the incidence of graft-versus-host disease (GVHD). The aim of this phase 2 trial was to determine the safety and efficacy of low-dose total body irradiation (TBI), cyclophosphamide, fludarabine and peri-transplant rituximab in patients with CD20+ B cell malignancies. Patients and Methods: This analysis includes 35 B-NHL patients with a median age of 54 years (range 33–67) at the time of allo-SCT. Diagnoses included: 15 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 9 follicular lymphoma (FL), 6 diffuse large B cell lymphoma (DLBCL)/ transformed lymphoma (B-tNHL), 3 mantle cell lymphoma (MCL) and 2 other. Patients were previously treated with a median of 3 prior chemotherapy regimens (range 1–5) and 6 patients had a previous ASCT. Twenty-five patients were chemosensitive at the time of allo-SCT by International Criteria (Cheson et al JCO 1999, Hallek et al Blood 2008 for CLL/SLL). Patients with DLBCL, B-tNHL and MCL were required to have chemosensitivity prior to allo-SCT. Patients with FL and CLL/SLL were not required to achieve chemosensitivity, but did require stable disease, prior to allo-SCT. Conditioning consisted of cyclophosphamide 50 mg/kg, fludarabine 25 mg/m2 daily over 5 days and 200 cGy TBI. Rituximab 375 mg/m2 was administered 1–2 days prior to the initiation of conditioning and weekly for 4 doses beginning d+21. Graft rejection prophylaxis with equine anti-thymocyte globulin (ATG), 30 mg/kg daily d-3 and d-2, was given to recipients of unrelated grafts. All patients received a G-CSF mobilized peripheral blood stem cell graft. GVHD prophylaxis consisted of tacrolimus and sirolimus beginning d-3 and methotrexate 5 mg/m2on d+1, d+3 and d+6. Twelve patients received a graft from a 10/10 HLA matched related donor, 19 from a 10/10 HLA matched unrelated donor and 4 from a 9/10 HLA mismatched unrelated donor. A survival event was defined as progression of disease (PD) or death from any cause, including transplant-related mortality (TRM). Results: All patients engrafted and full donor chimerism in neutrophils and T cells was documented at 3 months posttransplant in 30 evaluable patients. This regimen was well tolerated and no grade 3–4 oral mucositis was observed. Acute GvHD, grades 2 to 4, developed prior to d+100 in 20% of evaluable patients (8% grade 3–4). The 2-year incidence of chronic GVHD (CIBMTR criteria) in 32 patients at risk was 65% (23% mild, 34% moderate and 9% severe). Twenty six patients are alive with a median of 23 months (range 6–41). Of the 9 events, 6 were TRM (5 from GVHD) and 3 PD (all of which died of lymphoma). No events have occurred beyond 15 months. The 2-year EFS for all patients is 72%. No difference in EFS or OS was demonstrated according to: histology, graft source, number of previous lines of therapy, previous autologous transplant or age. The only variable associated with EFS was pre-allo-SCT chemosensitivity. The 2-year EFS for chemosensitive patients was 83% compared to 44% for patients without chemosensitivity pre-allo-SCT (see figure, p=0.02). Conclusions: This NMA regimen with peri-transplant rituximab is effective and safe allowing full donor myeloid and T cell chimerism with minimal toxicities and with notable anti-lymphoma effect, however chronic GvHD developed in a significant number of patients. In this trial, peri-transplant rituximab may provide disease control but its role on cGvHD prevention is not clear. These data confirm chemosensitivity as a significant prognostic factor to survival in B-NHL with NMA allo-SCT. Disclosures: No relevant conflicts of interest to declare.

Fludarabine, Low Dose Busulfan and Antithymocyte Globulin (ATG) Compared to Fludarabine and Low Dose Total Body Irradiation (TBI) for Reduced-Intensity Conditioning (RIC) Prior to Allogeneic Stem Cell Transplantation (allo-SCT) In Patients with Lymphoid Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3472-3472
Author(s):  
Florent Malard ◽  
Eolia Brissot ◽  
Patrice Chevallier ◽  
Thierry Guillaume ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Stem Cell ◽  
Total Dose ◽  
Relapse Rate ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Routine Practice ◽  
Unrelated Donor ◽  
Toxicity Profile ◽  
Lymphoid Malignancies ◽  
Grade 3

