Outcome of Busulfan and Fludarabine-Based Reduced Intensity Conditioning Regimen for Related and Unrelated HSCT in Fanconi Anemia Patients

Abstract Abstract 1964 Rationale: HSCT is the only curative treatment for Fanconi Anemia (FA) pts with either bone marrow failure or MDS/Leukemia. Due to characteristic chromosomal instability, the poor outcome of FA pts transplanted after so-called conventional myelo-ablative conditioning regimen has been proved. Then, reduced-intensity conditionning regimen (RIC) has been considered for years as a model for allogeneic HSCT in FA pts. The use of fludarabine-based cond' regimen from about 2000 increased dramatically the overall survival of FA pts. Different Flu-based RIC were developed. Patients and method: Between Feb'02 and Dec'10, 17 FA pts from 3 academic French centers were included: 11 from R. Debre hospital, 5 from St Louis hospital and 1 from J. de Flandre hospital. All pts underwent HSCT because of bone marrow failure. They presented no MDS or leukemia. All time-to-event outcomes were counted from the date of HSCT to the date of event or date of last follow-up, except acute GVHD that was arbitrarily censored at 200 days. Death was considered as a competing risk in analyses of neutrophil and platelet recovery and chronic and acute GVHD. Overall survival was estimated using Kaplan-Meier product-limit estimator. For competing risks analyses, cumulative incidences were estimated using usual methodology. Results: Median age at diagnosis and at HSCT were 4.7 years (range 1,8-9,3) and 7,4 years (range 4,4-15,2), respectively. 12 pts presented with less than 3 FA-related malformations and 5 with more than 3 malformations. 2 patients received more than 20 transfusions before HSCT, whereas 8 pts received less than 20 transfusions and 7 patients did not received any. 2 patients received androgen therapy before HSCT. All patients received the same RIC i.e. fludarabine 30mg/m2/d × 3d, cyclophosphamide 10mg/kg/d × 4d and IV busulfan (Bu) 0.75 of body weight- adjusted recommended dose (equivalent to 6.4mg/kg total dose of oral Bu). This RIC did not contain any irradiation. Graft versus-host disease (GvHD) prophylaxis consisted of CSA associated with MMF or corticosteroids. Donors were either matched related (sibling, n= 6; other, n=2) or unrelated (10/10, n= 6; 9/10, n= 3). Stem cell sources were BM (n=10), UCB (n=4) and PBSC (n=2). 9 out of 17 pts had a donor from the same gender whereas 4 male recipients received transplant from female donor. CMV status were −/−, −/+, +/− and +/+ for 8, 4, 1 and 4 D/R pairs, respectively. Median follow-up was 32 months (range 3–102). Successful engraftment was obtained in all patients with a median time for neutrophil recovery of 17 days (range 10–42). All patients presented with 100% donor chimerism. One patient experimented secondary graft failure and died at D291 from infection and renal failure. During transplant procedure, 13 pts experimented at least one severe infectious complication (staphylococcus n=2; pseudomonas n=1; aspergillus n= 2; candida n=2; viral reactivation n= 13). 1 pt presented with moderate hepatic veno-occlusive disease. Five pts died from TRM and 12 pts remained alive in a good health condition. 36 month OS was 69% (95%CI 50 to 96). Cumulative incidence of grade 2 to 4 acute GVHD was 71% (95%CI: 41–87). 5 pts presented with either limited (n=4) or extensive (n=1) chronic GvHD and 36 month cumulative incidence of chronic GVHD was 33% (95%CI 11 to 58). To date, no pt had secondary malignancy. Discussion: Our study confirms the good results obtained by other groups when using flu-based RIC in FA pts. Indeed, satisfying engraftment and long-time survival rates were obtained without any TBI, irrespective of the stem cell source and the donor type. However, we have a concern regarding the cGVHD rate we obtained. As demonstrated by an on-going study of EBMT registry, the risk of secondary malignancy in these pts is statistically correlated to cGvHD. Then, this rate still remains probably too high in our study, even though only one pt presented with extensive cGvHD and no pts developed any secondary malignancy. But this could be explained by the short follow-up. Suppression of one alkalyting agent may reduce both cGVHD incidence and other tissue injuries leading to secondary malignancies. Then, we claim for suppression of Bu for related donor HSCT. In FA pts receiving transplant from unrelated donor, the relative impact of either low-dose IV-Bu – as we used here - or low-dose irradiation on toxicity and especially development of secondary malignancies remains to be evaluated. Disclosures: No relevant conflicts of interest to declare.

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Alternative Donor Stem Cell Transplantation after Reduced Intensity Conditioning Regimen for Patients with Bone Marrow Failure.

