Results of a Multicenter Pilot Investigation of Bone Marrow Transplantation in Adults with Sickle Cell Disease (STRIDE)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 543-543 ◽  
Author(s):  
Lakshmanan Krishnamurti ◽  
Keith M. Sullivan ◽  
Naynesh R. Kamani ◽  
Edmund K Waller ◽  
Allistair Abraham ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell Disease ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Cell Disease ◽  
Event Free Survival ◽  
Eligibility Criteria ◽  
Free Survival ◽  
Reduced Toxicity

Abstract Background: Hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) is potentially curative, yet applied sparingly in adults due in part to limited donor availability and to concerns about safety. We conducted a multicenter pilot clinical trial to determine ways to broaden the availability of this therapy. Objective: To determine the feasibility, efficacy, and safety of a reduced toxicity transplant conditioning regimen in adults with severe SCD receiving related and unrelated donor HCT. Methods: Patients between 16-40 years of age were enrolled between October 2012 and June 2015 at 8 participating transplant centers. Eligibility criteria included stroke; recurrent episodes of acute chest syndrome (ACS) or sickle pain in the past 2 years; 8 or more RBC transfusions/year; or a tricuspid valve regurgitant jet velocity ³2.7 m/sec. Patients received unmodified bone marrow from a human leukocyte antigen (HLA)-matched sibling or an unrelated donor matched for 8 of 8 HLA loci. Patients were prepared for HCT with Busulfan from day -8 to -5 (13.2 mg/kg), Fludarabine from day -7 to -3 (150 mg/m2) and Thymoglobulin from day -5 to -2 (6 mg/kg). GVHD prophylaxis consisted of cyclosporine or tacrolimus with methotrexate. Outcomes and Measures: The primary endpoint was event-free survival 1 year after HCT, with events defined as graft failure, disease recurrence, or death. The Kaplan-Meier probabilities of event-free and overall survival were determined. Donor chimerism, transplant-related toxicities and clinical and laboratory measures of SCD were secondary endpoints obtained 1 year after HCT. Serious adverse events were monitored after transplantation. Results: Twenty-two patients (13 were female) who ranged in age from 17-36 (median 22) years were enrolled. Seventeen patients received a sibling and 5 an unrelated donor HCT. An eligibility review committee confirmed subject eligibility. Enrolled subjects had stroke (2 pts), ACS (3 pts), painful crises (14 pts), RBC transfusions (6 pts) and/or tricuspid valve regurgitant jet velocity (5 pts); 8 subjects satisfied eligibility criteria for more than 1 category. There were 6 severe adverse events after transplantation in 4 patients including one death from intra-cranial hemorrhage related to posterior reversible encephalopathy syndrome. None of the patients had graft failure or SCD recurrence after HCT. Currently, 21 of 22 patients survive with stable engraftment of donor cells at a median 9.7 months (range, 1-31) after HCT. The overall and event-free survival probabilities are both 95% (90% CI 76%; 99%, Figure 1) at 12-months after HCT. Two patients developed grade I skin acute GVHD and three patients developed chronic GVHD. Full donor myeloid chimerism was observed after HCT. The median donor T-cell and RBC chimerism at 28, 100 and 180 days after HCT was 55.5% and 100%, 80% and 100%, and 87.5% and 100%, respectively. Conclusions: We report excellent outcomes after HLA-matched HCT in adults with SCD using a reduced toxicity-conditioning regimen performed in a multi-center setting. We observed very low rates of graft rejection and GVHD in this pilot study. We speculate that these outcomes, if sustained long-term after HCT, will be superior to survival in adults with SCD who receive standard supportive care. If confirmed in a larger comparative trial, this approach would broaden the availability and application of transplantation for adults with severe SCD. Figure 1. Figure 1. Disclosures Walters: ViaCord and AllCells, Inc: Other: Medical director.

