Feasibility and efficacy of a PK-guided busulfan conditioning regimen for Allogeneic SCT with PTCY as GVHD prophylaxis in adult patients with hematologic malignancies.

Abstract <Introduction> HPS are rare but often-fatal conditions characterized by an inappropriate and sustained activation of the cellular immune system leading to accumulation of activated macrophages and a cytokine storm. HPS consists of primary and secondary Hemophagocytic Lymphohistiocytosis (HLH). Secondary HLH occurs at any age and the genetic contribution remains uncertain. Clinical features in patients with HLH are fever, cytopenias, liver dysfunction, hepato-splenomegaly, and the presence of hemophagocytosis in the bone marrow as well as other reticuloendothelical tissues. We will report on the hematological abnormalities and the clinical course of 20/152 patients who received RI-CBT and developed secondary HLH in adult patients with hematological disease in early phase after RI-CBT. <Object> The 1st purpose was to investigate the incidence of HLH and pattern of chimerism. The 2nd was to identify the risk factors after UCBT. <Patients and Methods> We reviewed medical records of 152 patients with hematological diseases who had received RI-CBT between January 2002 and April 2005 at Toranomon Hospital, Tokyo, Japan. Diagnosis of HLH was made with the followings; high fever, cytopenias, and hemophagocytic findings in bone marrow examination. Time to event curves were plotted by using the actuarial method of Kaplan-Meier, and differences between curves were analyzed by log-rank tests. The following factors were considered potential predictors of outcomes about 2nd purpose: patient’s age, HLA disparity, infused TNC dose/CD34 dose, disease/disease status at transplantation, GVHD prophylaxis and sepsis which coincided with HLH. All factors were tested for the proportional hazards assumption. <Results> Patient’s median age was 55 years (17–79), Primary diseases consisted of standard (n=31) and advanced (n=121). HLA disparities were 4/6 match (n=123), 5/6 (n=22), and others (n=7). Total nucleated cell/CD34 cell dose were 3.46×10E7/kg (1.6–5.2) and 0.78×10E5/kg (0.1–3.3), respectively. Main conditioning regimen was Fludarabine (125mg/m2) +Melphalan (80mg/m2) or Busulfan (8mg/kg) +TBI 4Gy with cyclospoline (n=89) and tacrolimus (n=63) as GVHD prophylaxis and received single cord blood unit. Twenty patients were diagnosis with HLH and the incidence of HLH was 13% (95%CI; 8–18) and median onset day was 18.5 days (range; 10–29). In patients with sepsis (n=46) and without sepsis (n=106), the incidence of HLH was 28% (95%CI; 15–41) and 7% (95%CI; 3–12), respectively (P<0.0002). All patients who were diagnosis with HLH using bone marrow examination achieved 100% of donor chimerism. In multivariate analysis, the most important risk factor of HLH after RI-CBT was sepsis which coincided with HLH at the same times (p<0.05), while other factors did not influence. <Discussion/Conclusion> HLH is fatal complication after allogeneic peripheral stem cell and unrelated bone marrow transplantation. However in RI-CBT, the incidence would be higher and earlier onset than other sources. The most of HLH patients died by multi-organ failure. In this report the most important risk factor was sepsis which coincided with HLH. Figure Figure

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High Rate of Engraftment and Low Regimen-Related Toxicity Using Fludarabine, Melphalan and Thiotepa Conditioning for Unrelated Donor Cord Blood Transplantation

Blood ◽

10.1182/blood.v112.11.4414.4414 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4414-4414

Author(s):

Stefan O Ciurea ◽

Partow Kebriaei ◽

Issa F Khouri ◽

Muzaffar H. Qazilbash ◽

Roy B Jones ◽

...

