Reduced Intensity Conditioning (RIC) with Cladribine, Busulfan and 4 Gy Total Body Irradiation (TBI) for Bone Marrow Transplantation (BMT) from an HLA-Matched Unrelated Donor (URD): A Prospective Multi-Institutional Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5397-5397 ◽  
Author(s):  
Sung-Won Kim ◽  
Masayuki Hino ◽  
Kazuo Hatanaka ◽  
Yasunori Ueda ◽  
Ryuji Tanosaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
High Response Rate ◽  
High Dose ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract [Background] We report the results of a prospective multi-institutional clinical trial of BMT from an HLA-matched URD following RIC. [Patients and Methods] The conditioning regimen included cladribine 0.11 mg/kg on day -8 to day -3, busulfan 4 mg/kg po on day -6 and day -5, and 4 Gy TBI on day -1. GVHD prophylaxis included cyclosporine and short-term methotrexate. Patients with hematologic diseases were eligible for this study if they were either older than 50 years or had significant medical contraindications to undergo conventional transplantation. Primary endpoints were neutrophil engraftment and achievement of complete donor-type chimerism (CD3+ cells >90%) on day 90. Regimen-related toxicities (RRT) between day -8 and day 28 were assessed by the NCI-CTC v2.0. A total of 27 patients were registered, but one patient was removed before transplant because of severe fungal infection. [Results] The median follow-up time was 722 days (range, 324–996) among survivors. The median age of patients was 56.5 years (36–64). Nine of the 26 patients (36%) had advanced-stage diseases and 3 (11%) had failed previous high-dose autologous or allogeneic transplantation. The diagnoses included AML (n=9), MDS/MPD (n=7), NHL (n=3), ALL (n=2), CML, ATLL, PCL, biphenotypic acute leukemia, and severe aplastic anemia (n=1). The median number of infused nucleated cells was 2.2 × 108/kg. After transplant, while one patient experienced engraftment failure and subsequent sepsis, and died on day 34, the remaining 25 patients achieved neutrophil engraftment (median, 17th day). Another patient was censored from the study due to grade 4 liver dysfunction, which developed on day 19, which left 24 patients for the chimerism analysis. The percentage of donor chimerism in CD3+ cells on days 28, 56 and 90 was, respectively, 88% (21/24), 100% (24/24) and 100% (24/24). Grade 3 RRT included arrhythmia (n=1), hypoxia (n=3), hyperbilirubinemia or hypertransaminasemia (n=7), stomatitis (n=18) and diarrhea (n=4), and grade 4 RRT included hypoxia (n=1) and hyperbilirubinemia (n=1). Acute GVHD of grade II, III and IV occurred in 27%, 27% and 4%, respectively. Ten of 15 evaluable patients (67%) had extensive chronic GVHD. CMV reactivation occurred in 23 patients (89%); 4 had histologically confirmed CMV colitis, 1 had CMV pneumonitis and 1 had CMV hepatitis, while the remaining patients had asymptomatic viremia. Of the 16 patients with measurable disease at the time of BMT, 15 achieved complete remission. The 100-day and 1-year cumulative incidences of non-relapse mortality (NRM) estimated by the Kaplan-Meier method were 20% and 54%, respectively. The cause of death that contributed to NRM was infection, with grade 0–I acute GVHD in 29% and grade II–IV acute GVHD in 71%. The 100-day and 1-year cumulative incidences of relapse were 8% and 35%, respectively, and the 1-year overall and progression-free survival rates were 42% and 30%, respectively. [Conclusions] The results support the feasibility of this procedure with a high response rate, but there is still a problem with the high NRM due to uncontrollable infections primarily associated with GVHD.

