pentostatin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

The purine nucleoside analogues (PNA), fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and 2'-deoxycoformycin (DCF), represent a novel group of cytotoxic agents with high activity in low-grade lymphoid malignancies. However, several investigations have revealed that these agents are active also in acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). Synergistic interaction between FA or 2-CdA with cytarabine (Ara-C) have been demonstrated in both preclinical and clinical studies. PNA enhance the cell concentration of Ara-CTP, which is active metabolite of Ara-C. It is likely that the addition of granulocyte colony stimulating factor (G-CSF) may further improve the effects of FA (FLAG) or 2-CdA (CLAG). The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. An alternative approach to increase FLAG activity might be the addition of investigational drugs with novel mechanism of action, such as topoiromerase I inhibitors. The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. Clinical studies have confirmed the efficacy of PNA alone or in combination protocols in the treatment of AML. These regimens seem to produce superior results with acceptable toxicities in previously treated and relapsed, poor risk AML. However, early relapses remain a significant problem in a majority of refractory or relapsed patients in CR after treatment with PNA based regimens. To prolong remission duration or even cure AML, auto--or allo stem cell transplantation should be considered. However, FAMP or 2-CdA containing regimens may impair mobilization and collection of stem cells from peripheral blood for autotransplantation. Few studies have analyzed the role of PNA in CML. 2-CdA, FAMP and DCF can induce hematologic response in chronic phase of CML but cytogenetic responses have not been observed. Preliminary results suggest, that PNA used alone or in combination may be used as palliation in blast phase of the disease. However, currently, the role of these agents in CML is insignificant because of the high activity of Glivec in this disease. Finally, PNA, especially FA play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients, possibly also with myeloid malignancies.

Topics: Acute Disease; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cladribine; Clinical Trials as Topic; Cytarabine; Drug Synergism; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Middle Aged; Pentostatin; Peripheral Blood Stem Cell Transplantation; Remission Induction; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Vidarabine

In vitro studies suggest that nucleoside analogs have an antileukemic effect against chronic myelogenous leukemia (CML). We investigated the antileukemia effect of deoxycoformycin (DCF) and fludarabine in patients with CML. Four patients with Philadelphia chromosome (Ph)-positive CML were treated with DCF at 4 mg/m2 every week for 4 weeks, then every other week for four doses, and then every month as maintenance. Two patients were in late chronic phase and two in accelerated phase. All had previously failed therapy with interferon-alpha (IFN-A). Nine patients were treated with fludarabine 30 mg/m2/day for 5 days every 28 days. Three had Ph-positive CML, and six Ph-negative disease. Five patients were in accelerated phase and four in late chronic phase. Three patients treated with DCF had normalization of WBC counts while on the weekly schedule but progressed when changed to every other week. The fourth patient had no objective response. There were no cytogenetic responses. DCF was well tolerated with only mild nausea and vomiting in all patients. Patients treated with fludarabine received a median of two courses (range 1-4). In two patients (both Ph-positive), disease progressed to blastic phase upon recovery. Two other patients died of hemorrhagic complications secondary to thrombocytopenia. In all other cases fludarabine produced a transient reduction of WBC counts, but counts recovered to levels equal to or greater than the pre-treatment values. There were no cytogenetic responses. These results, together with previous experience with 2-CDA producing only hematologic responses, suggest that nucleoside analogs may not have a significant role in the management of CML.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Drug Administration Schedule; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Middle Aged; Pentostatin; Vidarabine