PRECIS OF PROTOCOL 
Chronic myelogenous leukemia is a neoplastic process affecting a 
primitive hemopoietic stem cell which leads to an increase in a 
broad spectrum of differentiating cells. These predominately 
myeloid cells enter the blood to produce a leukocytosis and at 
times a thrombocytosis, and infiltrate organs leading to 
splenomegaly or hepatomegaly. A characteristic cytogenetic 
abnormality, the Philadelphia translocation (Ph+) , results in a 
molecular rearrangement with transposition of the abl gene from its 
position on chromosome 9 to a breakpoint region on chromosome 22, 
termed the breakpoint cluster region or bcr. The bcr-abl gene is 
translated into a protein with tyrosine kinase activity which in 
animal models is both necessary and sufficient to produce a 
myeloproliferative disease. Over a period of years the human 
disease becomes resistant to treatment or evolves to a blastic 
phase similar to acute leukemia. The only curative therapy for CML, 
allogeneic bone marrow transplantation, is usually restricted to a 
minority of those afflicted with the disease who are under the age 
of 50 and who have a compatible related donor or unrelated donor 
identified through the National Marrow Donor Program. The majority 
of patients with CML do not undergo allogeneic marrow 
transplantation and eventually succumb to their disease. Several 
small series have been reported in which autologous marrow 
transplantation has resulted in long-term r emission with complete 
reduction or suppression of the Ph+ cells./ We propose a Phase II 
trial of autologous transplantation of patients with CML. In an 
effort to induce a population of Ph- cells prior to harvest, we 
propose to pre-treat patients with interferon and intensive 
cytoreductive chemotherapy. Peripheral blood stem cells (PBSC) and 
marrow are then harvested and patients go on to receive high dose 
cyclophosphamide, total body irradiation and PBSC/marrow 
transplantation followed by interferon maintenance therapy after 
recovery of bone marrow function. The results will be compared to 
previously published studies. The initial patients will have small 
aliquots of harvested bone marrow and peripheral blood cells 
utilized for in vitro studies to assess frequency of Ph+ cells and 
the infectivity of purified stem, progenitor and tumor cells with 
retr oviral vectors.; In subsequent patients we “will propose, m an 
amendment to this protocol, the use of retroviral-mediated gene 
transfer to genetically mark peripheral blood and bone marrow 
populations in an effort to understand the relative contribution of 
each to hematopoietic reconstitution and to relapse of the 
malignant process. We anticipate that these initial studies will 
form the basis for future genetic therapy of CML perhaps via 
production of gene products such as leukemia inhibitory factor by 
normal bone marrow cells. 
Recombinant DNA Research, Volume 16 
[141] 
