Reduced Intensity Conditioning (RIC) Transplantation In Acute Leukemia: The Effect of Source of Unrelated Donor Stem Cells on Outcomes

Abstract Abstract 908 Peripheral blood progenitor cells (PBPC) are the preferred graft source for RIC transplantation. As in other settings, if a suitable unrelated adult donor is not available, primarily HLA mismatched unrelated cord blood (CB) is increasingly utilized, including the co-infusion of two CB units to overcome the cell dose limitation. We here report the relative efficacy of double CB (dCB, n=161) transplantation vs. PBPC whether from an 8/8 HLA matched (MUD, n=313) vs. 1 allele mismatched (MMUD, n=111) unrelated donor in patients with acute myeloid (AML, n=523) and lymphoblastic leukemia (ALL, n=62) transplanted between 2000 and 2009. Patients were aged 21 – 69 years. dCB recipients were more likely to be younger (median age: 54 vs. MUD 59 vs. MMUD 58 years, p<0.001), to have ALL (20% vs. MUD 6% vs. MMUD 10%, p<0.001) and to be in 1st or 2nd complete remission (83% vs. MUD 74% vs. MMUD 65%, p<0.001). Transplant conditioning regimens differed between dCB and PBPC transplants. Approximately 75% of dCB recipients received TBI 200 cGy + cyclophosphamide + fludarabine (TCF) ± ATG, 20% received melphalan or busulfan (Bu) or cyclophosphamide (Cy) + fludarabine ± ATG and the remaining 5%, TBI + fludarabine ± alkylating agent ± ATG. In contrast, approximately 75% of PBPC recipients received melphalan or Bu or Cy + fludarabine ± ATG. While there were no differences in overall survival by conditioning regimen in PBPC recipients, conditioning regimen influenced survival in recipients of dCB with the best survival in those treated with TCF. Therefore, 4 groups were created for multivariate analysis comparing transplant outcomes: dCB after TCF, dCB after other RIC regimens, MUD and MMUD; results are shown in the Table below. Compared to dCB after TCF, grade 2–4 but not grade 3–4 acute GVHD was lower in those with a MUD and chronic GVHD was higher in those with either a MUD or MMUD. Compared to dCB after other RIC regimens, transplant-related mortality (TRM) and overall mortality were lower after MUD and dCB after TCF transplants but similar to those after MMUD transplants. The 2-year probabilities of TRM in recipients of dCB after TCF, dCB after other RIC regimens, MUD and MMUD transplants are 19%, 52%, 21% and 28%, respectively. The corresponding probabilities for overall survival, adjusted for disease status and performance score were 38%, 19%, 44% and 37%. These data support dCB after TCF for adults with acute leukemia where a transplant is indicated but a suitably HLA matched unrelated adult donor is not available or when transplant is needed urgently. Although a center-effect could not be demonstrated statistically (p=0.2), a substantial proportion of dCB patients treated with TCF were done at a single center. Results of an ongoing multi-center phase II trial evaluating dCB after TCF will verify the reproducibility of these results. Grade 2–4 Acute GVHD* Chronic GVHD* TRM Relapse† Treatment failureμ Overall mortalityμ MUD vs. dCB after TCF HR 0.52 p=0.0001 HR 2.33 p=0.0001 HR 1.09 p=0.72 HR 0.79 p=0.15 HR 0.89 p=0.37 HR 0.93 p=0.60 MMUD vs. dCB after TCF HR 0.70 p=0.06 HR 2.22 p=0.0002 HR 1.77 p=0.04 HR 0.87 p=0.49 HR 1.14 p=0.43 HR 1.15 p=0.41 dCB after TCF vs. dCB after other RIC HR 1.64 p=0.09 HR 0.61 p=0.11 HR 0.34 p<0.0001 HR 1.37 p=0.29 HR 0.77 p=0.22 HR 0.60 p=0.02 MUD vs. dCB after other RIC HR 0.87 p=0.62 HR 1.41 p=0.22 HR 0.37 p=0.0001 HR 1.09 p=0.76 HR 0.68 p=0.05 HR 0.56 p=0.004 MMUD vs. dCB after other RIC HR 1.15 p=0.65 HR 1.35 p=0.33 HR 0.59 p=0.07 HR 1.20 p=0.55 HR 0.88 p=0.52 HR 0.69 p=0.09 * adjusted for transplant period † adjusted for disease status μ adjusted for disease status and performance score Disclosures: No relevant conflicts of interest to declare.

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Risks and Benefits of Unrelated Donor Peripheral Blood Progenitor Cells (PBPC) in Children and Adolescents with Acute Leukemia.

