CHEMOTHERAPY PROGRAMS TO GENERATE DIPLOID CELLS FOR AUTOLOGOUS BMT

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Interferon therapy can induce cytogenetic remissions which last for years in 26% of early chronic phase CML patients, but the remissions are produced only after long periods of daily therapy, often requiring months to years to achieve major or complete cytogenetic remission. In contrast, intensive but not ablative does of combination chemotherapy (such as Daunomycin Ara-C) rapidly produce major cytogenetic remissions in 30% of patients, but these remissions do not last for more than a few months. We have embarked upon a program to develop chemotherapy based alternatives for the therapy of CML patients who are interferon-resistant and do not have allograft donors. The goal of this program is to use chemotherapy to generate diploid (normal) cells for use in autologous bone marrow transplantation. To accomplish this, we have searched for forms of chemotherapy which are associated with more durable periods of myelosuppression than is the case with conventional dose chemotherapy, but are less toxic than standard chemotherapy. We also are collecting peripheral blood cells in the early stages of hematopoietic recovery at a time when diploid cells dominate the progenitor population. In addition, we use ex vivo fractionation of early hematopoietic progenitor cells to obtain populations of autologous marrow and peripheral blood which are enriched in diploid cells. We infuse these fractionated autologous cells, which are enriched in diploid cells, following systemic intensive therapeutic regimens which are ablative. We have developed very promising early clinical results with the chemotherapeutic agent, homoharringtonine (HHT), which are using in untreated patients. The myelosuppressive effect of HHT is more durable than that seen with conventional forms of chemotherapy. HHT produces major cytogenetic remissions in 33% of the early chronic phase patients treated. In addition, the clinical experience so far accumulated with the autologous transplant program suggests that chemotherapy with the combinations of fludarabine, Ara-C and mitoxantrone (FAM) or Daunomycin high dose Ara-C (DARAC) followed by CD34 selection, and autologous bone marrow transplant with the autologous cells selected ex vivo can produce major or complete cytogenetic remissions in interferon-resistant late chronic phase patients so treated, and that minor cytogenetic remissions with this program can be achieved even with accelerated phase or blast crisis patients. The PCR assay, the rare immunophenotype assay, and the metaphase FISH assay are used to measure response, and to optimize the formulation of this therapy so as to promote the collection of autologous diploid cells on the maximum number of diploid cells. We also hope to attempt to identify surrogate molecular endpoints for prolonged remission duration or survival. The work proposed in this project is designed to increase the number of patients who are eligible for autologous marrow transplants. Dr. Gehan and Terry Smith will work with us on this program and all clinical and laboratory programs to evaluate the correlations between laboratory data and clinical outcome in the therapeutic programs.