scholarly journals Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease

Blood ◽  
2020 ◽  
Vol 136 (5) ◽  
pp. 623-626 ◽  
Author(s):  
Ruta Brazauskas ◽  
Graziana M. Scigliuolo ◽  
Hai-Lin Wang ◽  
Barbara Cappelli ◽  
Annalisa Ruggeri ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Risk Score ◽  
Unrelated Donor ◽  
Cell Disease ◽  
Event Free Survival ◽  
Matched Unrelated Donor ◽  
Free Survival ◽  
Matched Sibling

Abstract We developed a risk score to predict event-free survival (EFS) after allogeneic hematopoietic cell transplantation for sickle cell disease. The study population (n = 1425) was randomly split into training (n = 1070) and validation (n = 355) cohorts. Risk factors were identified and validated via Cox regression models. Two risk factors of 9 evaluated were predictive for EFS: age at transplantation and donor type. On the basis of the training cohort, patients age 12 years or younger with an HLA-matched sibling donor were at the lowest risk with a 3-year EFS of 92% (score, 0). Patients age 13 years or older with an HLA-matched sibling donor or age 12 years or younger with an HLA-matched unrelated donor were at intermediate risk (3-year EFS, 87%; score, 1). All other groups, including patients of any age with a haploidentical relative or HLA-mismatched unrelated donor and patients age 13 years or older with an HLA-matched unrelated donor were high risk (3-year EFS, 57%; score, 2 or 3). These findings were confirmed in the validation cohort. This simple risk score may guide patients with sickle cell disease and hematologists who are considering allogeneic transplantation as a curative treatment relative to other available contemporary treatments.

Outcomes of Stem Cell Transplantation with Fludarabine and Melphalan Conditioning for Children with Acquired Bone Marrow Failure: A Nationwide Retrospective Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2559-2559 ◽  
Author(s):  
Nao Yoshida ◽  
Hiromasa Yabe ◽  
Kazuko Kudo ◽  
Ryoji Kobayashi ◽  
Miharu Yabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Bone Marrow Failure ◽  
Conditioning Regimen ◽  
Event Free Survival ◽  
Free Survival ◽  
Donor Type

Abstract Survival after stem cell transplantation (SCT) in children with acquired bone marrow failure (aBMF) has improved over decades. However, we have experienced a certain number of patients who presented with bone marrow aplasia with full donor chimerism after SCT, especially in the last decade. We named the complication “donor-type aplasia”, and now, this is one of the main causes of treatment failure after SCT in children with aBMF. Because fludarabine (FLU)-based conditioning regimen has been often used for Japanese children with aBMF since the 2000s, use of FLU was suspected to associate with donor-type aplasia. On the other hand, when FLU was introduced in the regimen for children with aBMF, the dose of cyclophosphamide (CY) was reduced by half, to reduce the toxicity. Given these, we previously investigated the risk factors for donor-type aplasia, and reported that the dose reduction of CY rather than the use of FLU in itself was relevant to the recent increase of donor-type aplasia (Yoshida N, et al. ASH 2012). To reduce the risk for donor-type aplasia, the conditioning regimen for children with aBMF needs to be reconsidered. The purpose of the present study is to evaluate the outcomes of SCT using FLU/melphalan (MEL)-based conditioning instead of the standard FLU/CY-based regimen in children with aBMF. We retrospectively reviewed the clinical data of 488 patients (<16 years) with aBMF (aplastic anemia and refractory cytopenia of childhood) who received the first SCT from 2000 to 2012 and whose records were available in the Japan Society for Hematopoietic Cell Transplantation Registry. Totally, 28 patients received the FLU/MEL-based regimen, while 233 received the FLU/CY-based regimen. Of the 28 patients, 11 received SCT from a related donor, whereas 17 received it from an unrelated donor. The stem cell source was bone marrow in 19 patients, peripheral blood in 1, or cord blood in 8. The conditioning regimen was based on FLU (100-180 mg/m2) and MEL (70-180 mg/m2), and ATG was included in the regimen in 17 patients, while low dose irradiation was used in 23 patients. The 5-year overall survival and event free survival of all patients who received the FLU/MEL-based regimen was 88%. Engraftment was achieved in 27 out of 28 patients (96%) and secondary graft failure including donor-type aplasia was not observed. Regarding the MEL dose, the favorable survival in patients who received 120 mg/m2 or more was observed (100% vs. 62%; P=0.006). Notably, all patients who received bone marrow transplantation (BMT) were alive without any complication. We then compared the outcomes in the setting of BMT with the FLU/MEL-based regimen (n=19) to those with the FLU/CY-based regimen (n=219). The event free survival was inferior in patients treated with the FLU/CY-based regimen (85% vs. 100%), although this difference was not statistically significant. With the FLU/CY-based regimen, engraftment was achieved in 214 patients (98%), whereas secondary graft failure including donor-type aplasia was seen in 18 patients. In conclusion, the FLU/MEL-based conditioning regimen provided excellent outcomes especially in the setting of BMT. To validate whether this regimen can reduce the risk of donor-type aplasia, a larger study is necessary. Therefore, a prospective study on SCT with this conditioning for aBMF children with high risk of donor-type aplasia is now planned by the Japan Childhood Aplastic Anemia Study Group. Disclosures No relevant conflicts of interest to declare.