Blood ◽

10.1182/blood.v106.11.2894.2894 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2894-2894

Author(s):

Nabil Kabbara ◽

Vanderson Rocha ◽

Marie Robin ◽

Agnes Devergie ◽

Patricia Ribaud ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Gvhd ◽

Bone Marrow Failure ◽

Conditioning Regimen ◽

Adenovirus Infection ◽

Reduced Intensity Conditioning ◽

Reduced Intensity Conditioning Regimen ◽

One Year ◽

Reduced Intensity

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) with HLA geno-identical sibling donor is the treatment of choice for children and young adults with constitutional or acquired (SAA) bone marrow failure (BMF). However, results of unrelated HSCT for BMF have been poorer due to high transplant related mortality mainly related to rejection and GVHD. Generally, a myeloablative regimen HSCT is used for acquired and some constitutional BMF but not for Fanconi anemia (FA) patients for whom a low dose conditioning regimen is employed. We have driven the hypothesis that immunosuppressive reduced intensity conditioning regimen should decrease TRM, decreasing GVHD and allowing engraftment. In a Phase I-II trial, 20 patients (pts) with BMF were enrolled and transplanted between 2002 and 2004. Thirteen pts had a constitutional aplasia: FA n=11, congenital megakaryocytopenia (CMK) n=1, Rothmund-Thomson syndrome n=1 and 7 pts had SAA among those two had paroxystic nocturnal hemoglobinuria (PNH). There were 12 male and 8 female. Median age was 8 years for constitutional BMF and 26 years for SAA. The HSC source was bone marrow for 11 pts, PBSC for 1 pt and cord blood for 8 pts. Ten of the twelve BM or PBSC donors were HLA matched for 10 loci (A, B, C, DRB1, and DQB1) and eight cord blood donors were HLA mismatched with 2 generic differences and were used for FA. All pts received the same conditioning regimen consisting of Busulfan (3mg/kg x 2), cyclophosphamide (10mg/kg x 4), fludarabine (30mg/m2 x3) and ATG (2.5mg/kg x4). The mean of nucleated stem cells infused and CD34 + cells was 2.8x108/kg and 5.9x106/kg respectively for the 12 pts who received BM stem cells and PBSC and 6.4x107/kg and 4.6x106/kg respectively for the eight pts who received CB cells. Acute GVH disease prophylaxis consisted of ciclosporine A (CsA) for pts with constitutional BMF and CsA and short course methotrexate for 6 of the 7 pts with acquired BMF, (one received tacrolimus instead of CsA due to thrombotic pre-existing co-morbidity). One pt (with CMK) died on day 0 from cerebral haemorrhage. Eighteen pts out of 19 had WBC recovery with a median time of 23 days (11–42); one FA pt did never reach sustained engraftment and died at D+291 from adenovirus infection. Three others had late graft rejection: in a context of acute GvHD and EBV infection and pulmonary aspergillosis for two pts with SAA who received BM graft and with acute GvHD and adenovirus infection for one FA pt who received CB graft. The conditioning was well tolerated without severe mucositis even in FA patients, sixteen patients experienced transient liver abnormalities. Nine patients developed reversible haemorrhagic cystitis at a median of 47 days post-transplant. There were 3 bacterial, 10 viral and 5 fungal infections with a cumulative incidence of TRM at one year of 45 ±24%. The cumulative incidence of acute GVH (II–IV) was 50 ±23%. Overall survival (OS) at one year was 55±11 %. It was 86%± 13 for SAA and 38% ± 13 for constitutional BMF. In spite of the short follow-up and few patients included, reduced intensity conditioning regimen provides encouraging results for patients with SAA. For constitutional BMF, low toxicity was observed, however the overall results seem similar to those reported in the literature using other RIC regimen and are probably related to other factors than the conditioning regimen.

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Outcomes of 40 Adult Patients after Double Cord Blood Transplantation Using a Reduced Intensity Chemotherapy Conditioning Regimen.

Blood ◽

10.1182/blood.v108.11.605.605 ◽

2006 ◽

Vol 108 (11) ◽

pp. 605-605

Author(s):

Karen K. Ballen ◽

Corey Cutler ◽

Thomas R. Spitzer ◽

Beow Yeap ◽

Steve McAfee ◽

...

Keyword(s):

Cord Blood ◽

Total Dose ◽

Aplastic Anemia ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cord Blood Unit ◽

