Melphalan and purine analog–containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation

Giralt, Sergío; Thall, Peter F.; Khouri, Issa F.; Wang, Xuemei; Braunschweig, Ira; Ippolitti, Cindy; Claxton, David F.; Donato, Michèle; Bruton, J.; Cohen, A.; Davis, M.; Andersson, Börje S.; Anderlini, Paolo; Gajewski, James; Kornblau, Steven M.; Andreeff, Michael; Przepiorka, Donna; Ueno, Naoto T.; Molldrem, Jeff; Champlin, Richard E.

doi:10.1182/blood.v97.3.631

Cited by 567 publications

(454 citation statements)

References 27 publications

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“…The delayed immune reconstitution following serotherapy with ATG may have been the cause of serious opportunistic infections observed in a proportion of patients, as previously observed in a study of patients receiving Campath-1H for GVHD prophylaxis . In addition, ATG administration may also lead to a reduced graft-versus-myeloma effect, which may explain the low rate of CR observed in the present study compared with other trials (Slavin et al, 1998;Badros et al, 2001;Giralt et al, 2001;Khouri et al, 2001;Michallet et al, 2001) and also progression during the first year post allograft documented in nine out of the 17 patients who could be evaluated.…”

Section: Discussioncontrasting

confidence: 42%

“…One of the reasons for the acceptable TRM in this study was the low incidence of severe, acute GVHD. Other non-myeloablative conditioning regimens have been reported to be associated with a higher incidence of acute GVHD grade II-IV of 38-60% (Badros et al, 2001;Giralt et al, 2001;McSweeney et al, 2001). The in vivo use of ATG, with its prolonged half-life, as part of the conditioning regimen in our study might have contributed to the low incidence of GVHD.…”

Section: Discussionmentioning

confidence: 69%

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Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning

Einsele¹,

Schäfer²,

Hebart³

et al. 2003

Br J Haematol

107

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Summary. Allogeneic stem cell transplantation (allo‐SCT) after reduced‐intensity conditioning was evaluated in 22 patients (median age 53, range 36–66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)‐identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA‐mismatched unrelated donor]. Graft‐versus‐host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant‐related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2–19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8–36 months) post allografting. Estimated 2 year overall and event‐free survival was, respectively, 25·5% and 22·0% for the whole patient group, and 62·5% and 57·1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0·0182) and absence of cGVHD (P = 0·069) were associated with shorter event‐free survival. Thus long‐term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.

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Section: Discussioncontrasting

confidence: 42%

Section: Discussionmentioning

confidence: 69%

Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning

Einsele¹,

Schäfer²,

Hebart³

et al. 2003

Br J Haematol

107

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“…6 Similarly the European BMT Registry (EBMT) has demonstrated a rapid uptake of RIC HSCT from 1998. 7 In Australia and New Zealand, the most commonly used RIC regimen is Fludarabine Melphalan (FluMel) with or without in vivo T-cell depletion, 5 as initially described by Giralt et al 8 At the recent Centre for International Bone Marrow Transplant Registry (CIBMTR) consensus meeting, FluMel p140 mg/m 2 was voted as one of the more common regimens used for RIC and considered to be a RIC regimen by 75% of attendees. 9 This recommendation from the panel of experts at the CIBMTR conference suggests a high utilisation of FluMel throughout the HSCT community; however, there are few large studies with more than 200 patients.…”

Section: Introductionmentioning

confidence: 99%

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients

Bryant

Nivison-Smith

Pillai

et al. 2013

Bone Marrow Transplant

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This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years . In all, 234 patients had myeloid malignancies, with AML (n ¼ 166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n ¼ 64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLAidentical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P ¼ 0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

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“…HSCT performed with various preconditioning regimens has been attempted to rescue these patients, and some positive effects have been obtained. [4][5][6][7][8][9] HSCT using myeloablative preconditioning regimens resulted in an increased frequency of TRM, [4][5][6] and therefore HSCT with nonmyeloablative preconditioning regimens has also been tried. However, early relapse and remission induction failure were often observed in such patients.…”

Section: Introductionmentioning

confidence: 99%

A novel reduced-intensity umbilical cord blood transplantation using a recombinant G-CSF combined with high-dose Ara-C for active myeloid malignancies

Gotoh

Yoshizawa

Katagiri

et al. 2014

Bone Marrow Transplant

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Non-remitting patients with hematologic myeloid malignancies have poor prognosis. To overcome this problem, we investigated the use of reduced-intensity preconditioning umbilical cord blood transplantation (RICBT) combined with recombinant G-CSF (rG-CSF) with high-dose Ara-C, fludarabine, melphalan, and 4 Gy of TBI in a phase I/II study in patients with non-remitting myeloid hematologic malignancies. Thirteen patients were enrolled, including 12 with non-remitting AML and one patient with blastic crisis CML (CML-BC). The patients' median age was 45 years, with a median comorbidity index of 4. All patients received 4/6 serological HLA-antigen matched unrelated umbilical cord blood. All patients were engrafted within 30 days after RICBT (median, 20 days; range, 14-29) and achieved complete remission without prior hematopoiesis. Common grade III non-hematologic toxicities included eight cases of transient mucositis (62%) and six cases of febrile neutropenia (46%). Transplant-related mortality was 7.7%. The 1-year overall survival was 28.6% in cases without post-RICBT treatment and 83.3% in cases with post-RICBT treatment. These data suggest that in active AML and CML-BC, the combination of rG-CSF with high-dose Ara-C and fludarabine/melphalan/4 Gy TBI with a reduced-intensity preconditioning regimen is well tolerated, secures engraftment and has significant anti-leukemia activity. In addition, performing post-RICBT treatment may provide high-quality long-term survival and remission.Bone Marrow Transplantation (2014) 49, 955-960;

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Melphalan and purine analog–containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation

Abstract: A reduced-intensity preparative regimen consisting of melphalan and a purine analog was evaluated for allogeneic transplantation in 86 patients who had a variety of hematologic malignancies and were considered poor candidates for conventional my-

Cited by 567 publications

References 27 publications

Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning

Follow‐up of patients with progressive multiple myeloma undergoing allografts after reduced‐intensity conditioning

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients

A novel reduced-intensity umbilical cord blood transplantation using a recombinant G-CSF combined with high-dose Ara-C for active myeloid malignancies

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