Keyword(s):

Acute Leukemia ◽

Cord Blood ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Adult Patients ◽

High Rate ◽

Unrelated Donor ◽

Platelet Recovery ◽

Blood Transplantation

Abstract BACKGROUND: Cord blood transplantation (CBT) represents an alternative source of stem cells for adult patients who lack a matched sibling or unrelated donor. However, the optimal type and intensity of the preparative regimen for patients receiving a CBT is not clear. We hypothesized that a conditioning regimen consisting of fludarabine, melphalan and thiotepa will be associated with an acceptable rate of engraftment and treatmentrelated mortality in patients receiving a CBT. METHODS: 37 patients, median age 31 years (2–57) and a median weight of 73kg, were treated between 8/2003 and 5/2008. All had advanced hematologic malignancies (24 with acute leukemia, 12 with lymphoma and one with CLL) At the time of transplant, 21 pts (57%) were in complete remission (CR) (first CR=20%) and 16 had relapsed/refractory disease. Grafts consisted of double (29 pts) or single (8 pts) CB units. Cytogenetics for patients with acute leukemia were poor in 11, intermediate in 9, good in 1 and unknown in 3 pts. Donor recipient HLA matching was (intermediate resolution class I HLA A and B and high-resolution DRB1): 3/6 (n=1, 1.5%), 4/6 (n=47, 71.2%) and 5/6 (n=18, 27.3%) alleles (n=66 units). Median total nucleated cell count was 1.8×107/kg (range 1–5.8). Nineteen patients received ex-vivo expanded units. The conditioning regimen consisted of melphalan 140 mg/m2 on day -8, thiotepa 10 mg/m2 on day -7, fludarabine 160 mg/m2 over 4 days on days -6, -5, -4, -3, and rabbit ATG 1.25 mg/kg on day -4 and 1.75 mg/kg on day -3 (FMT). Patients with CD 20+ lymphoid malignancies also received rituximab 375mg/m2 on day -9 (n=8, 22%). GVHD prophylaxis was tacrolimus and mini-methotrexate in 23 (62%) and tacrolimus and mycophenolate in 14 pts (38%). RESULTS: 36 patients (97%) were evaluable for engraftment. 1 patient died within 30 days due to progressive leukemia. 34/36 patients (95%) engrafted neutrophils and had hematopoietic recovery with 100% cord blood-derived cells. At day 30, of the 29 patients who received a double CBT, 75% had chimerism derived entirely from one donor while 25% had mixed donors chimerism. Neutrophil recovery to ANC >0.5 × 10e9/l occurred after a median of 21 days (range 6–45) and platelet recovery to >20 × 10e9/l after a median of 37 days (range 26–134, N=24; 67%). 32/37 pts (87%) were in CR after transplant with 16 surviving after a median follow-up of 12.1 months. Thirteen patients (36%) developed gr II–IV aGVHD (gr III–IV aGVHD in 5 patients, 14%), and 13 of 32 patients had cGVHD (40%), with the majority experiencing extensive GVHD. 11 patients (29.7%) relapsed after a median of 7 months post transplant and 12 died of nonrelapse causes. Day-100 treatment-related mortality in this heavily pre-treated population was 10%. Overall, causes of death included disease relapse (n=9), infections (n=6), organ failure (n=3), pulmonary hemorrhage (n=1) and GVHD (n=2). CONCLUSIONS: The FMT regimen was sufficiently immunosuppressive to support high rate of engraftment with acceptable TRM in heavily pre-treated adult patients with advanced hematologic malignancies undergoing CBT. These results support further evaluation of this regimen in CBT.

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Unrelated Cord Blood Transplantation: Comparison After Single Unit Cord Blood Intrabone Injection and Double Unit Cord Blood Transplantation In Patients with Hematological Malignant Disorders. A Eurocord-EBMT Analysis

Blood ◽

10.1182/blood.v116.21.223.223 ◽

2010 ◽

Vol 116 (21) ◽

pp. 223-223 ◽

Cited By ~ 4

Author(s):

Vanderson Rocha ◽

Myriam Labopin ◽

Annalisa Ruggeri ◽

Marina Podestà ◽

Dolores Caballero ◽

...