Blood ◽

10.1182/blood.v112.11.977.977 ◽

2008 ◽

Vol 112 (11) ◽

pp. 977-977

Author(s):

Mary Eapen ◽

Olle Ringden ◽

Franco Locatelli ◽

Haydar Frangoul ◽

Mats Remberger ◽

...

Keyword(s):

Overall Survival ◽

Acute Leukemia ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Unrelated Donor ◽

Platelet Recovery ◽

Free Survival ◽

Grade 3

Abstract Although PBPC is an acceptable alternative to bone marrow (BM) for transplanting children with leukemia, there are no published studies describing outcomes after unrelated donor PBPC transplants. We compared the results of 385 unrelated donor BM transplants that were allele-matched (n=186) or mismatched (n=199) at HLA A, B, C, DRB1 and 110 PBPC transplants that were matched (n=60) or mismatched (n=50) at HLA A, B, C, DRB1 in patients younger than 18 years of age. All patients had acute leukemia and were transplanted in 2000–2006. Median follow up of surviving patients was 2 years in both treatment groups. There were no significant differences in patient and disease characteristics, transplant conditioning regimen, graft-versus-host disease (GVHD) prophylaxis and donor-recipient HLA disparity by graft type. Though the early probability of neutrophil recovery (³500/ul) was faster after transplantation of PBPC (31% vs. 10% at day-14, p<0.001) the probability of recovery by day-28 was similar after PBPC and BM transplants (94% and 91%, p=0.391). In contrast, platelet recovery (³20,000/ul) was better after PBPC transplants (86% vs. 76% at day-60, p=0.022). Risks of grade 2–4 (hazard ratio [HR] 1.24, p=0.147) and grade 3–4 (HR 1.07, p=0.785) acute GVHD were similar after PBPC and BM transplants. The risk of developing chronic GVHD was significantly greater after PBPC transplants compared to BM transplants (HR 2.36, p<0.001). After adjusting for disease status, donor-recipient HLA disparity and age, the of transplant-related mortality (TRM) relapse, treatment failure (relapse or death from any cause; inverse of leukemia-free survival and overall survival were similar after PBPC and BM transplants. The Table below shows the day-100 probability of grade 2–4 acute GVHD and the 3-year probabilities of chronic GVHD, TRM, relapse, leukemiafree survival and overall survival by graft type. These results differ from transplantation of PBPC from HLA-matched siblings where higher chronic GVHD translated into higher TRM and lower LFS. It remains to be seen whether the observed higher chronic GVHD after PBPC transplants will eventually result in the long term in higher mortality or fewer leukemia recurrence. PBPC BM Grade 2–4 acute GVHD 53% 49% Chronic GVHD 58% 33% TRM 20% 24% Relapse 34% 28% Leukemia-free survival 46% 48% Overall survival 49% 49%

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Effect of Stem Cell Source From Unrelated Donors on Transplant Outcomes In Severe Aplastic Anemia (SAA): a Comparison of Unrelated Bone Marrow (BM) and Peripheral Blood Progenitor Cells (PBPC)

Blood ◽

10.1182/blood.v116.21.531.531 ◽

2010 ◽

Vol 116 (21) ◽

pp. 531-531

Author(s):

Mary Eapen ◽

Jennifer LeRademacher ◽

H. Joachim Deeg ◽

Joseph H. Antin ◽

Richard Champlin ◽

...

Keyword(s):