α4β7± Regulatory T Cells (Tregs) at Engraftment Predict Long-Term Graft-Versus-Host Disease (GVHD) Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2237-2237
Author(s):  
Brian G Engelhardt ◽  
Madan Jagasia ◽  
Michael T Rock ◽  
Adetola A. Kassim ◽  
Bipin N. Savani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Clinical Severity ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Treg Population ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract Abstract 2237 Poster Board II-214 Background: GVHD occurs unpredictably after allogeneic stem cell transplant (ASCT). GVHD is characterized by profound immune dysregulation, which suggests that abnormalities in suppressor lymphocytes known as Tregs may account for the clinical features of this disease. We have shown that the frequency of Tregs or α4β7± Tregs at neutrophil engraftment predict for recurrent grade II-IV GVHD or recurrent gut GVHD during the first 100 days of transplant, respectively. These data indicate that early lymphocyte populations may determine long-term immune-tolerance following ASCT. We hypothesized that Treg subsets present at engraftment would be associated with the occurrence, National Institutes of Health (NIH) phenotype, and severity of GVHD after day±100. Methods: Patients (pts) undergoing T cell replete ASCT were enrolled. GVHD after day±100 was classified prospectively as either: acute GVHD, overlap GVHD, or classic chronic GVHD using consensus criteria derived from the NIH. Clinical severity was determined by the modified Glucksberg criteria for acute GVHD and the NIH global assessment of severity for overlap/classic chronic GVHD. The frequency of CD45RO±CD25±Foxp3±CD127lo Tregs was quantified within the CD4± T-lymphocyte population at the time of neutrophil engraftment using polychromatic flow cytometry. Gut-homing Tregs were identified by the presence of α4β7±, and their frequency was expressed as a percentage of the total Treg population. Results: Treg analysis was performed at a median of 19 days post-transplant (range, 10-31) on 41 pts undergoing ASCT and surviving until day±100. Twenty-four (59%) pts received ablative conditioning and 17 (41%) pts received a reduced intensity regimen followed by matched related [N= 24 (59%)] or unrelated donor [N= 17 (41%)] ASCT. The stem cell source was peripheral blood, bone marrow, or cord blood for 30 (73%), 9 (22%), and 2 (5%) pts, respectively. GVHD prophylaxis consisted of calcineurin inhibitor and methotrexate [N=23 (56%)] or mycophenolate mofetil [N=18 (44%)]. The majority of patients had grade II-IV acute GVHD prior to day±100 [N=34 (83%)]. After a median follow-up of 15 months (range, 5-24) GVHD after day±100 occurred in 32 (78%) pts at a median of 152 days post ASCT (range, 103-533). GVHD phenotype was classified as: acute (N=19), overlap (N=9), or classic chronic (N=4). Grade III-IV acute and moderate to severe overlap/classic chronic GVHD occurred in 3 (7%) and 11 (27%) pts, respectively. Pts with GVHD after day±100 had lower frequencies of Tregs and α4β7± Tregs at engraftment (4.4% vs. 14.3%; P=0.145) and (9.9% vs. 20.7%; P=0.009), respectively. After excluding pts with gut GVHD, the association between α4β7± Tregs and GVHD after day±100 persisted (P=0.034). Median Treg percentages did not differ among GVHD phenotypes [acute (4.4%) vs. overlap (4.2%) vs. classic chronic (5%) vs. none (14.3%); P=0.464]. However, significant differences between α4β7± Treg frequencies and GVHD subtypes were noted [acute (11%) vs. overlap (9.6%) vs. classic chronic (11.6%) vs. none (20.7%); P=0.002]. α4β7± Treg differences were most apparent when pts with any acute GVHD (acute±overlap) were compared to pts without features of acute GVHD (none±classic chronic) (9.9% vs. 19.4%; P=0.009). Increased frequencies of Tregs and α4β7± Tregs at engraftment tended to be associated with lower grades of acute GVHD after day±100 [odds ratio (OR), 0.95; 95% confidence interval (CI), 0.87-1.04; P=0.255 (Tregs) and OR, 0.81; 95% CI, 0.70-0.92; P=0.002 (α4β7± Tregs)] and less severe overlap/classic chronic GVHD [OR, 0.91; 95% CI, 0.79-1.04; P=0.158 (Tregs) and OR, 0.93; 95% CI, 0.86-1.01; P=0.071 (α4β7± Tregs)]. Using Cox Proportional Hazard regression (adjusting for donor type and acute GVHD prior to day ±100), increased frequencies of α4β7± Tregs at engraftment continued to be associated with decreased risk of GVHD after day ±100 (hazard ratio, 0.93; 95%CI, 0.88-0.99; P=0.013). Conclusion: Frequency of α4β7± Tregs at engraftment is associated with the incidence and severity of GVHD after day ±100. These data suggest that early lymphocyte subsets and gut associated mucosal immunity are important in determining long-term graft tolerance. Treg subsets at engraftment could be used to risk stratify pts prior to development of GVHD or as an endpoint in future clinical trials examining interventions aimed at increasing Tregs and preventing GVHD. Disclosures: No relevant conflicts of interest to declare.