Reduced Intensity ◽

Related Mortality

Abstract Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit transplantation in adults is associated with high transplant related mortality, mostly due to infection. In this study, we used a reduced intensity conditioning regimen followed by infusion of two partially matched cord blood units. The conditioning regimen was fludarabine 30mg/m2/day Days -8,-7,-6,-5,-4,-3 (total dose 180mg/m2), melphalan 100mg/m2/day Day -2, and rabbit antithymocyte globulin (thymoglobulin) 1.5 mg/kg/day Days -7,-5,-3,-1 (total dose 6.0 mg/kg). Cord blood units were a 4/6 or better HLA A, B, DR match with each other and with the patient, and contained a minimum combined pre-freeze cell dose of 3.7 x 107NC/kg. GVHD prophylaxis was cyclosporine and mycophenolate mofetil, for the first 21 patients, and tacrolimus and sirolimus for the second cohort of 19 patients. Forty patients, 22 males (55%) and 18 females (45%) with a median age of 48 years (range 19–64 years) were treated. The diagnoses were AML (n=14), ALL (n=1), NHL (n=10), CLL (n=2), MDS (n=5), Hodgkins Disease (n=5), aplastic anemia (n=2), and chronic myelogeneous leukemia (n=1). Thirty-five patients have greater than 100 days of follow-up and are included in this analysis. The cell doses infused were a median of 4.0 x 10 7NC/kg (range 3.0–6.7 x 107) and 1.9 x 10 5 CD34+ cells/kg (range 0.5–10.0 x 105). Two patients (both with MDS complicating aplastic anemia) experienced primary graft failure, and received second cord blood transplants using a different conditioning regimen. Among the remaining patients, the median time to an absolute neutrophil count >500 was 21 days (range 14–70 days). There were two late graft failures. The median time to a platelet count >20,000 unsupported was 43 days (range 21–125 days). The incidence of acute GVHD Grades II–IV was 40% for the patients receiving cyclosporine/MMF and 29% for patients receiving tacrolimus and sirolimus. There were no deaths from acute GVHD in the cyclosporine/MMF group and one death from acute GVHD in the tacrolimus/sirolimus group. Seven patients (20%) developed chronic GVHD. The 100-day transplant related mortality was 14%. Two deaths were related to Epstein Barr virus related lymphoproliferative disorder, and the other deaths were due to a CNS bleed, staphylococcal sepsis, and respiratory failure due to aspergillus infection. Two patients have relapsed and one has progressive disease. With a median follow up of 14 months (range 3–31 months) the overall survival is 74% and the disease-free survival is 67%. Chimerism analysis showed predominance of one cord by Day +100. In 71% of patients, the first cord blood unit infused predominated. In conclusion, engraftment of adult patients appears to be acceptable using double cord blood products and reduced intensity, non TBI conditioning regimen; the risk of serious acute and chronic GVHD is low, survival is excellent in a selected group of patients and relapse rate is low, suggesting preservation of graft versus leukemia effect despite the low T cell dose.

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Low-Dose ATG-F Reduces Non-Relapse Mortality after Reduced-Intensity Bone Marrow Transplantation from an Unrelated Donor: A Single-Center Analysis of 65 Patients.

Blood ◽

10.1182/blood.v110.11.5070.5070 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5070-5070

Author(s):

Shigeo Fuji ◽

Takahiro Fukuda ◽

Sung-Won Kim ◽

Eiji Usui ◽

Saiko Kurosawa ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Graft Failure ◽

Low Dose ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Grade Ii ◽

Reduced Intensity

Abstract Background: In Japan, peripheral blood stem cell transplantation from an unrelated donor has not been approved. Therefore, for unrelated bone marrow transplantation with a reduced-intensity conditioning regimen (u-RIST), low-dose TBI has been added to facilitate engraftment. However, non-relapse mortality (NRM), which was mostly related to GVHD, was extremely high (54% at 1 year) after u-RIST with cladribine/busulfan/TBI 4 Gy (Kim et al. ASH 2006). To overcome this problem, we introduced antithymocyte globulin (Fresenius: ATG-F) at a lower dosage of 5–10 mg/kg to replace TBI. This study evaluated the feasibility of this regimen. Patients and Methods :From January 2000 to May 2007, 65 patients with hematological malignancies received u-RIST with a conditioning regimen including fludarabine (Flu 30 mg/m2 x 6 days) or cladribine (2CdA 0.11 mg/kg x 6 days) plus busulfan (oral Bu 4 mg/kg x 2 days, iv Bu 3.2 mg/kg x 2 days) with 4 Gy TBI (n=30), 2 Gy TBI (n=20) or low-dose ATG-F (n=15). The median age of the patients was 57 years (range, 20–65). Their diagnosis included AML/MDS (n=39), lymphoma (n=19) and others (n=7). There were no differences in pretransplant disease status or HLA-disparity among the 3 different groups. Results: The median follow-up of surviving patients was 381 days (range, 64–1832). Although more patients in the ATG-F group experienced graft failure, all 3 patients were rescued with a second transplant or DLI. Compared to low-dose TBI group, the incidences of grade II–IV and III–IV acute GVHD were significantly lower in the ATG-F group, which resulted in significantly lower NRM, better overall survival (OS) and better progression-free survival (PFS) (Figure). However, the incidences of disease relapse and CMV reactivation were not different among the 3 groups. A Cox proportional hazard model showed that low-dose ATG-F was associated with a significantly better PFS. Conclusions: Our study showed that very low-dose ATG-F (5–10 mg/kg) significantly reduced the incidence of acute GVHD without an increase in the relapse rate, which led to a significantly improved PFS rate. A slightly higher rate of graft failure was manageable. The optimal dose of ATG-F needs to be determined according to the source of stem cells and HLA-disparities, including ethnic differences, and our study should help to provide a model to pursue this. TBI 4 Gy (n=30) TBI 2 Gy (n=20) LD ATG-F (n=15) P (TBI vs ATG-F) 2CdA/Flu 11/19 5/15 0/15 0.01 CSP/TAC 28/2 4/16 4/11 0.01 CR/non-CR, pretransplant 10/20 9/11 5/10 0.74 HLA match/mismatch 17/13 13/7 10/5 0.64 Graft failure 3% 0% 20% 0.04 Acute GVHD, grade II–IV 55% 74% 8% <0.01 Acute GVHD, grade III–IV 31% 16% 0% <0.01 1-year NRM 46% 15% 0% 0.01 1-year OS 47% 69% 100% <0.01 1-year Relapse 19% 40% 12% 0.43 1-year PFS 43% 51% 88% <0.01 Figure Figure

