Overcoming the Negative Impact of Age Using Fludarabine-Based Conditioning Regimens for HLA-Identical Sibling HSCT in Patients with Severe Aplastic Anemia (SAA): A Study from the EBMT-SAA Working Party.

Abstract Background: Survival after HSCT from HLA-identical siblings is inferior in SAA patients 30 years or older as compared with younger patients. In order to improve survival in patients >30 years, the use of a less toxic regimen including reduced doses of chemotherapy in combination with ATG, while adding fludarabine, might be an option to explore with the aim to reduce transplant-related mortality. In the unrelated donor setting, we previously showed that a regimen combining fludarabine, ATG, and low-dose cyclophosphamide (CY) provided encouraging disease-free survival in 38 patients (Bacigalupo et al, Bone Marrow Transplant 2005). Patients and Method: In order to evaluate the toxicity profile, engraftment potential, and efficiency of HLA-identical HSCT using such fludarabine-based conditioning regimen, we conducted this study from the EBMT-SAA database, focussing on patients older than 30 years. From November 1996 to February 2005, 45 patients from 27 centres (median age 49 years, range 31–66 years) received HSCT for idiopathic SAA (n=40), or PNH clone-associated SAA (n=5). HSCT was performed either as first-line treatment (n=29), or after failure of ATG/ciclosporine (CsA) (n=10), or failure of a first allogeneic HSCT (n=6). The median interval between diagnosis and HSCT was of 10 months (range 1–350). Various fludarabine-based conditioning regimens were used (see Table), incorporating ATG +/− chemotherapy in the majority of patients (40 out of 45). We analyzed separately the outcome of patients receiving the combination of fludarabine, ATG and low-dose (<200 mg/kg) CY (n=27) from those receiving other fludarabine-based regimens (n=18). Marrow (n=21) or PBSC (n=24) grafts were unmanipulated. GVHD prophylaxis consisted of CsA/methotrexate (n=25), CsA alone (n=11), nothing (n=6), or other (n=3). Results: All patients alive at d21 (n=41) engrafted with a neutrophil (ANC>500/μL) recovery occurring at a median of 16 days after transplant. Acute GVHD occurred in 16 patients with a maximum grade II in 11 patients and grade III-IV in 5. Among 33 evaluable patients, 11 developed chronic GVHD (extensive in 6). With a median follow-up of 21 months, the Kaplan-Meier overall probability of survival was of 54% ± 1%. Infections (n=5) and multi-organ failure (n=3) were the primary causes of death. In univariate (UV) and multivariate (MV) analyses incorporating patient- and transplant-related variables, the only factor significantly associated with better outcome was the type of conditioning, the fludarabine/ATG/low-dose CY combination providing a 77% ± 1% probability of survival versus 24% ± 1% with other regimens (p=.02 in UV and MV analyses). Conclusion: Reduced intensity fludarabine-based conditioning regimen is feasible in SAA patients over the age of 30 and produces encouraging survival, especially when using a fludarabine, ATG and low-dose CY combination. A prospective trial is being conducted within the EBMT-SAAWP using this conditioning regimen.

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Dose-Reduced Conditioning Followed by Allogeneic Stem Cell Transplantation in Patients with Myelofibrosis. Results from a Multicenter Prospective Trial of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

Blood ◽

10.1182/blood.v110.11.683.683 ◽

2007 ◽

Vol 110 (11) ◽

pp. 683-683 ◽

Cited By ~ 5

Author(s):

Nicolaus Kroeger ◽

Ernst Holler ◽

Guido Kobbe ◽

Martin Bornhaeuser ◽

Rainer Schwerdtfeger ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Chronic Gvhd ◽