T Cell Replete HLA- Haploidentical Donor Transplantation (HIDT) with Post-Transplant Cyclophosphamide (pTcy) Is an Effective Salvage for Patients Relapsing after a Matched Sibling or a Matched Unrelated Donor Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1960-1960
Author(s):  
Melhem Solh ◽  
Katelin Connor ◽  
Xu Zhang ◽  
Stacey Brown ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Matched Sibling ◽  
Grade Ii ◽  
Matched Donor ◽  
Grade Iii

Abstract Objective: Relapse of high risk hematologic malignancies remains the major cause of mortality after matched sibling and matched unrelated allogeneic hematopoietic stem cell transplantation (HSCT). A second transplantation using the same donor or another fully matched donor yielded similar results with no clear advantage of choosing a newly matched donor (1). The purpose of this analysis was to evaluate the efficacy of HIDT with pTcy as a second HSCT among patients with high risk hematologic malignancies relapsing after a matched sibling or a matched unrelated donor. Methods and Population: All consecutive patients (n=20) who underwent a HIDT using ptCy at our center as a second allogeneic transplant for relapse of malignancy following a prior HLA-matched transplant were included in this retrospective analysis. Patient, disease and transplant related data was obtained from our institutional BMT database where it had been prospectively documented. Survival and disease-free survival (DFS) were estimated using the Kaplan-Meier method, Relapse and non-relapse mortality (NRM) were treated as competing risks. GVHD was prospectively documented and graded. Results: Patients (male n=13, female n=7) had a median age of 54 years (range 21-64). The median time from the first to the second HSCT was 20.7 months (range 2.7-65.8 months). 10 patients had AML/MDS, 6 ALL, 2 CLL and 2 myeloproliferative syndrome. Grafts from the first HSCT were 50% matched related (n=10) and 50% matched unrelated (n=10). The median number for HLA mismatches among HIDT recipients was 5/10 (range 4/10-8/10). All patients received cytoreductive therapy prior to the HIDT with 12 (60%) achieving a CR and 8 (40%) with active disease at the time of conditioning regimen initiation for HIDT. The conditioning regimen for HIDT was myeloablative in 3 patients (15%) with fludarabine/high dose TBI/pTcy in 2 (10%) patients and flu/busulfan/Cytoxan in 1 patient (5%) and non-ablative/reduced intensity (flu/low dose TBI/Cytoxan n=17; in 18 (90%) patients. All patients received pTcy and tacrolimus plus mycophenolate for graft versus host disease prophylaxis. All patients achieved sustained engraftment with median times to neutrophil and platelet engraftment of 17.5 (14-44) days and 32 (15-99) days respectively. The cumulative incidences (CI) of grade II-IV and grade III-IV acute GVHD at 180 days were 36% and 10% respectively. The CI of moderate-severe chronic GVHD was 13% at 1 year post HIDT. At a median follow-up of X months, The probability of overall survival, DFS, NRM and relapse post HIDT were 52%, 39%, 29% and 33% at 1 year and 34%, 31%, 29% and 40% at 3 years respectively. Conclusions: HIDT is an effective strategy to treat relapsed hematologic malignancies after a matched sibling or matched unrelated donor HSCT. Further and larger cohorts to confirm these observations are warranted. Table 1. Survival Estimates 6 months 1 year 3 years OS 72% 52% 34% DFS 53% 39% 31% NRM 22% 29% 29% Relapse 25% 33% 40% Mod-severe chronic GVHD 5% 13% 13% Grade II-IV acute GVHD 36% Grade III-IV acute GVHD 10% 1. Christopeit M, Kuss O, Finke J, Bacher U, Beelen DW, Bornhauser M, et al. Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change. J Clin Oncol. 2013;31(26):3259-71. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for Patients Aged ≥60 Years: a Retrospective Study of 629 Patients From the Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 194-194 ◽  
Author(s):  
Patrice Chevallier ◽  
Didier Blaise ◽  
Noel-Jean Milpied ◽  
Mauricette Michallet ◽  
Jean-Paul Vernant ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Older Age ◽  
Unrelated Donor ◽  
Age Group ◽  
Grade Ii ◽  
Grade Iii