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Secondary Malignancies After Allogeneic Stem-Cell Transplantation in the Era of Reduced-Intensity Conditioning; The Incidence Is Not Reduced

Blood ◽

10.1182/blood.v118.21.655.655 ◽

2011 ◽

Vol 118 (21) ◽

pp. 655-655

Author(s):

Avichai Shimoni ◽

Noga Shem-Tov ◽

Yulia Volchek ◽

Ronit Yerushalmi ◽

Arnon Nagler

Keyword(s):

Cumulative Incidence ◽

Chronic Gvhd ◽

Secondary Malignancy ◽

Secondary Malignancies ◽

Advanced Solid Tumor ◽

Reduced Intensity Conditioning ◽

Myeloablative Conditioning ◽

Reduced Intensity

Abstract Abstract 655 Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for a variety of hematological malignancies and non-malignant diseases. Secondary malignancies are a known complication in long-term survivors. The incidence and kinetics of secondary malignancies have been reported mostly after myeloablative conditioning (MAC). Reduced-intensity conditioning (RIC) has been introduced over the last decade to allow SCT in patients not eligible for standard SCT. RIC has been shown to reduce the incidence of transplant-related complications, however due to the relative limited long-term follow-up of RIC recipients, the incidence and risk-factors for secondary malignancies in the RIC era have not been well defined. We retrospectively reviewed a single institution database of 931 allogeneic SCTs given over the last 12 years to identify patients with secondary malignancies. Conditioning regimens included standard MAC (n=261, TBI-based in 111 pts), fludarabine-based RIC (n=463) or fludarabine-based reduced-toxicity myeloablative conditioning (RTC, n=207). The incidence of secondary malignancies was calculated by cumulative incidence analysis with death due to other causes considered a competing risk. The incidence was correlated with patient and transplant characteristics. Three patients with PTLD and 2 with therapy-related leukemia and relapse of the prior malignancy after SCT were not considered secondary malignancies in this analysis. Twenty-four patients had secondary malignancies including squamous cell carcinoma of the skin (n=5), penis (n=1) vagina (n=1), tongue (n=1) and esophagus (n=2), colon cancer (n=3), breast cancer (n=2), pancreatic cancer (n=2), metastatic cancer of unknown primary (n=1), melanoma (n=1), metastatic sarcoma (n=1), Kaposi sarcoma (n=1) and donor-derived MDS/AML (n=3). In all, 5 patients had metastatic or locally advanced solid tumor at presentation. The median age at SCT was 56 years (29-70). Thirteen patients had acute leukemia (of 545 patients in this cohort), 9 had lympho- proliferative malignancy (of 285), 2 had CML or MPD (of 75) and none had non-malignant disease (of 26). Twenty-one patients were given fludarabine-based RIC/RTC and none had total-body irradiation. The median time from SCT to diagnosis of secondary malignancy was 39 months (7 months-11.5 years). Nineteen patients had prior chronic GVHD, 12 of them moderate-severe, and 16 were still on immunosuppressive therapy at the time of diagnosis of secondary malignancy. The cumulative incidence of secondary malignancy 10 years after SCT was 6.1% (95%CI, 3.8–9.7%). It was higher in older patients (>50 years) than in younger patients; 7.0% Vs 5.0% (p=0.01). Secondary malignancies were less common in patients with CML and nonmalignant diseases compared with patients with prior chemotherapy; 1.0% and 7.3%, respectively (p=0.06). Patients given MAC had a cumulative incidence of 1.8%, compared with 9.1% for patients given fludarbine-based RIC or RTC (p=0.01). Among patients surviving more than 1 year after SCT, a history of moderate-severe chronic GVHD was associated with a higher incidence of secondary malignancies, 13.3% Vs 9.1% (p=0.04). Multivariate analysis identified chronic GVHD (HR 1.7, p=0.001), and RIC/RTC (HR 1.6, p=0.03) as adverse prognostic factors, while a diagnosis of CML or non-malignant disorder was protective (HR 0.4, p=0.001). Patients were treated with surgery for localized tumors and with chemo-radiotherapy or palliative therapy for metastatic disease. Currently, seventeen patients are alive and 7 have died including 4 patients with advanced solid tumor and the 3 with donor MDS/AML. The cumulative incidence of death due to secondary malignancy was 2.8% at 10 years after SCT. In conclusion, secondary malignancies are rare but significant complication after allogeneic SCT. Curative approach is feasible in a subset of patients. Chronic GVHD and treatment for hematologic malignancy other than CML predict for higher incidence. The incidence is not reduced in the RIC era, possibly due to the inclusion of older and more heavily pretreated patients to these protocols. The possible adverse effect of fludarabine in the conditioning regimen can not be ruled out. Although single center analysis has the advantage of more complete follow-up and minimal reporting bias, larger registry studies with a larger number of events are needed to confirm these observations. Disclosures: No relevant conflicts of interest to declare.

