Reduced Intensity Conditioning Unrelated Transplant Plus Cyclosporine and MMF as GVHD Prophylaxis: Results of a Prospective Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5312-5312
Author(s):  
J.A. Perez-Simon ◽  
R. Martino ◽  
R. de la Camara ◽  
J. Perez de Oteiza ◽  
J.M. Moraleda ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Similar Efficacy ◽  
Comorbid Condition ◽  
Gvhd Prophylaxis ◽  
Risk Patients ◽  
Related Donor ◽  
A Prospective Study

Abstract Some studies have suggested that mycophenolate mofetil (MMF) offers a similar efficacy in terms of GVHD prophylaxis as compared to methotrexate (MTX) but a faster engraftment and a lower incidence of mucositis. We have analyzed the results of fludarabine (150 mg/m2) and melphalan (140 mg/m2) or busulphan (10 mg/m2) plus Cyclosporine (CsA) and MMF instead of MTX as GVHD prophylaxis in a series of 30 patients undergoing unrelated allogeneic transplantation. Median age was 44 years (18–60). Patients younger than 40 were required to have a previous comorbid condition (8 had a previous autologous transplant; 2 had proven fungal infection; 1 had severe altered lung capacity). Twelve patients were diagnosed with AML, 4 had ALL, 4 MDS, 2 CML, 3 CLL, 3 NHL, 2 MM/WM. Disease status at transplant was 1st or 2nd CR in 12 patients, >2nd CR or PR in 11 patients while the remaining patients had active disease at the time of transplant (relapse, refractory, untreated diasease). Median day to reach > 0,5 x 109 granulocytes / L was +17 and to reach > 20 x 109 platelets / L was +13. At a median follow up of 445 days among patients alive, projected overall survival (OS) and event free survival at 3 years are 47% and 30%, respectively. Overall TRM was 32%. Cumulative incidence of grades 2–4 and 3–4 aGVHD was 67% and 33%, respectively while cumulative incidence of extensive cGVHD was 70%. Gut was the organ most severely involved in aGVHD in 10 out of 16 patients while liver was involved in only 3 cases. Interestingly, among patients who developed aGVHD, incidence of skin (80%) and liver (22%) involvement were similar to that observed in a similar series of patients receiving related donor transplant using the same RIC plus CsA and MTX instead of MMF while the incidence of gut involvement was significantly higher (64% vs 42%). In conclusion, the RIC used in the current study plus CsA and MMF offers promising results in high risk patients. In terms of GVHD prophylaxis, MMF shows a good efficacy at skin and liver but poor at the gastrointestinal tract.

Prognostic Effect of ASXL1 Mutations in Patients with MDS and Secondary AML Following MDS After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1709-1709 ◽  
Author(s):  
Christian Koenecke ◽  
Felicitas Thol ◽  
Patrick Löffeld ◽  
Stefanie Buchholz ◽  
Michael Stadler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Donor Age ◽  
Hematopoietic Stem ◽  
Frameshift Mutations ◽  
Gvhd Prophylaxis ◽  
Related Donor