scholarly journals Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in Patients with Symptomatic Sickle Cell Disease: BMT CTN Protocol 1507

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 802-802
Author(s):  
Adetola A. Kassim ◽  
Mark C. Walters ◽  
Mary Eapen ◽  
Brianne Allison ◽  
Adam M. Mendizabal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Rejection ◽  
Conditioning Regimen ◽  
Rejection Rate ◽  
Marrow Transplant ◽  
Cell Disease ◽  
Event Free Survival ◽  
Learning Collaborative ◽  
Free Survival ◽  
Post Transplant

Background: Hematopoietic cell transplantation (HCT) has curative potential in sickle cell disease (SCD). A reduced intensity haploidentical bone marrow transplant (haplo-BMT) platform piloted by investigators at Johns Hopkins, addressed key barriers in HCT for SCD, donor availability and toxicity, but had a graft rejection rate of 43%. (Blood. 2012;120(22):4285-4291). Subsequently, a Vanderbilt University Medical Center supported multi-institution learning collaborative with London, France and United States was developed in 2013 with the objective of reducing this graft rejection rate. Evolution of this haplo-BMT platform with the addition of only thiotepa, resulted in a reduction in the graft rejection rate to 7% (1 of 15), an event free survival (EFS) of 93% (14 of 15), &gt; 95% stable donor engraftment at 6 months and 100% overall survival (Biol Blood Marrow Transplant. 2019 Jun;25(6):1197-1209). Based on the preliminary data from the learning collaborative, we initiated an NIH sponsored BMT CTN, dual-strata, phase II, multi-center prospective clinical trial, (clinicaltrials.gov # NCT03263559) to estimate event free survival (EFS) at 2 years in children with neurological morbidity and adults with severe SCD. Study Design and Methods: Eligibility: Patients are stratified into 2 groups: (1) children with SCD (Hb SS or Sβ+ Thalassemia) between 5.00 - 14.99 years of age with central nervous system (CNS) disease (stroke, elevated transcranial Doppler (TCD) with evidence of intracranial vasculopathy; silent cerebral infarction) and (2) adults with severe SCD (Hb SS, SC, Sβ° thalassemia, Sβ+ Thalassemia, SD, S-OArab), between 15.00 - 45.99 years of age who have had a stroke, recurrent ACS, recurrent vaso-occlusive pain episodes, chronic transfusions to prevent sickle complications and tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec. Participants must have an HLA haploidentical first degree relative donor with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. Those with an HLA-matched sibling are excluded. Primary objective is to estimate EFS at 2 years after haplo-BMT in patients with SCD enrolled in each stratum. Secondary objectives include determining the effect of haplo-BMT on clinical and laboratory manifestations of SCD by 2 years post-transplant and determining the incidence of other transplant-related outcomes. A key secondary analysis will be central adjudication of CNS progression in children and adults with evidence of previous CNS injury. Treatment Description: Preconditioning with hydroxyurea 30mg/kg daily (Day -70 to Day -10). The conditioning regimen includes: Thymoglobulin (rATG) (0.5mg/kg on Day -9, 2mg/kg on Day -8, Day -7), Thiotepa 10mg/kg on Day -7, Fludarabine (30mg/m2 on Day -6 to Day -2), Cyclophosphamide 14.5mg/kg on Day -6 and Day -5, and TBI 200cGy on Day -1. Day 0 is the day of infusion with non T-cell depleted bone marrow. Cyclophosphamide 50 mg/kg and Mesna 40mg/kg is given on Days +3 and +4, and GVHD prophylaxis (sirolimus and mycophenolate mofetil) begin on Day +5 (Figure). Study Accrual and Endpoints: The target sample size is 40 patients enrolled and treated in each stratum; if the stopping rule for graft failure is triggered within the first 12 evaluable participants in either stratum using the 200cGy dose of TBI and the DSMB and sponsor approve the pre-defined switch in