Phase II Study Evaluating Busulfan and Fludarabine as Preparative Therapy In Adults with Hematopoietic Disorders Undergoing Matched Unrelated Donor Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1317-1317
Author(s):  
Adam Giermasz ◽  
Lloyd E. Damon ◽  
Lawrence D Kaplan ◽  
Willis H. Navarro ◽  
Kristen Hege ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 1317 Introduction: Allogeneic stem cell transplantation offers potentially curative therapy for selected patients with hematopoietic malignancies or bone marrow failure states. Only 20–25% of transplantation candidates have compatible related donors, and thus the majority of patients require stem cells from unrelated individuals matching their human leukocyte antigen (HLA) genes. Unrelated donor transplantation (NMUDT) is associated with higher rate of acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) resulting in significant treatment related morbidity and mortality. Severe aGVHD (grade III/IV) occurs in 30–40% of patients and many of these patients eventually die from the complications. The incidence of cGVHD following unrelated transplantation was reported to occur up to 80%. Treatment-related mortality in the first 100–180 days post-transplant ranges from 30–60% depending on the patient/donor age, disease status at time of transplant and HLA mismatch. This compares to a treatment-related mortality of approximately 20–30% for patients receiving sibling-donor transplants. More aggressive conditioning including total body irradiation is believed to result in severe organ toxicities fueling subsequent GVHD in the NMUDT patients. In this study we evaluated chemotherapy only based preparative therapy (busulfan and fludarabine) and tacrolimus plus methotrexate as the GVHD prophylaxis. Also the donors and recipients were matched with strict HLA compatibility. Patients and Method: Thirty-five patients meeting eligibility criteria for NMUDT were prospectively enrolled. Diagnoses included:14 AML, 6 NHL, 6 MDS, 5 ALL, 2 MPD, 2 CML. The median age was 46 years (18-61); 20 males and 15 females. Preparative therapy consisted of Fludarabine (F) 30mg/m2 daily for 5 doses, Busulfan (Bu) 0.8mg/kg IV q6 hrs for 16 doses. All patients received stem cells from allele-matched unrelated donors; 7/8 (n=1), 8/10 (n=1), 9/10 (n= 7) or 10/10 (n= 26) at HLA A, B, C, DR and DQ. 9 patients received bone marrow and 26 patients received G-CSF mobilized peripherial blood stem cells. All patients received TAC (target 5–10 ug/L), MTX (5mg/m2 d1,3,6,11) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy. Results: The engraftment was documented as follows: ANC >1.0 median: day 12 (SD3.5), Plt >50×10e9/L median: day 16 (SD 7.2), Plt >100×10e9/L median: day 20 (SD 40.7). The frequent (>20%) toxicities included bone marrow suppression (grade 4 100%) mucositis (gr≥1 91%), enteritis (gr≥1 43%); elevated AST (gr 1 27%), elevated total bilirubin (gr 1 20%) and alkaline phosphatase (gr1 40%). Other significant toxicities (gr ≥3) included neutropenic fever (20%), bacteremia (11%), infections (including pneumonia, fungal pneumonia, CMV viremia) (26%), enteritis 6%, ARF 9%, rash 9%, respiratory failure 14%. The incidence of aGVHD (Gr II-IV) was 43%. The incidence of cGVHD was 60% (90% extensive cGVHD). The 100 day non-relapse mortality (NRM) was 9% (2 GVHD, 1 VOD). The late TRM (beyond 100 days) was 11% (3 GVHD, 1 infection). Cumulative relapse related mortality was 17% at 6 months, 26% at 9 months and 31% at 24 months. Overall mortality at 1 year was 44%. Overall survival is currently 40% with median follow-up of 4.4 years. Conclusions: In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the busulfan/fludarabine preparative regimen is safe and resulting in reasonably low TRM and comparable GVHD rates. Disease relapse remains the most significant cause of death. Disclosures: No relevant conflicts of interest to declare.