Abstract Abstract 194 Age has been previously demonstrated to be a major prognostic factor for outcome after allo-SCT. Many centres usually use an age threshold around 50 years for considering a standard myeloablative conditioning regimen, and around 65 years for considering a RIC regimen. The aim of this report was to assess the outcome of 629 patients aged ≥60 years who received RIC allo-SCT, with a special emphasis on the comparison of the outcome of patients aged 60–65 years (y.) and patients aged >65 y. Between 1998 and 2008, 629 patients with different haematological diseases were treated with RIC allo-SCT, and reported to the SFGM-TC Registry. This series included 417 males (66%) and 212 females (34%). The median age for the whole cohort was 62 (range, 60–71) y. 378 patients (55%) were diagnosed with a myeloid malignancy, while 240 (38%) had lymphoid malignancies, and 11 (2%) had other non-classifiable diseases. 478 patients (76%) had high risk disease features, and 151 (24%) had a standard risk disease. 386 patients (61%) received allo-SCT from an HLA-matched related donor, while 199 patients (32%) received the graft from a matched-unrelated donor, and 44 (7%) from mismatched donors. Peripheral blood stem cells were used in 83% of patients (n=520). The conditioning regimen consisted of Fludarabine and Busulfan in 280 cases (44.5%), Fludarabine and low dose TBI in 150 cases (24%). The remaining 199 patients (32%) received other so-called RIC protocols. With a median follow-up of 9 (range, 1–90) months after allo-SCT, grade II-IV and grade III-IV acute GVHD occurred at a median of 31 days after allo-SCT in 29% (n=182) and 12% (n=76) of patients, respectively. Chronic GVHD was observed in 145 patients (23%; limited: n=67; extensive: n=72; unknown stage: n=6). At last follow-up, 347 patients (55%) were still alive (of whom 205 in CR; 65%): 147 patients (16%) died of disease progression, and 180 patients died of transplant-related causes (TRM: 29%). The Kaplan-Meier (KM) estimates of overall survival (OS) at one and 2 years were 57% (95%CI, 53–62%) and 47% (95%CI, 42–52%), respectively. In order to assess the applicability of RIC allo-SCT to the older age group, we next compared the outcome of patients aged from 60 to 65 y. (n=516) and those aged >65 y. (n=113; median 66 y.; range, 65–71). Except for age, in univariate analysis, these 2 groups were not statistically different in terms of demographic, disease or transplant characteristics. Overall, the median time to ANC>500/μL was 18 (range, 1–102) days, with this being comparable between the younger (60–65 y.) and elderly (>65 y.) age groups (p=0.19). The incidences of grade II-IV and grade III-IV acute GVHD were comparable between both groups (60–65 y.: 29% vs. >=65y.: 30%, p=NS; and 12% vs. 12%; p=NS). The TRM incidence was 29% in the younger group vs. 27% in the older group (p=NS). The KM estimates of OS at 1 and 2 years were 58% (95%CI, 53–62%) and 47% (95%CI, 42–52%) in the younger age group and 55% (95%CI, 44–65%) and 48% (95%CI, 37–60%) in the older age group (p=NS). In a Cox multivariate analysis accounting for all relevant factors, age >65 y. was not found to be a statistically significant factor associated with worsened survival. Despite its retrospective nature and the inherent selection biases, this data support the use of RIC-allo-SCT in patients >60 y. Moreover, outcome of patients aged >65 y. appears to be comparable to that of patients aged 60–65 y. Physiologic aging is likely more important than chronologic aging. With the refinement of comorbidities scoring systems, age per se (at least up to 70 y.) should not be a contraindication to perform RIC allo-SCT and this should be tested prospectively. Disclosures: No relevant conflicts of interest to declare.

Bortezomib, rituximab, and risk of graft-versus-host disease (GVHD) after BEAM conditioning for allogeneic stem cell transplantation (alloSCT).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18543-e18543
Author(s):  
Kamal Chamoun ◽  
Alison M Gulbis ◽  
Denai Milton ◽  
Elias Jabbour ◽  
Francesco Turturro ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Aggressive Lymphoma ◽  
Unrelated Donor ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Clinical Trial Information

e18543 Background: GVHD remains the main limitation of alloSCT and is exacerbated by the intensity of the conditioning regimen. In a recent study, the risk of acute grade II-IV GVHD and extensive chronic GVHD (cGVHD) after a nonmyelobaltive (NMA) regimen was 11%, and 26%, respectively (Khouri I. Blood 2014 124:2306). Higher rates were previously observed (32% and 54%, respectively) with the BEAM regimen. Based on clinical data showing a reduction in GVHD with the use of rituximab or bortezomib, we conducted a phase I/II study evaluating the addition of bortezomib to rituximab+BEAM in patients (pts.) who were not eligible for NMA alloSCT. Methods: Bortezomib was administered at 1.3 mg/m2 IV on days -13, -6, -1 and +2. The dose was later reduced to 1 mg/m2 after the occurrence of C. Difficile colitis in the first 3 pts. leading to 2 deaths. Rituximab was given on day -13 at a dose of 375 mg/m2, then at 1000 mg/m2 on days -6, +1, and +8 of alloSCT. BEAM was administered between days -6 and -1. All pts. received our standard GVHD prophylaxis with tacrolimus and methotrexate. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving matched unrelated donor (MUD) or mismatched (MM) transplants. Results: Thirty-nine pts. were studied. Median age was 54 yrs. Thirteen (33%) and 26 (67%) pts. had indolent or aggressive lymphoma histologies, respectively. Sixteen (41%) pts. were refractory. Twenty-two (56%) received alloSCT from HLA-compatible siblings, 16 (41%) from MUDs and 1 (3%) from mm donors. Peripheral blood was the source of stem cells in 97% of pts. ABO and CMV-mismatch rates were 56% had 50%, respectively. Median follow up surviving patients was 65 mos. Five-year OS and PFS rates were 35% and 28%, respectively. The CI of acute grade II-IV, III-IV, and cGVHD were 55%, 34%, and 41%, respectively. No predictor for acute GVHD was identified. Instead, we found that sex-mismatched transplants were predictive of a higher risk of cGVHD ( P= 0.01). Conclusions: The current trial is the first one evaluating the safety and efficacy of bortezomib plus rituximab as a part of the BEAM regimen for alloSCT. A better prophylaxis regimen is needed to lessen the risk of GVHD in this setting. Clinical trial information: NCT00439556.