Abstract Abstract 1709 Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for patients with myelodysplastic syndromes (MDS), but it is associated with high mortality and morbidity. Predictors for treatment outcome after HSCT are limited. Recently, mutations in ASXL1 have been described as an independent adverse prognostic marker for MDS patients not undergoing HSCT. The aim of this study was to investigate the prognostic impact of ASXL1 in a large cohort of patients with high risk MDS or secondary AML following MDS (sAML) undergoing HSCT. Patients and Methods: Patients (n=105) with a diagnosis of MDS (34.3%) or sAML (65.7%) who received an allogeneic HSCT at Hannover Medical School between 1996 and 2010 and for whom genomic DNA was available from a time when the disease was active, were evaluated for the presence of ASXL1 mutations by direct sequencing. Patients gave their informed consent in accordance with the Declaration of Helsinki, and the study was approved by the institutional review board of Hannover Medical School. Overall survival (OS) and cumulative incidence of non-relapse mortality endpoints, measured from HSCT, were death (failure) and alive at last follow-up (censored). A Cox proportional hazards model was constructed for multivariate analysis and the two-sided level of significance was set at P <.05. Results: Median follow up from time of transplantation was 3.67 years. Median patient age at time of HSCT was 58 years (range 22–72) and the median donor age was 39 years (range 0–71). Twenty-seven patients (26.0%) were in complete remission and 78 patients (74%) had active disease before transplantation. In MDS, 9, 21, and 6 patients had intermediate-1, intermediate-2, or high risk IPSS, respectively. Low, intermediate, and high risk cytogenetics according to IPSS were found in 40, 21, and 44 patients, respectively. Related donor HSCT was performed in 24 patients (23%), and unrelated donor HSCT in 81 patients (77%). Six patients received bone marrow (6%), two cord blood (2%), and 97 (92%) received peripheral blood stem cells. Myeloablative preparative regimens were used in 17 patients (16%), and a non-myeloablative regimen was given to 88 patients (84%). Mutations in ASXL1 were detected in 21 (20%) patients with 17 (16.2%) mutations being frameshift mutations. Previously, we showed that only frameshift mutations are prognostically relevant in MDS patients and therefore considered only those for further analysis. ASXL1 frameshift mutations were not correlated with clinical parameters (age, sex, MDS vs. sAML, cytogenetics, bone marrow blasts, blood group, CMV status of patient, type of previous treatment, and remission status prior to transplantation). ASXL1 frameshift mutated patients had received a graft from a related donor (41 vs. 19%, respectively, P=.05) and from bone marrow (17.6 vs. 3.4%, respectively, P=.03) more often compared to wildtype patients, however, there were no differences regarding other transplant-related characteristics (reduced intensity vs. standard conditioning, GvHD prophylaxis, donor age, donor sex, and CMV compatibility between recipient and donor). The presence of ASXL1 frameshift mutations was associated by trend with a shorter overall survival (5-year OS 31 vs. 47%, HR 1.87; 95%CI 0.96–3.64; p=.06). In multivariate analysis, when considering variables with P<.1 in univariate analysis (karyotype, stage [MDS vs. sAML], CMV serostatus of patient, donor type [related vs. unrelated], donor sex, donor age, and GvHD prophylaxis), ASXL1 frameshift mutations were an independent prognostic marker for OS (HR 2.63; 95%CI 1.29–5.38; P=.008) besides karyotype, stage, donor type, and GvHD prophylaxis. The cumulative incidence of relapse was similar between ASXL1 mutated and wildtype patients (P=.47). However, the cumulative incidence of non-relapse mortality was significantly higher in mutated compared to wildtype patients in univariate (61 vs. 34%, P=.01) and multivariate (P=.03) analysis. Grade III-IV acute GvHD was more frequent in ASXL1 mutated patients (37.5 vs. 7.4%, P=.002), while no extensive chronic GvHD was noted in these patients (0 vs. 20%, P=.14). Summary: ASXL1 frameshift mutations independently predicted worse patient outcome after allogeneic HSCT in MDS and sAML patients in our study. The high rate of non-relapse mortality in ASXL1 mutated patients warrants further investigation. *equal contribution Disclosures: No relevant conflicts of interest to declare.

The Addition of ONE-Day Rest Between LAST ATG Infusion and STEM CELL Infusion DID NOT Affect Gvhd Occurrence After Allogeneic TRANSPLANTATION with Fludarabine-Busulfan-ATG Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3029-3029
Author(s):  
Roberto Crocchiolo ◽  
Sabine Fuerst ◽  
Jean El-Cheikh ◽  
Angela Granata ◽  
Claire Oudin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Progression Rate ◽  
Gvhd Prophylaxis

Abstract Abstract 3029 Introduction: Antithymocyte globulin (ATG) is part of many conditioning regimens for allogeneic stem cell transplantation (AlloSCT) with the aim of reducing graft-versus-host disease (GvHD), due to in vivo T-cell depletion. ATG administration may be accompanied by fever, chills, headache or other side effects that affect patient's management and can cause a delay in stem cell infusion. In order to improve ATG tolerance, since November 2010 we modified our fludarabine-busulfan-ATG (FBA) conditioning for RIC transplants with the addition of 1-day rest between the last ATG administration and stem cell infusion. No modification of drugs or GvHD prophylaxis occurred: five days of fludarabine, two days of i.v. busulfan and two days of ATG Thymoglobuline (10 mg/kg total dose) were administered during conditioning, and ciclosporine for GvHD prophylaxis together with MMF only in the presence of a mismatched unrelated donor (MMUD). Aim: To analyse whether the addition of 1-day rest between ATG administration and stem cell infusion impacted on outcome of adult patients receiving AlloSCT after FBA conditioning with respect to previous no-rest modality, in particular acute grade 2–4 or grade 3–4 GvHD. Methods: The 1-day rest cohort (ATG-rest) was compared with a previous consecutive cohort of patients (no rest) transplanted at our center. Analysis of acute GvHD among the two groups was performed as well as of chronic GvHD, OS, PFS, NRM, relapse/progression. Results: A total of 64 and 63 patients were included in ATG-rest and no-rest cohorts respectively. First patient in the no-rest cohort received AlloSCT on November 2008. Follow-up was thus longer in this cohort: median 27 months (21–37) vs. 15 (11–20), p<0.0001. No significant differences of patients' age, diagnosis and disease status at AlloSCT between the two groups were observed; matched unrelated donors (MUDs) were higher in the ATG-rest group whereas the number of MMUDs was similar in both groups (see Table 1). Rate of acute and chronic GvHD and NRM, probabilities of OS and PFS did not differ between the two groups (Table 1). Unexpectedly, relapse/progression rate was lower in the ATG-rest groups (p=0.002), although disease status at AlloSCT was not significantly different between the two cohorts. Median day of relapse or progression from AlloSCT in the no-rest group was +165 (35–476) vs. +57 (8–215) in ATG-rest one, p=0.004. No difference in relapse/progression was observed according to donor (HLA-identical sibling vs. MUD vs. MMUD) and a lower relapse risk in 1-day rest group is confirmed after adjustment for type of donor: HR = 0.29 (0.12–0.72), p=0.01. Conclusion: The addition of 1-day rest between last ATG administration and stem cell infusion did not impacted on GvHD occurrence after AlloSCT after FBA conditioning. The finding of a reduced rate of relapse/progression in the ATG-rest group deserves to be investigated and requires longer follow-up. Disclosures: No relevant conflicts of interest to declare.

