Allogeneic Stem Cell Tranplantation (allo-SCT) for Adult Patients with Active Refractory/Relapsed Hematological Malignancies: a Survey From the Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3456-3456
Author(s):  
Patrice Chevallier ◽  
Noel Milpied ◽  
Karin Bilger ◽  
Gérard Socié ◽  
Ibrahim Yakoub-Agha ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Best Supportive Care ◽  
Adult Patients ◽  
Peripheral Blood Stem Cells ◽  
Hematological Diseases

Abstract Abstract 3456 Patients with active refractory/relapsed hematological diseases have a very poor outcome. Best supportive care or investigational therapies in phase 1 trials are usually proposed to these patients. However, some previous data suggested that allo-SCT might be an efficient therapy even in the setting of chemorefractory disease, because long-term immune-mediated disease control can be achieved in some patients after allo-SCT. The aim of this study was to evaluate on a large series the outcome of adult patients with active refractory/relapsed hematological diseases at time of allo-SCT and to determine which sub-group would most benefit from such approach. Between 2005 and 2009, 861 patients with various hematological diseases (AML, n=323; ALL, n=43; MDS, n=129, CMML, n=12; MPS, n=110; CML, n=28; NHL, n=100; HL, n=40; myeloma, n=36; CLL, n=24; and other, n=16) were treated with allo-SCT, and reported to the SFGM-TC Registry. Per study criteria, all patients presented with active refractory or relapsed disease at time of transplant. This series included 517 males (60%) and 344 females (40%). The median age at transplant was 50 (range, 16–71) years. The median interval between diagnosis and transplant was 17 (range, 1–99) months. 32% of patients failed at least one prior SCT (Autologous or allogeneic prior to allo-SCT). 350 (41%) patients received allo-SCT from an HLA-matched sibling donor, while the remaining 59% received an allogeneic graft from a matched unrelated or mismatched donor. The stem cell source was mainly peripheral blood stem cells (n=617; 72%). Bone marrow was used in 139 patients (16%), and cord blood in 107 patients (12%). Myeloablative conditioning regimen was used in 328 patients (38%), and various reduced-intensity regimens were used in other cases (62%). With a median follow-up of 290 (range, 1–1854) days after allo-SCT, engraftment was observed in 88% of cases. Grade II-IV and grade III-IV acute GVHD occurred in 35% (n=301) and 17% (n=144) of patients, respectively. Chronic GVHD was observed in 185 patients (21%; limited: n=77; extensive: n=82; missing data: n=24). At last follow-up, 347 patients (40%) were still alive (of whom 297 were in CR; 86%). 246 patients (28.5%) died of disease progression, and 232 patients died of transplant-related causes (NRM: 27%). The Kaplan-Meier (KM) estimates of overall survival (OS) at one and 2 years were 39% (95%CI, 36–43%) and 31% (95%CI, 28–35%), respectively. Of note, in patients with lymphoma (n=140), OS at 1 and 2 years were 57% (95%CI, 48–66%) and 49% (95%CI, 40–58%) versus 36% (95%CI, 32–40%) and 27% (95%CI, 23–31%), respectively, in all other diagnoses (P=0.00004). In a Cox multivariate analysis accounting for relevant factors, a diagnosis of lymphoma (NHL or Hodgkin) was the most significant factor associated with improved survival (RR=1.68; 95%CI, 1.3–2.2; P=0.0001). Despite its retrospective nature and the inherent selection biases, in case of availability of suitable donor, this data support the use of allo-SCT in adult patients with active refractory/relapsed hematological diseases, especially in patients with lymphomas. Results are expected to be further improved with the advent of novel conditioning regimens and maintenance therapies after transplant that are currently tested as part of prospective studies. Disclosures: No relevant conflicts of interest to declare.