Keyword(s):

Cord Blood ◽

Median Time ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Adult Patients ◽

Myeloablative Conditioning ◽

Blood Transplantation ◽

Gvhd Prophylaxis ◽

The Impact

Abstract Abstract 223 The use of single cord blood unit for transplantation in adult patients is limited due to the high risk of graft failure and delayed neutrophil and platelet recoveries. The limited hematopoietic progenitors in UCB grafts and their homing after IV injection, have prompted investigators to study the design of delivering CB grafts directly into the bone marrow (BM) space (IBCBT) or to use double cord blood transplantation (dUCBT) to improve engraftment. To evaluate the impact of IBCBT, we made a retrospective based registry comparison with dUCBT performed in the same time period (2006-2010) and reported to Eurocord-EBMT. We included 87 and 149 patients who received either IBCBT or dUCBT, respectively, after a myeloablative conditioning regimen for malignant disorders. IBCBT was performed in 8 EBMT centers whereas dUCBT was performed in 56 EBMT centers. Majority of patients in both groups had acute leukemia. IBCBT patients were older (p<0.001), more frequently received an autologous graft (p<0.001) and had positive CMV serology (p<0.001), and importantly had more advanced disease at transplantation (p=0.04). Median number of infused (after thawing) nucleated cells injected intrabone was 2.5×107/kg and it was 3.9×107/kg in dUCBT (p<0.001). In 72% of both groups, CB grafts were HLA 4/6 (the highest HLA disparity was taken into consideration in dUCBT). Other differences were regarding GVHD prophylaxis that was based on CSA+MMF in 100% of IBCBT and in 62% of dUCBT cases; ATG was used in all IBCBT and 40% of dUCBT. Median follow-up time was 18 months in IBCBT and 17 months in dUCBT. At day 30, cumulative incidence (CI) of neutrophil recovery (ANC >500) was 83% after IBCBT and 63% after dUCBT, and at day 60, it was 90% in both groups; the median time to reach ANC>500 was 23 and 28 days after IBCBT and after dUCBT (p=0.001) respectively. At Day-180 CI of platelets recovery was 81% after IBCBT and 65% after dUCBT (p<0.001) with a median time of 36 days and 49 respectively (p=0.002). At day 100, CI of acute GVHD (II-IV) was 19% and 47% (p<0.001) and chronic GVHD 34% and 37% respectively (p=NS) respectively. Unadjusted 2 years-CI of NRM and RI were 31% and 23% after IBCBT and 35% and 28% after dUCBT, respectively (p=NS). Unadjusted 2 y-DFS estimation was 47% after IBCBT and 37% after dUCBT (p=NS). In multivariate analysis adjusting for statistical differences between 2 groups (such as status of the disease at transplant, age, CMV, previous transplants, GVHD prophylaxis), recipients of IBCBT had improved DFS (HR: 1.64, p=0.035), faster platelet recovery (HR:2.13, p<0.001) and decreased acute GVHD (HR:0.31; p<0.001) compared to dUCBT recipients. We did not find a cut-off value of number of nucleated cells after IBCBT or dUCBT that could be associated with outcomes after both approaches. In conclusion, both strategies have extended the use of CB transplants to adults in need of cord blood transplantation. Therefore, IBCBT is an option to transplant adult patients with single CB units after myeloablative conditioning regimen and may impact the total costs of cord blood transplantation. Based on these results, intra-bone technique may disclose new transplant potentialities also with other HSC sources. Disclosures: No relevant conflicts of interest to declare.

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Partially Matched, Nonmyeloablative Allogeneic Transplantation: Clinical Outcomes and Immune Reconstitution

Journal of Clinical Oncology ◽

10.1200/jco.2006.07.0953 ◽

2007 ◽

Vol 25 (6) ◽

pp. 690-697 ◽

Cited By ~ 157

Author(s):

David A. Rizzieri ◽

Liang Piu Koh ◽

Gwynn D. Long ◽

Cristina Gasparetto ◽

Keith M. Sullivan ◽

...