Reduced Intensity Conditioning with Fludarabine, BCNU and Melphalan (FBM) for Allogeneic Hematopoietic Cell Transplantation in Elderly AML Patients: Factors Predicting Outcome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5523-5523
Author(s):  
Verena Wais ◽  
Stephan Bohl ◽  
Lukas Kündgen ◽  
Stephanie von Harsdorf ◽  
Katrina Scholl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hematopoietic Cell Transplantation ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Reduced Intensity Conditioning ◽  
Npm1 Mutation ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Predicting Outcome

Abstract Introduction: With the introduction of reduced-intensity conditioning (RIC), the age limit for allogeneic transplantation of AML patients has risen to 65 and above. In order to balance a low transplant-related mortality (TRM) with high anti-leukemic efficacy, Marks et al.1 introduced FBM conditioning consisting of 150mg/m2 Fludarabine, 300mg/m2 BCNU and 110mg/m2 Melphalan as RIC for elderly patients with encouraging results. However, no detailed analysis of factors predicting outcome in this subpopulation has been presented so far. Methods: In this two-center retrospective study, 51 patients (pts) with a median age of 64 y (range, 44-75y) diagnosed with AML were uniformly treated according to the FBM protocol. GvHD prophylaxis consisted of Ciclosporin A (CYA) and mycophenolate mofetil (MMF) in all patients. MMF was tapered after d50 and CYA after d90 in the absence of GvHD. Pts with matched unrelated donors (MUD) (n=33) or mismatched unrelated donors (MMUD) (n=9) received additional ATG or low dose alemtuzumab as GvHD and rejection prophylaxis. 9 pts with matched related donor (MRD) only received CYA and MMF as GvHD prophylaxis. Stem cell source was peripheral blood in 90% (n=46) and marrow in 10% (n=5) of the patients. The median number of transfused CD34+ cell was 7.1 million per kg body weight. The median follow-up at the time of analysis was 27 months. At the time of transplant 38 pts were in complete remission; the rest of the pts had active disease (partial remission or refractory disease). Molecular (NPM1, FLT3-ITD and CEBPA a) and cytogenetic characteristics (evaluable in 50 patients) were available for all patients. Results: Acute regimen-related toxicity was low, with a d30 mortality of 0 % in both centers. After 2 years, treatment failure was mainly due to relapse (CIR) with 36% (SE: 8%) in comparison to TRM (20%, SE: 7%). The resulting progression-free survival (PFS) and overall survival (OS) at 2 years was 50 % (SE: 5%) and 61% (SE: 7%), respectively. The median EBMT score was 4 (range 2-6). The EBMT score had no impact on different outcome variables (CIR (p=0.465), PFS (p=0.352) and OS (p=0.171)). Based on cytogenetic and molecular data patients were categorized according to the European LeukemiaNet (ELN) classification. 10% (n=5) of the patients belonged to the ELN favorable, 39% (n=20) to the ELN intermediate I, 29% (n=15) to the ELN intermediate II and 22% (n=11) to the ELN adverse risk group. Neither the ELN score itself nor stratification according to FLT3 -ITD or NPM1 mutation status or cytogenetic risk group impacted on outcome in our cohort. A trend for an improved OS in patients with NPM1 mutation (not stratified for FLT3-ITD or FLT3-TKD) was detected (p=0.255). By analyzing further risk factors such as remission status, donor type, age, CMV status, CD34+ cell number and acute or chronic GvHD we found the disease status at the time of transplant being the dominant predictor for OS. After 2 years patients transplanted not in remission had only an OS of 20% (SE: 8%) as compared to 75% (SE: 12%) in patients transplanted in CR (p<0.001) (Figure 1). Conclusion: In this cohort of elderly patients with AML receiving allogeneic transplantation after FBM conditioning, disease status at the time of transplant was the dominant prognostic factor for outcome. At the present follow-up neither molecular status nor cytogenetics impacted OS, PFS or CIR, significantly. We conclude that alternative strategies have to be applied using FBM conditioning in refractory patients, i.e. the early tapering of immunosuppression and the use of donor lymphocytes or cytoreduction immediately before the start of conditioning. An additional focus should be on novel compounds, which might help to increase CR rates at time of transplant. References 1. Marks R, Potthoff K, et al. Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies. Blood. 2008;112(2):415-425. Figure 1. Overall survival dependent on disease status at transplant. Figure 1. Overall survival dependent on disease status at transplant. Disclosures No relevant conflicts of interest to declare.