Overall Survival ◽

Chronic Gvhd ◽

Immunosuppressive Treatment ◽

Conditioning Regimen ◽

Hla Typing ◽

Unrelated Donor ◽

Performance Score ◽

Platelet Recovery ◽

Incidence And Mortality ◽

Unrelated Adult

Abstract Abstract 531 Unrelated donor HSCT has been considered a therapy of last choice in SAA, because of poor overall survival reported prior to 1998 (32% @ 5-years). This is due in large measure to low resolution donor-recipient HLA typing and the selection of patients. Survival after unrelated donor BM HSCT for SAA has improved in recent years with survival rates of approximately 75% @ 5-years when the donor and recipient are matched at HLA-A, -B, -C and –DRB1. Furthermore, improvements in conditioning regimen may also have reduced the rate of graft rejection. In recent years PBPC instead of BM are increasingly used and PBPC grafts now account for 25% of unrelated donor HSCT for SAA. An earlier report from the CIBMTR and the EBMT identified higher chronic graft-versus-host disease (GVHD) incidence and mortality after transplantation of PBPC from HLA-matched siblings compared to BM in patients with SAA aged ≤20 years. GVHD rates are higher after unrelated adult donor HSCT regardless of graft type, but the effects of PBPC on survival in patients with SAA are not known. Two hundred and forty nine patients transplanted in 2000–2007 received either BM (n=186) or PBPC (n=63) from unrelated adult donors matched at HLA-A, -B, -C, -DRB1. Median follow up was 3 years. Compared with recipients of BM, PBPC recipients were older (median age: 19 vs. 35 years), transplanted in 2006–2007 (37% vs. 46%), more likely to be male (47% vs. 65%), receive non-TBI containing transplant conditioning (fludarabine + cyclophosphamide or busulfan or melphalan ± anti-thymocyte globulin; 34% vs. 55%) and tacrolimus-containing GVHD prophylaxis (29% vs. 57%). Among patients who received TBI-containing regimens, approximately 90% of BM and PB recipients received TBI 200 cGy. There were no differences in patient performance score at HSCT, immunosuppressive treatment prior to HSCT and interval from diagnosis to HSCT (median time to HSCT was 13 months in BM recipients and 11 months, in PBPC recipients). As shown after HLA-matched sibling transplantation, the cumulative incidence of neutrophil recovery (30.5 × 109/L at day-28) and platelet recovery (≥20 × 109/L) was similar in recipients of BM (92% and 83%, respectively) and PBPC (95% and 90%, respectively). The day-100 probability of grades 2–4 acute GVHD was higher after PBPC than after BM (51% vs. 33%, p=0.01). The 3-year probability of chronic GVHD was higher after PBPC than after BM, in patients older than 20 years at HCT (60% vs. 41%, p=0.001) but not in younger patients (23% vs. 26%, p=NS). In multivariate analysis, the risk of mortality was higher after PBPC than after BM (HR 1.79, p=0.02). Other factors that predicted mortality included poor performance score (HR 1.95, p=0.009) and non-TBI transplant conditioning regimens (HR 1.96, p=0.006). Although patient age (>20 vs. ≤20 years) was significantly associated with chronic GVHD there was no significant effect of age on mortality (HR 1.21, p=0.47). The 3-year probability of overall survival adjusted for performance score and transplant conditioning regimen was 76% for BM and 60% for PBPC recipients (p=0.02). These data suggest that: 1) outcomes after URD HSCT for SAA are now similar to outcomes observed in MRD HSCT, 2) BM is the preferred graft source when considering unrelated donor HCT in patients with SAA and 3) the data also support low dose TBI in the preparative regimen for transplant conditioning. Disclosures: No relevant conflicts of interest to declare.

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Thiotepa-Based Conditioning for Allogeneic Stem Cell Transplantation (allo-HSCT) in Acute Lymphoblastic Leukaemia (ALL) - a Survey from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v126.23.4316.4316 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4316-4316

Author(s):

Sandra Eder ◽

Eric Beohou ◽

Myriam Labopin ◽

Jaime Sanz ◽

Jürgen Finke ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Working Party ◽