Influence of recipient's Age On the Outcome of HLA-Matched Sibling Transplants in Adult Patients with Severe Aplastic Anemia Who Conditioned with Fludarabine-Based Regimen

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1921-1921 ◽  
Author(s):  
SeungHwan Shin ◽  
JaeHo Yoon ◽  
SeungAh Yahng ◽  
SungEun Lee ◽  
ByungSik Cho ◽  
...  
Keyword(s):  
Stem Cell ◽  
Aplastic Anemia ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Adult Patients ◽  
Severe Aplastic Anemia ◽  
Age Group ◽  
Increased Risk ◽  
Significant Difference

Abstract Abstract 1921 Background: There is a controversy concerning upper age limit of recipient in allogeneic stem cell transplantation (allo-SCT) of severe aplastic anemia (SAA) because older patients have an increased risk of transplant-related mortality (TRM). Recently, a less toxic regimen comprising reduced dose of cyclophosphamide (CY), fludarabine (Flu), and ATG (Flu/CY/ATG) was introduced for conditioning the patients with SAA scheduled for HLA-identical sibling allo-SCT. We analyzed the outcome of these patients after conditioning with Flu/CY/ATG regimen according to recipient's age. Method: We analyzed 82 consecutive adult patients transplanted from March 2002 to June 2011, followed conditioning with CY (50 mg/kg/day × 2 days), Flu (30 mg/m2/day × 6 days), and ATG (2.5 mg/kg/day × 4 days). Results: The median age of patients was 39 years (range, 13–58 years). 29 (35.4%) patients were very SAA at the time of allo-SCT. Stem cell sources were bone marrow (BM, n=59), peripheral blood stem cell (PBSC, n=12), and BM+PBSC (CD34+ cell selection, n=11). The conditioning regimen was well tolerated, with low TRM (4.9%). Neutrophil engraftment was observed in all patients; the median time to engraftment of neutrophils and platelets was 12 and 17 days, respectively. The 100-day cumulative incidence (CI) of acute graft-versus-host disease (GVHD, grade °Ã2) was 3.7% and 2-year CI of chronic GVHD was 4.4%. With a median follow-up of 3 years, overall survival (OS) and failure-free survival was 93% and 83%, respectively. Seven patients (8.5%) developed delayed graft failure and 6 patients of them have successful durable engraftment after second allo-SCT without TRM. Seven patients died of veno-occlusive disease (n=1), cytomegalovirus pneumonia (n=2), sepsis (n=2), clonal evolution after allo-SCT (n=2, 1 acute myeloid leukemia and 1 myelodysplastic syndrome), respectively. 3-year probability of OS by age group were 88% at less than 20 years old (n=8), 97% at 20–39 (n=34), 92% at 40–49 (n=26), 86% at 50–59 (n=14). There is no significant difference in OS according to age group (p=0.426). Conclusion: These data indicate that the Flu/CY/ATG conditioning regimen is well tolerable with low TRM and CI of GVHD in all age group. Similar OS according to 4-divided age group suggest that patient's age more than 50 years old might be possible candidate for allo-SCT in SAA with Flu/CY/ATG conditioning regimen. Disclosures: No relevant conflicts of interest to declare.

Bone Marrow (BM) Versus Peripheral Blood Stem Cell (PBSC) For Haploidentical Transplantation With Nonmyeloblative (NMA) Conditioning Regimen and Post Infusion Cyclophosphamide

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2119-2119
Author(s):  
Luca Castagna ◽  
Roberto Crocchiolo ◽  
Sabine Furst ◽  
Stefania Bramanti ◽  
Barbara Sarina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Median Time ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Haploidentical Transplantation ◽  
Post Infusion