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Dyskeratosis Congenita: Evaluation of Immune Status and Hematopoietic Stem Cell Transplantation. A Literature and EBMT Data Base Survey of 75 Patients,

Blood ◽

10.1182/blood.v118.21.4144.4144 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4144-4144

Author(s):

Elisabeth T Korthof ◽

Judith Van der Zalm ◽

Martine F Raphael ◽

Dorine Bresters ◽

Jakub Tolar ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Immune Status ◽

Bone Marrow Failure ◽

Chronic Gvhd ◽

Dyskeratosis Congenita ◽

Telomere Maintenance ◽

Immune Defect ◽

Reduced Intensity

Abstract Abstract 4144 Dyskeratosis congenita (DC) is a rare inherited disease characterized by mucocutaneous abnormalities, progressive hematopoietic bone marrow failure as well as a predisposition to pulmonary fibrosis and malignancies. Unknown is if the lymphocytic lineage is affected as well. DC is a disease of defective telomere maintenance; the known mutations are located in the telomere biology genes DKC1, TERC, TERT, TINF2, NHP2 and NOP10 with X-linked, autosomal dominant and recessive inheritance patterns. Allogeneic stem cell transplantation (SCT) is the only potential curative treatment for bone marrow failure in patients with classical DC; however available data on SCT is scarce. Our objectives in this retrospective literature and database study on classical DC were to evaluate immune status at diagnosis, transplant procedures performed, engraftment, complications and survival. Data from all accessible English, French, German and Dutch articles of PubMed, UptoDate, EMBASE and Cochrane presenting classical DC patients with SCT were collected in a DC specific database. Corresponding authors were asked for additional data and for registration at the European Blood and Marrow Transplantation group (EBMT) database to prevent double inclusion. Forty-seven patients were found this way. From the EBMT Working Parties Inborn Errors and Severe Aplastic Anemia data bases we included 28 patients. In total 75 patients with DC who underwent 83 SCTs (8 patients were grafted twice) were included. Immune status at diagnosis could be studied in 26 patients, comparing data to age-matched controls. One or more decreased lymphocyte subset counts (CD3, CD4, CD8, NK or B cells) were found in 9/13 evaluable patients (69%) while IgG, IgM and IgA values were normal in 16/22 evaluable patients (73%). For the whole group, data on gene mutations were only available for 6 patients; data on 13 cases are pending. Median age at SCT was 11.1 (1.0–28.8) years. Most donors were matched siblings, matched unrelated or mismatched unrelated (n=32, 20, and 10, resp.). Stem cell source was BM in 56, PB in 7 and CB in 9 cases (unknown, 3). Conditioning was myeloablative in 30, reduced intensity (RIC) in 32 and unknown in 13 cases without difference in engraftment and chimaerism but with a tendency towards less TRM and better survival in RIC. Acute graft-versus-host-disease (GvHD) grade II-IV was seen in 13/54 evaluable cases, chronic GvHD in 13/50 evaluable cases. Cyclosporine monotherapy was associated with an OR of 5.5 (CI 1.073–28.198) for chronic GvHD when compared to cyclosporine combination therapy. Alive at last follow-up were 34/75 patients; causes of death in 11/26 evaluable patients were transplant related in 6/11 and DC related in 5/11. Probability of survival was 66% at 5 years and 28% at 10 years post SCT. Pulmonary fibrosis was diagnosed in 6/75 cases; malignancies in 3/41 evaluable cases. This is the largest study ever conducted on immune status and SCT in DC suggesting an immune defect inherent to DC and a superiority for reduced intensity conditioning. DC related complications are the main cause of death later than 5 years after SCT, underlining the need for prolonged follow-up after SCT. At this moment we are adding data of another 8 patients from the Eastern Mediterranean Bone Marrow Transplant group. Continuing international collaboration is vital to understand the immune defect which could be primary related to the genotype or secondary to general attrition of rapidly dividing cells with inefficient telomere maintenance, and find ways to improve transplant procedures in this rare disease, classical DC. Disclosures: No relevant conflicts of interest to declare.

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Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

Bone Marrow Transplantation ◽

10.1038/s41409-021-01323-9 ◽

2021 ◽

Author(s):

Michael H. Albert ◽

Mehtap Sirin ◽

Manfred Hoenig ◽

Fabian Hauck ◽

Catharina Schuetz ◽

...

Keyword(s):

T Cell ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Reduced Intensity

AbstractGraft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.

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Bone marrow transplantation in Fanconi anemia using matched sibling donors

Blood ◽

10.1182/blood.v84.6.2050.2050 ◽

1994 ◽

Vol 84 (6) ◽

pp. 2050-2054 ◽

Cited By ~ 57

Author(s):

M Kohli-Kumar ◽

C Morris ◽

C DeLaat ◽

J Sambrano ◽

M Masterson ◽

...