Disease Status ◽

P Value ◽

Unrelated Donor ◽

Free Survival ◽

One Year

Abstract Background Thiotepa is an alkylating compound with an effective antineoplastic activity that was used in the past mainly for solid tumors and lymphoma, partially due to its ability to penetrate the blood-brain-barrier. Moreover, beside its myelosupressive activities, thiotepa has immunosuppressive properties making it an attractive agent to be used in the conditioning pre-transplantation. In the current retrospective registry study, we analyzed thiotepa-based conditioning regimen for allo-HSCT in adult patients with ALL using the EBMT ALWP database. Methods Inclusion criteria were: adults with de novo or secondary ALL who underwent first allo-HSCT between 2000 and July 2014 with a thiotepa-based regimen. Donors were either HLA-matched siblings or matched unrelated donors. Haploidentical and cord blood transplantations were excluded as well as patients who received a previous allo-HSCT. Results A total of 323 patients with adult ALL were identified. Median age was 43 years (range, 18 - 76); 59% were males and 41% females. Disease status at allo-HSCT was CR1 in 48.9%, CR2 in 21.7%, CR3 in 6.2% and 23.2% of the patients had an active disease at time of transplant. Transplantation was performed from a HLA-matched sibling (49.8%) or a matched unrelated donor (51.2%). Sixty-five per cent of patients received a myeloablative and 35% a reduced-intensity conditioning regimen, respectively. Stem cell source was peripheral blood stem cells in 84% of the transplants, while 16% received bone marrow grafts. Neutrophil engraftment (defined as >0.5x109/L) was 98% with a median day of 15 (range, 2 - 41). Platelets engraftment (defined as >20x109/L) was 92% with a median day of 14 (range, 7 - 98). Incidence of acute GvHD (Grade> II) was 26.6%, while chronic GvHD occurred in 35.9% at one year (24.6% with extensive disease). With a median follow-up of 16.8 months, the non-relapse mortality was 12.4% and 25.3% at 100 days and one year, respectively. Relapse incidence at 1 year was 33.3%.The one-year leukemia-free survival and overall survival incidences were 57% and 66%. Table 1 shows the outcome according to donor and disease status at time of allo-HSCT. When looking for conditioning regimen more precisely, comparing thiotepa / busulfan ± melphalan (n=213) to thiotepa / other (n=110), higher relapse incidence at one year (34.9% vs 30.3%, p=0.016) and lower leukemia-free survival (38.8% vs 45.9%, p=0.0203), respectively were observed, without difference in non-relapse mortality (23.8% vs 26.3 %, n.s.) and overall-survival (59.6% vs 51.1%, p=0.109). Conclusion This large survey suggests that TTP-based conditioning therapy in adult ALL is feasible and effective, with main outcomes being comparable to literature published results achieved with other regimens. Table 1. Donor LFS,1 year p-value OS,1 year p-value Relapse,100 days Relapse,1 year p-value NRM,100 days NRM,1 year p-value HLA-matchedsibling 49% 0.0262 62% 0.0133 13.1% 31.9% 0.4641 8.7% 18.3% 0.0042 matchedunrelateddonor 33% 46% 15.2% 34.7% 16.2% 32.1% Table 2. Disease status at allo-HSCT LFS,1 year p-value OS,1 year p-value Relapse,100 days Relapse,1 year p-value NRM,100 days NRM,1 year p-value CR1 49% <0.0001 68% <0.0001 6.4% 27.5% 0.0028 7.6% 22.6% 0.1859 CR2+ 33% 40% 21.5% 39% 17% 27.8% Disclosures Mohty: Riemser: Honoraria, Research Funding.

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Myeloablative Fractionated Busulfan Conditioning Regimen in Older Patients: Results of a Phase II Study

Blood ◽

10.1182/blood-2019-122124 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 256-256 ◽

Cited By ~ 1

Author(s):

Uday Popat ◽

Rohtesh S. Mehta ◽

Roland Bassett ◽

Amanda L. Olson ◽

Julianne Chen ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Very High

Background: Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study. Methods: Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM. Results: We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was >3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor. With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table]. There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets (> 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001. Conclusion: Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival. Table Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; StemLine: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Nieto:Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy; Novartis: Research Funding. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Autolous: Consultancy; Bioclinica: Consultancy; Speaker: Other: Speaker; Amgen: Other: Advisory Board. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. OffLabel Disclosure: Fludarabine & Busulfan as conditioning agent prior to transplant

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Use of Thymoglobulin with Lower Dose of Busulfan Results in Less Acute Gvhd Following Unrelated Donor Allogeneic Stem Cell Transplantation for AML without Affecting Relapse-Free and Overall Survival

Blood ◽

10.1182/blood-2019-125418 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4488-4488

Author(s):

Dipenkumar Modi ◽

Vijendra Singh ◽

Seongho Kim ◽

Abhinav Deol ◽

Asif Alavi ◽

...

Keyword(s):