Abstract Introduction Transplantation from alternative donors has been used since several years for patients with hematological malignancies lacking of HLA identical donors. The Baltimora group pioneered the use of cyclophosphamide (Cy) after haploidentical unmanipulated (BM) stem cells infusion. BM was chosen to reduce the risk of acute and chronic graft versus host disease (GVHD). PBSC could replace BM, fastening engraftment and immunological reconstitution. However, the risk of GVHD could be higher. We retrospectively analyzed a cohort of patients from two institutions, receiving haploidentical transplantation with nonmyeloablative conditioning regimen (NMA) and PSBC or BM, with post-infusion Cy. Patients and Methods From April 2009 to April 2013, 72 patients with poor prognosis hematological malignancies received haploidentical transplantation. Conditioning regimens consisted of Cy 14.5 mg/kg d -5 and -6, fludarabine 30 mg/m2 d-6 to d-2, and low dose TBI (2 Gy) at d-1. GVHD prophylaxis consisted of Cy 50 mg/kg day +3 and +4, tacrolimus (FK, 1 mg total dose, in continuous infusion) until days +180 (Milan cohort) or cyclosporine (CsA, 3 mg/kg) (Marseille cohort) and MMF (15 mg/kg 3 per day) until day +35. FK, CsA and MMF were started at d +5. G-CSF was started at d +5 in all patients. Donors underwent bone marrow harvest under general anesthesia and a total of 4 x 10e8 nuclear cells per kg of recipient was targeted. Unmanipulated bone marrow was used as stem cell support at d0. In Marseille, donors were mobilized using 5 to 6 days of subcutaneous G-CSF (Neupogen®) (10 mcg/kg/day). A minimum of 4 x 10e6 CD34/kg was harvested. Results The median follow-up was 12 months (range: 1-48). For the population as a whole, the median time to ANC more than 0.5 x 10e9/L was 20 days (14-32) and the median time to transfusion-independent platelet (PLT) count was 29 days (14-52). Engraftment results in the two cohorts of patients (BM vs PBSC) were not significantly different [ANC 21 days (14-32) vs 20 days (14-27), and PLT 29 days (16-46) vs 27 days (14-52)]. Overall, aGVHD 2-4 incidence was 27% and cGVHD was 13%. No difference was founded in the two cohorts: aGVHD 2-4 24% vs 33% and cGVHD 11% vs 17%. The 1-year non relapse mortality was 18% overall, and it was not statistically different even if numerically lower in the PBSC group (22% vs 9%). Conclusion This retrospective study showed that there was not significant differences in terms of hematological reconstitution and both acute and chronic GVHD, using unmanipulated BM and PBSC after NMA conditioning regimen and post-infusion Cy. The 1-year NRM, even if not statistically different, was lower with PBSC. These data warrant confirmation with more patients and longer follow-up. Disclosures: No relevant conflicts of interest to declare.

Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4326-4326
Author(s):  
Malek Benakli ◽  
Redhouane Ahmed nacer ◽  
Amina Talbi ◽  
Rachida Belhadj ◽  
Farih Mehdid ◽  
...  
Keyword(s):  
Complete Remission ◽  
Hodgkin Lymphoma ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Lymphoid Leukaemia ◽  
Autologous Transplant

Abstract Abstract 4326 Background Patients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT. Patients and methods Between April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6). Results Neutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively. Conclusion This study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using Alemtuzumab and Cyclophosphamide as Conditioning Regimen.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3198-3198
Author(s):  
Fernanda Lodi ◽  
Gustavo Teixeira ◽  
Antonio Vaz Macedo ◽  
Rosana Lamego ◽  
Simone Silva Magalhaes ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Median Number ◽  
Off Label Use ◽  
Hematopoietic Stem ◽  
Off Label