Long-Term Follow-Up Of Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation For High Risk Follicular Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5519-5519
Author(s):  
Silvana Novelli ◽  
Albert Esquirol ◽  
Javier Briones ◽  
Pilar Leoz ◽  
Rodrigo Martino ◽  
...  
Keyword(s):  
High Risk ◽  
Median Time ◽  
Risk Score ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Related Donor

Abstract Introduction Follicular lymphoma (FL) is the most frequent indolent lymphoma. Autologous hematopoietic stem cell transplantation (ASCT) allows durable progression-free survival in selected relapsed patients. Recently, the EBMT lymphoma working party has published the recommendations for ASCT and allogeneic hematopoietic transplantation (alloTPH) in FL. For those high-risk young patients relapsing after ASCT, alloTPH is a valid therapeutic option; the majority being done with reduced intensity conditioning (alloRIC). Aims Our aim is to describe the outcome of patients with FL who underwent an alloTPH in our cente. Factors potentially influencing outcome such us age, sex, FLIPI at diagnosis, disease status prior alloTPH, EBMT risk score, type of donor, graft vs host disease (GVHD) prophylaxis and development of GVHD were also analized. Methods Actuarial estimates of OS and PFS rates were calculated using the Kaplan-Meier method. OS was estimated from the date of transplantation to the date of death or last follow-up. PFS was defined as the time from transplantation until progression or death from any cause. Patients We retrospectively found 26 alloTPH in the period 1999 - 2013. Two alloTPH were conditioned with a myeloablative regimen. Patients who underwent an alloRIC (n=24) were all conditioned with Fludarabine 30 mg/m2/5 days and Melphalan 70 mg/m2/1 day. Results AlloTPH was from a matched related donor in 70.8% of cases, from a mismatched related donor in 4.2%, matched unrelated donor in 8.3% and from a mismatched unrelated donor in 16.7%. The median age was 49.5 years (range 35-61). The median time from diagnosis to alloTPH was 48 months (range 9 – 190), male: female ratio was 2:1. FLIPI at diagnosis was 0 in 16.7%, FLIPI 1 in 25%, FLIPI 2 in 33.3%, FLIPI 3 in 8.3% and FLIPI 4 in 16.7. Mean number of treatment pre alloTPH was 4.5 (range 2-6). Ten patients (41.7%) had previously received an ASTC. Response before alloTPH was complete response in 54.2%, partial response in 37.5% and stable disease in 8.4%. The majority of patients (95.8%) had an EBMT risk score higher than 3. Graft vs host disease prophylaxis consisted on cyclosporine + short course of methotrexate in 54.2%, cyclosporine + micophenolate in 41.7% and sirolimus + tacrolimus in 4.2%. In vivo T-cell depletion was done in 4 patients receiving grafts from a mismatched unrelated donor (ATG or alemtuzumab, 2 patients each). Mean CD34 cells/Kg infused was 6.45 x106/kg (range 1.92 – 15.6). The median time to granulocyte recovery (>0.5x109/L) was 15 days (range 11-19) and the median time to platelets recovery (>50x109/L) was 14 days (range 6-56). Acute GVHD was developed in 45.8% of patients; it was global grade 1-2 in 36.4% ,and grade 3-4 in 63.6%. Chronic GVHD was present in 58.3% of patients. The median time of chronic GVHD presentation was 196 days after alloTPH (range 101 – 569 days). Regarding opportunistic infections, 20.8% of patients reactivated CMV with no disease, 16.7% had intestinal disease due to CMV. Thirteen per cent of patients developed pulmonary fungal infection (i.e Aspergillus sp). With a median follow up of 48.50 months (range 0-161), the 5 years OS was 66.1% (CI 95% 43.76 - 88.44) and the 5 years PFS was 63.8% (CI 95% 43.22 - 84.4). Overall morbidity at 3, 6 and 12 months after alloTPH was 5%, 5% and 10.3% respectively. Only 1 patient relapsed at 38 months after alloTPH but is still alive. Causes of death were refractory GVHD (n=5), sepsis (n=3) and acute renal failure due to microangiopathy (n=1). Survival was influenced by GVHD prophylaxis. At the median time of follow up (48.50 months) patients receiving cyclosporine-methotrexate had an OS of 82.5% vs 30% for patients receiving cyclosporine-MMF (p<0.01). Other variables (FLIPI at diagnosis, sex, age older than 60 years, the EBMT risk score pre alloTPH and disease status) had no influence on survival. Conclusions AlloTPH for high risk FL patients seems to overcome the negative effect of FL prognostic factors at diagnosis. This strategy shows an excellent disease control with a low transplant-related mortality. Disclosures: No relevant conflicts of interest to declare.