Prospective Trial ◽

Conditioning Regimen ◽

Working Party ◽

Unrelated Donor ◽

Jak2 Mutation ◽

Cytogenetic Abnormalities ◽

Excellent Outcome

Abstract The major limitation of allogeneic stem cell transplantatiopn (SCT) in patients (pts) with myelofibrosis is the high treatment related mortality. We performed a prospective multicenter trial of a dose-reduced conditioning regimen, consisting of busulfan (10 mg/kg orally or 8mg/kg i.v), fludarabine (180 mg/m2) and anti-thymocyte globulin (ATG Fresenius: 30–60 mg/kg) followed by allogeneic SCT in pts with myelofibrosis. From 2002 to 2006, 104 pts with a median age of 55 years (range: 32–68) andlow risk with constitutional symptoms (18%) or intermediate risk (n= 58%) and high risk (n=19%) were included. Cytogenetic abnormalities and JAK2 mutation were noted in 22% and 48%, respectively. Bone marrow histology showed advanced fibrosis (MF 2 and 3) in all pts. All but 3 pts received peripheral blood stem cells as graft source either from related (n=33) or unrelated donor (n=71). All but one (1%) pts showed leukocyte and platelet engraftment after a median of 18 and 21 days, respectively. The median duration of leukocyte aplasia was 9 days (range: 3–21). Acute GvHD grade II to IV occurred in 19% and severe aGvHD III/IV in 7%, while chronic GvHD was seen in 32% of the pts. Non-relapse mortality at 1 year was 19% (95% CI: 11–27%) and significantly lower for pts younger than 50 years of age (0% vs 27%, p=0.004) and for pts with low risk vs intermediate/high risk disease (0% vs 27%, p= 0.02). The cumulative incidence of relapse at 3 years was 29% (95%CI: 15–43%). The 3 year overall (OS) and event-free survival (EFS) was 70% (95% CI 60–80%) and 55% (95% CI 42–68%). Significant factors for improved 3 year OS and EFS were age less than 50 years (92% vs 62%, p=0.003 and 79% vs 46%, p= 0,004) and low vs intermediate/high risk (100% vs 62%, p=0.01 and 72% vs 48%, p= 0.02), while no impact on survival was seen for cytogenetic abnormalities, JAK2 mutation status and donor (related vs unrelated). These prospective multicenter study show excellent outcome of an busulafan/fludarabine based reduced conditioning regimen followed by allogeneic SCT in pts with myelofibrosis.

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No Improvement of Overall-Survival in Children with High-Risk Acute Myeloid Leukemia by Stem Cell Transplantation in 1st Complete Remission.

Blood ◽

10.1182/blood.v108.11.320.320 ◽

2006 ◽

Vol 108 (11) ◽

pp. 320-320 ◽

Cited By ~ 2

Author(s):

Dirk Reinhardt ◽

Bernhard Kremens ◽

Martin Zimmermann ◽

Josef Vormoor ◽

Michael Dworzak ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Complete Remission ◽

Children And Adolescents ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Hla Typing ◽

Unrelated Donor ◽

The Impact

Abstract One aim of the AML-BFM 98 study was to evaluate prospectively the impact of matched sibling donor (MSD)-SCT in 1st complete remission (CR) in children with high-risk (HR)-AML. Patients: Between 7/1998 and 3/2004 494 children and adolescents were enrolled in the studies AML-BFM 98 and the AML-BFM 98 Interim 2003. Patients with favorable cytogenetics [t(8;21), inv(16), t(15;17)], corresponding morphology (AML FAB M1/2 with Auer rods, M4eo, M3) and < 5% blasts on day 15 were defined as standard risk (SR)-group (n=177). All others were stratified to HR-group (n=317) and eligible for SCT in 1st CR. Out of 275 patients achieving 1st CR (87%) 63 patients had a MSD and 188 had no MSD (intent-to-treat group, ITT) while 24 patients had to be excluded due to missing HLA typing or initial refusal to SCT. Thirty-six patients received MSD-SCT (=as-treated group), another two children were transplanted from a matched unrelated donor (MUD) although an MSD was available. The reasons not performing SCT in 1st CR in the remaining 25 children with a donor available were early relapse (n=7), death in CR (n=2), clinical reasons (n=8), or refusal of SCT (n=8). Chemotherapy (CHT) only was given in 192 patients (n=167 without MSD, n=25 with a MSD). Another 21 children were transplanted from an unrelated donor (n=18), family donor (n=1), haploidentical donor (n=2). The reasons were slow response, very poor cytogenetics or other clinical reasons. Treatment: All patients received double induction and consolidation. MSD-SCT in 1st was scheduled after 4 blocs of treatment. Children who were not transplanted in 1st CR received intensification and a 1-year maintenance therapy. The recommended conditioning regimen consisted in busulfan and cyclophosphamide. Results ITT analysis revealed no significant differences in of 5 year disease-free survival (DFS) and overall survival (OS) between children with or without a donor (no donor vs. donor: DFS 43±4% vs. 47±7% plog rank 0.52; OS 56±4% vs. 58±9%, plog rank 0.16). The as-treated analysis gave similar results: CHT only vs. MSD-SCT: DFS 35±11% vs. 59±9% p Mantel-byar 0.13; OS 59±13% vs. 62±12%, p Mantel-byar 0.51). The major reasons of treatment failures were relapses in all groups [CHT only n=100 (52%), MSD-SCT n=13 (34%), MUD-SCT n=9 (50%)]. A 2nd CR was achieved in 71% of the CHT only group (n=74). After SCT in 2nd CR, OS was 40±6%. By contrast, only two children (9%) of 22 children after relapse following SCT in 1st CR could be salvaged. Severe late adverse events (e.g. severe chronic GvHD CTC grade IV, destruction of big joints, intracerebral bleedings) were more frequent in children transplanted in 1st CR (15%) than in those with CHT only (including SCT in 2nd CR; 5%, p×2< 0.05). Conclusion: In the population-based, prospective multi-center study AML-BFM 98 allogeneic MSD-SCT in 1st CR showed no advantage in children and adolescents with HR-AML. Considering the higher toxicity of allogeneic SCT, in the ongoing trial AML-BFM 2004, this SCT (MSD or MUD) is restricted to patients in 2nd CR and refractory AML.