Abstract Abstract 3198 Poster Board III-135 Introduction Cyclophosphamide (Cy) with/without antithymocyte globulin (ATG) as conditioning regimen for allogeneic hematopoietic stem cell transplantation (AlloHSCT) is the treatment of choice for young patients with severe aplastic anemia (SAA). In developing countries, and particularly in Brazil, ATG costs limit its use in AlloHSCT for SAA patients. Alternative low-cost regiments, like busulfan (BU) with Cy as conditioning regimen is still associated with a significant rate of rejection, especially in heavily transfused patients, and long-term infertility. Alemtuzumab (Cam) was reported as an alternative to ATG for SAA patients, with similar activity and a lower cost. Material and Methods In order to study the effect of the combination of Cy and Cam, we reviewed all AlloHSCT performed for SAA using this conditioning regimen. Between April 2007 and Mai 2009, fifteen patients with SAA (defined by Camitta criteria) underwent an AlloHSCT in our institution. Median age at transplantation was 25 (range 5-42) years. All but one patient had positive CMV serology. Median number of transfusions was 20 (range 10-67). One patient received a second AlloHSCT due to a late (> 4 years) graft rejection. Patients received an unmanipulated bone marrow (n=11) or peripheral blood (n=4) graft as stem cell source and all but one patient were transplanted with an HLA-identical sibling. Median number of nucleated cell infused was 2.86 (range 1.65-6.50)x10 8/kg. Cyclosporin alone (n=10) or in combination with methotrexate (n=5) was used as GVHD prophylaxis. Results Thirteen out of 15 patients presented neutrophil recovery with a median time to > 0.5×10 9 neutrophil/L of 23 (range 13-30) days. Platelet recovery (> 20×10 9 platelets/L) occurred in thirteen patients with a median time of 16.5 (range 9-45) days. Acute graft versus host disease (GVHD) was observed in just one patient (grade II). None of 12 patients alive 100-days after AlloHSCT presented chronic GVHD. Seven patients presented CMV reactivation. One patient did not engrafted and other presented a late (14 months) rejection. One patient became pregnant after alloHSCT and gave birth to a healthy child. With a median follow-up of 315(range 4-782) days, two patients died and the estimate 1-year overall survival rate is 87%. One patient died due to complications of a CNS bleeding that occurred hours before marrow infusion and the other of GI infection while still on neutropenia. Conclusion Use of cyclophosphamide and alemtuzumab as conditioning regimen is a valid option in SAA patients undertaking AlloHSCT, with significant lower rates of acute and chronic GVHD. Nevertheless, a longer follow-up is required to properly evaluate rejection incidence. Disclosures Off Label Use: Drug: Alemtuzumab Off-label Use: Aplastic Anemia.

5-Azacytidine Before or After Stem Cell Transplantation in Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4267-4267
Author(s):  
Ana Garrido ◽  
Miguel Ortín ◽  
Rodrigo Martino ◽  
Josep Nomdedeu ◽  
Ana Aventin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Complete Response ◽  
Cell Transplant ◽  
Safe Procedure

Abstract Abstract 4267 The acceptable toxic profile of 5-aza-citidine (5-aza) allows its use in fragile or elderly patients in whom intensive chemotherapy should be avoided. Whether it is possible to take advantage of this low toxicity in patients awaiting for donor search and/or stem cell transplant (SCT) and in those experiencing leukemia recurrences after the procedure remains unknown. We analysed the clinical results of using 5-aza in these two settings to define the feasibility, safety and results of this approach. Patients and methods: From 2007 to 2011, 15 patients (11 males, 4 females) received 5-aza as last treatment prior to an allogeneic SCT (n=13) or as rescue after an early post-transplant relapse (n=2) at our centre. Diagnosis was MDS in 3 cases (median age 62; range 58–63) and AML in 12 cases (median age 58; range 37–67). Patients with MDS received a median of 6 courses of 5-aza (range 3–8) as the only treatment from diagnosis, except for one patient who had received panobinostat prior to 5-aza. Amongst patients with AML, 12 patients received 5-aza either as treatment for AML (2/12) or after remission (8/12) because of the high relapse risk while awaiting for a suitable donor to be found. Two patients with AML received 5-aza as treatment for early post-SCT relapse. AML patients treated with 5-aza before SCT received a median of 5 courses (range 1–19), whilst patients receiving treatment for relapse received 1 and 3 courses, respectively. Ten patients received a nonmyeloablative conditioning regimen, 1 received a conventional conditioning regimen, 2 patients are still in the process of donor search and the other 2 patients received 5-aza after an autologous stem cell transplantation relapse. RESULTS: All MDS patients engrafted and are in complete remission (CR) after a median of 696 days of follow-up (range 377–1227). One of those patients died because of aGvHD. Nine of 12 AML patients receiving 5-aza prior to SCT are alive after a median 373 days follow-up (133–995). One patient showing refractoriness to 3 different lines of treatment died from disease progression after 211 days. All patients receiving 5-aza as treatment for early relapse are dead, 41 and 401 days after starting treatment. Most interestingly, AML patients receiving 5-aza as maintenance of an already-achieved CR while awaiting transplantation did not experience disease progression despite the median time they remained on this treatment was prolonged (9 months). Graft-versus-host disease ≥ grade II was seen in 3 patients. No graft failures were seen and all patients who received an allogeneic stem cell transplantation remain in complete response. CONCLUSION: The use of 5-aza for maintaining or achieving a response in patients with AML who are awaiting SCT is a safe procedure and adds flexibility to schedule the treatment without the need to administer potentially toxic therapy. The use of 5-aza before transplant did not appear to interfere either with engraftment, incidence of GvHD or short-term relapse after transplant. Disclosures: No relevant conflicts of interest to declare.