Durable Remission with Decreased HTLV-I Proviral Load after Reduced-Intensity Stem Cell Transplantation (RIST) in Patients with Adult T-Cell Leukemia/Lymphoma (ATL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3347-3347
Author(s):  
Ryuji Tanosaki ◽  
Kisato Nosaka ◽  
Shin Mineishi ◽  
Shin-ichiro Mori ◽  
Sung-Won Kim ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Disease Status ◽  
Donor Lymphocyte Infusion ◽  
Acute Type ◽  
Adult T Cell Leukemia ◽  
Trial Testing ◽  
Grade Ii ◽  
Related Donor ◽  
Healthy Carriers

Abstract Background. ATL is an HTLV-I-associated hematological malignancy. The majority of ATL patients are not curable using current chemotherapy with median survival time of 13 months. Recently, patients undergoing allo-SCT with conventional conditioning regimen were reported to have a 3-year overall survival (OS) rate of 45%, however, with high transplant-related mortality (TRM) rate as much as 40% (Fukushima T. Leukemia19:829, 2005). Since most ATL patients are over 50 years old with various complications, limited numbers of patients are eligible for conventional transplant. We have already conducted a phase I multi-center trial testing the feasibility of RIST in ATL patients, where 2-year OS was 33% and some differences in the outcome were suggested among participating institutes. Hence, we investigated the efficacy of RIST performed exclusively in our single institute (NCCH, Japan). Patients and Methods. Between Oct 2000 and Jun 2005, 16 ATL patients underwent RIST from a related donor. Since 3 have been enrolled into an on-going multi-center trial, 13 patients were analyzed in this retrospective study, including 3 who were enrolled into the above-mentioned multi-center trial (Okamura J. Blood105;4143, 2005). Median age was 51 years old (range, 44–61), 8 males and 5 females, and 8 were of acute type and 5 of lymphoma. The disease status at transplant was 3 CR, 7 PR and 3 primary refractory. Three donors were HTLV-I healthy carriers. Eleven were HLA 6/6, 2 were 5/6, 12 were PBSCT and 1 was BMT. Conditioning regimen was fludarabine 30 mg/m2 x6, busulfan 4 mg/kg x2 with (n=5) or without (n=8) rabbit ATG 2.5 mg/kg x2. Prophylaxis of GVHD was CSP alone. Results. Engraftment was rapid (median, 11 days) in all cases, and there was no TRM. Acute GVHD of grade II–IV developed in 7, and chronic extensive GVHD in 5. Eleven patients achieved CR after RIST, and 6 relapsed or progressed, among whom 2 achieved CR after cessation of CSP, donor lymphocyte infusion and local irradiation, and have been disease-free for more than 1 year. Ten patients are alive, 9 without disease, with median follow-up time of 26 mos (range, 4–45 mos). HTLV-I proviral titers determined using real time PCR decreased after RIST and became undetectable in 8 out of 13 patients. In 3, including one transplanted from an HTLV-I carrier donor, anti-HTLV-1 antibody transiently decreased and became nearly undetectable. Conclusions. RIST is feasible and safe in ATL patients, and it has not only an anti-ATL but also an anti-HTLV-I activity. This is the first report documenting the efficacy of RIST for ATL in terms of survival and remission durability. Figure Figure

Busulfan Dosing May Affect Survival Following Reduced Intensity Stem Cell Transplantation in Patients with Acute Myelogeneous Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4328-4328
Author(s):  
Karen K Ballen ◽  
Steven L McAfee ◽  
Bimalangshu R Dey ◽  
Christine Dube ◽  
Eyal C Attar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Total Dose ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Acute Myelogeneous Leukemia ◽  
Reduced Intensity