Keyword(s):

Bone Marrow ◽

Fanconi Anemia ◽

Low Dose ◽

Chronic Gvhd ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Feasible Option ◽

Matched Sibling ◽

Low Incidence

Abstract Eighteen patients with Fanconi anemia (FA) with evidence of bone marrow (BM) aplasia underwent allogenic BM transplants (BMT) from matched sibling donors (MSD). Median age at BMT was 7.6 years. Conditioning consisted of low-dose cyclophosphamide (CY; 5 mg/kg x 4 days) and thoracoabdominal irradiation (TAI; 400 cGy). Graft-versus-host disease (GVHD) prophylaxis included cyclosporin A and prednisone. In addition antithymocyte globulin (ATG) was administered in the pretransplant period to promote engraftment and in the posttransplant period for additional GVHD prophylaxis. Engraftment occurred rapidly (median, 12 days for an absolute neutrophil count > or = 0.5 x 10(9)/L; median, 22 days for platelet count > or = 50 x 10(9)/L). Seventeen patients have sustained engraftment and are transfusion-independent, with Lansky scores of 100% at median follow-up of 27 months. One patient developed graft failure 4 months after initial engraftment and required a second BM infusion. None of the patients developed acute GVHD; 3 patients (16%) developed chronic GVHD. BMT is a feasible option for FA patients having an MSD and should be performed at a young age and early in the course of the disease, before the development of complications. We believe the addition of ATG to the transplant regimen of low-dose CY, TAI, and cyclosporin was responsible for improvement in the survival of FA patients undergoing BMT. The regimen was well tolerated and was associated with a low incidence of complications including GVHD.

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Sirolimus, Tacrolimus and Reduced-Dose Methotrexate as Graft Versus Host Disease (GVHD)Prophylaxis after Non-Myeloablative Stem Cell Transplantation: Low Incidence of Acute GVHD Compared with Tacrolimus/Methotrexate or Cyclosporine/Prednisone.

Blood ◽

10.1182/blood.v104.11.730.730 ◽

2004 ◽

Vol 104 (11) ◽

pp. 730-730 ◽

Cited By ~ 3

Author(s):

Edwin P. Alyea ◽

Shuli Li ◽

Haesook Kim ◽

Corey Cutler ◽

Vincent Ho ◽

...

Keyword(s):

Serum Level ◽

Low Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Peripheral Blood Stem Cells ◽

Dose Methotrexate ◽

Gvhd Prophylaxis ◽

Low Incidence

Abstract Sirolimus (rapamycin) is a macrocyclic lactone similar in structure to tacrolimus and cyclosporine (CSA) but with a distinct mechanism of action. Sirolimus binds to both FKBP12 and mTOR and inhibits signal transduction and cell cycle progression. The drug is synergistic with tacrolimus but has a distinct toxicity profile, thereby allowing their use in combination. We report results of a phase II trial combining sirolimus with tacrolimus and low-dose methotrexate (MTX) as GVHD prophylaxis in matched related and unrelated donor NST. Results of this trial were compared with patients who had previously undergone NST receiving tacrolimus/MTX alone or CSA/prednisone(pred). All patients received fludarabine (30 mg/m2/d x 4days) and intravenous busulfan (0.8mg/kg/d x 4 days) as conditioning. All patients received G-CSF mobilized peripheral blood stem cells with a targeted cell dose of 1 x 107 CD34+ cells/kg. G-CSF 5 mcg/kg was started on day 1. Sirolimus containing GVHD prophylaxis included sirolimus 12 mg loading dose on day −3 and then 4 mg po qd targeting a serum level of 3–12 ng/ml. Tacrolimus was initiated at 0.05 mg/kg po b. i.d. beginning day −3 with a targeted serum level of 5–10 ng/ml. MTX (5 mg/m2) was given days, 1, 3 and 6. Planned taper of the GVHD medications was ~30% at days 60, and 120 with discontinuation by day 180. The median follow up is 14 months for patients receiving sirolimus and all evaluable patients have been followed for >100 days. 40 patients have been transplanted, 20 from related and 20 from unrelated donors. The median age was 57 years (range 20–69). Diseases included: NHL (9), MDS (7), Hodgkin’s disease (6), CLL (6), AML(5), CML (5), MM (1) and CMML(1). 18 patients (45%) had received prior myeloablative transplantation. 31 patients (78 %) had advanced disease at the time of transplantation. Patients receiving tacrolimus/MTX (n=36) and CSA/pred (n=49)had similar characteristics. Sirolimus was well tolerated and no severe adverse events related to the drug were noted. Acute grade 2–4 GVHD was significantly reduced in patients receiving sirolimus/tacrolimus/MTX, 8% vs 18% in patients receiving tacrolimus/MTX and 37% in those receiving CSA/Pred (p=0.003). Time to neutrophil engraftment was slower in methotrexate containing regimens (13 days vs 9 days, p=0.01), but there was no difference between sirolimus/tacrolimus/MTX and tacrolimus/MTX alone. Median donor derived hematopoiesis, measured 1–2 months after transplant, was high in all groups (sirolimus/tacrolimus/MTX 91%, tacrolimus/MTX 95% and CSA/pred 90%, p=0.91). The 1 year overall survival was sirolimus/tacrolimus/MTX 71%, tacrolimus/MTX 48% and CSA/pred 45% (p=0.17). 1-year progression free survival was 49%, 27% and 37%, respectively (p=0.11). The addition of sirolimus to tacrolimus and low dose MTX is well tolerated and is associated with a low incidence of acute GVHD. The addition of sirolimus does not delay engraftment compared with tacrolimus/MTX and results in a similar high level of donor derived hematopoiesis. Further patient accrual and longer follow-up is needed to yield information on the incidence of chronic GVHD and overall outcome.