Keyword(s):

Survival Rate ◽

Conditioning Regimen ◽

Allogeneic Transplantation ◽

Hematologic Malignancies ◽

High Rate ◽

Immune Recovery ◽

Gvhd Prophylaxis ◽

Severe Infections ◽

Related Donor ◽

Standard Risk

Purpose Allogeneic transplantation is typically limited to younger patients having a matched donor. To allow a donor to be found for nearly all patients, we have used a nonmyeloablative conditioning regimen in conjunction with stem cells from a related donor with one fully mismatched HLA haplotype. Patients and Methods Fludarabine, cyclophosphamide, and alemtuzumab were used as the preparatory regimen. Additional graft-versus-host disease (GVHD) prophylaxis included mycophenolate with or without cyclosporine. Patients with persistence of disease had a donor lymphocyte boost planned. Toxicities, engraftment, response, survival, and immune recovery are reported. Results Forty-nine patients with hematologic malignancies or marrow failure and no other available donors were enrolled. Ninety-four percent of patients had successful engraftment, and 8% had secondary graft failure. The treatment-related mortality rate was 10.2%, and 8% of patients had severe GVHD. Encouraging evidence of quantitative lymphocyte recovery through expansion of transplanted T cells was noted by 3 to 6 months. Seventy-five percent of patients attained a complete remission, and 1-year survival rate was 31% (95% CI, 18% to 44%). A standard-risk group of 19 patients with aplasia or in remission at transplantation demonstrated a 63% 1-year survival rate (95% CI, 38% to 80%) and 2.9-year median overall survival time (95% CI, 6.2 to 48 months). Conclusion Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.

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Outcomes of Unrelated Umbilical Cord Blood Transplantation Using a Conditioning Regimen of TBI/Ara-c/CY without ATG for Adolescent and Adults Patients with High-Risk Hematologic Malignancies

Blood ◽

10.1182/blood.v120.21.4525.4525 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4525-4525

Author(s):

Zimin Sun ◽

Huilan Liu ◽

Liangquan Geng ◽

Xingbing Wang ◽

Kaiyang Ding ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Adult Patients ◽

Myeloablative Conditioning ◽

Blood Transplantation

Abstract Abstract 4525 To retrospectively analyze the curative efficacy of umbilical cord blood transplantation (UCBT) using total body irradiation (TBI)-based myeloablative conditioning regimen without antithymocyte globulin (TBI/Ara-c/CY w/o ATG) in adolescent and adult patients with high-risk hematological malignancies. Outcomes of forty-five consecutive adolescent and adult patients with high-risk hematological malignancies treated with TBI-based myeloablative UCBT without ATG in a single center between September 2006 and February 2012 were retrospectively analyzed. The conditioning regimen included TBI/Ara-c/CY:TBI 12GY (four fractionated) + Ara-C 8g/m2 (two days fractionated) + CY 120mg/kg (two days fractionated), and rhG-CSF was administered for myeloid leukemia by continuous infusion at a dose of 5μg·kg−1·d−1. Infusion of G-CSF was started 24 hours before the first dose of Ara-C and stopped at the completion of the last dose. The patients included 31 males and 14 females, with a median age of 21 years (range: 14–40) and a median weight of 58 kg (range: 42–76). Of those, 17 patients (37.8%) had advanced disease. Double UCB grafts were used for 16 patients, while single UCB graft was used for 29 patients. The median number of nucleated cells infused was 3.57 (1.94∼6.76)×107/kg and the median CD34+cells infused was 2.11 (0.71∼4.95)×105/kg. All patients received a combination of cyclosporine (CSA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. All patients successfully engrafted. The median times to neutrophil (ANC≥0.5×109/L) and platelet (PLT PLT≥20×109/L) recovery were 19 days (range: 13–35 days) and 36 days (range: 24–90 days) respectively after transplantation in 40 evaluable patients. Acute GVHD occurred in 21 patients and the cumulative incidences of gradeII-‡W and grade III-‡W acute GVHD were 24.4% and 11.1%, respectively. Chronic GVHD occurred in five of 40 evaluable patients (12.5%). Of the 45 patients, 9 (20%) had relapse. After a median follow-up of 25.1 months (range: 6–65.1) among survivors, treatment-related mortality (TRM) within 100 days and within one year was 8.9% and 24.4%, respectively. The main causes of death were pneumonia and severe acute GVHD. The probability of three-year disease-free survival and overall survival (OS) was 53.3% and 57.8%, respectively. The TBI/Ara-c/CY myeloablative conditioning regimen has been well tolerated by patients at our institution and seems to be able to establish sustained donor cell engraftment and decrease the risk of transplant-related death. For high risk patients and patients with advanced disease, this conditioning regimen could reduce relapse and chronic GVHD, indicating the feasibility of TBI/Ara-c/CY as a conditioning regimen for CBT in adolescent and adult patients with hematologic malignancies. Disclosures: Sun: Key Scientific and Technological Project of Anhui province “Twelfth Five-Year Plan” (11010402164): Research Funding; the Fund of the Key Medical Project of Anhui Provincial Healthy Department (2010A005): Research Funding; Anhui Provincial “115” Industrial Innovation Program (2009): Research Funding.