Abstract Abstract 4328 The prognosis for patients with acute myelogeneous leukemia over age 60 is poor, with a 5 year survival of less than 10%. Reduced intensity allogeneic transplantation has been employed in an attempt to improve survival. We report 23 patients who received reduced intensity allogeneic transplantation after a conditioning regimen of busulfan and fludarabine. Fifteen patients received a transplant from a matched sibling donor,1 patient from a 5/6 matched child and 7 patients from a fully matched (10/10) unrelated donor. We treated 10 patients with the reduced intensity conditioning regimen of busulfan IV 0.8 mg/kg daily Days -6, -5, -4, -3 (total dose 3.2 mg/kg) and fludarabine IV 30 mg/m2 Days -6,-5, -4, -3 (total dose 120mg/kg). After November, 2007, 10 patients were treated with twice daily busulfan IV 0.8mg/kg (total dose 6.4 mg/kg) with the same dose of fludarabine. Three patients were treated on a national protocol in which the same dose of busulfan (6. 4 mg/kg) was administered but given at 0.8 mg/kg four times daily for 2 days on Days -4 and -3 with fludarabine. GVHD prophylaxis was cyclosporine or tacrolimus with either cellcept or (after July, 2008) methotrexate. Seven recipients of unrelated donor or mismatched transplants also received rabbit antithymocyte globulin 1.5 mg/kg Days -3, -2, -1 (total dose 4.5 mg/kg) as part of their GVHD prophylaxis. Median age was 65 years (range 46-70 years). Fourteen patients were in 1st complete remission, 8 were in 2nd complete remission, and one patient had active disease at the time of transplant. Two patients had received a prior autologous stem cell transplant and 2 patients had received a prior allogeneic transplant. The median days to neutrophil (ANC >500) and platelet engraftment (plt >20K) were 15 and 14 respectively. The median length of stay was 25 days (range 13-40 days). Median follow-up was 12 months among the 10 patients still alive. The incidence of acute GVHD Grades II-IV and chronic GVHD were 44% and 35% respectively. Transplant related (non relapse) mortality at 100 days and at 6 months was 0. The overall non-relapse mortality was 4%. Relapse rate was 67% in the daily busulfan group and 46% in the higher dose busulfan group. The one-year overall and disease-free survivals for all patients were 44% and 25% respectively. Causes of death were relapse in 12 patients and in one patient sepsis six years after transplant. In multivariate analysis, disease status, age, and GVHD did not predict for survival, perhaps due to the small sample size. There was a trend to improved survival in the higher dose busulfan group but the follow up was shorter for these patients. In summary, 1) Reduced intensity transplantation is tolerated well in an older population with acute myelogeneous leukemia, with no transplant related mortality at Day 100 or at 6 months post transplant; 2) Relapse rermains the most common cause of death; 3) There was a trend to improved survival with a twice daily busulfan dosing. Future studies will address the outcomes of twice daily busulfan dosing in a larger cohort of older patients with AML in complete remission. Disclosures: Spitzer: Genzyme: Consultancy.

Long-Term Outcomes of TBI-Based Myeloablative SCT In 292 Consecutive Adults with Ph-Negative ALL: Similar Outcomes for Transplantation Using Related Donor, Well-Matched Unrelated Donor, or Partially Matched Unrelated Donor Sources

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2355-2355
Author(s):  
Seok Lee ◽  
Seung-Ah Yahng ◽  
Sung-Eun Lee ◽  
Byung-Sik Cho ◽  
Ki-Seong Eom ◽  
...  
Keyword(s):  
High Risk ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
Long Term Outcomes ◽  
Matched Unrelated Donor ◽  
No Donor ◽  
Risk Patients ◽  
Related Donor ◽  
Standard Risk