Peripheral Blood Stem Cells Vs Bone Marrow: Stem Cell Source Comparison for Patients Acute Myeloid Leukemia and Myelodysplastic Syndrome Receiving an Allogeneic Stem Cell Transplantation from a 10/10 Matched Donor. Study from the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2552-2552 ◽  
Author(s):  
Aurélie Ravinet ◽  
Aurélie Cabrespine ◽  
Gerard Socie ◽  
Noel Milpied ◽  
Ibrahim Yakoub-Agha ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
French Society ◽  
Peripheral Blood Stem Cells ◽  
Cell Therapies ◽  
Gvhd Prophylaxis

Abstract Introduction: Peripheral blood stem cells (PBSC) are increasingly used for unrelated donor (UD) hematopoietic stem cell transplantation (HSCT). A recent randomized prospective trial did not detect significant survival differences between PBSC and bone marrow (BM) transplantation from a UD. The use of PBSC reduced the risk of graft failure, whereas BM reduced the risk of chronic graft versus host disease (GVHD) (Anasetti & al, NEJM 2012). However, HLA matching was based on HLA-A, HLA-B, HLA-C &HLA-DRB1 (8/8 but also 7/8), some of the patients (pts) received a reduced intensity conditioning regimen (22%) and diseases consisted of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but also other hematological malignancies. We thus conducted this study to compare mobilized PBSC with BM for matched 10/10 UD HSCT after standard conditioning regimen (MAC) in pts with AML and MDS only. Patients and methods: We included all consecutive pts in France who received a first HSCT for AML or MDS with PBSC or BM from a matched 10/10 UD after a MAC (fractionated total body irradiation (TBI)-Cyclophosphamide(Cy), n=165 or Endoxan-Cy, n=203) between 2000 and 2013. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). HLA typing data were collected from the SFHI (French Society of Histocompatibility and Immunogenetic) and the ABM (French Biomedical Agency). This study is in accordance with Helsinki declaration for clinical research. Results: We included368 adults pts (221 [60%] received BM; 147 [40%] received PBSC). Median follow-up was of 16.5 months [0-156]. The BM and PBSC groups were well balanced with respect to age, diagnosis, disease risk, use of antithymocyte globulins (ATG) (67 [30%] BM and 52 [35%] PBSC recipients,) and cytomegalovirus (CMV) recipient and donor status. PBSC recipients were more likely to be male and received less TBI-based regimen. GVHD prophylaxis mainly combined cyclosporine A (CSA) and methotrexate (MTX) (82%). The median number of nucleated cell dose infused was higher in the PBSC group compared with the BM group: CD34+ cells, 6.96 x10⁶/kg [1.2-37.8] vs 2,78 x10⁶/kg [0.6-89] p<0.01) and total nucleated cells, 9.8 x10⁸/kg [1.3-663] vs 2.3 x10⁸/kg [0.3-305.3] p<0.01). Two hundred and seven (90%) pts engrafted after BM and 144 (99.3%) after PBSC HSCT (p=0.1). Among pts who received PBSC as compared with those who received BM, the median time to neutrophils engraftment (> 0.5 x 109 /L) was 6 days shorter and 8 days shorter to platelets engraftment (>20x109 /L) (p<0.01). The cumulative incidence (CI) for severe acute GVHD III-IV was 21.1% and 16.3% in the PBSC and the BM group, respectively (p=0.18). CI of chronic GVHD was higher after PBSC (47.1% vs 34.3% for BM, p=0.05). By multivariate analysis, the absence of ATG in the conditioning regimen (HR 0.4 95%CI [0.22-0.72] p<0.01) and PBSC as stem cells source (HR 0.6 95%CI [0.34-0.97] p=0.04) were associated with an increased chronic GVHD. At 2-years, the CI of non relapse related mortality (NRM), relapse as well as disease free survival (DFS) and overall survival (OS) were similar between the 2 groups (Table 1). In multivariate analysis, better OS was associated with complete remission (CR) disease status (HR 0.5 95%CI [0.32-0.69] p<0.01) and pts’s age<38.1 years (HR 0.67 95%CI [0.48-0.93] p=0.02) at time of HSCT, and the use of CSA-MTX as GVHD prophylaxis (HR 0.6 95%CI [0.41-0.95] p=0.03). Conclusion: OS, NRM and relapse rates are similar with PBSC and BM after HLA 10/10 matched UD for AML or MDS using MAC, but engraftment is better with PBSC and the CI of chronic GVHD is lower with BM. Better results are obtained for pts <38 years old with a disease in CR at time of HSCT using CSA-MTX as GVHD prophylaxis. The absence of ATG with PBSC was associated with chronic GVHD. This study thus favors the use of ATG in the setting of matched 10/10 PBSC. However, the role of ATG in the context of BM after HLA 10/10 matched UD MAC HSCT remains unclear and warrants further investigation. Table 1: 2-year CI of NRM*, relapse, DFS** and OS*** Parameters BM % (95% CI) PBSC % (95%CI) p value NRM 23 (20-26) 18 (15-21) 0.8 Relapse 30 (27-33) 28 (25-31) 0.83 DFS 47.1 (44-51) 54.4 (50-58) 0.2 OS 54 .4 (50.8-57.9) 60.2 (55.7-64.6) 0.31 *NRM: non-relapse mortality **DFS: disease free survival ***OS: overall survival Disclosures No relevant conflicts of interest to declare.

