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Novel Strategies Boost Outcomes of Bone Marrow Transplantation, Others Reduce Its Toxicities
Adding radioimmunotherapy to standard bone marrow transplantation (BMT) regimens may improve
disease-free outcomes, especially in hematologic malignancies, while strategies to alter regimen-related
toxicities promise to decrease the immediate and long-term complications. With some variations, these
themes pervaded the field of abstracts presented at Saturday’s Bone Marrow Transplantation and
Cytokines Oral Abstract Presentation Session, which was co-chaired by Mary M. Horowitz, MD, MS,
from the Medical College of Wisconsin, and Julie Vose, MD, from the University of Nebraska Medical
Center.
Dr. Vose presented the findings of a phase I/II study of 23 patients with relapsed and resistant
non-Hodgkin’s lymphoma (follicular, diffuse large cell, or mantle cell lymphoma) who were treated in an
outpatient setting with radioimmunotherapy with Bexxar (I-131 tositumomab), an antibody with attached
radioactive iodine 131 that binds to a protein found on the surface of B-lymphocytes. The radioactivity of
Bexxar targets and destroys the B cells. The findings of the study showed that Bexxar produces a
synergistic treatment effect when it is combined with the transplant regimen of high-dose chemotherapy
with BEAM (BCNU, Etoposide, Ara-C, and Melphalan), followed by autologous hematopoietic stem
cell transplantation (ASCT). At a median follow-up of 12 months (range, 4 - 39 months), the
Bexxar-enhanced regimen resulted in an estimated 60% event-free survival and an estimated overall
survival of 78% (95% CI: 61%, 95%). These rates are considered favorable for patients whose prognosis
is poor with standard high-dose chemotherapy and ASCT. There were no early deaths from toxicity in
this trial, and no added toxicities could be attributed to the addition of Bexxar.
Commenting on the overall outcomes from studies evaluating the combination of radioimmunotherapy and
standard transplant regimens, Joseph G. Jurcic, MD, from Memorial Sloan-Kettering Cancer Center,
pointed out that the positive results found with hematologic cancers have not been matched in solid
tumors, for reasons that include variations in tumor vascularity, high interstitial pressure within solid tumors,
poor antibody diffusion, and radioresistance. He said that optimal regimens for all such combination
therapies must be established and more randomized trials are needed to prove a benefit. In addition, he
suggested several strategies that might improve results from radioimmunotherapy for patients with solid
tumors:
• Identification of better targets
• Use of radiometals
• Use of novel chelates and pre-targeting methods to increase tumor-to-normal-tissue dose
ratios
• Coadministration of radiosensitizing agents
• Alpha particle therapy for micrometastatic disease
Another study presented during the session found that the type and intensity of pretransplant
chemotherapy was the largest contributor to MDS/leukemia risk after autologous transplantation for
lymphoma. Douglas Rizzo, MD, from the Autologous Blood and Marrow Transplant Registry, presented
the results of multivariate analyses from a large, multicenter case-controlled study. The study involved the
examination of transplant registry records of 56 patients with MDS/leukemia, taken from a large cohort of
patients with Hodgkin’s disease and non-Hodgkin’s lymphoma who were treated in the U.S and Canada
over a six-year period. The authors found a four-fold greater risk in patients receiving MOPP-like
regimens and a 10-fold greater risk in patients given chlorambucil, compared with patients given
cyclophosphamide-based treatment before transplant. This finding helps to clarify the individual
contributions of pre-transplant, transplant, and post-transplant therapy to MDS and leukemic
transformation, which have not been well characterized to date, in part due to incomplete data on
pre-transplant therapies.
No association was found between graft purging or use of mobilization chemotherapy or growth factors
and risk of MDS and leukemia. The authors acknowledged that some transplant-related factors,
particularly dose of total body radiation, may play a role, and that the findings require further confirmation
in other patient populations.
Ricardo T. Spielberger MD, from the City of Hope National Medical Center in California, reported
encouraging results of a multicenter, double-blind, placebo-controlled phase II study involving
recombinant human keratinocyte growth factor (rHuKGF). Dr. Spielberger and his coinvestigators found
that rHuKGF significantly reduced the duration of severe (WHO Grades 3-4) oral mucositis and
improved the quality of life in 129 patients with hematologic malignancies undergoing total body irradiation
and high-dose chemotherapy with autologous peripheral blood progenitor cell transplantation (PBPCT).
This therapy alone has induced mucositis in as many as 80% of patients.
The patients were randomized to receive placebo or KGF 60 mcg/kg/day for 3 days before total body
irradiation and/or 3 days after PBPCT, resulting in three parallel arms: placebo (pre/post), rHuKGF (pre
only), and rHuKGF (pre/post). The duration of severe oral mucositis was significantly reduced in the
patients who received KGF (pre/post) compared with those who received the placebo. Health-related
quality-of-life assessments also showed improvements in mucositis-related concerns in patients who
received rHuKGF; functions such as mouth and throat soreness, swallowing, drinking, eating, talking, and
sleeping were all found to be improved with the growth factor. Importantly, patients receiving rHuKGF
experienced less severe mucositis-related sequelae, such as analgesic use of a class IV opioid and total
parenteral nutrition, than did patients taking placebo. The agent was well tolerated, with transient adverse
events of mild-to-moderate skin and oral erythema, tongue edema (experienced by patients as a
temporary sensation of thickening of the tongue).
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