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Allogeneic Stem Cell Transplantation (AlloSCT) for the Treatment of Therapy-Related Myelodysplastic Syndrome (tMDS) and Acute Myeloid Leukemia (tAML): Results from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Blood ◽

10.1182/blood.v110.11.3057.3057 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3057-3057

Author(s):

Mark Litzow ◽

Waleska S. Pérez ◽

Sergey Tarima ◽

Armand Keating ◽

Jorge Sierra ◽

...

Keyword(s):

Radiation Therapy ◽

Hodgkin Lymphoma ◽

Poor Prognosis ◽

Clinical Decision Making ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Peripheral Blood Stem Cells ◽

Term Survival

Abstract Cytotoxic chemoradiotherapy may lead to the development of tMDS and tAML. These disorders are associated with a poor prognosis with non-transplant therapy. We report outcomes of alloSCT for tMDS and tAML in 868 subjects transplanted between 1990 and 2004 at 211 centers in 33 countries. Subjects were excluded (n=322) if they had a prior disease predisposing to MDS or AML, if they had a diagnosis of tALL or had received a twin or cord blood transplant. 21% were ≤19 years old (yo); 55% were female and 63% had tAML (including 30% with prior tMDS). Prior diagnoses included Hodgkin lymphoma (23%) and non-Hodgkin lymphoma (21%), breast cancer (16%), ALL (12%), sarcoma (8%), germ cell tumor (6%), and autoimmune disorders (5%). There were rare cases (≤3%) of CLL, plasma cell disorders, neuroblastoma, Wilms and CNS tumors or other cancers. Prior treatment was chemotherapy in 43%, chemotherapy and radiation therapy in 51% and radiation therapy alone in 4%. Cytogenetic data (cd) at the time of transplant were known in 84%: good prognosis 4%, intermediate 61% and poor 34%. The IPSS score at diagnosis for subjects with tMDS was intermediate-2 or high in 54%. At transplant, 51% of subjects with tAML were in first complete remission (CR1), 7% ≥CR2, 15% in relapse and 27% were primary induction failures. For the tMDS pts, 37% had been treated with other modalities before receiving an alloSCT. Pre-transplant conditioning regimen was myeloablative (M) 77% and reduced intensity (RI or non-M) in the remainder. Donors were related 38% and unrelated 62%; 66% of the grafts were bone marrow and 34% peripheral blood stem cells. Cumulative incidence of acute GVHD (grade II-IV) @100 days was 39% (95% confidence interval [CI]), 35–42). Outcomes, with a median follow-up of 61 (range, 3–187) months were: Outcome: 5 year probability (95% CI) Chronic GVHD 30 (27–33) Treatment-related mortality (TRM) 48 (44–51) Relapse 31 (28–34) Disease-free survival (DFS) 21 (18–24) Overall survival (OS) 22 (19–26) In multivariate analysis (MVA), TRM was significantly higher in subjects >35 yo, in those with a poor (<90%) performance score (PS), with untreated MDS or if a mismatched related or unrelated donor was used. Relapse risk was higher for subjects >35 yo, with preceding ALL or poor prognosis cytogenetics or tAML not in CR. DFS and OS were lower in subjects >35 yo, with poor prognosis cd, AML not in CR or untreated MDS, or with a mismatched related or unrelated donor. Of 649 pts who died, the cause of death was tMDS or tAML in 33% and TRM in the others. The use of a RI or non-M conditioning regimen did not improve outcomes in the MVA. Approximately 20% of pts with tMDS and tAML achieve long term survival following alloSCT. Survival was significantly better in pts <35 yo, with good or intermediate risk cd, disease control at the time of transplant and having a matched related or complete or partially matched-unrelated donor. The 5 year survival was 50% (95% CI, 39–61) with all 4 good risk factors (grf); 25% (95% CI, 20–31) with any 3 grf, 19% (95% CI, 14–24) with any 2 grf, 12% (95%CI, 8–18) with only 1 grf, and only 4% (95%CI, 0–15) without any of these factors. In conclusion, these data may be helpful in guiding clinical decision-making on the role of alloSCT in the management of t-AML and t-MDS.