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Post-Transplantation Cyclophosphamide (PT-CY) After Myeloablative Conditioning Regimen (MAC) In Unmanipulated Haploidentical Bone Marrow Transplantation (hBMT) Is Highly Effective As Gvhd Prophylaxis and Disease Free Survival In Pediatric and Adult Patients With High Risk Leukemia

Blood ◽

10.1182/blood.v122.21.4576.4576 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4576-4576

Author(s):

Maria Domenica Simone ◽

Anna Proia ◽

Alessandro Severino ◽

Alison Shardlow ◽

Novella Natale ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Conditioning Regimen ◽

Marrow Transplant ◽

Adult Patients ◽

High Rate ◽

Myeloablative Conditioning ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Disease Free

Introduction BMT from HLA haploidentical family members (hBMT), using either T-cell depleted or T-cell replete grafts, is increasingly employed in patients who urgently need (but lack) a donor. After the promising results in hBMT obtained by the Baltimore group (Luznik et al., Biol Blood Marrow Transplant 2008, Blood 2010) introducing post-transplant high-dose cyclophosphamide (PT-CY) following a non-myeloablative conditioning regimen, the Genoa group (Raiola et al., Biol Blood Marrow Transplant 2013) has shown, in the haploidentical setting that a myeloablative conditioning (MAC) with PT-CY (on day +3 and +5), cyclosporine from day zero and mycophenolate mofetil (MMF) from day +1, is associated with a high rate of engraftment, acceptable TRM and GVHD, and induces durable remission with low incidence of relapse in a high proportion of patients with high-risk hematologic malignancies. We now report a series of 13 heavly pretreated high-risk leukemia patients who underwent a MAC protocol consisted of TBF regimen: Thiotepa (10 mg/kg), Busulfan (9,6 mg/kg) and Fludarabine (150 mg/mq). As graft versus host disease (GVHD) prophylaxis, 2 patients received a 5 drugs combination (ATG-Fresenius, CSA, MTX, MMF and Basiliximab) and stem cells source was G-CSF-primed haploidentical bone marrow (hBM) cells (Di Bartolomeo et al., Blood 2013). In 11 patients stem cells source was non-primed unmanipulated hBM cells, and GVHD prophylaxis consisted of PT-CY (50mg/kg) iv on day +3 and +4, CSA 2.5 mg/kg/day and MMF 45 mg/kg/day from day +4. Results From 2008 to 2013, 11 adult patients (M/F=8/3; median age 40 years, range 23 to 62) and 2 pediatric patients (M/F=1/1, age 4 and 7 years) with high risk ALL (1 pediatric; 2 adult), AML (1 pediatric; 8 adults) and one Richter evolution of CLL, underwent T replete hBMT. At time of transplant 10 patients were in CR (CR1=9, CR2=1), 1 in a good PR and 2 had refractory disease. Grafts contained a median of 5.68 x 108/kg nucleated BM cells (range 0.7-62.1), 2.14x106/kg CD34+ cells (range 0.55-7.09) and 34.7x106/kg CD3+ cells (range 16-93.4). 12 patients are evaluable for engraftment. This occurred in 100% for neutrophils and 93% for platelets, with a median time to neutrophil recovery (> 0.5 x 109/L) of 22.5 days (range, 13-40) and to platelet recovery (> 20.0 x 109/L) of 27.5 days (range, 17-49). All patients had full donor chimerism by day +30. Non relapse mortality (NRM) was 23%: 2 pt died for sepsis (one before engraftment), 1 for aGVHD. 4 patients had grade I and 3 grade II aGvHD, respectively. Only one patient had a grade III, and another had grade IV fatal GVHD. 3 patients had only limited chronic GvHD. Up to now, only 3 patients have relapsed and of these 2 have died. 8 patients (61.5%) are currently surviving, 7 of them are disease-free with median follow-up time of 165 days (range 32-896 days) from transplant. Conclusion Our preliminary results confirm that haplo-BMT following a MAC regimen, is a feasible treatment in pediatric and adult patients, and that PT-CY is highly effective as GVHD prophylaxis, producing a high rate of stable engraftment with encouraging non relapse mortality and relapse-free survival. Disclosures: No relevant conflicts of interest to declare.