The Best of Both? Megadose Stem Cells with CD34 Selection and T-Cell Addback Enables Engraftment from Mismatched Unrelated Donors Using Reduced Toxicity Conditioning in Primary Immunodeficiency

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4303-4303
Author(s):  
Juliana Montibeller Silva ◽  
Kanchan Rao ◽  
Robert Chiesa ◽  
Stuart Adams ◽  
Margaret Brocklesby ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
T Cell ◽  
Primary Immunodeficiency ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Stem Cell Source ◽  
Reduced Toxicity

Abstract Background: The optimal approach for transplanting patients with primary immunodeficiency from a mismatched unrelated donor (MMUD) remains unclear. With reduced intensity conditioning, when bone marrow (BM) was used as the stem cell source in such patients we have previously observed a high rate of very low level donor chimerism (4 of 12 patients) requiring a second transplant procedure. The use of peripheral blood stem cells (PBSC) can overcome this but results in a high incidence of acute (≥ Gde II 10/21, Gde III-IV 5/21) and chronic (10/21, extensive 7/21) graft-versus-host disease (GVHD) (Rao et al in press). We hypothesized that the use of megadose CD34 selected stem cells from PB with addback of a T-cell dose akin to BM might facilitate engraftment through improved competition for the stem cell niche without severe GVHD. Methods: We prospectively analysed outcomes on 20 consecutive patients with primary immunodeficiency (SCID n=5, HLH n=3, Other PID n=12) transplanted from 8/10 (n=4) or 9/10 (n=16) HLA MMUD at our institution between 2011-2015. The mean age at transplant was 5.1 years. All patients received reduced toxicity conditioning regimens (12/20 Fludarabine/Melphalan/Alemtuzumab; 8/20 Fludarabine/Treosulphan/Alemtuzumab) with Cyclosporin (CsA) and mycophenolate mofetil (MMF) GvHD prophylaxis. CD34 selection of donor PBSC was performed using CliniMACs and the mean CD34+ dose was 20.1x106/kg. At day 0 either 108 CD3/kg (cohort 1, n=6) or 3x108 CD3/kg (cohort 2, n=14) T-cells from the CD34- fraction were infused with the graft. Mean follow up was 31.9 months. Results: In cohort 1, all patients engrafted and 2 developed high level donor mixed chimerism (both curative) in the myeloid and lymphoid lineages at last follow up. Two patients had Grade II acute GvHD and 1 had moderate chronic GvHD. In view of the slow immune reconstitution in this cohort, the T-cell addback dose was increased to 3x108/Kg in subsequent patients. In cohort 2, all patients achieved full donor haemopoiesis initially, 6/14 developed high levels of donor chimerism in both myeloid and lymphoid lineages later and 1/14 progressed with 10% donor T-cell engraftment but remains disease-free. The incidence of significant aGVHD was low (grade II n=4, no grade III or IV) and no patient developed cGvHD. Overall across both cohorts, 10 patients had viral reactivations and there were 5 deaths (3 viral complications, 1 pulmonary vasculopathy, 1 cGVHD lungs). The disease free survival at 2 years 7 months follow up was 70% which compares favorably with a previous cohort transplanted with unmanipulated BM as the stem cell source (Fig 1). Immune reconstitution was delayed (mean CD3 and CD19 counts at day 100 post-transplant was 245 x 109/L and 315 x 109/L) with similar kinetics in both cohorts (Fig 2), comparable to RIC transplant using unmanipulated BM. By 1 year post transplant 11/14 evaluable patients achieved normal CD3+T-cell numbers and 8/14 normal CD19+ B-cell counts. Conclusion: The use of megadose peripheral blood stem cells with T-cell addback in the mismatched unrelated donor transplant setting results in high rates of curative engraftment and a low incidence of acute and chronic GvHD following reduced toxicity conditioning. However, T-cell reconstitution remains delayed (presumably reflecting the effect of Alemtuzumab on the infused T-cells) with a high incidence of viral complications. Disclosures No relevant conflicts of interest to declare.