Steroid Refractory Acute and Chronic Graft Versus Host Disease (GVHD) - Response to Photophoresis+/− Rituximab.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5358-5358 ◽  
Author(s):  
Ramakrishnan Parameswaran ◽  
Maggie Sekeramayi ◽  
Kelly McCaul ◽  
Bill Bradfeldt
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Bk Virus ◽  
High Dose ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Gi Tract ◽  
Steroid Refractory

Abstract Acute GVHD is an important complication following hematopoeitic stem cell transplantation (HSCT), with significant attendant morbidity and mortality. High dose steroids remain the cornerstone of therapy. Steroid refractory GVHD carries a very poor prognosis. Various therapies are available for steroid refractory acute GVHD, but response is not uniform. Among the less intensive regimens, extracorporeal photopheresis (ECP) and rituximab, a chimeric humanized anti CD 20 monoclonal antibody have been shown to be useful in treating refractory acute and chronic GVHD. We describe 8 patients who developed GVHD following transplantation of HLA-identical stem cells, from siblings in 7 and from an unrelated donor in one. 2 patients had steroid refractory chronic GVHD of the liver, 3 patients had a refractory chronic GVHD of the skin and one had a steroid responsive restrictive pulmonary syndrome. Of the patients with skin GVHD, 2 had chronic scelrodermatous GVHD, which was of 20 years duration in one patient and 8 in the other. 2 patients had acute GVHD of the GI tract. The age range was 21– 53 years. All patients were in complete remission from their primary disease at the time of therapy for GVHD. 3 patients had a diagnosis of acute lymphoblasitc leukemia and 5 acute myeloid leukemia All had failed treatment with high dose steroids and/or tacrolimus and/or cellcept, and, one had also failed ATG therapy. Then therapy for refractory GVHD was initiated with rituximab in 3 patients and with photopheresis in 5. 7 patients received ECP. One patient with refractory chronic GVHD of the liver received rituximab alone in addition of steroids and tacrolimus. The patients with acute GVHD were treated with daily ECP for 10 days and then were weaned down to two procedures every 2 weeks. Patients with chronic GVHD received ECP 2 to 3 times a week for 6 weeks and were subsequently similarly weaned down. In the patients with acute GVHD of the GI tract complete responses occurred at 10 days in one patient and 45 days in the second as determined by complete cessation of diarrhea, cramps and nausea. Both patients with chronic GVHD of the liver achieved normalization of the serum bilirubin by 26 and 38 days after initiation of therapy. All patients tolerated successful taper of steroid therapy. The two patients with sclerodermatous GVHD have shown marked improvement in skin texture and range of motion at the involved joints. The patient with the pulmonary symptoms has shown complete normalization of pulmonary function. 5 patients were at risk of CMV reactivation, but failed to do so. One patient developed BK virus associated hemorrhagic cystitis that required therapy with cidofovir. There were 3 admissions for neutropenic fever, three for pneumonia and one each for gastroenteritis, HSV gingivostomatitis and line related sepsis. Two patients had line related thrombosis. None of the patients had relapse of their disease. 2 of the responders had an ECOG performance status 2, two of 3, one of 4 and four of </= 1 while being treated. All patients demonstrated improvement in functional status. ECP and rituximab is a well tolerated and effective modality for therapy of steroid refractory chronic and acute GVHD in both related and unrelated marrow stem cell transplant recipients.