Overall Survival ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Board ◽

Unrelated Donor ◽

Hla Matching ◽

Reduced Intensity Conditioning ◽

Post Transplant ◽

Reduced Intensity

Introduction: Post-transplant relapse and GVHD are two major barriers of success of allogeneic hematopoietic stem cell transplantation (AHSCT) for AML. These outcomes are often dependent on the complex interaction between the post-transplant immunosuppression and the conditioning regimen. We as well as others have used rabbit thymoglobulin for the reduction of both acute and chronic GVHD in unrelated transplant in AML. The interaction between different conditioning regimens and thymoglobulin may play an important role in the outcomes, but it has not been fully investigated. In this study, we compared outcomes of patients undergoing unrelated donor AHSCT for AML using thymoglobulin with either a myeloablative or reduced intensity conditioning regimen. Patients received busulfan/fludarabine (Bu/Flu)-based myeloablative conditioning (MAC) regimen with 4 days of busulfan or reduced intensity conditioning (RIC) regimen using 2 days of busulfan with fludarabine. Since 2 days of busulfan as RIC may have a higher relapse rate, we added low dose TBI (200cGY) to the RIC regimen (Bu/Flu/TBI). Methods: We retrospectively evaluated outcomes of adult AML patients who underwent unrelated donor AHSCT utilizing tacrolimus, mycophenolate (MMF) and thymoglobulin as GVHD prophylaxis. All patients received either a Bu/Flu/TBI-based RIC or a Bu/Fu-based MAC regimen. Thymoglobulin was administered at a total dose of 4.5mg/kg in divided fashion (0.5mg/kg on day-3, 1.5mg/kg on day -2, 2.5mg/kg on day -1). Tacrolimus and MMF were started on day -3. The objectives were to determine the rates of acute and chronic GVHD, overall survival (OS), relapse free survival (RFS) and non-relapse mortality (NRM) using Cox proportional hazard regression and competing risk models. Results: One hundred twenty-two patients with AML received unrelated donor AHSCT between January 2005 and December 2017. Of these, 88 (72%) patients had de-novo and 34 (28%) had secondary AML. Sixty-four patients received Bu/Flu/TBI-based RIC, and 58 received Bu/Flu as MAC regimen. All patients received peripheral blood stem cells. The patients receiving RIC regimen were older (median age 66 vs 53 years, p<0.001), had higher proportion of patients with normal cytogenetics (47% vs 31%, p=0.02) and 8/8 HLA match (88% vs 64%, p=0.004) as compared to MAC regimen. The 6-month cumulative incidence rate (CIR) of grade III-IV acute GVHD (aGVHD) was 6% in RIC and 26% in MAC regimen (p=0.004). The 2-year CIR of chronic extensive GVHD was 35% and 29% in RIC and MAC regimen, respectively (p=0.50). Median follow-up of surviving patients after RIC and MAC regimen was 4.4 years and 4 years, respectively. Two-year OS after RIC and MAC regimen was 50% and 49%, respectively (p=0.69). Two-year relapse rate with RIC and MAC was 37% and 24%, respectively (p=0.25), whereas two-year NRM with RIC and MAC was 21% and 31%, respectively (p=0.41). Two-year RFS was 43% with RIC and 45% with MAC regimen (p=0.80). In all, CMV and EBV reactivation rates were 34% and 7%, respectively. Eight patients (7%) developed gastrointestinal CMV disease. Multivariable analysis revealed that relapsed and refractory AML at AHSCT was associated with adverse OS (HR 1.71, p=0.04), RFS (HR 1.84, p=0.01) and higher NRM (SHR 2.96, p=0.006) compared to first complete remission. Secondary AML was associated with higher NRM (HR 2.44, p=0.02). No impact of HLA matching and conditioning regimen on OS, relapse, NRM and RFS was observed. Subgroup analysis showed that HLA matching had an interaction with the conditioning regimen for RFS (p=0.03). Otherwise, none of the factors appeared to have any significant interaction with the conditioning regimen for survival outcomes. Conclusion: Our study shows that thymoglobulin when used with lower dose of busulfan (in the form of Bu/Flu/TBI-based RIC regimen) provided significantly lower rate of acute GVHD compared to Bu/Flu-based MAC in AML patients undergoing unrelated donor AHSCT without affecting leukemia-free and overall survival. Disease status at transplant remains a significant predictor of post-transplant outcomes. Disclosures Deol: Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board.

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Outcomes of c Hematopoietic Stem Cell Transplantation (HCT) after Non-Myeloablative Conditioning in Relapsed, Refractory, or Transformed Indolent Non-Hodgkin Lymphoma (NHL).

Blood ◽

10.1182/blood.v108.11.3124.3124 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3124-3124 ◽

Cited By ~ 1

Author(s):

Andrew R. Rezvani ◽

Brenda M. Sandmaier ◽

Barry Storer ◽

Michael Maris ◽

Edward Agura ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Disease Status ◽

Aggressive Lymphoma ◽

Optimal Timing ◽

Unrelated Donor ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Allogeneic Hct ◽