Abstract Abstract 3472 Allo-SCT procedures are currently undergoing a profound evolution. The spectra of patients and diseases for which this approach is now considered have increased considerably over the past years. This is mainly due to the introduction in routine practice of the so-called nonmyeloablative or RIC regimens. While it is well established that fludarabine is the backbone drug to secure engraftment, there is a wide variability in the degree of myeloablation between the different RIC protocols, and the toxicity profile might vary significantly from one protocol to another. The combination of fludarabine and Busulfan (usually 8 mg/Kg total dose) with or without ATG, is among the most widely used RIC protocols worldwide. In an attempt to further decrease the toxicity of the transplant procedure, we hypothesized that further reduction (50%) of the Busulfan dose can allow improving transplant outcome for lymphoid neoplasms. With this background, this retrospective analysis was performed to assess whether a RIC regimen including fludarabine (120 mg/m2), low dose busulfan (4 mg/Kg total dose administered orally over a single day) and ATG (Thymoglobuline®, 2.5 mg/Kg/d for 2 days; FB1A protocol, n=44), is a valid alternative to the classical RIC regimen including fludarabine (90 mg/m2) and TBI (2 Gy.) (FTBI, n=27) prior to allo-SCT. The cohort included 37 males (52%) and 34 females (48%) treated consecutively in a single centre, with a median age at time of allo-SCT of 53 (range, 15–66) y. Diagnoses included 39 NHL (55%), 17 Hodgkin lymphomas (24%), 12 CLL (17%) and 3 myeloma (4%). PBSCs were used as stem cell source in 42 patients (91%), while 4 patients (9%) received classical bone marrow. A matched-related donor was used in 18 cases (39%) and an unrelated donor in 28 cases (61%). With a median follow-up of 43 (range, 3.7–85) months after allo-SCT, all patients, but one (from the FTBI group) engrafted. In the FB1A group, the acute grade 3–4 GVHD rate was 20.5% (n=9), the chronic GVHD rate was 32% (n=14), the relapse rate was 23% (n=10) and the TRM rate was 25% (n=11). In the FTBI group, the rate of grade 3–4 acute GVHD rate was 44% (n=12; P=0.03 in comparison to the FB1A group), the chronic GVHD rate was 52% (n=14; P=0.09), the relapse rate was 15% (n=4; P=NS) and the TRM rate was 37.0% (n=10; P=NS). At 2 years, overall survival was 66% (95%CI, 51–78%) in the FB1A group versus 55% (95%CI, 36–73%) in the FTBI group (P=NS). Disease-free survival (DFS) was also comparable between both groups (at 2 years, 59% in the FB1A group, vs. 48% in the FTBI group, P=NS). In a Cox multivariate analysis for OS or DFS, the type of RIC regimen was not significantly associated with outcome. In all, these results suggest that in patients with lymphoid malignancies, a RIC regimen including Fludarabine, ATG and low dose busulfan (4 mg/Kg total dose) is a valid alternative to the classical Fludarabine and low dose TBI-based RIC regimen with a favorable toxicity profile and efficient disease control. Disclosures: No relevant conflicts of interest to declare.

Unrelated Donor Marrow Transplantation for B-Cell Chronic Lymphocytic Leukemia After Using Myeloablative Conditioning: Results From the Center for International Blood and Marrow Transplant Research

2005 ◽  
Vol 23 (24) ◽  
pp. 5788-5794 ◽  
Author(s):  
Steven Z. Pavletic ◽  
Issa F. Khouri ◽  
Michael Haagenson ◽  
Roberta J. King ◽  
Philip J. Bierman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Cell Chronic Lymphocytic Leukemia

Purpose To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). Patients and Methods A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Results Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. Conclusion These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

Outcome of Patients Developing GVHD after DLI for CML Relapse from HLA-Identical Sibling or VUD HSCT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1817-1817
Author(s):  
Yves Chalandon ◽  
Christoph Schmid ◽  
Kimmo Porkka ◽  
Alvaro Urbano-Ispizua ◽  
Bernd Hertenstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Gvhd ◽  
Median Number ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Initial Cell ◽  
Cell Dose ◽  
Stem Cell Source ◽  
Related Mortality