Unrelated Donor Hematopoietic Cell Transplantation after Non-Myeloablative Conditioning for Patients with High Risk Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3158-3158
Author(s):  
Roberto Sorasio ◽  
Luisa Giaccone ◽  
Francesca Patriarca ◽  
Vittorio Montefusco ◽  
Stefano Guidi ◽  
...  
Keyword(s):  
Disease Progression ◽  
Initial Treatment ◽  
Response Rate ◽  
Treatment Plan ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Response ◽  
High Dose ◽  
Unrelated Donor

Abstract Allografting can induce long-term molecular remissions and possibly cure in myeloma patients. The recent development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) typically associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pre-treated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at disease relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning regimen consisted of fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis included oral cyclosporine (CyA) and mycophenolate mofetil (MMF). CyA was administered at 6.25 mg/Kg every 12 hours from day -3; levels were targeted to the upper therapeutic range (450–500 ng/ml, Abbott TDX, Abbott Park, IL) for the first month post-transplant. In the absence of GVHD, CyA was tapered from day +100 and discontinued on day +177. MMF was administered from day 0 after PBSC infusion to day +40 at 15 mg/Kg every 8 hours, and then tapered till day +96. Twenty/22 (91%) patients readily engrafted. Two patients experienced graft failure and eventually recovered autologous hematopoiesis. After a median follow up of 11 months (3–27), TRM was 18% and 16/22 patients (73%) are alive. Deaths occurred in 10% of patients transplanted upfront and in 42% of those transplanted at relapse: 3 patients died from infections, 1 from hemolytic uremic/ thrombotic thrombocytopenic purpura syndrome, and 2 from disease progression (both were transplanted at relapse). Ten/20 engrafted patients (50%) had grade II–IV acute GVHD (10% grade III–IV), and 59% had extensive chronic GVHD. Overall response rate was 60% (including 20% CR): 78% in patients transplanted upfront (no disease progression observed) and 45% in those transplanted at relapse. In the two groups, progression-free and one year event-free survival were 100% and 44% (p<0.025), and 90% and 28% respectively (p<0.005). Unrelated donor non-myeloablative allografting is feasible with relatively low TRM and high response rate. Graft-versus-myeloma effect appears to be more efficient when patients are treated soon after diagnosis. Longer follow-up is needed to assess response duration.

Randomized Phase II Trial Comparing Cyclosporine (CSP) and Tacrolimus (TAC) for Methotrexate (MTX)-Free Graft-Versus-Host Disease (GVHD) Prophylaxis after Allogeneic Transplantation from a Matched Related Donor (MRD) with a Reduced-Intensity Regimen Containing Cladribine and Busulfan

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1170-1170 ◽  
Author(s):  
Sung-Won Kim ◽  
Takahiro Fukuda ◽  
Shotaro Hagiwara ◽  
Tsunehiko Komatsu ◽  
Tetsuya Goto ◽  
...  
Keyword(s):  
Whole Blood ◽  
Acute Gvhd ◽  
Trough Level ◽  
Chronic Gvhd ◽  
Gvhd Prophylaxis ◽  
Starting Dose ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii ◽  
Neutrophil Engraftment