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

Blood ◽

10.1182/blood.v112.11.965.965 ◽

2008 ◽

Vol 112 (11) ◽

pp. 965-965

Author(s):

David Valcarcel ◽

Fangyu Kan ◽

Tao Wang ◽

Stephanie J. Lee ◽

Stephen R Spellman ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Related Donor ◽

Disease Free

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

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Ex Vivo T Cell-Depleted Haploidentical HCT for Children with Acute Leukemia after a Reduced-Intensity Preparative Regimen Containing Low-Dose TBI

Blood ◽

10.1182/blood.v128.22.4673.4673 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4673-4673

Author(s):

Yeon Jung Lim ◽

Ho Joon Im ◽

Sung Han Kang ◽

Hyery Kim ◽

Kyung-Nam Koh ◽

...

Keyword(s):

T Cell ◽

Acute Leukemia ◽

Low Dose ◽

Pediatric Patients ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Reduced Intensity

Abstract Background: Recent advances in haploidentical hematopoietic cell transplantation (HHCT) enabled this transplant using haploidentical family donor to be a viable option for pediatric patients lacking matched related or unrelated donor. In our center, HHCT using ex vivo T cell-depleted (TCD) grafts after reduced-intensity conditioning (RIC) was conducted since 2008. The safety and efficacy of this transplantation modality for pediatric with acute leukemia were investigated. Methods: Thirty-one pediatric patients with acute leukemia received ex vivo T cell-depleted HHCT at Asan Medical Center Children's Hospital between July 2008 and June 2016. Four patients received CD3-depleted grafts and 27 received TCRαβ-depleted stem cells. Among 31 patients, 9 had ALL (3 CR1, 6 CR2-3), 22 had AML (18 CR1-3, 4 NR). Seven patients had relapsed after previous allogeneic HCT. All 31 patients underwent a uniform RIC regimen consisting of low-dose total body irradiation (LD-TBI; 600 cGy), fludarabine (FLU; 180 mg/m2), cyclophosphamide (CY; 100 mg/kg), and rabbit anti-thymocyte globulin (r-ATG; 3 mg/kg). Results: The median age at HHCT was 14 years (range, 1-19). All 31 patients achieved sustained neutrophil engraftment at a median of 10 days (range, 9-17) post-transplant. The cumulative incidence of acute GVHD grade II-III and III were 30% and 21%, respectively. None developed grade IV. Two of 26 evaluable patients developed extensive chronic GVHD. As of July 2016, 18 of the 31 patients survive free of disease with a median follow-up of 26 months (range, 2-98 months). Ten patients have died. Causes of death were relapse (n=9) and disseminated tuberculosis (n=1). Only one patient died of non-relapse cause, leading to TRM of 5.3% at 1 year. EFS and OS at 2 years for all patients were 51% and 60%, respectively. Sixteen patients with AML who received a first HHCT in any CR showed a favorable outcome (EFS of 85%), whereas, 6 patients with ALL who received a first HHCT in CR showed a poor EFS of 28%. In addition, all patients (6 with AML and 3 with ALL) who received a subsequent HCT in CR or were not in remission developed relapse. Conclusions: This study demonstrated that our ex vivo T cell-depleted HHCT using RIC is a feasible therapy with low TRM for pediatric patients with acute leukemia. The outcome of patients with AML who received their first transplant in CR was excellent in this treatment modality. However, the outcome of ALL was poor suggesting that more intensified conditioning regimen may be required for those diseases. Furthermore, an innovative treatment strategy is warranted to improve the outcome for patients with relapsed or refractory acute leukemia. Disclosures No relevant conflicts of interest to declare.

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Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Flurabine Improves Transplant Outcomes in Older MDS Patients

Blood ◽

10.1182/blood-2019-121970 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 253-253

Author(s):

Betul Oran ◽

Kwang Woo Ahn ◽

Caitrin Fretham ◽

Mithun Vinod Shah ◽

Ryotaro Nakamura ◽

...