Low Relapse without Excessive Transplant-Related Mortality Following Allogeneic Stem Cell Transplantation in Patients with High Risk Secondary Acute Myeloblastic Leukaemia and Myelodysplastic Syndromes, Long-Term Outcomes in a Single Centre Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4308-4308
Author(s):  
Jean El-cheikh ◽  
Luca Castagna ◽  
Sabine Furst ◽  
Catherine Faucher ◽  
Benjamin Esterni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Allogenic Stem Cell Transplantation ◽  
Related Mortality

Abstract Abstract 4308 Allogenic stem cell transplantation (Allo-SCT) as a therapy for secondary acute myeloid leukaemia (sAML) and myelodisplastic syndromes (MDS) is the most powerful treatment option. However, (Allo-SCT) is also complicated by a high risk for treatment-related morbidity and mortality. We analysed retrospectively the data of 70 patients transplanted at our institution from June 1995 to december 2008, 44 patients (63%) with sAML and 26 patients (37%) with MDS was treated with (Allo-SCT); median age at diagnosis was 41 years, (15-70), and the median age of 42, 5 years (16-70) at transplantation; The conditioning regimen was myeloablative combining (cyclophosphamide and TBI) in 16 patients (23%) and 54 patients (77%) was with a reduced intensity conditioning (RIC) regimens combining fludarabine, busulfan, and antithymocyte globulin; 11 patients (16%) were infused with bone marrow (BM), 55 patients (79%) peripherical blood stem cells (PBSC), and 4 patients (5%) cord blood cells; in 49 cases (70%) donor was a HLA identical sibling and in 21 (30%) was a matched unrelated donor; 41 patients (59%) carried high risk cytogenetic features, like (7q-, 5q-, > 3 alterations), while was normal in 24 patients (34%), and in 5 patients (7%) was unknown. Disease status at transplantation was as follow: CR in 24 patients (34%), 34 patients (49%) was refractory or in progression after treatment, and 12 patients (17%) was with a stable disease. With a median follow-up of 55 months (3-150), 30 patients (43%) are alive, the overall survival OS at 2 years and 5 years was 48 % and 39% respectively, and after ten years of follow up, OS was 30%, 95%CI [17.8-50.8]. We observed also that 26 % of refractory patients and 54% of patients in CR are alive at five years of transplantation. The probability of progression after transplantation at five and ten years was 31% with 95%CI [20.-46.5]. 2 years and 5 years treatment related mortality (TRM) was 23% and 26% respectively, and no modification at ten year, 95%CI [14.3-37.3]. TRM occurred in 16 patients (23%). Cause of death was; infections in 5 patients (7%), GvHD in 3 patients (4%), GvHD and infection in 3 patients (4%), multi organ failure (MOF) in 5 patients (7%). In multivariate analysis; OS, PFS or TRM, were not influenced by donor type (HLA id sibling vs others), conditioning regimen (RIC vs MAC), and stem cell source (bone marrow vs PBSC). Allogenic stem cell transplantation can be considered as a good option for the treatment of patients with high risk sAML and MDS when compared with the remission rate at five years of the other nonallogeneic SCT therapies. Disclosures: No relevant conflicts of interest to declare.

Haploidentical Allogeneic Hematopoietic Cell Transplantation as Salvage Therapy for Engraftment Failure After Unrelated and Autologous Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4529-4529
Author(s):  
Yamin Tan ◽  
Huarui Fu ◽  
Yi Luo ◽  
Xiujin Ye ◽  
Li Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Bone Marrow Examination ◽  
Pcr Analysis ◽  
Unrelated Donor ◽  
Haploidentical Transplantation ◽  
Engraftment Failure

