Reduced intensity conditioning regimen with fludarabine, busulfan, and low-dose TBI (Flu-BU2-TBI): Clinical efficacy in high-risk patients

2010 ◽  
Vol 85 (4) ◽  
pp. 243-248 ◽  
Author(s):  
Mutsumi Takahata ◽  
Satoshi Hashino ◽  
Kohei Okada ◽  
Masahiro Onozawa ◽  
Kaoru Kahata ◽  
...  
Keyword(s):  
High Risk ◽  
Clinical Efficacy ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
High Risk Patients ◽  
Reduced Intensity Conditioning Regimen ◽  
Risk Patients ◽  
Reduced Intensity

Phase I/I Clinical Trial for the Evaluation of Bortezomib within the Reduced Intensity Conditioning Regimen (RIC) and Post-Allogeneic Transplantation As Gvhd Prophylaxis Among High-Risk Myeloma Patients. EudraCT: 2005–004858-27

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3025-3025
Author(s):  
Jose Antonio Perez-Simón ◽  
Teresa Caballero-Velazquez ◽  
Cristina Encinas ◽  
Cristina Castilla-Llorente ◽  
Rodrigo Martino ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract Abstract 3025 Introduction: Although allogeneic stem cell transplantation (allo-SCT) is the only curative treatment for MM, it is associated to a high morbility and mortality. Moreover, relapses are common after allo-RIC. Accordingly, new strategies are required to reduce both the risk of relapse and the toxicity of the procedure. As we have previously demonstrated, Bz induces a selective depletion of alloreactive T-cells and has immunomodulatory properties which might be of potential benefit for GVHD control. The primary end point of this study was to evaluate the efficacy of allo-RIC in terms of response when Bz was added as part of a reduced intensity conditioning prior to allo-SCT. Secondary end points included incidence of GVHD and analysis of the toxicity of the procedure when Bz is also administered post-infussion as part of the GVHD prophylaxis. Method: Prior to allo-RIC, patients received two cycles of Bz plus dexamethasone. Conditioning consisted of fludarabine (30 mg/m2 intravenously on days -9 to -5) and melphalan (70 mg/m2 intravenously on days -4, -3) plus Bz 1, 3mg/m2 on day - 11 and -2. GVHD prophylaxis included cyclosporine (CsA) and methotrexate for the first 9 patients and CsA plus MTX and Bz on days +3 and +7 for the remaining 7 patients. From day +50 post allo-RIC 7 cycles of Bz (+1, +8, +15) were administered, the first two cycles every 28 days and the rest every 56. Results: 16 patients from the Twenty-one initially enrolled, were evaluable. All 16 patients had received at least 2 lines of therapy including autologous-SCT. Disease status was CR or nCR in 4 patients, 9 had PR and the remaining 3 patients had relapsed / progressive disease. 15 patients maintained or improved status at transplant including all × patients with active disease at transplant. Eight patients (50%) relapsed, four with extramedullary involvement. No patient developed grade 4 aGVHD.Grades 2–3 aGVHD occurred in 6 patients (37%). Interestingly, two out of the nine (29%) patients who received Bz on days +3 and 7 developed grades 2–3 acute GVHD as compared to four of the nine (44%) who did not receive it. In terms of toxicity, one patient did not achieve platelet engraftment and 2 patients developed peripheral neuropathy requiring treatment withdrawal. 8 patients died, four of them due to relapse (MRT: 25%). With a median follow-up of 457 days overall survival was 46%. Conclusions: The current trial is the first evaluating the efficacy and safety of Bz as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Regarding the efficacy of the procedure all but one patient improved disease status post-alloRIC although relapse rate was still high in this heavily pretreated population. In addition, Bz post-alloSCT is well tolerated and may decrease the incidence of GVHD. Disclosures: Perez-Simón: Janssen-Cilag: Patents & Royalties. Off Label Use: This study evaluates the efficacy of Bortezomib as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

A Phase II Trial Combining Radiolabeled Anti-CD45 Antibody with Fludarabine and Low-Dose Total Body Irradiation (TBI) Followed by Related or Unrelated Hematopoietic Cell Transplantation for Patients Under Age 50 with Advanced Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1924-1924
Author(s):  
Raya Mawad ◽  
Ted A. Gooley ◽  
Joseph G Rajendran ◽  
Darrell R. Fisher ◽  
Ajay K. Gopal ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Reduced Intensity Conditioning ◽  
Younger Patients ◽  
Reduced Intensity Conditioning Regimen ◽  
Total Body ◽  
Reduced Intensity