Keyword(s):

Total Dose ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Sensitivity Analyses ◽

Unrelated Donor ◽

Advisory Committees ◽

Hematopoietic Stem

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only potentially curative therapy in eligible patients with myelodysplastic syndromes (MDS). Reduced-intensity conditioning (RIC) regimens that have been developed to extend HSCT to older patients resulted in encouraging outcomes. However, several retrospective studies have raised concerns about disease control when RIC is used in MDS and the ideal conditioning regimen has not yet been found. In this study, we aimed to compare two most commonly used RIC regimens; intravenous use of fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel). Study population: Through the CIBMTR, after excluding patients with ex-vivo T cell depletion, we identified 1045 MDS patients aged ≥ 60 years and underwent first HSCT with matched related or matched (8/8) unrelated donor (MRD and MUD) using RIC between 2007-2016. RIC was defined via CIBMTR criteria as a regimen that incorporated an IV busulfan (BU) total dose ≤ 7.2 mg/kg or low-dose melphalan (MEL) total dose ≤ 150 mg/m2. By that, we identified 697 MDS patients who received FluBu (BU 6.4 mg/kg: 87%, BU 3.2 mg/kg: 13%) and 448 receiving FluMel (MEL 140 mg/m2: 80%, MEL 100 mg/m2: 20%). Results: The two groups, FluBu and FluMel, were comparable for disease and transplant related characteristics except the more frequent use of ATG or Campath in FluBu group (39% vs. 31%). The median age was 67 in both groups, and 26% and 19% of FluBu and FluMel groups were aged ³70, respectively. Hematopoietic comorbidity index (HCT-CI) was ³3 in 61% and 59% of FluBu and FluMel groups and MDS risk score by CIBMTR at HCT was high/very high in 34% in both groups. FluMel was associated with a reduced relapse incidence (RI) after HSCT compared with FluBu as presented in Table 1 and Table 2. Adjusted RI at 1-year was 43% with FluBu and 25% with FluMel (p=<0.0001). On the other hand, transplant related mortality (TRM) was higher with FluMel compared with FluBu (27% vs. 15%, p=<0.0001). The difference persisted at 2- and 3-years after HSCT as presented in the figure. Since the magnitude of improvement in RI was greater with FluMel than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 41% at 1-year, p=0.030, and 38% vs 28% at 3-years, p=0.0030). These outcome differences remained significant when sensitivity analyses were performed excluding patients who received RIC with either BU 3.2 mg/kg or Mel 100 mg/m2. FluMel, did not lead to higher incidence of severe grade 3-4 aGvHD (HR=1.2, 95%CI, 0.9-1.6, p=0.3) or chronic GvHD (HR=0.9, 95%CI=0.7-1.06, p=0.2). However, grade 2-4 aGVHD was observed more often with FluMel than FluBu (HR=1.3, 95%CI, 1.1-1.6, p=0.006). This led to inferior outcomes of GRFS within the first 2 months with FluMel (HR=1.9, HR=1.4-2.6, p<0.001) but superior outcomes of GRFS beyond 2 months with FluMel compared with FluBu (HR=0.7, 95%CI=0.6-0.8, p<0.001). Conclusion: Our results suggest that between the two most commonly used RIC regimens in older MDS patients, FluMel was associated with superior DFS and overall survival compared with FluBu due to reduced RI despite higher TRM. Disclosures Oran: AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Nakamura:Kirin Kyowa: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Celgene: Other: support for an academic seminar in a university in Japan; Merck: Membership on an entity's Board of Directors or advisory committees. Scott:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Popat:Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding.

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Peripheral Blood Stem Cells Versus Bone Marrow Grafts For HLA-Matched Unrelated Donor Transplantation In Adult Patients With Acute Myeloid Leukemia; The Role Of Low-Dose Rabbit Anti-Thymocyte Globuline In The Prophylaxis Of Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v122.21.2109.2109 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2109-2109

Author(s):

Seung-Hwan Shin ◽

Jung-Ho Kim ◽

Young-Woo Jeon ◽

Jae-Ho Yoon ◽

Seung-Ah Yahng ◽

...