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Absence of Graft Failure and Excellent Long Term Survival Following Fludarabine-Based Reduced Intensity Hematopoietic Stem Cell Transplantation In Heavily Transfused Patients with ATG-Refractory Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes

Blood ◽

10.1182/blood.v116.21.517.517 ◽

2010 ◽

Vol 116 (21) ◽

pp. 517-517

Author(s):

Jeremy Pantin ◽

Xin Tian ◽

Nancy Geller ◽

Catalina Ramos ◽

Lisa Cook ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Graft Rejection ◽

Graft Failure ◽

Acute Gvhd ◽

Bone Marrow Failure ◽

Chronic Gvhd ◽

Abo Incompatibility ◽

Bone Marrow Failure Syndromes

Abstract Abstract 517 Heavily transfused and alloimmunized patients with bone marrow failure syndromes including aplastic anemia have an increased risk of graft rejection following conventional allogeneic bone marrow transplantation. Results from pilot trials suggest the addition of fludarabine to the conditioning regimen reduces the risk of graft rejection in patients at high risk for this complication. Here we report the results of a fludarabine-based transplant approach in 56 patients with severe aplastic anemia (SAA) or other bone marrow failure syndromes (SAA n=31, MDS-RA n=6, PNH n=16, PRCA n=2, DBA n=1) who were transplanted from May 1999 to November 2008 at the NHLBI. Forty one percent of patients were found to be alloimmunized (median 82% PRA) prior to transplantation as a consequence of prior transfusions. Seventy three percent of patients had received antibody-based immunesuppressive therapy at a median of 303 days (range 21 to 2588) prior to transplantation (horse-ATG n=34, rabbit-ATG n=5, alemtuzumab n=1 and daclizumab n=1). Conditioning with fludarabine (25 mg/m2 × 5 days), ATG (40mg/kg × 4 days) and cyclophosphamide (60mg/kg × 2 days) was followed by infusion of an un-manipulated G-CSF mobilized allograft from an HLA matched (n=52) or single antigen mismatched (n=4) relative. GVHD prophylaxis consisted of cyclosporine (CSA) either alone (n=2) or combined with mycophenolate mofetil (n=10) or mini-dose methotrexate (n=44). The median CD34+ cell dose was 6.6 × 106 cells/kg (range 1.7 to 21.1 × 106 cells/kg) and the median CD3+ cell dose was 2.6 × 108 cells/kg (range 0.5 to 6.9 x108 cells/kg). Nearly half (46 %) of patients received an ABO incompatible allograft (major mismatch n=15; minor mismatch n=11). Despite a high prevalence of pre-transplant alloimmunization, graft rejection and/or graft failure did not occur, with all patients achieving sustained donor engraftment in both myeloid and T-cell lineages. The median time to achievement of full donor (>= 95%) myeloid and T-cell chimerism was 15 and 30 days respectively. Neutrophil and platelet recovery occurred at a median 15 (range 6 to 24) and 12 (range 5 to 168) days respectively. Major ABO incompatibility was associated with delayed donor erythropoiesis; reticulocyte recovery (> 60 K/μ L on two occasions) occurred at a median 17 days in those without major ABO incompatibility and 42 days in the recipients of a major ABO mismatched graft, where clearance anti-donor isohemagglutinins was delayed a median 171 days following transplantation. CMV reactivation occurred in 31/50 (62%) patients at risk although no patients died from CMV related mortality. With a median follow-up of 4.5 years (range 1.8–11 years) in surviving patients, overall survival was 87.1%. There were 5 treatment related deaths with two attributable to steroid refractory acute GVHD and one attributable to extensive chronic GVHD. The cumulative incidence of Grade II-IV, III-IV and steroid refractory acute GVHD was 51.8%, 30.4% and 21.4% respectively. The cumulative incidence of chronic GVHD was 72% (23.2% limited and 48.9% extensive), with 42.5% who developed cGVHD having resolution of symptoms allowing discontinuation of systemic immunosuppressive therapy. Conclusion: Fludarabine-based allogeneic peripheral blood stem cell transplantation achieves excellent donor engraftment and long-term disease free survival in heavily transfused and alloimmunized patients with ATG refractory SAA and other nonmalignant hematological disorders associated with bone marrow failure. Efforts to reduce the high incidence of GVHD associated with this approach without increasing the risk of graft failure by manipulating the cellular content of the allograft are currently being explored. Disclosures: No relevant conflicts of interest to declare.