conditioning regimen, then accrual for that strata will restart under the modified conditioning regimen with 400 cGy TBI. The estimated accrual period is 4 years. The rate of overall mortality by Day 180 after starting hydroxyurea therapy pre-transplant, acute grade III-IV GVHD at 100 days, and severe chronic GVHD at 18 months post-transplant will be monitored by a sequential probability ratio test (SPRT) for censored exponential data for each of these. Graft failure at 100 days post-transplant will be monitored by using a SPRT for binary data. Conclusion: This NIH sponsored BMTCTN phase II trial of HLA-haploidentical HCT is active at 30 BMT CTN sites. This study will determine if a modulated conditioning regimen has adequate donor engraftment, with acceptable risks of transplant-related morbidity and mortality to support a future comparative clinical trial in SCD. Figure Disclosures Walters: AllCells, Inc: Consultancy; TruCode: Consultancy; Editas Medicine: Consultancy. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding.

scholarly journals Conditioning Regimens and Outcomes after Allogeneic Hematopoietic Cell Transplant for Hyperinflammatory Inborn Errors of Immunity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Rebecca A. Marsh ◽  
Soyoung Kim ◽  
Kyle Hebert ◽  
Christopher C. Dvorak ◽  
Victor Aquino ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Graft Failure ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
Inborn Errors ◽  
Free Survival ◽  
Inborn Errors Of Immunity ◽  
Conditioning Regimens

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged &lt;21 years with HLH (n=263) and CGD (n=102) were transplanted in the US between 2005-2018. Included are recipients of HLA-matched sibling (n=58; 16%) and HLA-matched (n=149; 41%) and mismatched unrelated (n=158; 43%) donor HCT. The analysis considered 3 conditioning regimen intensity groups: 1) fully myeloablative conditioning with busulfan (Bu; median dose 16 mg/kg [IQR 13-17]), cyclophosphamide (Cy) ± anti-thymocyte globulin (ATG) or alemtuzumab, n=142; 2) reduced intensity conditioning consisting of fludarabine (Flu), melphalan (Mel; 140mg/m2 [60%], 100 mg/m2 [40%]) ± alemtuzumab or ATG, n=131; and 3) reduced toxicity myeloablative conditioning consisting of either Flu, Mel (140mg/m2 [75%], 100 mg/m2 [25%]), and thiotepa (TT; 8 mg/kg or 10 mg/kg), or Flu, Bu (12mg/kg, IQR 9-15) ± alemtuzumab or ATG, n=92. The cumulative incidence rates of veno-occlusive disease (VOD) and infections were calculated. The probabilities of overall survival and event-free survival were calculated using Kaplan-Meier estimator. For event-free survival, an event was defined as the first occurrence of any of the following: primary graft failure, secondary graft failure, cellular product intervention for mixed chimerism, donor chimerism &lt;5%, second transplant, or death. The Fine and Gray method for acute and chronic GVHD and Cox regression analysis for event-free and overall survival were used to determine factors affecting outcomes. Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p&lt;0.001). The 6-month incidence of bacterial infection was higher after Bu/Cy (50%) and Flu/Mel (58%) compared to Flu/Mel/TT or Flu/Bu (43%) regimens (p=0.013). Viral infections were higher in Flu/Mel group (72%) compared to Bu/Cy (44%) and Flu/Mel/TT or Flu/Bu (56%), p&lt;0.001. There were no differences in overall survival (Figure 1A), but event-free survival (Figure 1B) was lowest with the Flu/Mel regimen, after adjusting for donor type (Table 1). Compared to matched sibling, survival was lower with matched (HR 2.41, p=0.05) and mismatched (HR 2.89, p=0.01) unrelated donor HCT. Chronic GVHD but not grade II-IV acute GVHD was lower with Flu/Mel regimen. Table 2 shows the results of multivariate analysis for HLH disorders and findings consistent with the main analysis. Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