Abstract Using data submitted to the EBMT registry, we analyzed outcome on 344 patients (pts) who had received donor lymphocyte infusions (DLI) for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) in 31 centers. 113/344 pts (33%) developed acute graft-versus-host disease (aGVHD) a median of 50 days post DLI (max grade: I=42, II=30, III=31, IV=6)(60% grade II–IV). Organs involved (%): skin (88), liver (42), gut (30). Median age was 38 (4–59), 58% pts were male, 62 transplants were HLA-identical sibling and 51 unrelated. 74 were T-cell depleted, 92 transplanted in CP1, 21 beyond CP1. Relapse was molecular in 19 pts, cytogenetic in 31, hematological in 49, accelerated or blastic in 12. Median initial cell dose was 107CD3+ cells/kg (0.01–32), median number of DLI was 1 (1–10). aGvHD was treated with prednisone in 92% of pts, CSA in 52 %, ATG and monoclonal antibodies in 2% and other in 19%. aGVHD resolved in 53% of the pts within a median of 63 d (7–546). 82/344 pts (24%) had chronic GVHD (cGVHD)(30 limited, 50 extensive, 2 not specified), of those 46 (56%) following aGVHD post DLI. Organs involved (%): skin (75), liver (35), lungs (13), mouth (43), eyes (22) and gut (5). Median age was 35 (6–58), 51% were male, stem cell source was PB in 15% and marrow in 85%, 43 underwent HLA-identical sibling HSCT and 39 unrelated donor HSCT. Forty-three were T-cell depleted, 66 transplanted in CP1, 16 beyond CP1. Relapse was molecular in 21 pts, cytogenetic in 29, hematological in 22, accelerated or blastic in 7. Median initial cell dose was 107 CD3+ cells/kg (0.05–40), median number of DLI was 1 (1–7). 61 pts are alive with a median follow-up of 50 mth. Treatment was with steroids in 83% of pts, CSA in 58 %, MMF in 20%, thalidomide in 15%, photopheresis in 15%, PUVA in 10% and other in 17%. cGVHD resolved in 39% of the pts within a median of 354 d (44–1588). The estimated 5-y OS post-DLI was significantly lower in pts who developed aGVHD post-DLI, 61 ± 10% vs 74 ± 7% in the one that did not, p=0.007 and also a tendency to have a lower 5-y EFS, 58 ± 10% vs 65 ± 7%, p=0.19. Median duration of response to DLI in aGVHD pts was 4 y. aGVHD post-DLI did not influence the relapse rate (5 ± 5% vs 6 ± 5% in the absence of aGVHD). 5-y DLI related mortality was significantly higher in aGVHD pts, 31 ± 8% vs 4 ± 4%, p<0.00001. On the other hand, pts that developed cGVHD post-DLI had a tendency to have a better 5-y OS and EFS, 74 ± 11% and 71 ± 11% respectively vs 69 ± 6% and 62 ± 7% in those that did not, p=0.32 and 0.09. This was related to a tendency to lower incidence of relapse, 2 ± 3% in pts with cGVHD vs 9 ± 6% without, p=0.2. DLI related mortality was not different, 11 ± 8% vs 10 ± 5%, p=0.77. aGVHD post-DLI for CML relapse is mainly of advanced stage and negatively influence OS and EFS with a higher DLI related mortality. cGVHD post-DLI is mainly extensive, but pts with cGHVD tend to have better outcome with better 5-y OS, EFS and less relapse than those without, although this was not statistically significant.

Outcomes of c Hematopoietic Stem Cell Transplantation (HCT) after Non-Myeloablative Conditioning in Relapsed, Refractory, or Transformed Indolent Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3124-3124 ◽  
Author(s):  
Andrew R. Rezvani ◽  
Brenda M. Sandmaier ◽  
Barry Storer ◽  
Michael Maris ◽  
Edward Agura ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Aggressive Lymphoma ◽  
Optimal Timing ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Allogeneic Hct ◽  
Grade 3

