Autologous Bone Marrow Transplantation - Blog Science Connections

290 ABMT Timing in Lymphoma
Role of Intensive Chemotherapy
Clinical trials of intensive chemotherapy are most promising in diseases
in which an improved response rate can be expected with escalating doses of
cytotoxic drugs, radiation, or both. One approach is to treat diseases that
have a high response rate but also a high relapse rate. Such diseases are
acute myeloblastic leukemia (AML), breast cancer, small cell cancer of the
lung, neuroblastoma, and non-Hodgkin's lymphoma when patients have poor
prognostic features. Drugs that have been found effective for each
malignancy can then be considered for dose escalation trials. As would be
expected from animal models, there is some evidence that higher doses of
chemotherapy give better results than lower doses in AML (43), non-
Hodgkin's lymphoma (44), Hodgkin's disease (45), and breast cancer (46). In
dose escalation trials, the nonhematopoietic toxicities must also be evaluated
and appropriate dose adjustments made to lower the morbidity and mortality
from the procedure (25-27,47). Because of the reasons stated above, we
elected to use large B-cell lymphoma as a model to evaluate the timing for
intensive chemotherapy trials.
In 1980, when designing this protocol, we had been unsuccessful with
four previous protocols in curing more than 20% of patients with poor prognostic
features, and toxicity to the normal hematopoietic stem cells was also a
concern. We had been encouraged by the remarkable success with our
previous L-2 and LSA-L2 protocols (28,48) in pediatric lymphoma patients,
and a variant of the L-2 and LSA-L2 protocols (i.e., L-17M) had shown
improved results in adults with acute lymphoblastic leukemia (28). In our
preliminary trials, the L-l 7M induction regimen caused minimal toxicity to the
bone marrow in lymphoma patients, so we elected to use it for induction
treatment for this protocol. Pretransplantation cytoreduction with hematoablative
doses of HF-TBI and cyclophosphamide was chosen because of its
known therapeutic benefit in allogeneic BMT (24,25). The drug doses chosen
in our study were the same as the ones used for allogeneic BMT at this
institution and are known to result in the need for hematopoietic rescue
(25-27).
Method and Timing of Hematopoietic Stem Cell Harvesting
Bone mafrow was usually harvested 16-40 days after the last dose of
chemotherapy, when the blood counts had recovered from their nadir. The
effects of treatment with various drugs prior to bone marrow harvest have
been evaluated in an animal model system (49,50), but there is still a need for
more information on how different drugs and drug combinations used for
induction therapy before marrow harvest affect human progenitor cells. Most
investigators try to transplant 2 x 10 8
mononuclear marrow cells per kilogram
body weight, and the bone marrow is usually cryopreserved in liquid nitrogen
in 10% DMSO using controlled-rate freezing (38-42,51). Upon thawing, the
bone marrow has a tendency to aggregate (25,26,46). Marrow cryopreserved