scholarly journals Related and unrelated donor transplantation for β-thalassemia major: results of an international survey

2019 ◽  
Vol 3 (17) ◽  
pp. 2562-2570 ◽  
Author(s):  
Chunfu Li ◽  
Vikram Mathews ◽  
Soyoung Kim ◽  
Biju George ◽  
Kyle Hebert ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Thalassemia Major ◽  
Early Age ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
Matched Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Suitable Alternative ◽  
Free Survival ◽  
Donor Type

Abstract We studied 1110 patients with β-thalassemia major aged ≤25 years who received transplants with grafts from HLA-matched related (n = 677; 61%), HLA-mismatched related (n = 78; 7%), HLA-matched unrelated (n = 252; 23%), and HLA-mismatched unrelated (n = 103; 9%) donors between 2000 and 2016. Ninety percent of transplants were performed in the last decade. Eight-five percent of patients received ≥20 transfusions and 88% were inadequately chelated. All patients received myeloablative-conditioning regimen. Overall and event-free survival were highest for patients aged ≤6 years and after HLA-matched related and HLA-matched unrelated donor transplantation. The 5-year probabilities of overall survival for patients aged ≤6 years, 7 to 15 years, and 16 to 25 years, adjusted for donor type and conditioning regimen were 90%, 84%, and 63%, respectively (P &lt; .001). The corresponding probabilities for event-free survival were 86%, 80%, and 63% (P &lt; .001). Overall and event-free survival did not differ between HLA-matched related and HLA-matched unrelated donor transplantation (89% vs 87% and 86% vs 82%, respectively). Corresponding probabilities after mismatched related and mismatched unrelated donor transplantation were 73% vs 83% and 70% vs 78%. In conclusion, if transplantation is considered as a treatment option it should be offered early (age ≤6 years). An HLA-matched unrelated donor is a suitable alternative if an HLA-matched relative is not available.

scholarly journals Tortoise and hare win for SCD

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2223-2224
Author(s):  
John F. Tisdale
Keyword(s):  
Stem Cell ◽  
Conditioning Regimen ◽  
Standard Of Care ◽  
Long Term Results ◽  
Cell Disease ◽  
Event Free Survival ◽  
Free Survival ◽  
Matched Donor ◽  
Over Time

Bernaudin and colleagues report, in this issue of Blood, the long-term results of the largest study of related myeloablative stem-cell transplantation for sickle cell disease (SCD). Their results show that slow, steady improvements over time, along with the addition of rabbit anti–thymocyte globulin (ATG) to the conditioning regimen, combine to produce an event-free survival (EFS) of 95.3%. They argue that for children with a suitable sibling-matched donor, myeloablative transplantation should be considered the standard of care in those at high risk for stroke.

