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BioOncology Watch Timely Information for Practicing
Physicians |
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SEPTEMBER 2000 Non-Hodgkin Lymphoma (NHL) In vivo purging with chemotherapy and rituximab. Michele Magni and coworkers investigated
the ability of in vivo purging with
high-dose sequential chemotherapy (HDS) alone (n=10) or HDS plus rituximab
(n=15) to allow harvesting of peripheral blood progenitor cells free of
contaminating tumor cells in 25 consecutive patients with CD20+ mantle cell
or follicular lymphoma. In this pilot
study all patients had bone marrow involvement, polymerase chain reaction
(PCR)-detectable molecular rearrangement, initial therapy with 2 or 3 cycles
of standard-dose chemotherapy, treatment with nonmyeloablative high-dose
chemotherapy (4-step sequence of high doses of cyclophosphamide, cytarabine,
melphalan, and mitoxantrone plus melphalan) with growth factor support, and 3
progenitor cell infusions (at approximately weeks 3, 6, and 9 during
high-dose chemotherapy). Progenitor
cells were harvested after high-dose cyclpohosphamide and, if necessary,
following high-dose cytarabine.
Patients receiving rituximab were given 6 infusions (rituximab 375
mg/m2/infusion): 2 infusions prior to the first and second
progenitor cell infusions and 2 infusions following the third progenitor cell
infusion. Progenitor cell harvests
were PCR-negative for lymphoma in 14 (93%) patients in the HDS-rituximab
cohort compared to 4 (40%) patients in the HDS cohort (P=.007). Clinical and molecular remissions were
achieved in all 14 (100%) evaluable patients treated with HDS and rituximab
versus 7 (70%) patients treated with HDS alone. These short-term results suggest that chemoimmunotherapy can
successfully purge hematopoietic progenitor cells in vivo. Clinical outcome
benefit (relapse-free or overall survival) has not been determined. (Magni M, et al. Blood 2000;96:864-869) In vitro biologic response to rituximab. Josee Golay and colleagues performed in vitro studies of the mechanism of
action of rituximab (Roche Italia) in 4 follicular lymphoma (FL) cell lines,
1 Burkitt’s lymphoma cell line, 3 fresh FL cell samples, and normal B
cells. They found that antibody-dependent
cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) are
the major mechanisms of antitumor activity for rituximab. No antiproliferative or apoptotic
responses to rituximab were observed in lymphoma cells. Rituximab consistently activated ADCC in
all cell lines, however the efficiency of CDC activation was variable. Further investigation showed that
complement inhibitors, especially CD55 and CD59, are regulators of CDC and
that blocking antibodies to CD55 and/or CD59 increased CDC. These in
vitro findings need to be confirmed clinically as they suggest a basis
for predicting clinical response to rituximab in CD20+ NHL patients. (Golay J, et al. Blood 2000;95:3900-3908) Multiple Myeloma
Effects of aminobisphosphonates on T cells. Bisphosphonates are known to inhibit
osteoclastic bone resorption and have recently been discovered to share
structural homologies with gdT cell
ligands. Thus, Volkar Kunzmann et al
studied the in vitro effects of
several bisphosphonates on peripheral blood mononuclear cells (PBMCs)
obtained from 6 healthy donors. The
aminobisphosphonates (pamidronate, alendronate, ibandronate) induced an
expansion of gdT cells
in cell cultures of these healthy-donor PBMCs (etidronate and clodronate did
not have a T cell effect). Further
experiments showed that pamidronate-activated gdT cells produced cytokines and had activity against
lymphoma and myeloma cell lines. In
addition pamidronate-treated bone marrow cultures derived from 24 patients
with multiple myeloma showed decreased plasma cell survival. This cytoreductive effect was abolished by
gdT cell
depletion. These in vitro data indicate that aminobisphosphonates may exert an
antitumor effect through activation of gdT
cells. Clinical trials are needed to
confirm an aminobisphosphonate-induced antitumor activity. (Kunzmann V, et al. Blood 2000;96:384-392) Leukemia
T-cell depletion of bone marrow transplants. Richard Champlin and colleagues reviewed the
leukemia-free survival (LFS) data from 1982-1994 for 1,868 transplant
recipients with chronic myelogenous, acute myelogenous, or acute
lymphoblastic leukemia reported to the International Bone Marrow Transplant
Registry (IBMTR) to evaluate the different strategies of T cell depletion. The 5-year LFS was 29% for transplants T
cell depleted by narrow-specificity antibodies (n=450) compared to 16% for
transplants T cell depleted by other techniques (n=420) (P<.0001). The 5-year LFS for the non-T cell depleted
transplants was 31% (n-998). This
retrospective analysis shows that T cell depletion by narrow-specificity
antibodies results in higher 5-year LFS rates than that associated with other
techniques, but the 5-year LFS rate is similar to that achieved with non-T
cell depleted transplants despite reducing acute GVHD. (Champlin RE, et al. Blood
2000;95:3996-4003) Mechanisms of resistance to the tyrosine kinase inhibitor STI571. STI571 is an inhibitor of Bcr-Abl tyrosine
kinase activity and has demonstrated activity against Philadelphia chromosome
(Ph)-positive leukemias. However,
some Ph-positive cell lines have been found to be resistant to STI571. Francois Mahon and associates recently
studied clones of Ph-positive human cell lines and murine cell lines
transfected with Bcr-Abl that had been generated to be resistant to
STI571. The mechanisms of resistance
were found to vary among the cell lines and included Bcr-Abl overexpression,
an increased threshold for tryrosine kinase inhibition, P-glycoprotein
overexpression, and possibly an acquisition of compensatory gene
mutations. These findings show that
resistance to STI571 may develop through multiple mechanisms and may
potentially develop in leukemic stem cells in vivo. (Mahon FX, et
al. Blood 2000;96:1070-1079) |
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