Abstract Abstract 2355 Background: The graft-versus-leukemia effect in adult acute lymphoblastic leukemia (ALL) has now been definitely confirmed from the ‘matched related donor (RD) versus no donor' comparisons. However, no definite conclusions can be extracted from these data as to whether or not there is a survival advantage to RD-stem cell transplantation (SCT) over other therapeutic modalities for both high-risk and standard-risk patients with Philadelphia (Ph)-negative ALL. In addition, ‘RD versus no donor' approach is becoming outmoded, as in many studies those previously in a ‘no donor' category are now undergoing unrelated donor (URD)-SCT. Aims: We report long-term outcomes of total body irradiation-based myeloablative SCT in 292 consecutive adults with Ph-negative ALL who received transplants at our center between 1995 and 2008 (median follow-up of survivors, 85 months). This study focused on following questions: (1) How different are the outcomes of SCT according to the donor sources? (2) Which factors are important to determination of transplantation outcome? (3) Which URD should be chosen? (4) Is there a role of autologous (AUTO)-SCT plus maintenance chemotherapy? Methods: Median age was 25 years (range, 15–63 years). Overall, 237 (81.2%) of 292 patients had one or more high-risk features, including adverse cytogenetics [t(4;11), t(8;14), complex (>=5 abnormalities), Ho-Tr], older age (>=35 years), high leukocyte counts (>=30×109/L for B-ALL, >=100×109/L for T-ALL), or delayed first complete remission (CR1; >28 days). Two hundred and forty-one patients (82.5%) were transplanted in CR1; 22 (7.6%) in CR2; and 29 (9.9%) in advanced status. URD sources were classified as well-matched (WM), partially matched (PM), and mismatched (MM) based on a new proposed guideline from the NMDP-CIBMTR. Donor sources were RD (n=132), WM-URD (n=30), PM-URD (n=19), MM-URD (n=19), and AUTO (n=92). All patients and donors provided written informed consent, and the treatment protocol was approved by the institutional review board of The Catholic University of Korea. Results: Cumulative incidence of relapse at 5 years was 48.5% for AUTO versus 32.6% for RD, 19.4% for WM-URD, 32.3% for PM-URD, and 51.0% for MM-URD (RR, 2.70; 95% CI, 1.65 to 4.42; p<0.001). In multivariate analyses, other factors associated with higher relapse risk included transplantation in CR2 or later (p<0.001), T-lineage ALL (p=0.020), and adverse cytogenetics (p=0.038). Cumulative incidence of non-relapse mortality (NRM) at 5 years was 40.5% for MM-URD versus 19.6% for SD, 20.3% for WM-URD, 15.8% for PM-URD, and 9.8% for AUTO (RR, 3.09; 95% CI, 1.32 to 7.25; p=0.010). Patients older than 35 years had higher NRM (p=0.007). As a result, disease-free survival (DFS) at 5 years was inferior using AUTO (46.1%; RR, 1.69; 95% CI, 1.14 to 2.51; p=0.010) or MM-URD (26.3%; RR, 2.03; 95% CI, 1.05 to 3.95; p=0.036), compared to RD sources, while DFS from all other donor sources was approximately equivalent (53.5% for RD, 63.3% for WM-URD, and 57.0% for PM-URD). Transplantation in CR2 or later (p<0.001), older age (p=0.020), and adverse cytogenetics (p=0.041) were associated with poorer DFS. In a pairwise comparison of outcomes between RD-SCT and AUTO-SCT for patients in CR1, the inferiority of AUTO-SCT was observed, particularly in high-risk patients. Conversely, in standard-risk patients, AUTO-SCT yielded comparable outcomes to RD-SCT. Summary/Conclusions: Our long-term data suggest that outcomes are similar for transplantation using SD, WM-URD, or PM-URD sources, and these may be considered the best donor sources for adults with Ph-negative ALL, especially for those with high-risk features. 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.

Prophylactic Extracorporeal Photopheresis for Gvhd Prevention after Reduced Intensity Conditioning and Allogeneic Stem Cell Transplantation from Identical Siblings and 10/10 HLA Unrelated Hematopoietic Stem Cells Donors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3916-3916
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Aline Praire ◽  
Frederic Garban ◽  
Claude Eric Bulabois ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cumulative Incidence ◽  
Phase 2 ◽  
Extracorporeal Photopheresis ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Related Mortality

Abstract Background: Graft-versus-host disease (GVHD), and complications of its treatment, are the major causes of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and represent a limiting factor for transplantation in candidate patients. The pathophysiology of GVHD involves tissue damage, presentation of host antigen by host dendritic cells to donor T cells, and the activation and release of inflammatory cytokines. Even with the use of standard GVHD prophylaxis with calcineurin inhibitors and methotrexate, the incidence of acute and chronic forms of GVHD remains not negligible. Extracorporeal photopheresis (ECP) has shown very promising results in several immune-mediated disorders, including GVHD, with a direct impact on transplant-related mortality (TRM) rates and overall survival (OS). Objective: We performed this prospective multicenter phase 2 study to evaluate the safety and efficacy of prophylactic use of ECP early after allo-HSCT in patients with hematological malignancies. Patients and methods: Eligible patients were adults with hematological malignancy candidate for allo-HSCT, with controlled disease at transplantation and having a 10/10 HLA identical related or unrelated peripheral blood stem cells (PBSC) donor. All patients must have received a reduced intensity conditioning regimen consisting on Fludarabine (30 mg/m²/day, from day -5 to day -1), iv. Busulfan (0.8 mg/kg every 6 hours, from day -4 to day -3) and rabbit anti-thymocyte globulins (2,5 mg/kg, on day -2 and day -1). GVHD prophylaxis consisted on cyclosporine A (CsA) alone, associated to methotrexate in case of major ABO incompatibility; mycophenolate mofetil could be used instead of CsA in case of intolerance or toxicity. ECP was initiated at day 21 after transplantation, twice per week during the first two weeks and then once per week for the next four weeks, a total of 8 ECP courses had to be performed for each patient. ECP related toxicity and adverse events were evaluated according to NCI/NIH common toxicity criteria up to day 100 after transplantation. Transplantation outcomes have been assessed. Results: Between June 2009 and May 2014, a total of 20 patients were included in this study; 10 males and 10 females with a median age of 60 years (range: 47-66); 7 (35%) had acute myeloid leukemia (4 de novo and 3 secondary), 4 (20%) chronic lymphocytic leukemia, 3 (15%) Non-Hodgkin lymphoma, 2 (10%) multiple myeloma, 2 plasma cell leukemia and 2 myelodysplastic syndrome. At transplantation, 14 (70%) patients were in complete response, 2 patients in very good partial response and 4 patients in partial response; all patients received PBSC from 8 (40%) identical siblings and 12 (60%) 10/10 HLA unrelated donors. For sex matching, only 3 (15%) were female donors to male patients. The median number of injected CD34+ cells was 6.106/Kg (range: 2.7-10.4). After transplantation, all patients engrafted, 17 (85%) could achieve the full 8 ECP courses, one patient received 7 courses due to catheter dysfunction, one patient received 5 courses due to severe infection and one patient received only 4 courses due to early death. There were no unexpected adverse effects related to ECP. Among 11 (55%) patients evaluated for chimerism at day 100, all had full donor cells. Seven patients developed acute GVHD, all were resolutive, 3 grade I, 1 grade II, 1 grade III and 2 grade IV with a cumulative incidence of 20% (confidence interval: 11-29) for grade ≥ II. Only 4 patients experienced chronic GVHD, all limited and resolutive, with a cumulative incidence of 23% (confidence interval: 12-33) at 2 years. After a median follow-up of 21 months (range: 2-49), the probability of overall survival at 2 years was 84% (range: 75-93), the two years probability of progression-free survival was 78% (range: 68-88), and the cumulative incidence of transplant-related mortality was 11% (range: 4-18) at two years. At the last follow-up, 14 patients were alive in CR and without GVHD, 6 patients died (4 from relapse and 2 from GVHD after receiving DLI for relapse). Conclusion: This prospective phase 2 multicenter study demonstrated the safety of prophylactic ECP after allo-HSCT. We showed encouraging results with good potential in overall survival, very low GVHD incidence and no interference with GVL effect in view of low relapse rate after transplantation. Larger phase 3 study is now required to validate the benefit of this strategy. Disclosures No relevant conflicts of interest to declare.