A Phase II Study of Yttrium-90-Ibritumomab Tiuxetan In Combination with a Fludarabine-Based Reduced Intensity Regimen Followed by Allogenic Stem Cell Transplantation In Patients with Relapsed or Chemorefractory CD 20 Positive Non-Hodgkin's Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4565-4565
Author(s):  
Krimo Bouabdallah ◽  
Sabine Furst ◽  
Reda Bouabdallah ◽  
Stephane Vigouroux ◽  
Reza Tabrizi ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Conditioning Regimen ◽  
Hodgkin's Lymphoma ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
Ibritumomab Tiuxetan ◽  
Free Survival ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Bayer Healthcare

Abstract Abstract 4565 Background: The outcome of patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) is very poor despite aggressive treatments or novel therapeutic agents. Allogenic STC (allo-STC) remains the only curative approach with an interesting reduced treatment-related-mortality (TRM) commonly associated with reduced intensity conditioning regimens (RIC). Radio immunotherapy (RIT) as part of conditioning regimen for autologous stem cell transplantion (ASCT) as well as for allo-SCT has demonstrated its safety and many studies are now suggesting an improved outcome. This phase II study (ClinicalTrials.gov: NCT 00607854) evaluated the safety and efficacy of Yttrium-90 ((90)-Y)-ibritumomab tiuxetan in combination with a fludarabine-based RIC followed by allo-SCT in patients with relapsed or chemorefractory CD 20 positive non-Hodgkin's lymphoma. Patients and Method: Patients with relapsed or refractory CD 20 positive NHL where eligible for the study if they had a sensitive disease (at least partial response) to the last salvage regimen and a suitable donor: related (RD) or unrelated donor (MUD or with a C or DQ mismatch). Each patient received a single dose of ((90)-Y)-ibritumomab tiuxetan (0,4 mci/Kg on day -14) followed from day -6 by a combination of fludarabine (30 mg/m2 d -6 to d -2), busilvex ((3,2 mg/Kg d -5 and d -4) and antithymocyte globulin (2,5 mg/Kg d -1). GVH prophylaxis was based on cyclosporine (CsA) alone or in combination with methotrexate (Mtx) in case of mismatched unrelated donor. The trial was designed to enroll 30 evaluable pts and the study started on January 2008. At time of this writing, 27 pts have been included and we report the preliminary results of the first 14 consecutive pts. The primary objective (PO) of the study was to evaluate the day 100 TRM. Secondary objectives were response (CR, PR) and event-free survival at 1 year. RESULTS: Fourteen pts are evaluable for the PO. The median age was 55 years (35-60), and the sex ratio (M/F) 10/4. Prior disease was DLBCL (5), MCL (4), FL (5). Pts received a median number of 2 previous treatment regimens and all pts had undergone ASCT before. Median time between diagnosis and allo-SCT and between ASCT and allo-SCT were 39 mo (range 8 – 106) and 14, 5 mo (range 3–52) respectively. At time of transplant 10 pts were in CR and 4 in PR. There were 10 RD and 4 MUD transplants. All pts received peripheral blood stem cells transplantation and GVH prophylaxis with CsA alone. Two pts died from a-GVH at day 40 and 117 post-transplant respectively with a TRM at day 100 of 7%. Both were in CR. The median time to ANC engraftment (ANC > 500/mm3) was 17 days (range 12 – 22) and time to platelets engraftment (Plt > 20.000/mm3) was 11 days (range 0–16). Acute GVH occurred in 7 pts with only 3 pts with grade ≥ 2. At day 100 after transplantation, 8 out of the 10 (80%) evaluable pts achieved a complete T-cell donor chimerism. With a median follow-up of 10 month (range 6 – 26), 12 pts are alive and in CR. The estimated event-free survival at 1year is 86% (CI 78% - 94%). CONCLUSION: ((90)-Y)-ibritumomab tiuxetan is safe and well tolerated when used in combination with a fludarabine-based RIC regime. Preliminary data suggest that the TRM is not increased by adding RIT in this conditioning regimen. Disclosures: Bouabdallah: Bayer Healthcare: The Trial has been partially sponsored by Bayer Healthcare. Off Label Use: Zevalin is off-label use in conditioning regimen in France.