Abstract Background: Although GVHD prophylaxis without MTX might enhance a graft-versus-leukemia effect, no randomized controlled trial (RCT) of GVHD prophylaxis has investigated this possibility in a reduced-intensity stem cell transplantation (RIST) setting. Therefore, we conducted a prospective randomized trial to compare CSP and TAC without MTX as GVHD prophylaxis in RIST from a MRD. Methods: Patients with hematological malignancies in complete remission or with a chemosensitive status were eligible for this study if they were either older than 50 years or had significant medical contraindications for conventional transplantation. The primary endpoint was the incidence of grade II-IV acute GVHD on day 100. Regimen-related toxicities (RRT) between day −8 and day 28 were assessed by NCI-CTC ver 2.0. The conditioning regimen consisted of cladribine (0.11 mg/kg × 6 days) and oral busulfan (4 mg/kg × 2 days). All patients received unmanipulated G-CSF-mobilized peripheral blood stem cells from a MRD. CSP (starting dose 3 mg/kg/day, target whole blood conc. 250–350 ng/mL, target trough level 150–250 ng/mL) or TAC (starting dose 0.03 mg/kg/day, target whole blood conc. 10–20 ng/mL, target trough level 5–10 ng/mL) was given as GVHD prophylaxis from day −1. G-CSF was administered from day +6 until neutrophil engraftment. Results: Sixty-eight patients were enrolled between 2/2003 and 2/2008, but 3 were removed before transplant because of disease progression or infection. The diagnoses included lymphoma (n=27; 10 FL, 6 DLBCL, 6 PTCL and 5 HL), AML (n=14), MDS (n=12), MM (n=5), MPD (n=4) and ALL (n=3). The median age of the patients (56 y vs. 55 y) and the median number of CD34+ cells infused (3.7 ×106/kg vs. 3.1 ×106/kg) were similar in the CSP and TAC arms. The median day of neutrophil engraftment in both arms was day 11. The proportion of patients in the CSP or TAC arm who achieved complete chimerism in CD3+ cell fraction on days 28, 56 and 90 was, respectively, 61% vs. 48%, 80% vs. 76% and 80% vs. 97%. Grade 4 RRT was hepatic disease (n=1, CSP arm), and grade 3 RRT included cardiac (n=1, CSP), renal (n=1, CSP), hepatic (n=2, CSP), oral mucosal (n=1, TAC) and gastrointestinal disease (n=4, CSP vs. n=3, TAC). The incidence of grade II–IV acute GVHD in the TAC arm was significantly lower than that in the CSP arm (Table & Figure). The incidences of grade III–IV acute GVHD and extensive chronic GVHD were not significantly different between the two arms. The non-relapse mortality (NRM) in the TAC arm was significantly lower than that in the CSP arm. The causes of death that contributed to NRM were infection in 6 (CSP arm), GVHD in one (CSP), ARDS in one (TAC) and lung cancer in one (CSP). The relapse rate and relapse-related mortality were not significantly different between the two arms. The median follow-up for surviving patients was 1295 days (169–1954). The overall survival (OS) and progression-free survival (PFS) rates in the TAC arm tended to be higher than those in the CSP arm. Figure Figure Conclusions: A regimen with TAC alone without MTX as GVHD prophylaxis was associated with significantly lower rates of grade II–IV acute GVHD and NRM compared to a regimen with CSP alone after RIST from a MRD. OS and PFS with TAC alone tended to be higher than those with CSP alone. Nevertheless, these results must be considered with care due to the small number of patients, and the optimal use of both drugs is still under investigation. A large-scale RCT to identify suitable GVHD prophylaxis in the RIST setting is warranted. Table: Study Outcomes CSP arm (n=33) TAC arm (n=32) P P value was evaluated with logrank test or Wilcoxon test*. Grade II–IV acute GVHD 64% 39% 0.040 Grade III–IV acute GVHD 30% 23% N.S Extensive chronic GVHD 63% 61% N.S 1-year/3-year NRM 26%/38% 0%/5% 0.008 1-year/3-year relapse 35%/43% 25%/49% N.S 1-year/3-year relapse mortality 27%/33% 10%/42% N.S 1-year/3-year OS 57%/45% 90%/56% 0.135 (0.039*) 1-year/3-year PFS 48%/35% 75%/48% 0.120 (0.047*)

One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 965-965
Author(s):  
David Valcarcel ◽  
Fangyu Kan ◽  
Tao Wang ◽  
Stephanie J. Lee ◽  
Stephen R Spellman ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Related Donor ◽  
Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

The Use of Bone Marrow Graft for Hematopoietic Stem Cell Transplantation From Matched Unrelated Donors After Reduced Intensity Conditioning Regimen Improves Survival : Analysis of the Societe Française De Greffe De Moelle Et De Therapie Cellulaire.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 873-873
Author(s):  
Andrea Toma ◽  
Marie-Lorraine Balère-Appert ◽  
Jean-Michel Boiron ◽  
Pierre Bordigoni ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Unrelated Donors ◽  
Grade Ii

Abstract Abstract 873 The use of peripheral blood stem cells (PBSC) for hematopoietic stem cell transplantation (HSCT) is associated with a higher risk of chronic graft versus host disease (GvHD) but its impact on survival is not clear since it may favor a greater graft versus leukemia (GvL) effect. However, in the context of HSCT from unrelated donors (UD), the balance between GvH and GvL may differ from the context of sibling donors and thus the use of PBSC may be deleterious. In this retrospective study, we analyzed 103 patients from the french registry who received a graft from an UD after a reduced intensity conditioning regimen (RIC) to evaluate the role of various parameters including the source of stem cells on the outcome. Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The median age was 46 years (18-67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. The conditioning regimen was Fluda/TBI 2Gys for 26 patients, Bu/Fluda/ATG for 24 patients, Fluda/Melph for 16 patients and others for 37 patients. Overall, anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The source of stem cells was PBSC for 65 patients and bone marrow (BM) for 38 patients. The median follow up of the cohort is 61,3 months (1,2-113,7). The results showed that 95% of patients engrafted. Five patients did not engraft (4 in the BM group and 1 in the PBSC group). Acute GvHD grade II to IV and grade III/IV occurred in 47% and 19% of patients, respectively. The risk of developing chronic GvHD was 49% at 2 years. Overall survival (OS) was 36% at five years. The median disease free survival (DFS) was 55 months among the 36 patients alive. We performed univariate and multivariate analysis of factors susceptible to impact on GvHD and survival. The multivariate analysis included the impact of HLA mismatch, disease status, diagnosis, source of stem cells, patient's and donor's ages. This multivariate analysis performed on the global population shows a trend towards an improved OS with the use of BM instead of PBSC. However, when focusing the multivariate analysis on the 71 patients transplanted with a 10/10 match donor, the most potent factor influencing the outcome is the use of BM which is associated with an improved OS (p=0.03) and DFS (p=0.02), less acute GvHD grade II-IV (p=0.05), or grade III/IV (p=0.05) and less chronic GvHD (p=0.05). These results suggest that the use of BM as the source of stem cells should be reconsidered in the context of matched UD after RIC transplantation. Disclosures: No relevant conflicts of interest to declare.