Grade 3

Abstract Sixty-two patients (pts) with chemotherapy-refractory indolent or transformed NHL were treated at 10 centers with allogeneic HCT from related (n=34) and unrelated (n=28) donors after 2 Gy total body irradiation with or without fludarabine. Diagnoses included follicular lymphoma (FL) (n=54, including 10 with grade 3 FL), small lymphocytic lymphoma (n=6), and marginal zone lymphoma (n=2). Median age was 54 years (range 33–66 years), and median time from diagnosis to HCT was 4.4 years (range 0.5–18.5 years). Sixteen pts had histologically documented transformation to diffuse aggressive lymphoma prior to HCT. Twenty-seven pts (44%) had failed autologous HCT. Disease status at the time of HCT was complete response (CR, n=16), partial response (PR, n=22), refractory (n=13), untested relapse (n=9), or unknown (n=2). Eleven of the 28 unrelated donor/recipient pairs (39%) had HLA mismatches: 2 at a single allele, 7 at a single antigen, and 2 at an antigen and an allele. One pt had non-fatal graft rejection from a 1-antigen-mismatched unrelated donor. Median follow-up of survivors after HCT was 36.6 months (range 2.3–60 months). Responses (CR [n=18] and PR [n=7]) were seen in 25 of 44 (57%) pts with evaluable disease prior to HCT, while 5 had stable disease, 9 progressed, and 5 were not evaluable due to early non-relapse mortality (NRM) on d27–d108. Two of 16 pts (13%) transplanted in CR relapsed; one was treated with donor lymphocyte infusion and achieved a persistent CR. The incidences of acute GVHD grades II–IV, III–IV, and chronic GVHD were 63%, 19%, and 53%, respectively. At 3 years, the risks of relapse/progression and NRM were 19% and 42%, respectively. There was a trend toward increased mortality with unrelated donors (HR 1.87 [0.9–3.7, p=0.08]). Progression-free and overall survival (PFS and OS) were significantly better in the non-transformed group (see tables 1 and 2). Table 1. Outcomes Non-transformed Transformed Relapse 6/46 (13%) 6/16 (38%) NRM 20/46 (43%) 6/16 (38%) 3-year OS 24/46 (52%) 4/16 (25%) 3-year PFS 20/46 (43%) 4/16 (25%) Table 2. Hazard Ratios (HR) for Transformed vs. Non-Transformed Pts HR (95% CI) p All-cause Mortality 2.39 (1.2–4.9) 0.02 Relapse/progression 4.75 (1.5–15) 0.01 Grade 3+ acute GVHD 1.84 (0.5–6.3) 0.35 Extensive chronic GVHD 1.96 (0.8–5.0) 0.18 Figure Figure Allogeneic HCT after non-myeloablative conditioning can produce durable responses and prolonged survival in pts with refractory indolent or transformed NHL. Pts transplanted before histologic transformation had significantly better outcomes. Future efforts will focus on reducing NRM and identifying optimal timing of HCT.

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Unrelated Donor Hematopoietic Cell Transplant (HCT) for Hemophagocytic Lymphohistiocytosis (HLH).

Blood ◽

10.1182/blood.v108.11.174.174 ◽

2006 ◽

Vol 108 (11) ◽

pp. 174-174 ◽

Cited By ~ 2

Author(s):

K. Scott Baker ◽

Mary Eapen ◽

Thomas Gross ◽

Gregory A. Hale ◽

Robert Hayashi ◽

...

Keyword(s):

Overall Survival ◽

Systemic Disease ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Early Mortality ◽

Unrelated Donor ◽

Cell Transplant ◽

Peripheral Blood Stem Cells ◽

Disease Specific ◽

Overall Mortality

Abstract HLH is a rare immunoregulatory disorder characterized by widespread infiltration of histiocytes and T cells into organs, including the central nervous system (CNS), and is fatal in most cases without HCT. HLH can be inherited in an autosomal recessive pattern with unaffected sibling donors available for fewer than 20% of patients thus necessitating alternative donor HCT in the majority of cases. Data on 91 patients who underwent unrelated donor HCT and reported to the Center for International Blood and Marrow Transplant Research between 1989–2005 were analyzed. Fifty-one percent of patients were <1 yr at HCT and 29% had a Lansky performance score ≤80%. In a subset of patients (n=51) additional disease specific characteristics were available: 8 had a family history of HLH, of patients tested, 19 were confirmed to have either a perforin or MUNC-13 gene mutation; CNS disease was present at diagnosis in 21 patients and remained active in 4 at HCT; and 5 patients had active systemic disease at HCT. Most patients (80%) were conditioned with busulfan (BU), cyclophosphamide (CY), and etoposide (VP16) with or without anti-thymocyte globulin. Graft sources were bone marrow (86%), peripheral blood stem cells (4%) and cord blood (10%). Graft vs. host disease (GVHD) prophylaxis was cyclosporine or tacrolimus based in 89% of patients and T-cell depletion in 11%. Fifty-nine percent of grafts were matched at HLA A, B and DRB1, 34%, mismatched at 1-locus and 7%, mismatched at 2-loci. Neutrophil recovery was achieved by day 42 in 91% of patients. The probabilities of grades 2–4 acute at day-100 and chronic GVHD at 3-years were 41% and 23%, respectively. In multivariate analysis, the risk of overall mortality was 2-fold higher in patients who did not receive BU/CY/VP16 as their conditioning regimen (RR 1.99, p=0.03). In the sub-set of patients from whom disease-specific characteristics were available, overall mortality was higher in those with active systemic disease at HCT (RR 3.11, p=0.04). Early mortality was high, 35% at day-100 after HCT. Causes of early mortality included GVHD (n=5), infections (n=8), interstitial pneumonitis (n=8), organ failure (n=6), hemorrhage (n=3) and persistent disease (n=2). With a median follow-up of 49 months (range, 5–145) the 1- and 3-year probabilities of overall survival were 52% and 47%, respectively. For 46 patients with documented systemic remission at HCT, the 1- and 3-year probabilities of overall survival were 56% and 49%, respectively. These data represent the largest experience with unrelated donor HCT for HLH and demonstrate that a BU/CY/VP16 conditioning regimen provides cure in over 50% of patients. Outcome of HCT for patients with active systemic disease was poor with only 1 of 5 such patients surviving, demonstrating a need for novel therapies in patients who fail to respond to standard pre-transplant treatment. Unrelated donor HCT for HLH was associated with high early mortality and future studies should explore strategies to decrease early HCT-related mortality.