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Results of T Cell Depleted (TCD) Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) from HLA Matched (HLA-M) or Partially Mismatched (HLA-MM) Unrelated Donors (URD) in Patients with Hematologic Malignancies: Sustained Engraftment and Low Incidence of Graft-vs-Host Disease (GvHD).

Blood ◽

10.1182/blood.v108.11.3133.3133 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3133-3133

Author(s):

Ann A. Jakubowski ◽

Esperanza B. Papadopoulos ◽

Nancy A. Kernan ◽

Farid Boulad ◽

H.R. Castro-Malaspina ◽

...

Keyword(s):

High Risk ◽

Acute Leukemia ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Hla Typing ◽

Entire Group ◽

Hematopoietic Stem ◽

Prior Therapy ◽

Gvhd Prophylaxis ◽

Low Incidence

Abstract Curative strategies for hematologic malignancies include alloHSCT, which has become a treatment option for older pts, as well as those with more extensive prior therapy and comorbidities. This has stimulated research on the development of less toxic but comparably effective approaches to transplantation at the level of cytoreduction, alternate graft sources, graft manipulation, and GvHD prophylaxis. To this end, between 7/2001 and 12/2005, we administered TCD HSCTs, derived from HLA-M or HLA-MM URDs, to 36 adult pts as treatment for a variety of hematologic malignancies on a clinical trial. The conditioning regimen was designed to reduce regimen related toxicity while preserving adequate immunosuppression to allow for engraftment. The TCD grafts allowed transplantation across HLA disparate pt-donor pairs without the use of additional renal and hepatotoxic GvHD prophylaxis. The conditioning regimen consisted of hyperfractionated total body irradiation (HFTBI) (1375 cGy), thiotepa (5mg/kg) x 2d, fludarabine (25mg/m2) x 5d and antithymocyte globulin (ATG) x 2d. HLA typing was performed by DNA SSOP analyses for A,B,C, DRB1, and DQB1, and donors were matched at ≥8 of 10 alleles. Pts received TCD-PBSC (n=29) or TCD-BM (n=7) from HLA-M (21 pairs) or HLA-MM (15 pairs) URDs. PBSCs were TCD by Isolex 300i CD34+ selection followed by sheep E-rosette depletion, and BMs were depleted with soybean agglutination and sheep E-rosette depletion. The median age was 40.6 (range 18–63)yrs; 10 pts ≥ 50 yrs. Diseases included AML and ALL CR1 (only standard or high risk), AML and ALL CR2, ALL ≥ CR3, acute biphenotypic leukemia, CML in CP, MDS, T-PLL. The median followup is 22 (range 6–55) mos. All evaluable pts engrafted neutrophils, 31 of 35 evaluable pts engrafted platelets. Four pts died of complications prior to platelet engraftment, including one pt with late graft failure. The 100d non-relapse mortality was 20% with most (>50%) deaths due to infection. The incidence of acute (a) grade II–III and chronic (c) GvHD was low for the entire group of 36 pts at 11% and 28%, respectively, when compared to that of unmodified transplantation. The incidence of aGvHD was 14% and 7%, and cGvHD (majority - limited) was 26% and 30% for HLA-M and HLA-MM transplant pairs, respectively. Estimated 3 yr DFS is 60% for both HLA-M and HLA-MM transplants, and 83% for standard risk and 41% for high risk disease pts. Only one pt has relapsed. These results indicate that a transplantation strategy using HFTBI, thiotepa, fludarabine and ATG followed by TCD PBSC or BM, but without posttransplant immunomodulating agents, is well-tolerated in an older patient group (median age 40 yrs) even with HLA-MM URDs. Although this approach appears to provide an antileukemic effect for acute leukemia pts transplanted in remission of acute leukemia, this will need to be confirmed with longer followup.