Abstract Abstract 4529 Engraftment failure is a rare but life-threatening complication of hematopoietic stem cell transplantation. The treatment of this condition is often challenging. We firstly reported haploidentical donor stem cells transplantation resulted in hematological reconstitution and long-time disease-free survival in a patient who developed engraftment failure after unrelated donor allogeneic stem cell transplantation and failure rescue treatment by re-infusion of autologous “back-up” stem cells. The 39-years-old male patient with acute myeloid leukemia(AML)-M2a achieved complete remission (CR) after one course of induction chemotherapy. He entered a lasting CR with 7 courses post-remission consolidation therapy and decided to receive unrelated donor allogeniec stem cell transplantation. In case of engraftment failure after allo-HSCT, autologous “back-up” cells were harvested after the last course chemotherapy (IDA 15 mg on days 1–2, 10 mg on day 3, Ara-c 300 mg on days 1–3, 200 mg on day 4), and mobilized with G-CSF 5 mg/kg/day for 5 days. The “back-up” cells consisting of 9.94×106/kg CD34+ cells were cryopreservated in liquid nitrogen. Fifteen months after de novo AML, the patient received a myeloablative conditioning regimen of busulfan and cyclophosphamide (busulfan 3.2 mg/kg/day on days -7 to -4, and cyclophosphamide 60 mg/kg/day on days -3 to -2), and an infusion of unrelated allogeneic peripheral stem cells from the Chinese Marrow Donor Program with a HLA-Cw allele mismatch on day 0. The graft contained 11.07×108/kg nucleated cells and 6.35×106/kg CD34+ cells. Pancytopenia was continuously observed during 28 days after transplantation and short tandem repeat-polymerase chain reaction (STR-PCR) analysis showed no donor chimera. As a rescue attempt for graft failure, cryopreservated autologous cells were re-infused on day +28. Unfortunately, pancytopenia was still continuously observed during 23 days after re-infused of “back-up” cells(51 days after unrelated transplantation), and bone marrow examination revealed severe bone marrow hypoplasia. On day +57 and +58 after unrelated transplantation, bone marrow cells containing 2.1×106/kg CD34+ stem cells and peripheral blood cells containing 2.81×106/kg CD34+ stem cells from a haploidentical donor sister (HLA matched in 5/10 alleles by high-resolution genotyping) were infused respectively after reduced-intensity conditioning with fludarabine and ATG (fludarabine 30mg/m2/d on day -5 to -1, ATG 100mg/d on day -4 to -1). Absolute neutrophil count >0.5×109/L was documented on day 12 after haploidentical transplantation. He achieved platelets count >20×109/L on day 28 after haploidentical transplantation. Twenty-nine days after haploidentical transplantation, bone marrow examination showed reconstitution and STR-PCR analysis indicated complete donor chimera. No grades III -IV aGVHD, extensive chronic GVHD, and severe infection after transplantation were observed. Recurrent bone marrow aspiration examinations showed the patient had been in CR. The patient remained alive during a 18-month follow-up after haploidentical transplantation. Our experience suggests that combined haploidentical donor BM and PBSC transplantation after Flu- and ATG-based conditioning could provide an effective therapeutic strategy for engraftment failure after unrelated allo-HSCT in adult patients. Considering the accessibility of haploidentical donors, haploidentical transplantation has the potential to act as a first-line choice for salvage therapy. Disclosures: No relevant conflicts of interest to declare.

Favourable Overall Survival with Myeloablative Allogeneic Stem Cell Transplantation for Follicular Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3005-3005
Author(s):  
John Kuruvilla ◽  
Qikun Bao ◽  
Erica Messner ◽  
Vikas Gupta ◽  
Thomas L. Kiss ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Follicular Lymphoma ◽  
Disease Control ◽  
Allogeneic Stem Cell Transplantation ◽  
Unrelated Donor ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Introduction Allogeneic stem cell transplantation (Allo-SCT) remains an option for patients with follicular lymphoma (FL). Our program employs a strategy using allo-SCT for patients (pts) with high risk disease based on clinical characteristics. We performed a retrospective analysis to examine long-term disease control and treatment-related mortality. Methods 41 pts with indolent FL (follicular small cleaved [FSC], follicular mixed [FM] or FL grade 1,2 by WHO criteria) underwent allo-SCT at our institution between Jan 1989 and Dec 2005. Patients were in a chemosensitive remission at the time of SCT. The conditioning regimen consisted of busulfan (1 mg/kg PO q6h X4 days between 1989–200 and 3.2 mg/kg IV daily X 4days subsequently) and cyclophosphamide 60 mg/kg X 2 days. Cyclophosphamide 60 mg/kg X 2 days and TBI 12 Gy was used for unrelated donor SCT. GVHD prophylaxis was with cyclosporine A and methotrexate. Results There were 21 males and 20 females. The median age at the time of transplant was 45 years (range 24 to 58). Histologic subtype was: unclassified indolent FL: 3, Grade 1 or FSC: 17, Grade 2 or FM: 21. The median number of prior chemotherapy regimens was 2 (range 1 – 6) and was unavailable in 5. Prior anthracycline: 37, prior purine analog: 9, prior platinum-based: 20, prior auto-SCT: 1, prior rituximab: 11. The median time from diagnosis to allo-SCT was 23 months (range 6 – 161). 38 pts received BuCy conditioning. 2 patients underwent RIC SCT. Graft source was: matched related (MRD) bone marrow (BM): 28, MRD peripheral blood stem cells (PBSC): 4, Mismatch related (MMRD) bone marrow (BM): 1, MMRD PBSC: 2, matched unrelated donor (MUD) BM: 1, MUD PBSC: 1, and syngeneic BM: 4. The five year overall survival is 77% (95% confidence intervals 73 – 91%) with a median follow-up of 48 months post-SCT. Treatment-related mortality was 5 of 41 pts (12%). Non-relapse mortality was seen in one patient (3%). One patient has relapsed at over 3 years post-SCT while all recipients of syngeneic SCT remain in remission. Conclusions These results demonstrate that in selected patients, a fully myeloablative allo-SCT utilizing Busulfan-Cyclophosphamide conditioning provides excellent overall survival and disease control with low TRM. Prospective comparisons of RICSCT with myeloablative SCT should be performed in order to better evaluate these strategies.