Abstract Sixty-two patients (pts) with chemotherapy-refractory indolent or transformed NHL were treated at 10 centers with allogeneic HCT from related (n=34) and unrelated (n=28) donors after 2 Gy total body irradiation with or without fludarabine. Diagnoses included follicular lymphoma (FL) (n=54, including 10 with grade 3 FL), small lymphocytic lymphoma (n=6), and marginal zone lymphoma (n=2). Median age was 54 years (range 33–66 years), and median time from diagnosis to HCT was 4.4 years (range 0.5–18.5 years). Sixteen pts had histologically documented transformation to diffuse aggressive lymphoma prior to HCT. Twenty-seven pts (44%) had failed autologous HCT. Disease status at the time of HCT was complete response (CR, n=16), partial response (PR, n=22), refractory (n=13), untested relapse (n=9), or unknown (n=2). Eleven of the 28 unrelated donor/recipient pairs (39%) had HLA mismatches: 2 at a single allele, 7 at a single antigen, and 2 at an antigen and an allele. One pt had non-fatal graft rejection from a 1-antigen-mismatched unrelated donor. Median follow-up of survivors after HCT was 36.6 months (range 2.3–60 months). Responses (CR [n=18] and PR [n=7]) were seen in 25 of 44 (57%) pts with evaluable disease prior to HCT, while 5 had stable disease, 9 progressed, and 5 were not evaluable due to early non-relapse mortality (NRM) on d27–d108. Two of 16 pts (13%) transplanted in CR relapsed; one was treated with donor lymphocyte infusion and achieved a persistent CR. The incidences of acute GVHD grades II–IV, III–IV, and chronic GVHD were 63%, 19%, and 53%, respectively. At 3 years, the risks of relapse/progression and NRM were 19% and 42%, respectively. There was a trend toward increased mortality with unrelated donors (HR 1.87 [0.9–3.7, p=0.08]). Progression-free and overall survival (PFS and OS) were significantly better in the non-transformed group (see tables 1 and 2). Table 1. Outcomes Non-transformed Transformed Relapse 6/46 (13%) 6/16 (38%) NRM 20/46 (43%) 6/16 (38%) 3-year OS 24/46 (52%) 4/16 (25%) 3-year PFS 20/46 (43%) 4/16 (25%) Table 2. Hazard Ratios (HR) for Transformed vs. Non-Transformed Pts HR (95% CI) p All-cause Mortality 2.39 (1.2–4.9) 0.02 Relapse/progression 4.75 (1.5–15) 0.01 Grade 3+ acute GVHD 1.84 (0.5–6.3) 0.35 Extensive chronic GVHD 1.96 (0.8–5.0) 0.18 Figure Figure Allogeneic HCT after non-myeloablative conditioning can produce durable responses and prolonged survival in pts with refractory indolent or transformed NHL. Pts transplanted before histologic transformation had significantly better outcomes. Future efforts will focus on reducing NRM and identifying optimal timing of HCT.

Donor Type Impacts the Incidence of Severe Acute but Not Chronic Graft- Versus-Host Disease (GVHD) after Reduced Toxicity Conditioning and Allogeneic Stem Cell Transplantation (ASCT) for Treatment of AML/MDS.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2227-2227
Author(s):  
Ri ma M. Saliba ◽  
Krishna V. Komanduri ◽  
Ebru Koca ◽  
Amin M. Alousi ◽  
Sergio Giralt ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Donor Type ◽  
Grade Ii ◽  
Reduced Toxicity ◽  
Grade Iii