Antithymocyte Globulin-Based Prophylaxis for Graft Versus Host Disease Compared to Post-Transplant Cyclophosphamide-Based Prophylaxis in Matched Unrelated Donor Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2307-2307
Author(s):  
Sara Redondo Velao ◽  
Mi Kwon ◽  
Diana Champ ◽  
MJ Pascual Cascon ◽  
Pascual Balsalobre ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Antithymocyte Globulin ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract INTRODUCTION Post-transplant high-dose cyclophosphamide (PTCy) has shown to prevent graft versus host disease (GvHD) after haploidentical allogeneic hematopoietic cell transplantation (HSCT). Although less extended, its use after matched unrelated donor (MUD) HSCT in combination with additional immunosuppression has been encouraging. The aim of this study was to analyze and compare outcomes of antithymocyte globulin based (ATG) versus PTCy-based GvHD prophylaxis in matched unrelated donor HSCT. MATERIAL AND METHODS We retrospectively analyzed 51 MUD (8/8 HLA-matched) transplants performed in two Spanish centers: 25 received ATG-based prophylaxis and were performed from 2010 to 2013, and 26 received PTCy-based prophylaxis and were performed from 2013 to 2016. RESULTS Characteristics of patients and post-HSCT complications are detailed in Table 1. There were no significant differences in age, gender, diagnosis and Disease risk index. For the ATG group, conditioning regimen consisted of fludarabine combined with busulfan (80%) or melphalan (12%), and TBI plus cyclophosphamide (8%). All patients received ATG 2 mg/kg from day -4 to day -2 followed by methotrexate and cyclosporine (CsA). Conditioning regimen for patients from the PTCy group consisted of fludarabine and busulfan (85%) and thiotepa combined with busulfan and fludarabine (15%). GvHD prophylaxis consisted of PTCy 50 mg/kg on days +3 and +4, combined with: CsA plus MMF in 57%, CsA alone in 31%, or tacrolimus plus MMF or sirolimus in 8%, and tacrolimus alone in 4%. With a median follow-up of 58 months for the ATG group and 12 months for the PTCy group, there were no statistically significant differences in overall survival at 18 months (56% vs 85%, p=0.08), in event free survival (56% vs 68%, p=0.5), and in cumulative incidence of relapse (12% vs 18%, p=0.3). Non-relapse mortality at 12 months was significantly higher in the ATG group (32% vs 10%, p = 0.04). The ATG group presented more cases of hepatic toxicity grades I-IV and hemorrhagic cystitis than PTCy group (Table 1). Cumulative incidence of acute GvHD grades II-IV was higher in the ATG group as well as acute GvHD grades III-IV, with no differences in moderate/severe chronic GvHD incidence (Figure A). CONCLUSION In our experience, albeit differences in follow-up and limited number of patients, we conclude that PTCy combined with additional immunosuppression after MUD allogeneic HSCT offers lower rates of acute GvHD together with less toxicity and non-relapse mortality compared to ATG-based prophylaxis. Further analysis including larger series and follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document