Autologous bone marrow transplantation for acute myeloid leukemia using 4-hydroperoxycyclophosphamide-purged bone marrow and the busulfan/etoposide preparative regimen: a follow-up report

Abstract

Summary:We studied the use of autologous bone marrow transplantation (ABMT) as treatment for acute myeloid leukemia (AML) in adults up to age 60. We used a preparative regimen of busulfan 16 mg/kg plus etoposide 60 mg/kg and bone marrow purged with 100 g/ml of 4-hydroperoxycyclophosphamide (4HC). We treated 50 first remission patients; there were two treatmentrelated deaths and 13 relapses. With median follow-up of 6.8 years (minimum 4.5) disease-free survival (DFS) is 70%, relapse rate 27% and overall survival 72%. Patients with favorable cytogenetics had DFS 78% and relapse 18% whereas unfavorable patients had DFS 63% and relapse rate 35%. For 25 patients in second or third remission there were five treatment-related deaths and seven relapses. DFS is 52% and relapse rate 35%. None of six patients with primary refractory AML had long-term disease control. These data support the use of ABMT with an intensive preparative regimen and purged bone marrow as a highly effective treatment for adults with AML. Keywords: ABMT; AML; 4HC During the past decade there have been a number of improvements in the treatment of young adults with acute myeloid leukemia. All-trans retinoic acid (ATRA) has been identified as an important new agent in the treatment of acute promyelocytic leukemia. 1 High-dose Ara-C (HDAC) has been confirmed as superior to standard-dose Ara-C for post-remission therapy. 2 HDAC has been identified as especially helpful in the favorable cytogenetic groups with t(8; 21) and inversion 16q. 3 However, the majority of young adults with AML lacking favorable prognostic factors still fare poorly with conventional chemotherapy. Even with the use of repeated courses of HDAC post-remission therapy, only 20-25% of these patients will remain in long-term remission. 2 Experience with allogeneic bone marrow transplantation demonstrates that intensive therapies can lower the relapse rate and improve disease-free survival (DFS) for young adults with AML. 4 Furthermore, studies comparing preparative regimens have demonstrated the principle that more intensive preparative regimens can lower the relapse rate. 5 However, in the allogeneic transplant setting, these improvements in disease control have been offset by increases in treatment-related mortality (TRM). The use of targeted radiation through radioimmunoconjugates has produced very promising results and may allow this impasse to be broken. 6 Although allogeneic transplantation consistently produces improved DFS when compared to conventional chemotherapy, this treatment is limited by donor availability and by the 25% TRM which raises the question as to whether reserving allogeneic transplant as a salvage therapy would be an equal or better strategy.Autologous bone marrow transplantation (ABMT) has been actively investigated as an alternative way to improve outcome for AML patients. The treatment is attractive because of the potential for broad use in adults up to and perhaps beyond age 60 and because of relatively low TRM. Because of the absence of graft-versus-host ...

High-dose chemotherapy (CTM) for breast cancer

“…The marrow buffy coat was separated from the marrow suspension by centrifugation (COBE 2991 or COBE Spectra, Denver, CO, USA) and cryopreserved as previously described. 19 On day zero of HDCT, the bone marrow was rapidly thawed in a 37°C water bath at the patient's bedside and infused through a central venous catheter following 25 g of intravenous mannitol as renal failure prophylaxis. One hundred and thirty-three patients had stem cells collected from their peripheral blood in lieu of pelvic bone marrow.…”

Continuous infusion idarubicin and oral busulfan as conditioning for patients with acute myeloid leukemia aged over 60 years undergoing autologous stem cell transplantation

“…The median number of days to stable recovery of neutrophils of 0.5 Â 10 9 /l and platelets of 20 Â 10 9 /l was 11 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)) and 12 (6-38), respectively. The median number of platelet and blood units transfused was 3 (1-7) and 4 (0-5), respectively.…”

“…10,11 Different approaches including in vivo or ex vivo purging, immunotherapy post-ASCT and intensification of the conditioning regimen have been investigated in an attempt to achieve more durable disease control. [23][24][25] Although the adoption of alternative regimens such as BAVC result in lower TRM as compared to BuCy2, the relapse rate is higher.…”

“…In the autologous setting, alternative chemotherapy combinations have been proposed to induce superior antileukemic activity and/or reduce toxicity. [10][11][12] In particular, a recent survey from the European Cooperative Group for Blood and Marrow Transplantation (EBMT) reported that the BAVC regimen (BCNU 800 mg/ m 2 , amsacrine 150 mg/m 2 /day for 3 days, VP-16 150 mg/m 2 / day for 3 days and ara-C 300 mg/m 2 /day for 3 days) demonstrated comparable survival with lower TRM. 13 In young/adult AML patients, we previously demonstrated the feasibility and efficacy of an original conditioning regimen, called IBu, consisting of high-dose idarubicin (IDA) administered at 20 mg/m 2 /day as continuous infusion (CI) for 3 days (day -13 to day -11) followed by oral busulfan (Bu) given at 4 mg/kg/day from day -5 to day -2.…”

Negative selection and protection of normal progenitor cells for autografting

“…Autologous bone marrow transplantation (ABMT) and peripheral blood stem cell (PBSC) reinfusion 2 have emerged as alternative approaches for the treatment of hematologic malignancies and selected tumors that respond to dose-escalation therapy. There is clear evidence of the clinical benefits of high-dose therapy with ABMT for the treatment of acute leukemias, [3][4][5][6][7] non-Hodgkin's lymphoma, [8][9][10][11] Hodgkin's disease, 10 multiple myeloma, 12 breast cancer, [13][14][15] and germ cell carcinoma of the testes. 16 Studies examining ABMT or PBSC reinfusion are also underway for patients with chronic myelogenous leukemia [17][18][19] and neuroblastoma.…”