Significant Reduction of Treatment Related Mortality after Stem Cell Transplantation in 647 Children and Adolescents with ALL within BFM Trials during the Last 12 Years: A Long Term Analysis from 1996 to 2007

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 567-567
Author(s):  
André Schrauder ◽  
Martin Schrappe ◽  
Arend Stackelberg ◽  
Peter Bader ◽  
Wolfgang Holter ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Unrelated Donor ◽  
Chi Square ◽  
Cytogenetic Aberrations ◽  
Gvhd Prophylaxis ◽  
Subsequent Relapse ◽  
Over Time ◽  
Related Mortality

Abstract Although allogeneic stem cell transplantation (alloSCT) effectively prevents relapse of acute lymphoblastic leukemia (ALL), transplant related mortality (TRM) associated with the procedure may counterbalance that beneficial effect. To asses the risk for TRM after alloSCT we analyzed the different transplantation outcome data within the Berlin-Frankfurt-Münster (BFM)-trials. Between January 1996 and December 2003 403 patients were transplanted within ALL-BFM and ALL-Rez BFM trials (185 in CR1, 218 in CR2 or after subsequent relapse). These chemotherapy protocols included recommendations for alloSCT, however donor selection, conditioning regimen and GvHD prophylaxis frequently were modified by transplant centers. In 2003 the BFM Study Group initiated a prospective international multicenter trial (ALL-SCT-BFM 2003) aiming to standardize and harmonize the SCT procedure in order to minimize risk of TRM. Between January 2004 and December 2007 244 patients (109 in CR1, 135 in CR2 or after subsequent relapse) were recruited by 27 participating SCT centers in Austria, Germany and Switzerland. Indications for SCT were poor response to induction treatment, either detected by morphology on day 33 (NRd33) or by minimal residual disease load measured after 12 weeks of treatment, cytogenetic aberrations [t(9;22), t(4;11)], early bone marrow relapses of ALL, or any subsequent ALL relapse. More than 80% of all patients who were enrolled in ALL-SCT-BFM 2003 received the recommended conditioning regimens and GVHD prophylaxis (TBI+VP16 for MSD, TBI+VP16+ATG for MD, and TBI+Flu+VP16+ATG for MMD; in children younger than 2 years, TBI was substituted by BU+Cy; CSA in MSD-SCT, CSA plus short MTX in MD-SCT). Patients of both time periods (1996 to 2003 vs 2004 to 2007) were comparable regarding gender, immunophenotype, cytogenetic aberrations, NRd33 and type/time of relapse (if SCT in CR2). However, in the second time period there was a trend to older age at diagnosis (54.5% vs. 43.9% patients older than 10 years). Moreover, unrelated donors were used more frequently over time (61.9% vs 50.1%). Nevertheless TRM was significantly lower within ALL-SCT-BFM 2003 (11.5% vs 19.9%; p(Chi-Square)=0.006). In a logistic regression analysis including age above 10 and donor other than matched related as covariables the p-value was 0.001. TRM reduction over time was observed in MSD transplants (n=229) from 13.6% to 6.7% (p(Chi-Square)=0.12), in unrelated donor SCT (n=353) and mismatched related donor SCT (n=65) TRM decreased from 23.7% to 13.6% (p(Chi-Square)=0.01). Despite a trend to higher age at diagnosis and a higher percentage of unrelated donor transplantations, TRM reduced significantly since start of ALL-BFM SCT 2003. The experience of participating centers as well as high compliance to the recommended regimen, improved donor selection by HLA-high resolution typing, better diagnostic measures and (preemtive) treatment of infections, and close and prospective monitoring of all patients may contribute to the reduced TRM after alloSCT in children with ALL.