Keyword(s):

Low Dose ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Hazard Ratio ◽

Unrelated Donor ◽

Peripheral Blood Stem Cells ◽

Free Survival ◽

Graft Versus Host ◽

Blood Stem Cells

Abstract Background In the setting of unrelated donor stem cell transplantation (URD-SCT), several data showed that peripheral blood stem cells (PBSC) resulted in faster engraftment but increased the risk of acute or chronic graft-versus-host disease (GVHD), while other transplant outcomes were comparable. However, there are some limitations in these data due to heterogeneous diseases or registry data characterized by various other treatment strategies. Notably, we have added low-dose rabbit anti-thymocyte globuline (ATG) only to the patients who received URD-SCT with PBSC because of their higher risk of developing GVHD. In this setting, we compared the long-term outcomes of URD-SCT using PBSC and bone marrow (BM) and studied the role of low-dose rabbit ATG in the prophylaxis of GVHD. Methods Between March 2004 and April 2012, 115 adult patients with AML underwent myeloablative (n=87) or reduced-intensity (n=28) conditioning HLA-matched URD-SCT with PBSC (n=70) or BM (n=45) grafts. All patients received tacrolimus and short-course methotrexate for GVHD prophylaxis. Low-dose rabbit ATG (Thymoglobuline®, 1.25 mg/kg for 2 days) was added only to the patients who received URD-SCT with PBSC grafts. The median follow-up of survivors was 44 months (range, 2-100) for PBSC transplants and 54 months (range, 8-105) for BM transplants (P=0.01). Results Baseline characteristics were not significantly different between the two groups except for total-body irradiation conditioning regimen (72.9% vs. 91.1%; P=0.02). PBSC transplants showed faster recovery of neutrophil (11 days vs. 13 days; P=0.03) and platelet (12 days vs. 18 days; P=0.01) counts than BM transplants. No difference was observed in the cumulative incidence of acute GVHD (grade ≥2) at 100 days (54.3% vs. 64.4%; P=0.38) and chronic GVHD at 4 years (61.4% vs. 60.0%; P=0.88) between the two groups. In spite of adding low-dose rabbit ATG, PBSC transplants did not show higher incidence of relapse compared to that of BM transplants (30.8% vs. 31.2%; P=0.53). Other transplant outcomes including non-relapse mortality (13.5% vs. 6.9%; P=0.24), disease-free survival (55.7% vs. 61.9%; P=0.80), and overall survival (63.3% vs. 63.2%; P=0.59) were comparable between the two groups. In multivariate analysis, graft source had no impact on transplantation outcomes. Regardless of graft source, transplants in ≥CR2 had higher relapse risk (hazard ratio, 2.45; 95 % CI, 1.04-5.76; P=0.04), poorer disease-free survival (hazard ratio, 2.68, 95% CI, 1.29-5.56; P=0.01) and overall survival (hazard ratio, 2.59; 95% CI, 1.20-5.59; P=0.02). Conclusion Adding low-dose rabbit ATG to the patients who received URD-SCT with PBSC may lower the incidence of acute and chronic GVHD comparably to that of URD-SCT with BM without increasing the incidence of relapse. Disclosures: No relevant conflicts of interest to declare.

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Long Term Follow up of Two Randomized Trials on Antithymocyte Globulin (ATG) for GVHD Prophylaxis in Unrelated Donor Transplants: Chronic GVHD, Bronchiolitis and Quality of Life.

Blood ◽

10.1182/blood.v104.11.438.438 ◽

2004 ◽

Vol 104 (11) ◽

pp. 438-438

Author(s):

Andrea Bacigalupo ◽

Maurizio Vignola ◽

Teresa Lamparelli ◽

Paolo Bruzzi ◽

Stefano Guidi ◽

...

Keyword(s):