Abstract The use of reduced intensity conditioning has resulted in a significantly lower incidence of severe acute GVHD (aGVHD) compared with myeloablative conditioning. It is not known if reduced toxicity myeloablative conditioning has a similar impact. To answer this question, we evaluated the incidence of acute and chronic GVHD in a homogeneous group of AML/MDS patients treated with Fludarabine (Flu) and IV Busulfan (IVBu) between April 2001 and August 2005 at MD Anderson Cancer Center. METHODS: Retrospective analysis of all 195 consecutive AML/MDS patients (pts) who received conditioning with IVBu (130 mg/m2 for 4 days) and Flu (40 mg/m2 for 4 days) and allogeneic stem cell transplantation (ASCT). The cumulative incidence of GVHD was estimated considering disease progression or death in the absence of GVHD as competing risks. Cox’s proportional hazards regression analysis was used to compare the rates of GVHD. RESULTS: Median age at the time of transplantation was 46 years (12–65) with 4 pts being younger than 18 years. 45% of pts (n=93) were females and 47% (n=92) were in complete remission at the time of transplant. 55% (n=107) received a graft from a matched related donor (MRD), 38% (n=74) from a matched unrelated donor (MUD), and 7% (n=14) from a 1 Ag mismatched related or unrelated donor. Stem cell source was peripheral blood in 85% of recipients of a MRD graft and bone marrow in 88% of recipients of a MUD graft. The median number of CD34+ cells infused was 4.6 x 106/Kg (range 1.1–8.9) and 3.8 x106/Kg (range 0.2–13) in the two groups respectively. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. In addition, 29/74 recipients of a MUD graft received varying doses of pentostatin on a phase I/II clinical trial. Evaluation of GVHD was limited to pts who received a graft from a MRD or MUD and engrafted (n=179/181). With a median follow-up among survivors of 48 months (range 16–80), 100 day actuarial survival was similar in recipients of a MRD (96%) and MUD (93%) graft (p=0.3). A total of 50 pts (28%) developed grade II-IV and 15 pts (8%) grade III-IV aGVHD within 100 days after ASCT. Donor type was the most significant predictor of the incidence of grade II-IV aGVHD with a cumulative incidence of 18% (95% CI: 12–27) in recipients of a MRD graft and 38% (95% CI: 29–51) in recipients of a MUD graft (HR=0.4, p=0.001). Similarly the rate of grade III-IV aGVHD was significantly lower in recipients of a MRD graft (4% vs. 15%, HR=0.2, p=0.007). In contrast, donor type did not impact the incidence of chronic GVHD with a comparable cumulative incidence by 2 years in recipients of a MRD (53%, 95% CI: 44–63) and MUD graft (45%, 95% CI: 35–58), (HR=0.9, p=0.8). Similar results were observed when the comparison was restricted to de novo chronic GVHD (n=32). Use of peripheral blood stem cells was the only significant factor associated with a higher rate of chronic GVHD in recipients of a MRD graft (56% vs. 35%; HR=2.5, p=0.03). Female gender was associated with a significantly lower rate of chronic GVHD in recipients of a MUD graft (HR=0.4, p=0.006). There was no significant impact for age, percent donor chimerism at the time of engraftment, diagnosis (AML versus MDS), or donor/recipient CMV serostatus on the rate of grade II-IV aGVHD or chronic GVHD. CONCLUSION: The incidence of grade II-IV aGVHD is low following IVBuFlu conditioning and ASCT in AML/MDS patients. In this setting, donor type affects the incidence of acute but not chronic GVHD. Figure Figure

Conditioning Intensity In Middle Aged Patients With AML In CR1. No Advantage For Myeloablative Regimens Irrespective Of The Risk Group. An Observational Analysis By The Acute Leukemia Working Party Of The EBMT