scholarly journals Allogeneic Stem Cell Transplantation with Immunodepleted Grafts for Lymphoproliferative Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1252-1252
Author(s):  
Nicolas Novitzky ◽  
Valda Thomas
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Ex Vivo ◽  
Univariate Analysis ◽  
Disease Recurrence ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Introduction: The treatment of lymphoproliferative disorders that fail initial therapy remains unsatisfactory. Allogeneic stem cell transplantation can be curative but has been associated with high treatment related mortality, particularly from graft vs. host disease (GvHD). Immunodepletion of the peripheral blood stem cell (PBSC) graft with alemtuzumab effectively prevents GvHD. Methods: Patients with lymphoma (excluding diffuse large B-cell) in second or subsequent response were offered allogeneic stem cell transplantation if they had a human leukocyte antigen (HLA) compatible donor. Haematopoietic stem cells were mobilized with filgrastim (5-10 ug/kg) and PBSC were collected by apheresis. Patients were conditioned with myeloablative doses of chemotherapy or radiotherapy. For GvHD prophylaxis mobilized donor blood stem cells were incubated ex vivo with alemtuzumab (in the bag) for 30 minutes and infused intravenously. Post transplantation patients received therapeutic blood levels of cyclosporine until day 90. The end points of the study were frequency of GvHD, transplant mortality, disease recurrence and overall survival (OS) rates. Results: Sixty one consecutive patients with lymphoma (follicular 17, marginal zone 2, Waldestrom’s macroglobulinaemia 2, transformed 16, peripheral T-cell 16 [all ALK negative] and lymphoblastic 8) underwent allogeneic transplantation. None had received a previous transplant. PBPC were from siblings in 53 patients and 8 from unrelated donors. Twenty patients were female and the median age was 47 years. The median CD34+ cell number infused was 4.71 (1.31 – 17.88) x10^6/kg. The median dose of alemtuzumab added into the bag was 10 mg. All recovered the blood counts at median of 13 days. Seventeen (28%) patients died, 11 (18%) of transplant related causes. Chimerism studies performed in 42 patients showed full donor chimerism in each case. GvHD (> grade 1) was seen in 8 patients (13%). Cytomegalovirus reactivation occurred in 21% but all responded to gancyclovir. Seventeen patients died, 11 (18%) of treatment related complications. Eight patients had disease recurrence, two of three achieved further response after donor leukocyte infusion and six died of the malignancy. At median follow up of 2260 15-4412) days 71% are alive in response. There was no difference in survival among the 4 histological groups or between chemotherapy and radiotherapy based conditioning. In univariate analysis female donor gender (for male patients) and GvHD were significant adverse factors for survival. Cox analysis showed that occurrence of GvHD (p= 0.001) was an independent significantly adverse factor for survival. Conclusions: We conclude that ex vivo immunodepletion of grafts with alemtuzumab leads to reduced rates of GvHD and results in lesser treatment related mortality despite myeloablative conditioning. Recurrence rates appear low suggesting that in the absence of GvHD prescribing dose intense conditioning and allogeneic stem cell transplantation earlier, before the malignancy is refractory, could be an effective strategy for patients with advanced lymphoma. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document