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Equivalent Survival Following Fludarabine/Melphalan Reduced Intensity Conditioning with or without Rabbit ATG As Part of GvHD Prophylaxis

Blood ◽

10.1182/blood.v118.21.1959.1959 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1959-1959

Author(s):

J. Mark Prichard ◽

Samatha Muppidi ◽

Christopher R Flowers ◽

Jonathan L. Kaufman ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Donor Cell ◽

Hematologic Malignancies ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Gvhd Prophylaxis ◽

Reduced Intensity

Abstract Abstract 1959 Introduction: Reduced intensity conditioning (RIC) prior to allogeneic transplantation allows donor cell engraftment with the maintenance of a graft versus malignancy effect. A recent CIBMTR registry study suggested worse outcomes for patients receiving anti-thymocyte globulin (ATG) as part of the conditioning regimen. To further study the role of ATG when added to a fludarabine and melphalan RIC regimen in the unrelated donor (URD) setting, we have retrospectively studied 76 consecutive patients with advanced hematologic malignancies who underwent URD transplantation. Comparisons were made between cohorts that did or did not receive ATG (given primarily for HLA disparity) for pretransplant graft vs. host disease (GvHD) prophylaxis. Pateints and Methods: Seventy six patients with advanced hematologic malignancies (43% CIBMTR high-risk) received fludarabine and melphalan (FluMel) conditioning with or without pre-transplant rabbit ATG 6 mg/kg as part of GvHD prophylaxis. Twenty five patients who received ATG (24 of whom received grafts from donors mismatched at 1 or 2 HLA loci) were compared with 51 patients who did not receive ATG (45 of whom received grafts from HLA matched donors with six donors mismatched at a single locus). The majority of patients received post-transplant tacrolimus with either methotrexate (MTX) or mycophenolate mofetil for GvHD prophylaxis. With the exception of HLA disparity, pre-transplant patient characteristics were similar between groups (Figure 1). Results: With median follow up of 481 days and 376 days for the ATG and no ATG cohorts, respectively, K-M overall survival estimates were similar, with 2 year OS of 62 vs. 47 percent, respectively, for the ATG vs no ATG groups (p=.34). On multivariate analysis, the inclusion of MTX in GvHD prophylaxis was favorably associated with overall survival (p=.004), and was associated with a significant reduction in the incidence of severe (gr 3–4) acute GvHD (p=.03). There were no significant differences in pre-transplant creatinine, age, or comorbidity index scores between patients who did or did not receive MTX. Conclusions: Fludarabine and melphalan RIC, with or without pre-transplant ATG, produced similar outcomes following URD transplantation, despite the fact that patients receiving ATG in this series were more likely to have received a HLA mismatched graft. The inclusion of MTX for GVHD prophylaxis resulted in less severe acute GVHD and better survival when compared with tacrolimus/MMF. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Kaufman:Merck: Research Funding; Keryx: Consultancy; Novartis: Consultancy; Onyx Pharmaceuticals: Consultancy; Millenium: Consultancy; Celgene: Research Funding. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Sinha:Celgene: Research Funding.

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