High-Dose Rituximab In The Conditioning Regimen Before Allogeneic Stem Cell Transplantation Decreases Deaths Related To Gvhd Without Affecting The Anti-Lymphoma Effect

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2059-2059 ◽  
Author(s):  
Anna Dodero ◽  
Francesco Spina ◽  
Barbara Sarina ◽  
Cristiana Carniti ◽  
Francesca Patriarca ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Dose ◽  
Group A ◽  
Group B

Abstract Introduction Allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed B-cell lymphomas. Different studies have shown that Rituximab (R) is implicated in the pathophysiology of acute and chronic GVHD. Methods: We analyzed 153 adult patients who received alloSCT for relapsed/refractory B-cell lymphomas. All patients received the same preparative conditioning consisting of thiotepa/cyclophosphamide/fludarabine, and GVHD prophylaxis consisting in cyclosporine and short course methotrexate. ATG (7 mg/kg) was added to patients allografted from class I antigen mismatched sibling or unrelated donors. Eighty-two patients (group A) received high-dose Rituximab (R 500 mg/ms on day -6) and were enrolled in a prospective multicenter study, whereas 71 consecutive patients (group B, control group) were part of a previous study without R. The two groups were not significantly different in terms of diagnosis (p=0.10), donor types (p=0.74), rate of complete remission at transplant (p=0.51). Results: The cumulative incidence (CI) of non-relapse mortality (NRM) at 2-years was 16% in group A and 18% in group B (p=0.84). Main cause of death were infections without GVHD in group A (7/13) and extensive GVHD in group B (6/14). Deaths associated to acute or chronic GVHD were significantly lower in group A (5 of 13) as compared to group B (13 of 14) (p=0.004). The CI of grade II-IV and III-IV acute GVHD was 23% versus 35% (p=0.11) and 7% versus 14% (p=0.11) in group A versus B, respectively. The CI of chronic GVHD was 48% versus 47% (p=0.73) in group A versus group B, respectively. The CI of acute GVHD and chronic GVHD in unrelated recipients was 20% versus 31% (p=0.41) and 32% versus 40% (p=0.83) in patients who received R in the conditioning comparing to group B. A delayed immune reconstitution of B-cells was still evident at 2 years after alloSCT in group A versus B [median value CD19+: 126/µL versus 300/µL with a significant higher percent of IgD+CD27- in group A and reduced immunoglobulin production: 502 versus 778 mg/dL of IgG (p=0.04)]. Progression free survival (PFS) and overall survival (OS) at 3-years were similar in group A and group B [PFS: 54% versus 58% (p=0.50); OS: 64% versus 67% (p=0.51)]. PFS at 3-years in indolent and aggressive lymphomas was 66% versus 75% and 42% versus 43% with and without R; OS at 3-years in indolent and aggressive lymphomas was 74% versus 78% and 55% versus 57% with and without R. In multivariate analysis, acute GVHD, extensive chronic GVHD and aggressive hystotype were associated to a lower OS [HR=3.6, p=0.0003; HR=2.3,p=0.03;HR=2.1,p=0.01] and only acute GVHD and aggressive hystotype to lower PFS [HR=2.7, p=0.002; HR=2.3, p=0.001]. Rituximab in the conditioning regimen, year of transplant and donor type did not influence the outcome. Conclusions: Rituximab administration in the setting of alloSCT is associated with reduced GVHD-related deaths and increased infection-related deaths, likely due to delayed B-cell immune-reconstitution. Disclosures: No relevant conflicts of interest to declare.

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