Quality Of Life ◽

Antithymocyte Globulin ◽

Randomized Trials ◽

Chronic Gvhd ◽

Prospective Trial ◽

Conditioning Regimen ◽

Unrelated Donor ◽

One Year

Abstract Background . We have reported that rabbit antithymocyte globulin (ATG Sangstat-Genzyme) prevents acute and chronic graft versus host disease (GvHD) in patients undergoing an unrelated donor transplant (Blood2001; 98 (10): 2942–2947). Patients had entered two consecutive randomized trials: in trial-1, 54 patients were randomized to non-ATG (n=25) or 7.5mg/kg rabbit ATG (n=29). In trial-2, 28 patients were randomized in the non-ATG arm and 27 in the ATG 15mg/kg arm. Aim of the study: to assess the risk of extensive chronic GvHD, bronchiolitis obliterans , quality of life, survival and transplant related mortality (TRM) 4 years later. Patients. Seventy five patients survived 100 days after BMT, and were available for analysis : in trial-1 there were 20 patients per arm, in trial-2 there were respectively 18 and 17 patients. The median follow up was 7.4 years for trial-1 and 5.3 years for trial-2. Each patients was updated and assessed for survival, chronic GvHD, for bronchiolitis , relapse of the original disease and quality of life. Results. Results are given in percentage, in the order non-ATG vs ATG patients. At last follow up chronic GvHD (limited+extensive) was scored in 74% vs 33% respectively for non-ATG and ATG of patients in trial 1 (p=0.01) and in 61% vs 29% in trial-2 (p=0.06): when the two trials are combined cGvHD is scored in 68% vs 31% of non-ATG vs ATG patients (p=0.002). Extensive chronic GvHD was scored in both trials in 35% and 13% of patients (0.03). Bronchiolitis was present at last follow up in trial-1 in 50% vs 0% (p=0.01), and in 33% vs 8% in trial-2 (p=0.1). Combined data show bronchiolitis in 40% vs 4% of non-ATG vs ATG patients (p=0.002). Median timing of bronchiolitis was 1155 days. When patients developed bronchiolitis, the mortality was high (50%). Quality of life was assessed by looking at proportion of patients with Karnowski score of 100% at last follow up: the proportion was 37% vs 91% patients in trial-1 (p=0.02), it was 75% vs 100% patients in trial-2 (p=0.2) and overall in 56% vs 95% of all non-ATG vs ATG patiens (p=0.007). Relapse related deaths were 13% in the non-ATG and 11% in the ATG group. Survival: the actuarial survival at 5 years in trial-1 is 48% vs 53% (non-ATG vs ATG) and in trial-2 30% vs 41%. The actuarial TRM is 48% vs 40%, and in trial-2 it is 62% vs 47% (non-ATG vs ATG patients). Actuarial 5 year TRM in patients surviving one year (late TRM) is 28% vs 4% (p=0.02). Conclusions. This updated analysis of two randomized GITMO trials, confirms with longer follow up, that ATG pre-transplant produces (1) a significant reduction of chronic GvHD (from 68% to 31%) and (2) a significant reduction of extensive chronic GvHD (from 35% to 13%). As a consequence quality of life is significantly improved in ATG patients. This study also shows that ATG reduces the risk of chronic bronchiolitis (from 40% to 4%), and late TRM (beyond one year) (from 28% to 4%). These data give strong support for the inclusion of ATG in the conditioning regimen of unrelated transplants: dosing and timing should be considered (Blood2003; 102 (11); 242a) and could be tested in a prospective trial. This work was supported by Fondazione CARIGE, GENOVA

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Comparison of Outcomes After Unrelated Cord Blood Transplantation and Matched Unrelated Donor RIC Transplantation for Lymphoid Malignancies - A Eurocord-Netcord Group/ Lymphoma Working Party and Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation Study.

Blood ◽

10.1182/blood.v114.22.663.663 ◽

2009 ◽

Vol 114 (22) ◽

pp. 663-663 ◽

Cited By ~ 1

Author(s):

Celso Arrais Rodrigues ◽

Carmen Canals ◽

Claudio Brunstein ◽

Jürgen Finke ◽

Arnon Nagler ◽

...

Keyword(s):

Cord Blood ◽

Low Dose ◽

Chronic Gvhd ◽

Working Party ◽

Progression Free Survival ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Free Survival ◽