Abstract Abstract 1924 Innovative therapeutic approaches are needed to reduce the morbidity and high relapse rates in patients with advanced AML or high-risk MDS following myeloablative hematopoietic cell transplantation (HCT). Success with stable donor chimerism and low toxicity following infusion of allogeneic peripheral blood stem cells (PBSC) with reduced-intensity regimens affords an opportunity to induce a graft-versus-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burden at the time of HCT. In an attempt to improve outcomes, we previously transplanted 58 patients older than age 50 with advanced AML (beyond first remission) or high-risk MDS (≥5% marrow blasts at the time of HCT) in a Phase I trial using 131I-labeled anti-CD45 antibody (BC8) in conjunction with fludarabine (FLU) and 2Gy total-body irradiation (TBI). Data from this study suggested that 131I-anti-CD45-targeted radiotherapy could be safely integrated into a reduced-intensity conditioning regimen for older, high-risk patients with AML or MDS yielding encouraging survival outcomes. These results prompted us to evaluate a similar strategy in younger patients (ages 16–50) with advanced AML or high-risk MDS who may not be able to receive a high dose HCT conditioning regimen. In this phase I dose–escalation trial 14 patients received a dose of 131I-BC8 that delivered 10–27 Gy of targeted radiation to the healthy organ receiving the highest dose combined with FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 7) or unrelated (n = 7) PBSC grafts. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The 131I radiation dose was escalated until the maximum planned dose of 28 Gy was reached without any appreciable dose limiting toxicity. The median patient age was 39.5 (range, 23.8–49.7) years. Thirteen patients had AML, with 9 patients in second complete remission, 3 with primary refractory disease, and 1 in active relapse. One patient had advanced CMML with >5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a complete remission in 7 patients (50%), and 11 of the 12 evaluable patients had 100% donor CD3+ and CD33+cell engraftment by day 28 after HCT; an additional patient had 79% CD3 and 82% CD33 positive donor marrow cells at day 28. The absolute neutrophil count surpassed 500/μL at a median of 15 (range, 13–22) days. Self-sustained platelet levels of 20,000/μL were reached at a median of 11 (range, 11–27) days after HCT. Five patients (36%) are surviving relapse-free 46 to 99 months (median 87 months) after HCT. Seven patients (50%) have died, with five patients relapsing 0.9 to 45 months after HCT. No non-relapse mortality occured by day 100; however, two patients died 14 and 18 months after HCT of cardiomyopathy and GVHD complications, respectively. This study demonstrates that, in addition to a standard reduced intensity conditioning regimen, an average of 27 Gy of targeted 131I radiotherapy can be delivered to bone marrow, an average of 20Gy to the liver, and an average of 84 Gy to the spleen without a marked increase in day 100 mortality for younger patients. This strategy may thus provide a reasonable alternative for patients with high-risk AML/MDS who may not be able to tolerate a high dose conditioning HCT. Disclosures: No relevant conflicts of interest to declare.

Tacrolimus and Mycophenolate Mofetil as Post-Grafting Immunosuppression After Conditioning with Fludarabine and Low-Dose Total Body Irradiation for Recipients of HLA-Matched Sibling or Unrelated Donor Hematopoietic Cell Transplants in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3354-3354
Author(s):  
Tara Gregory ◽  
Mark W. Brunvand ◽  
Peter A. McSweeney ◽  
Scott I. Bearman ◽  
Michael Maris ◽  
...  
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity Conditioning Regimen ◽  
Matched Sibling ◽  
Total Body ◽  
Reduced Intensity

Abstract Abstract 3354 Poster Board III-242 Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder of hematopoiesis that results in bone marrow failure and myelodysplasia. Hematopoietic cell transplantation is the only curative therapy. The success of allogeneic stem cell transplantation has been limited, in part, by regimen-related toxicity associated with high-dose preparative regimens. Nonrandomized studies suggest that long-term remissions are achievable when using allogeneic SCT as treatment for PNH. Mikolajewska, et al. reported treatment of 7 patients with high risk PNH with a reduced intensity conditioning regimen of fludarabine and total body irradiation (TBI). Mycophenolate mofetil (MMF) and cyclosporine were utilized as graft versus host disease (GvHD) prophylaxis (2008 ASH Annual Meeting Abstracts, 4407). The objective of this study is to evaluate the combination of tacrolimus and MMF as GvHD prophylaxis after conditioning with fludarabine and low dose TBI in PNH patients who are not candidates for conventional ablative allografting. This is a novel approach to immunosuppression incorporating an early but extended taper of tacrolimus on day +80. Patients and Methods: Four patients with PNH underwent allogeneic SCT after a reduced intensity regimen. Patients received fludarabine (30mg/m2/day) on days -4 to -2 and low dose TBI (200 or 400 cGy at 6-7 cGy/min from a linear accelerator) on day 0. Two patients received TBI 200 cGy and three received 400 cGy. One patient failed to engraft with TBI 200 cGy and was transplanted again with TBI 400 cGy. GvHD prophylaxis was with tacrolimus (0.06mg/kg PO BID) starting on day -3 and MMF (15mg/kg PO BID for related and TID for unrelated donors) starting from day 0. All patients received filgrastim-mobilized peripheral blood stem cells from either from an HLA-matched sibling (n=1) or matched unrelated (n=4) donor. Results: The median follow up was 20 (range 3 to 36) months after SCT. One patient who received TBI at 200 cGy failed to engraft after an unrelated transplant. She underwent a second transplant from a different unrelated donor with TBI with 400 cGy with engraftment after the second procedure. The patients engrafted reaching a neutrophil count ≥ 500 a median of 16 (range 15 to 18) days post-transplant. Each achieved eradication of their PNH clone based on subsequent marrow and blood chimerism studies together with absence of clinical signs of PNH. Acute GvHD (grades II-IV) occurred in three patients. Chronic GvHD occurred in two patients. Day 100 mortality was 0% and all four patients are alive with an EGOG status of 0-1. Conclusions: A reduced intensity conditioning regimen consisting of fludarabine and TBI at 200 cGy or 400 cGy with tacrolimus and MMF as post grafting immunosuppression appears well tolerated for performing allogeneic transplants in PNH. Donor cell engraftment with eradication of the PNH clone was observed with this approach. The higher dose of TBI (400 cGy) might be more effective in overcoming graft rejection and warrants further investigation. Disclosures: No relevant conflicts of interest to declare.

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