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Long-Term Outcome After Matched Allogeneic Hematopoietic Stem Cell Transplantation for Fanconi Anemia On Behalf of the FA Committee of the Severe Aplastic Anemia Working Party (SAA WP) and the Pediatric Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v118.21.325.325 ◽

2011 ◽

Vol 118 (21) ◽

pp. 325-325

Author(s):

Régis Peffault de Latour ◽

Raphael Porcher ◽

Jean-Hugues Dalle ◽

Mahmoud Aljurf ◽

Elisabeth T Korthof ◽

...

Keyword(s):

Risk Factors ◽

Stem Cells ◽

Bone Marrow ◽

Clonal Evolution ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Working Party ◽

Secondary Malignancies ◽

Hematopoietic Stem

Abstract Abstract 325 Background: Fanconi anemia (FA) is a rare, genetically and phenotypically heterogeneous inherited disorder. The natural history of FA is characterized by progressive bone marrow failure (BMF) and an increased risk for development of malignancies. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is considered the treatment of choice for FA patients with BMF or clonal evolution (acute myeloid leukemia or MDS). Most deaths related to HSCT occur within the first year after HSCT. Risk factors for the development of malignancies after HSCT are still incompletely defined in patients with FA. Our objectives were to evaluate risk factors for late mortality and secondary malignancies in 1-year survivors in the largest cohort of FA patients post-HSCT ever studied, so far. Patients and methods: Patients with FA reported to the European Blood and Marrow Transplant (EBMT) Group alive 1 year after a matched allogeneic HSCT were reviewed. Donor and recipient were matched if HLA A and B were identical at the generic level and HLA DRB1 at the allelic level. Cord blood as source of stem cells was excluded because of a few number of FA patients with very long-term follow-up (FU). Data was analyzed using proportional hazards and proportional cause-specific hazards models. Results: Between May 1972 and January 2009, 789 patients with FA who underwent first SCT were reported to the EBMT registry. 509 patients were alive 1 year post-HSCT and were included in the present study. 273 patients were male. Median age at HSCT was 9 years (range, 10 months to 44 years). The majority (77%) of patients had received stem cells from a related donor and bone marrow (80%) was the main source of stem cells. Irradiation was used as part of the conditioning regimen in 27% of the cohort, while fludarabine-based regimen was used in 29%. T-cell depletion (ex vivo and in vivo) was used in 41%. In January 2010, 15% (n=74) of the patients had died. Median age at death was 19 years. With a median FU of 6 years (1 to 28 years), the probability for survival after HSCT was 49% at 20 years (95%CI 38–65). The main causes of death were secondary malignancies in 52% of cases and treatment related mortality in 21%. Solid tumor represented 89% of the secondary malignancies. Cumulative incidence of death and secondary cancer are presented in Figure 1. A worse survival was observed in patients transplanted before year 2000 (Hazard ratio - HR: 2.24; 95%CI 1.06–4.71; p=0.034), in those transplanted because of clonal evolution (acute myeloid leukemia or MDS) (HR: 3.88; 95%CI 2.03–7.41; p<0.0001), in patients older than 10 years at SCT (HR: 2.00; 95%CI 1.26–3.18; p<0.004), and in patients transplanted more than a year after FA diagnosis (HR: 1.98; 95%CI 1.10–3.54; p=0.02). Without taking into account transplant period, HSCT after the age of 10 (HR 1.88 [1.17 to 3.03], P=0.009), clonal evolution before HSCT (HR 3.31 [1.72 to 6.39], P=0.0004) and previous chronic GVHD (HR 2.72 [1.65 to 4.46], P<0.0001) were associated with decreased survival. After adjustment for these factors, patients transplanted before 2000 still showed a worse survival (HR 2.09 [0.99 to 4.41], P=0.052). Using occurrence of a secondary malignancy as a time-dependent covariate, the hazard of death after this event was extremely high (HR 17.3 [9.70 to 30.7], P<0.0001). Independent risk factors for secondary malignancies included HSCT after the age of 10 (HR 2.89 [1.53 to 5.45], P=0.001), peripheral blood as source of stem cells (HR 3.06 [1.18 to 5.45], P=0.001) and previous chronic GVHD (HR 2.89 [1.53 to 5.45], P=0.001). Irradiation in the conditioning regimen and donor type (related versus unrelated) did not correlate with outcomes (both late survival and secondary malignancies). Conclusion: We found improved outcomes for patients with FA post-HSCT in recent years (>2000). However, long-term survival in FA patients after HSCT is still mainly affected by secondary malignancies (89% of solid tumors). Patients should be transplanted before the age of 10 with bone marrow as source of stem cells to try to avoid this complication. Moreover, chronic GvHD still emerges as a major cause for both secondary malignancies and mortality. Clearly improved method for prevention, early diagnosis and treatment of this complication are urgently needed. This study also highlights the need for very long-term FU for FA patients after HSCT. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

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