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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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Reduced Intensity Conditioning (RIC) with Cladribine, Busulfan and 4 Gy Total Body Irradiation (TBI) for Bone Marrow Transplantation (BMT) from an HLA-Matched Unrelated Donor (URD): A Prospective Multi-Institutional Clinical Trial.

Blood ◽

10.1182/blood.v108.11.5397.5397 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5397-5397 ◽

Cited By ~ 2

Author(s):

Sung-Won Kim ◽

Masayuki Hino ◽

Kazuo Hatanaka ◽

Yasunori Ueda ◽

Ryuji Tanosaki ◽

...

Keyword(s):

Clinical Trial ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Survival Rates ◽

Conditioning Regimen ◽

High Response Rate ◽

High Dose ◽

Unrelated Donor ◽

Grade Ii ◽

Neutrophil Engraftment

Abstract [Background] We report the results of a prospective multi-institutional clinical trial of BMT from an HLA-matched URD following RIC. [Patients and Methods] The conditioning regimen included cladribine 0.11 mg/kg on day -8 to day -3, busulfan 4 mg/kg po on day -6 and day -5, and 4 Gy TBI on day -1. GVHD prophylaxis included cyclosporine and short-term methotrexate. Patients with hematologic diseases were eligible for this study if they were either older than 50 years or had significant medical contraindications to undergo conventional transplantation. Primary endpoints were neutrophil engraftment and achievement of complete donor-type chimerism (CD3+ cells >90%) on day 90. Regimen-related toxicities (RRT) between day -8 and day 28 were assessed by the NCI-CTC v2.0. A total of 27 patients were registered, but one patient was removed before transplant because of severe fungal infection. [Results] The median follow-up time was 722 days (range, 324–996) among survivors. The median age of patients was 56.5 years (36–64). Nine of the 26 patients (36%) had advanced-stage diseases and 3 (11%) had failed previous high-dose autologous or allogeneic transplantation. The diagnoses included AML (n=9), MDS/MPD (n=7), NHL (n=3), ALL (n=2), CML, ATLL, PCL, biphenotypic acute leukemia, and severe aplastic anemia (n=1). The median number of infused nucleated cells was 2.2 × 108/kg. After transplant, while one patient experienced engraftment failure and subsequent sepsis, and died on day 34, the remaining 25 patients achieved neutrophil engraftment (median, 17th day). Another patient was censored from the study due to grade 4 liver dysfunction, which developed on day 19, which left 24 patients for the chimerism analysis. The percentage of donor chimerism in CD3+ cells on days 28, 56 and 90 was, respectively, 88% (21/24), 100% (24/24) and 100% (24/24). Grade 3 RRT included arrhythmia (n=1), hypoxia (n=3), hyperbilirubinemia or hypertransaminasemia (n=7), stomatitis (n=18) and diarrhea (n=4), and grade 4 RRT included hypoxia (n=1) and hyperbilirubinemia (n=1). Acute GVHD of grade II, III and IV occurred in 27%, 27% and 4%, respectively. Ten of 15 evaluable patients (67%) had extensive chronic GVHD. CMV reactivation occurred in 23 patients (89%); 4 had histologically confirmed CMV colitis, 1 had CMV pneumonitis and 1 had CMV hepatitis, while the remaining patients had asymptomatic viremia. Of the 16 patients with measurable disease at the time of BMT, 15 achieved complete remission. The 100-day and 1-year cumulative incidences of non-relapse mortality (NRM) estimated by the Kaplan-Meier method were 20% and 54%, respectively. The cause of death that contributed to NRM was infection, with grade 0–I acute GVHD in 29% and grade II–IV acute GVHD in 71%. The 100-day and 1-year cumulative incidences of relapse were 8% and 35%, respectively, and the 1-year overall and progression-free survival rates were 42% and 30%, respectively. [Conclusions] The results support the feasibility of this procedure with a high response rate, but there is still a problem with the high NRM due to uncontrollable infections primarily associated with GVHD.