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 542-542
Author(s):  
Jakob Passweg ◽  
Myriam Labopin ◽  
Jan J Cornelissen ◽  
Liisa Volin ◽  
Gérard Socié ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Intermediate Risk ◽  
Poor Risk ◽  
Conditioning Intensity ◽  
Good Risk ◽  
Related Mortality

Abstract Introduction In younger patients with AML achieving CR1 with intermediate or high risk disease allogeneic HSCT is the treatment of choice. Conditioning intensity is varied, reduced intensity (RIC) conditioning regimens are usually given to older patients, whereas young patients traditionally receive myeloablative regimens (MAC). In patients between the ages of 40-60 both types of regimens are used with little knowledge about factors that would lead physicians to prefer one over the other. Previous studies had shown that RIC regimens were associated with somewhat higher relapse risks but lower risks of transplant related mortality (TRM). We hypothesized that in low-intermediate risk disease based on cytogenetic classification RIC is superior to MAC whereas in high risk leukemia MAC is superior to RIC given higher antileukemic activity. Patients and Methods This study included 2974 of 5388 eligible patients with AML transplanted in CR1 in 2000-2011 based on the availability of cytogenetics to classify by risk status at diagnosis. Only sibling or unrelated donors and marrow or peripheral blood stem cell transplants were considered. Regimens were classified as MAC (n=1638) or RIC (n=1336) based on published criteria. Median follow-up of surviving patients was 46 and 41 months respectively. Groups differed by many variables. MAC recipients were significantly younger (37.6 vs 53.8 years), had a shorter interval from diagnosis to transplantation (143 vs 165 days), were more frequently male (53% vs 48%), had less frequently poor risk cytogenetics 19% vs 22%, received less frequently stem cells from an unrelated donor (20% vs 33%), and had more frequently marrow as a stem cell source (36% vs 7%). The Kaplan-Meier estimator, the cumulative incidence function and Cox proportional hazards regression models were used where appropriate. Results Table 1 shows similar overall (OS) and leukemia free survival (LFS) in both groups but a lower relapse incidence (RI) and a higher transplant related mortality incidence (TRM) in the MAC group. Acute grade II-IV GvHD was higher with MAC, incidence of chronic GvHD did not differ significantly. In univariate analysis overall survival was higher with RIC in cytogenetic good risk AML (55±5% vs 77±7% MAC vs RIC) but not in intermediate risk (61±1% vs 62±2%) or poor risk AML (42±3% vs 40±3%). Relapse incidence was lower with MAC in poor risk AML (36±3% vs 51±3%) and intermediate risk AML (21±1% vs 30±1%) but not in good risk AML (19±4% vs 13±5%). TRM was higher in MAC vs RIC in all three cytogenetic risk groups. Multivariate analysis confirmed a significant LFS and OS advantage of RIC in good risk but not in intermediate and poor risk leukemia. Conclusions In patients aged 40-60 MAC conditioning has no advantage over RIC conditioning in spite of RIC transplant recipients being generally in a poorer risk category. We confirm lower relapse rates but higher TRM risks with MAC compared to RIC. We fail to show superiority of MAC in patients with high risk cytogenetics but there appears to be an advantage for RIC over MAC in the small cohort of patients with good risk leukemia. Disclosures: Kuball: Miltenyi: GMP product development Other.