Bone Marrow Transplantation Arrests Cerebrovascular Disease Progression and Improves Psychometric Outcomes in Children with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 11-11
Author(s):  
Neha Bhatnagar ◽  
Ruth Erskine ◽  
Farah O'Boyle ◽  
Subarna Chakravorty ◽  
Irene Roberts ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Magnetic Resonance ◽  
Sickle Cell Disease ◽  
Cerebrovascular Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Graft Failure ◽  
Psychometric Testing ◽  
Cell Disease ◽  
Moya Moya Disease

Abstract Abstract 11 Stem cell transplantation (SCT) is currently the only curative option for sickle cell disease. Cerebrovascular disease (CVD) is one of the main indications to undertake this procedure as even with best conventional approaches there is a significant risk of recurrence or progression and there is evidence that SCT arrests disease progression, though more detailed study of outcomes is awaited. Early studies of SCT in sickle cell disease showed a high rate of neurological complications that led to the optimization of protocols. We conducted a retrospective analysis of related SCT in children with severe SCD between 2001 and 2010 at our institution to study the effect of transplantation. 20 patients (11 male, 9 female) received a BMT for sickle CVD (n=11) or recurrent vaso-occlusive crises (n=9). One patient with CVD was a second procedure following primary graft failure in a previous sibling transplant. CVD was investigated with clinical history and examination, transcranial Doppler ultrasound, magnetic resonance imaging/magnetic resonance angiography and psychometric testing using WISC-IV: 7 patients had no evidence of CVD, 5 had silent infarcts, 6 ischaemic stroke and 2 Moya-Moya disease. The median age at transplantation was 136 months (range 34 – 210 months). Donor source was HLA-matched siblings in 18 patients, one 9/10 mismatched sibling and HLA-matched relative in another. Bone marrow was used in all (n=19) but one patient who received combined bone marrow and umbilical cord. All patients (n=18) but two received conditioning with oral busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and alemtuzumab 0.3 mg/kg; 1 patient received fludarabine 160 mg/m2, treosulfan 42 mg/m2, thiotepa 10mg/kg and ATG (Thymoglobulin) 11.25 mg/kg and 1 patient received oral busulfan 16mg/kg, cyclophosphamide 200 mg/kg and antilymphocyte globulin (45 mg/kg). GvHD prophylaxis was provided with ciclosporin and short course methotrexate (n=18), ciclosporin and MMF (n=1) and ciclosporin alone (n=1). Mean cell dose was 3.70 × 108 TNC/kg (range 1.45 – 6.16 × 108 TNC/kg). Neutrophil engrafment (>0.5 × 109/L) occurred at a median of 19.5 days (range 12 – 28 days) and platelet engrafment (>50 × 109/L) at median of 26 days (range 21 – 52 days). The median follow up is 974 days (range 270 – 3622 days). 18 patients achieved stable donor haemopoiesis, one patient suffered secondary graft failure due to Parvovirus B19 infection and one patient died on day +21 post-transplant due to sepsis and multi-organ failure. No significant sickle related neurological events occurred during these transplants. All 18 patients with long-term engraftment achieved radiological stabilization of the underlying CVD. Imaging performed at least 12 months post SCT showed no further changes from pre-transplant images. There were no clinical neurological events after SCT. Psychometric testing demonstrated improvements in all areas in patients transplanted for silent infarcts, particularly those affecting processing speed. In summary, SCT appears safe even in patients with severe CVD, arrests further progression and shows functional improvement. Disclosures: No relevant conflicts of interest to declare.