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A Randomized, Controlled Trial of Graft-Versus-Host Disease (GVHD) Prophylaxis Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate: Analysis of GVHD, Relapse and Survival.

Blood ◽

10.1182/blood.v112.11.2235.2235 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2235-2235 ◽

Cited By ~ 1

Author(s):

Janelle Perkins ◽

Melissa Alsina ◽

Claudio Anasetti ◽

Ernesto Ayala ◽

Hugo F. Fernandez ◽

...

Keyword(s):

Overall Survival ◽

Randomized Controlled Trial ◽

Mycophenolate Mofetil ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Controlled Trial ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Randomized Controlled ◽

Gvhd Prophylaxis

Abstract The selective IMPDH inhibitor, mycophenolate mofetil (MMF), has entered the clinic with the promise to provide potent immune suppression without the side effects of methotrexate (MTX) or other broad-spectrum immunosuppressants. The use of MMF in the prevention of GVHD after hematopoietic cell transplantation (HCT) has been increasing worldwide, but only one small controlled study comparing cyclosporine + MMF to cyclosporine + MTX has been conducted to date. We compared GVHD prophylaxis with tacrolimus + MTX (TAC/MTX) to tacrolimus + MMF (TAC/MMF) in a single institution, randomized, controlled trial. Eligible patients were to receive T-replete peripheral blood HCT from 10/10 or 9/10 HLA-A, B, C, DRB1 and DQB1 matched donors, and have no contraindications to the use of TAC, MTX, or MMF. Randomization was stratified based on conditioning regimen intensity. Ninety-two pts were randomized, 45 to TAC/MMF and 47 to TAC/MTX and were all included in the intent-to-treat (ITT) analysis. Two pts were not transplanted and one pt withdrew consent prior to transplant. These pts were all randomized to TAC/MMF and excluded in the modified ITT (MITT) analysis. Pts received TAC 0.03 mg/kg/24hr as a continuous IV infusion beginning day -3 with doses adjusted to maintain whole blood levels of 5–15ng/ml. Pts were converted to PO therapy as tolerated and tapered after 6 months in the absence of GVHD. MTX was given IV at doses of 15mg/m2 day +1 and 10mg/m2 on days +3, +6 and +11. In pts with renal insufficiency, MTX doses were adjusted per pts’ pretransplant creatinine clearance. MMF was dosed at 15 mg/kg every 12 hours (up to 3g/d) IV beginning day 0, switched to PO as tolerated and continued for 12 months. Acute GVHD was graded weekly by Thomas’ criteria, modified per ASBMT consensus criteria; chronic GVHD was scored monthly based on NIH consensus criteria. The groups were balanced with respect to age, diagnosis, disease risk, recipient/donor CMV status, conditioning regimen, donor type and relation. The incidences of grade 2–4 and 3–4 acute GVHD were 79% and 4% in the TAC/MTX arm and 79% and 17% in the TAC/MMF arm (p=1.0 and 0.08, respectively). The incidence of moderate or severe chronic GVHD was 55% in the TAC/MTX arm and 59% in the TAC/MMF arm (p=0.91). By ITT analysis, the cumulative incidence of non-relapse mortality suggested an early difference in favor of TAC/MTX, but at 2 years it was 28% for TAC/MTX arm compared to 32% for the TAC/MMF arm (p=0.41; MITT p=0.33). The cumulative incidence of relapse was 33% in TAC/MTX arm compared to 18% (ITT; 16% MITT) for the TAC/MMF pts (p=0.06; p=0.04 MITT). Overall survival was similar between groups in both the ITT (p=0.76; 62% TAC/MTX vs. 66% TAC/MMF at 1 year) and MITT analysis (p=0.75; 62% TAC/MTX vs. 66% TAC/MMF at 1 year). We conclude that MMF was no better than MTX in preventing acute or chronic GVHD and may perhaps be less effective in preventing more severe forms of acute GVHD. Given the direction of effect we observed in severe acute GVHD, it is unlikely that a larger trial would show benefit for this endpoint. There was a strong suggestion that relapse of malignancy was more frequent after MTX than MMF, apparently in relation to the drug interference with the graft-vs.-leukemia effect. The beneficial effect of MMF on relapse was offset by the early increase in nonrelapse mortality, so that overall survival was unaffected.

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