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

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

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

Novel Conditioning Regimen for Haploidentical Hematopoietic Cell Transplant for Severe Aplastic Anemia in Children

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5651-5651 ◽  
Author(s):  
Hasan Hashem ◽  
Rawad Rihani ◽  
Eman Khattab ◽  
Mayada Abu Shanap ◽  
Abdelghani Tbakhi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Stem Cell Source ◽  
Cell Source

New hematopoietic cell transplant (HCT) approaches are urgently needed for patients with severe aplastic anemia (SAA) who lack an HLA-identical donor. Haploidentical HCT with post transplant cyclophosphamide (PTCy) represent a potential universal available option for almost all children with SAA. We present a novel conditioning regimen for haploidentical HCT in children with SAA in a center where horse ATG is not available. Conditioning regimen consists of rabbit ATG 2.5 mg/kg/day from day -9 to -7, Fludarabine 30 mg/kg/day from day -6 to -2, Cyclophosphamide 14.5 mg/kg/day from day -6 to -5, Thiotepa 5 mg/kg/day from day -4 to -3, and 4 Gy TBI on day -1 in in two fractions. GvHD prophylaxis consist of PTCy 50 mg/kg/day on days +3 and +4 along with Cyclosporine A and Mycophenolate mofetil (MMF) starting on day +5. Four consecutive children with SAA referred to our center for haploidentical HCT starting in 2018. Median age at HCT was 9 years (5-16) with 3 males and 1 female. All patients were heavily transfused with both blood and platelets prior to referral for HCT. Two patients had strong and one had weak positive anti-HLA antibodies (DSAs) and received desensitization with IVIG, Rituximab and plasmapheresis. One patient received buffy coat infusion on day -1 due to persistent strong DSAs despite desensitization. Median CD34+ dose received was 12 x 10e6, and median CD3+ dose was 29 x 10e6. Donors were all same blood group to patients. All patients successfully engrafted neutrophils at median of 13 days (12-14). Platelets engraftment in 3/4 patients at median of 7 days (5-10). All patients received peripheral blood as stem cell source. Three of four patients survived and doing well at last follow up. One patient had toxic death on day +38 due to chemotherapy related toxicity causing multi-organ failure. Chimerism analysis was full donor in all four patients at median follow up time of 11 months (2-12). Patients were sent home at median of 24 days post HCT. None developed grade 2-4 acute GvHD nor chronic GvHD. Acute GvHD of skin grade 1 stage 1 developed in 2 patient and managed with topical steroids. Viral reactivations consisted of CMV viremia and BK hemorrhagic cystitis in all patients, and have all resolved. No post transplant autoimmune complications. Haploidentical HCT with PTCy represents a quick and first line approach in heavily transfused children with SAA. Although yet limited number of patients, this regimen is feasible and appears to be safe. A great advantage of this regimen is the rapid engraftment of both neutrophils and platelets. Moreover, although using peripheral blood as a stem cell source, there was no severe acute or chronic GvHD. Disclosures No relevant conflicts of interest to declare.