Fludarabine/Treosulfan/Thiotepa/ATG Conditioning for Matched and Single Antigen Mismatched Unrelated Bone Marrow Transplantation in Haemoglobinopathies Is Feasible and Leads to Early and Sustanined Engraftment with No Long-Term Toxicity or GvHD

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2468-2468
Author(s):  
Farah O'Boyle ◽  
Leena Karnik ◽  
Anne Bradshaw ◽  
Richard M Szydlo ◽  
Josu de la Fuente
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Thalassaemia Major ◽  
Cell Disease

Abstract Related haemopoietic stem cell transplantation is a well-established treatment modality for haemoglobinopathies, but it is limited by the availability of related donors. The results of unrelated transplantation have been variable with historical variable results, concern about GvHD and usually restricted to 10/10 matches. From 2011 to 2016 twelve consecutive unrelated bonemarrow transplants were conditioned with fludarabine 160 mg/m2, treosulfan 42 g/m2, thiotepa 10 mg/kg and ATG (Thymoglobulin) 11.25 mg/kg (FTTA). Endogenous haemopoiesis was suppressed pre-transplantation with hypertransfusions for a minimum of 8 weeks. GvHD prophylaxis was provided with ciclosporin and MMF. 7 patients were transplanted for β thalassaemia major, one of α thalassaemia major and 4 for sickle cell disease. The median age was 9.5 years (2 - 17). The source of stem cells was BM in all patients: five 10/10 matched, six 9/10 matched and one 11/12 matched. The median cell dose was 3.01 x 108 TNC/kg (range 1.53 - 11.07) and 4.27 x 106 CD34+/kg (range 1.16 - 27.41). The median survival was 9.9 months (6.9-44.1). Patients with thalassaemia were Pesaro class I or II (Pesaro class III patients were intensively chelated pre-transplantation to return to class I or II). Patients with sickle cell disease were transplanted for stroke or recurrent vaso-oclusive crises and/or acute chest syndrome not responding to hydroxycarbamide. All patients were evaluated with liver biopsy pre-transplantation and defibrotide prophylaxis given if Ishak stage ≥3. All patients engrafted and achieved evidence of donor haemopoiesis on day +28 and achieved transfusion-independence and donor haematological values. No patient suffered primary or secondary graft failure. There was one death, one on day +257 due to idiopathic pneumonia syndrome in a patient with b thalassaemia major. Acute GvHD ≥ grade 2 occurred in 5 patients (41.7%). Chronic limited GvHD did not occur in any patient, but extensive occurred in the 5 patients developing acute GvHD. None of the patients had chronic GvHD at 18 months. VOD occurred in 4 patients (33.3%) and responded to standard measures and defibrotide treatment. The median neutrophil engraftment was 13 days (range 9 to 22). Patient with sickle cell disease had the platelet count maintained >50 x 109/L at all times. The median platelet engraftment >50 x 109/L was 37 days (range 15 to 86) and >50 x 109/L was 32 days (range 15 to 111). The median time to cessation of immunosuppression was 134 days (68-219). Chimerism studies on day +28 demonstrated 100% in whole blood (WB) and 88.9% in T cells (T) >95%, and 0% WB and 11.1% T >50-89% [n=11]; day +90: 91.7% WB and 91.7% T >95%, 8.3% WB and 0% T >50-89%, 0% WB and 8.3% T <50% [n=12]; day +180: 91.7% WB and 91.7% T >95%, and 8.3% WB and 8.3% T >50-89% [n=12]; and day +365: 50% WB and 50% T >95%, 25% WB and 25% T >90-95%, and 25% WB and 25% T >50-89% [n=4]. In conclusion, unrelated bone marrow transplantation for all haemoglobinopathies is feasible and the overall survival and disease-free survival is 90.9%. FTTA leads to early and sustained engraftment with low rate of graft failure, and whilst the occurrence of VOD despite adequate chelation pre-transplantation and the incidence of GvHD was significant, these complications resolved with standard therapies and long-term outcomes approach those of related transplantation with no treatment required by 18 months. Disclosures No relevant conflicts of interest to declare.

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