Intensive combination chemotherapy and autologous bone marrow transplantation leads to the reappearance of philadelphia chromosome-negative cells in chronic myelogenous leukemia

Abstract

Fifteen patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who were ineligible for allogeneic bone marrow transplantation (BMT) or alpha-interferon therapy were included in this study. Eight patients were in the first late chronic phase, five were in the second chronic phase, one was in the accelerated phase, and one was in the blastic phase. Autologous bone marrow cells (median, 2.5 x 10(8) nucleated cells/kg) were stored at a median of 30 months after diagnosis. Patients were treated with cyclophosphamide (1.5 g/m2 daily for 4 days), carmustine (BCNU) (300 mg/m2), and etoposide (VP-16) (250 mg/m2 daily for 3 days) (CBV), followed by reinfusion of autologous bone marrow. Hematopoietic recovery was rapid, and toxicity was mild to moderate in 14 patients. One patient died of cytomegalovirus pneumonitis. Eight of 15 patients showed Ph suppression to less than 90% Ph-positive metaphases after autologous BMT. Major cytogenetic responses (Ph suppression to less than 35% Ph-positive metaphases) developed in four patients. Cytogenetic responses were observed in 4 of 11 patients infused with 100% Ph-positive marrows, and in all 4 patients infused with Ph-mosaic marrows (mixture of diploid and Ph-positive cells). Better results were observed when autologous BMT was performed in the chronic phase compared with the advanced phases. The major cytogenetic responses have lasted for 3, 4, 12, and 15+ months, whereas minor cytogenetic responses lasted for only a short time (less than 2 months). Three of seven patients (43%) in the chronic phase with previous resistance to alpha-interferon therapy became sensitive to alpha-interferon therapy after autologous BMT. The authors concluded that intensive chemotherapy followed by autologous BMT produced cytogenetic remissions in patients with Ph-positive CML and reinduced disease sensitivity to alpha-interferon therapy in patients previously resistant to it. This is particularly useful when treatment is given during the chronic phase and stem cells are collected at a time of previous cytogenetic remission.

Introducing Graft-Versus-Leukemia into Autologous Stem Cell Transplantation

“…IFN-a and IL-2 have undergone clinical studies after transplantation either alone or in combination (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Recombinant IFN-a, despite its known antiproliferative and immunomodulatory effect, has not been widely used to prevent relapse after autologous SCT.…”

“…Some patients subsequently achieved a cytogenetic remission, but their original selection on the basis of a greater content of Philadelphia (Ph)-negative cells makes the interpretation difficult. Other groups (22)(23)(24) have reported the use of IFN-a early postautografting for chronic phase CML to prevent disease recurrence. Again, because of the uncontrolled nature of the data collection, no conclusions can be drawn.…”

New Directions in the Biology and Therapy of Chronic Myeloid Leukemia

“…Another very interesting discovery in this trial is the occurrence of collateral sensitivity to a-interferon among CML4. [21][22] . interferon-resistant patients which is very high following this autologous transplant2 I .…”

Collection of Philadelphia-negative peripheral blood progenitor cells in unselected patients with chronic granulocytic leukaemia

“…In some patients reengrafted bone marrow has been Ph negative. 10,11 There is now a suggestion that autologous transplantation also improves survival in CGL. 12 Recently some centres have reported attempts to improve the quality of autologous material available for transplant by eliminating or reducing the size of the Ph-positive clone.…”