Fludarabine/Melphalan Conditioning for Allogeneic Stem Cell Transplantation (SCT) in Elderly Patients with AML/MDS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5410-5410
Author(s):  
Glen A. Kennedy ◽  
Jason Butler ◽  
Simon Durrant ◽  
Geoff R. Hill ◽  
Robyn Western ◽  
...  
Keyword(s):  
Stem Cell ◽  
Elderly Patients ◽  
Survival Data ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Term Survival ◽  
Phase 2 Trial ◽  
Kaplan Meier

Abstract Aims: To assess the tolerability and efficacy of a reduced-intensity, non-TBI based allogeneic SCT conditioning regimen utilising fludarabine and melphalan (FluMel) in elderly patients with AML /MDS. Methods: Fludarabine (25mg/m2 D-7 to D-3) and melphalan (120mg/m2 D-2) allogeneic SCT was performed as part of a prospective phase 2 trial to assess the tolerability of the preparative regimen across a range of haematological malignancies. For this analysis, all patients aged &gt;50yrs with AML /MDS who underwent FluMel transplantation were retrospectively reviewed. Standard GVHD prophylaxis was cyclosporine + methotrexate (D1–11). Both HLA-matched siblings and volunteer unrelated donors (VUD) were permitted as stem cell donors. Graft source was G-CSF stimulated PBPC; all grafts were T-cell replete. Survival data was calculated utilising the Kaplan-Meier product-limit method. Results: In total 20 patients &gt;50yrs (16M and 4F) had received FluMel allogeneic SCT for AML (n=15) or MDS (n=5). Median age at SCT was 60yrs (range 50 to 67yrs). AML transplants were performed in CR1 (n=5), early 1st relapse (n=3), CR2 (n=3), MDS phase post CR1 (n=2), early 3rd relapse (n=1), and primary refractory disease (n=1); 7/15 AML patients had intermediate risk and 7/15 poor risk cytogenetics (1 no data available). All 5 MDS patients were previously untreated; all had INT-1 risk disease on IPSS. Donors were HLA-matched siblings in 14 cases and VUD in 6. A total of 6 patients have died, including 2 prior to engraftment (1 of hepatic failure and 1 from idiopathic pneumonia syndrome) and 4 after day 75 (relapsed AML 2 cases; acute GVHD 1 case; multi-organ failure 1 case). All 18 patients who survived the initial cytopenic period achieved durable engraftment; 10 (50%) subsequently developed acute GVHD, including grades II-IV in 9 cases (45%) and grades III-IV in 3 (15%). Of the 12 patients with follow-up &gt;3mths post-SCT, 9 (75%) developed chronic GVHD, which was extensive-stage in 8 (67%). At a median follow-up of 2.4 yrs (range 0.1–5.2 yrs), overall and event-free survival at 2 years for the whole cohort are both 66%. Conclusions: Our experience suggests that allogeneic SCT with FluMel conditioning in elderly patients AML /MDS is associated with acceptable treatment-related toxicity and significant long-term survival. Further studies on this transplant approach in older patients are warranted.

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