Lymphoid Malignancies ◽

Unrelated Cord Blood

Abstract Abstract 663 We have recently reported encouraging results after unrelated cord blood (UCBT) for patients with lymphoid malignancies (Rodrigues et al, 2009). Progression free survival (PFS) was improved in patients with chemosensitive disease, who have received a higher CD34 cell dose, and low-dose TBI in the preparative regimen. However, whether outcomes after reduced intensity conditioning (RIC) UCBT are comparable to outcomes after RIC-MUD for lymphoid malignancies remains to be defined. We studied 359 adult patients with lymphoma or chronic lymphocytic leukemia (CLL) who received an UCBT (n=75) or a MUD (n=284) after a RIC regimen between January 2000 and December 2006, and registered in the EBMT and/or the Eurocord databases were analyzed. In the MUD group, we included only patients receiving peripheral blood stem cells and with a 6/6 or a 8/8 match. Patients from 111 centers were included: UCBTs were performed in 28 centers and MUD transplants in 98 centers. Only 15 centers performed both types of transplant. One hundred sixty eight patients had a non-Hodgkin lymphoma (NHL), 108 had Hodgkin's lymphoma (HL), and 83 had CLL. In the UCBT group, patients were slightly younger (median age 44 vs. 48 in the MUD group, P=0.05), aggressive histologies and HL were more frequent (P=0.04), and more patients underwent the transplant in refractory or chemoresistant disease (P<0.001). There were also differences in the conditioning regimen: low-dose TBI was more often used in the UCBT group than in the MUD group (75% vs. 30%, respectively, P=0.002), while T-cell depletion with ATG/ALG (23% vs. 41%, p<0.001) or alemtuzumab (0% vs. 34%, p<0,001) was more often used in the MUD group. In the UCBT group, 31 patients (41%) received a double UCBT and, based on antigen-level HLA-A and B and allele-level HLA-DRB1 typing, at least one cord blood unit had 2 mismatches with the patient in 75% of cases. Median follow-up time of surviving patients was 28 months (32 months in the MUD group and 24 months in the UCBT group). The cumulative incidence (CI) of engraftment at day 60 was 85% in the UCBT group and 98% in the MUD group (P<0.001). At 100 days, CI of grade II-IV acute graft-versus-host disease (GVHD) was not statistically different between UCBT and MUD recipients (33% vs. 31%, P= not significant–NS). At 2 years, CI of chronic GVHD was 48% after MUD as compared to 37% after UCBT, (P=0.05). Non-adjusted 2 years CI of NRM was 28% after UCBT and 30% after MUD, (P=NS). There was also no difference in 2-year relapse or progression after UCB or MUDT (38% vs. 35%, P=NS). Two-year progression-free survival (PFS) was 34% after UCBT and 34% after MUD (P=NS) and overall survival was 44% and 47%, respectively (P=NS). In a multivariate analysis, after statistical adjustments for the differences between the 2 groups, NRM, relapse or progression, PFS and OS were not statistically different between UCBT and MUD. In conclusion, engraftment rate and incidence of chronic GVHD were lower after RIC-UCBT than after RIC-MUD but final outcomes were not different between the two groups. Therefore, UCBT may be considered as a valuable alternative for patients with advanced lymphoma and CLL, lacking an HLA-matched unrelated donor. Disclosures: No relevant conflicts of interest to declare.

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Clofarabine Containing Conditioning Regimen for Allo-SCT in AML/ALL Patients: A Survey From the Acute Leukemia Working Party of EBMT

Blood ◽

10.1182/blood.v118.21.3004.3004 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3004-3004

Author(s):

Patrice Chevallier ◽

Myriam Labopin ◽

Stefanie Buchholz ◽

Arnold Ganser ◽

Fabio Ciceri ◽

...

Keyword(s):

High Risk ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Working Party ◽

Acute Leukemias ◽

Conditioning Regimens ◽

Reduced Toxicity ◽

Active Disease

Abstract Abstract 3004FN2 Clofarabine (CLO), a second generation purine analogue, has demonstrated an efficient anti-leukemia activity while showing a favorable toxicity profile. The aim of our study was to analyse the results of CLO as part of the conditioning regimen prior to allo-SCT for the treatment of patients with AML or ALL. This retrospective multicenter report assessed the outcome of 90 patients who received a clofarabine-containing conditioning regimen allogeneic stem cell transplantation (allo-SCT) for AML (n=69) or ALL (n=21) between November 2006 and September 2010 and reported on the EBMT registry. The median age was 42 years (range: 18–69) at transplant. The majority of patients presented with an active disease at transplant (CR1 n=8; CR2 n=16, active disease n=66). All patients had received a CLO-containing conditioning regimen (RIC n=88; MAC n=2) with the following combinations: CLO/TBI n=27; CLO/Busulfan n=10; CLO/Busulfan/ATG n=32; CLO/others drugs n=21. With a median follow-up of 14 months (range: 1–45), 2-years OS, LFS, relapse incidence, non-relapse mortality (NRM) and chronic GVHD were 28+-5%, 23+-5%, 41+-6%, 35+-5% and 38+-7%, respectively. When comparing AML and ALL patients, OS and LFS were significantly higher for AML patients (OS: 35+-6% vs 0%, p<0.0001); LFS: 30+-6% vs 0%, p<0.0001). Overall, engraftment was achieved in 84% of patients with no difference between AML and ALL patients. Patients achieving CR from an active disease were 66.5% in AML vs 40% in ALL (p=0.06). Also, 2-year chronic GVHD was 35% in AML vs 17% in ALL, p=0.32. In a Cox multivariate analysis, AML was the only factor associated with a better LFS (HR=0.37; 95%CI: 0.21–0.66, P=0.001). We conclude that the use of CLO-containing conditioning regimen for allo-SCT is an effective treatment for high-risk AML patients as CLO seems to provide higher anti-tumor and alloreactivity effects. In high-risk ALL patients, disappointing results are observed. Prospective studies are needed to evaluate the potential role of CLO as part of reduced toxicity conditioning regimens in acute leukemias. Disclosures: No relevant conflicts of interest to declare.

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