scholarly journals Allogeneic Stem Cell Transplantation for Relapsed / Refractory (R/R) Follicular Lymphoma (FL). a Joint Study Between the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 198-198
Author(s):  
Anna Sureda ◽  
Mei-Jie Zhang ◽  
Peter Dreger ◽  
Jeanette Carreras ◽  
Timothy S. Fenske ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Karnofsky Performance Score ◽  
Hematopoietic Stem ◽  
Long Term Outcome ◽  
Grade 3

Abstract Introduction. The definitive management of R/R FL remains controversial due to various treatment options, including chemoimmunotherapy, pathway inhibitors, and autologous stem cell transplantation (auto-SCT). These options can provide prolonged progression-free survival (PFS). Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the sole curative therapy for FL. Herein, we report the long term outcome of the largest sample of allo-SCT for FL ever studied as well as the identification of patient and disease related factors that were significantly associated with treatment failure. Patients. Eligible were adult patients with R/R FL having received a first allo-SCT between 2001 and 2011 from an HLA identical sibling donor (SIB) or a well-matched unrelated donor (MUD). Patients with transformed lymphoma were excluded from the analysis as well as planned second transplants, allotransplants from cord blood, mismatched donors, and transplants with ex vivo T cell depletion (TCD). Results. 1567 patients met the eligibility criteria (EBMT, n = 1115; CIBMTR, n = 452). Demographics separated by data source demonstrate some differences in transplant practices between the two regions. The CIBMTR cohort had a higher proportion of MUD recipients [167 (37%) vs 252 (23%), p < 0.001], more cases with chemoresistant disease [113 (25%) vs 145 (13%), p < 0.001], less patients having received a prior auto-SCT [53 (12%) vs 403 (36%), p < 0.001], more use of myeloablative conditioning (MAC) (145 (32%) vs 220 (20%), p < 0.001) and less use of alemtuzumab in-vivo TCD [29 (6%) vs 201 (18%), p < 0.001] compared to the EBMT cohort. Median (range) follow up of survivors in months was 58 (3 - 130) and 54 (3 - 160) for CIBMTR and EBMT patients, respectively. Cumulative incidence of acute (grades II-IV) graft versus host disease (GVHD) was 20% (18-22) at 100 days and of chronic GVHD 45% (42-48) and 55% (52-58) at 1 and 3 years, respectively for the whole series; this risk was slightly but significantly reduced in the EBMT cohort. All major outcomes [non-relapse mortality (NRM), relapse/progression (R/P), overall survival (OS) and PFS] were comparable between the CIBMTR and EBMT samples (Table 1). Table 1. Outcomes CIBMTR EBMT p-value NRMN@ 1 y@ 3 y@ 5 y 45021 (17-25)27 (23-32)31 (26-35) 108819 (16-21)24 (21-27)28 (25-31) 0.3630.1720.114 R/PN@ 1 y@ 3 y@ 5 y 45013 (10-16)16 (13-20)17 (13-21) 108813 (11-15)18 (15-20)21 (18-23) 0.8740.4800.114 PFSN@ 1 y@ 3 y@ 5 y 45066 (62-71)56 (52-61)52 (47-57) 108869 (66-72)58 (55-61)52 (48-55) 0.3750.4950.792 OSN@ 1 y@3 y@ 5 y 45274 (70-78)65 (60-69)61 (56-65) 110475 (72-78)67 (64-70)62 (59-65) 0.5890.4550.695 Multivariate analysis indicated that NRM was significantly affected by age (HR 1.04, 1.02-1.05, p < 0.0001), chemoresistant disease (HR 1.61, 1.28-2.03, p < 0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.62, 1.20-2.19, p=0.0015) and Karnofsky performance score (KPS) < 80 (HR 2.05 (1.32-3.19, p=0.0014); R/P was significantly affected by grade 3 histology (HR 1.63, 1.16-2.26, p=0.0049) and chemoresistant disease (HR 1.46 (1.07-1.97), p=0.0156); PFS by grade 3 histology (HR 1.42, 1.15-1.76, p=0.0012), chemoresistant disease (HR 1.54, 1.28-1.86, p<0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.45, 1.13-1.85, p=0.0031), MAC (HR 1.36, 1.14-1.63, p=0.0008) and KPS < 80 (HR 1.78, 1.23-2.58, p =0.0022) and OS by age (HR 1.03, 1.02-1.04, p<0.0001), grade 3 histology (HR 1.44, 1.13-1.83, p=0.0031), chemoresistant disease (HR 1.59, 1.30-1.95, p<0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.63, 1.25-2.13, p=0.0003), MAC (HR 1.42, 1.16-1.73, p=0.0006) and KPS < 80 (HR 2.23, 1.52-3.25, p<0.0001). Of note, outcomes between SIB and MUD were similar (3y OS 68% and 62%, P=0.114). Moreover a significant impact of TCD and prior auto-SCT could not be detected. Conclusions. This study represents an example of a fruitful cooperation between two important scientific transplant societies, the EBMT and CIBMTR. Despite significant differences in patient characteristics and transplant strategies between these 2 hitherto largest samples on allo-SCT for R/R FL, long-term disease control was similar and remarkably good with an R/P risk of about only 20% at 5 years. Chemoresistant disease, higher age, multiple pretreatment lines, poor KPS, and MAC all were predictors for an adverse outcome, whereas MUD, TCD, and prior auto-SCT had no impact on any survival endpoint. Disclosures Sureda: Takeda: Consultancy, Honoraria, Speakers Bureau. Fenske:Celgene: Honoraria; Millennium/Takeda: Research Funding; Pharmacyclics: Honoraria; Seattle Genetics: Honoraria. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy.

scholarly journals Myeloablative Conditioning Haploidentical Stem Cell Transplantation (MAC-HAPLO) with Post-Transplant Cyclophosphamide (PTCy) As GvHD Prophylaxis in High Risk Leukemias/Myelosdysplastic Syndromes (MDS): Geth Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4690-4690 ◽  
Author(s):  
Jorge Gayoso ◽  
Pascual Balsalobre ◽  
Mi Kwon ◽  
Pilar Herrera ◽  
Arancha Bermúdez ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Disease Control ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Myeloablative Conditioning ◽  
Haploidentical Stem Cell Transplantation ◽  
Gvhd Prophylaxis

Abstract Introduction: Allogeneic transplantation is the only curative option for patients with high risk leukemias or MDS. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why haploidentical stem cell transplantation (HAPLO-HSCT) offers a therapeutic option to most of these patients. Myeloablative conditioning (MAC) produce better disease control than reduced intensity conditioning regimens (RIC), but with higher toxicity, rendering long term similar results. Patients and methods: We retrospectively evaluated the results of our MAC-HAPLO regimens in patients diagnosed with high risk leukemias or MDS (Fludarabine 30 mg/m2 x5 days, Cyclophosphamide14,5 mg/kg x2 days, IV Busulfan 3,2 mg/kg x 3 days (BUX3), or Fludarabine 40 mg/m2 x4 days and IV Busulfan 3,2 mg/kg x 4 days (BUX4)) with GVHD prophylaxis based on PT-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5, performed in GETH centers (Spanish Group for Hematopoietic Transplantation). Results: From Feb-2012, 65 MAC-HAPLO HSCT have been reported by 14 centers. Median age was 41 years (15-67), 66% were males and all were in advanced disease phase or presented high risk features (AML 47/ALL 8/MDS 5/ Others 5). Previous HSCT had been employed in 12% (autologous in 5, allogeneic in 3), and in 88% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was morphologic CR in 80%, but disease persisted in 52% (MRD+ by flow or molecular markers 32%, morphologic disease 20%). Their disease risk index (DRI) was high or very high in 65%, and the comorbidity index (HCT-CI) was higher than 2 in 18%. PBSC was the graft source in 56 (86%), non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21.5%), father (12%), siblings (43%) or offspring (23%). MAC regimen was BUX3 in 25 (38.5%) and BUX4 in 40 patients (61.5%). Median infused CD34+ cells were 5.31 x10e6/kg (2.75-11.42). There were no graft failures. Median neutrophils engraftment was reached at day +17 (12-29) and platelets >20K at day +26 (11-150). Complete chimerism was obtained at a median of 28 days (13-135) in 60 evaluated patients. Cumulative incidence (CI) of non-relapse mortality (NRM) was 12.5% at day +100 and 19% at 1 year. CI of grade II-IV acute GVHD was 28.5% at day +100, and grade III-IV was 6.5%. CI of chronic GVHD at 2 years was 28%, being extensive in 8% . No differences in acute or chronic GvHD CI were seen when comparing BUX3 against BUX4. After a median follow-up of 17 months (5-50), estimated 24-months event-free survival (EFS) and overall survival (OS) were 58,5% and 60% respectively. CI of relapse or progression was 21%. No significant differences in NRM, EFS, OS and relapse incidence were detected between BUX3 and BUX4. The impact of CR prior to MAC-HAPLO, the DRI or chronic GvHD in the disease control have not been apropiately demostrated probably due to the limited number of events in our series. Conclusions: IV Busulfan based MAC-HAPLO with PT-CY in the treatment of high risk leukemias and MDS offers good disease control with manageable toxicity, with either BUX3 or BUX4. These efective MAC regimens combined with peripheral blood HAPLO donors could control high risk hematologic diseases in the long term. Severe acute or chronic GvHD are low frecuency events, but relapses persist as the main problem in this patients population. Disclosures No relevant conflicts of interest to declare.

Impact of antithymocyte globulin on new HLA groups for unrelated donor allogeneic stem cell transplantation.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18017-e18017
Author(s):  
Yoo Jin Lee ◽  
Jong Gwang Kim ◽  
Soo Jung Lee ◽  
Byung Woog Kang ◽  
Yee Soo Chae ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Favorable Effect ◽  
Unrelated Donor ◽  
Matched Group ◽  
Gvhd Prophylaxis ◽  
Grade 3

e18017 Background: The outcomes of unrelated donor transplantation have improved with refinements in HLA testing. Recently, grouping of HLA matching for unrelated donor was suggested, defining by well-matched, partially-matched, and mismatched. In the current study, the role of anti-thymocyte globulin (ATG) for each group was evaluated. Methods: A total of 120 patients diagnosed as hematologic diseases and received allogeneic stem cell transplantation (SCT) from unrelated donor were retrospectively analyzed. Results: 28 patients were classified as well-matched, 52 as partially-matched, and 40 as mismatched. Among them, 73 patients received ATG as graft-versus-host disease (GVHD) prophylaxis. The overall survival (OS) rate was higher for well-matched group (82%) compared to partially-matched (53%) and mismatched (34%, p=0.076). For partially-matched group, the OS was significantly improved with ATG (83.3% vs. 38.6%, p=0.018). But, the OS was not different between groups with or without ATG for well-matched (87.5% vs. 66.7%, p=0.487) and mismatched (32.4% vs. 41.7%, p=0.215). ATG decreased the cumulative incidence of grade 3-4 acute GVHD (10% vs. 40.2%, p=0.068) and severe chronic GVHD (21.2% vs. 52.2%, p=0.037). The use of ATG (HR=0.248, p=0.029) was related with favorable OS for partially-matched group. However, the favorable effect of ATG was not observed in well-matched and mismatched groups. Conclusions: ATG effectively improved survival rate for partially-matched group in unrelated donor transplantation. However, the positive effect of ATG was not observed in well-matched and mismatched group.

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