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BioOncology Watch Timely Information for Practicing
Physicians |
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OCTOBER 2000 Non-Hodgkin's
Lymphoma (NHL) Rituximab retreatment. Treatment
of patients with low-grade or follicular NHL with single-agent rituximab
(IDEC Pharmaceuticals Corp), a chimeric anti-CD20 monoclonal antibody, has
previously been shown to result in an overall response rate (ORR) of 48% and
a median time to progression (TTP) of 13.2 months. Thomas Davis and associates conducted a phase II study in which
58 patients with low-grade or follicular NHL who had relapsed after
responding to rituximab therapy were retreated with rituximab (375 mg/m2
I.V. weekly x 4). The median
interval between rituximab courses was 14.5 months (range, 3.8 to 35.6
months). The ORR was 40% and the
Kaplan-Meier estimated median TTP was 17.8 months (range, 3.7+ to 26.6
months). No patient developed human
anti-chimeric antibodies and hematologic toxicity was generally mild and
reversible. This study shows that
retreatment of patients with low-grade or follicular NHL with rituximab is
effective and is not associated with cumulative bone marrow suppression. (Davis TA, et al. J Clin Oncol 2000;18:3135-3143) Long-term follow-up after
radioimmunotherapy (RIT). Mark Kaminski and colleagues
report long-term data (up to 8 years) on 59 B-cell NHL patients following a
single treatment with CD20-targeted RIT (iodine 131I tositumomab; Coulter
Pharmaceutical, Inc) at the University of Michigan. Forty-two patients (71%)
achieved a response and the median progression-free survival for responders
was 12 months. Sixteen patients were
retreated after disease progression and 9 responded (5 CRs). Late adverse events included 5 patients
who developed secondary myelodysplasia (MDS) 1.2 to 7.5 years after RIT. The MDS evolved to acute myeloid leukemia
in one patient. These patients had
received a median of 4 prior chemotherapy regimens and all had previously
been exposed to alkylating agents. An
additional 3 patients were diagnosed with solid tumors following RIT. Five patients developed elevated
thyroid-stimulating hormone levels, but none were symptomatic. These data show that RIT can be effective
therapy for patients with advanced NHL.
Further studies are needed to fully assess the risk for secondary
malignancies. (Kaminski MS, et al. Blood 2000; 96:1259-1266) Allogeneic
Stem-Cell Transplantation
Therapy for renal-cell carcinoma. Renal-cell
carcinoma responds to immunomodulatory therapies and Richard Childs et al.
postulated that a graft-versus-tumor effect might also be generated by
non-myeloablative bone marrow transplantation. A pilot study was performed in which 19 patients with
refractory metastatic renal-cell carcinoma received a preparative regimen of
cyclophosphamide and fludarabine followed by an infusion of a
peripheral-blood stem-cell allograft from an HLA identical sibling or a sibling
with a mismatch of a single antigen.
Cyclosporine therapy was used to prevent graft-versus-host disease and
patients with no initial response received up to 3 infusions of donor
lymphocytes. Ten patients (53%)
achieved a response, which developed only after all T-cells in the recipient
were of donor origin (complete chimerism).
Thus, the onset of tumor regression occurred at a median of 4 months
(range, 1 to 8 months) after transplantation. In 8 patients tumor regression was not observed until after the
cyclosporine had been withdrawn.
These preliminary results demonstrate that allogeneic T-cells can
survive following non-myeloablative conditioning and induce antitumor
activity in patients with refractory advanced renal-cell carcinoma. (Childs
R, et al. N Eng J Med 2000;343:750-758) Donor lymphocyte infusion (DLI)
therapy for relapsed multiple myeloma. H. M. Lokhorst and coworkers
administered DLI treatments to 27 patients with relapsed multiple myeloma
after allogeneic stem-cell transplantation.
Thirteen patients received reinduction chemotherapy and 8 patients
responded partially. Fourteen of the
27 patients (52%) achieved a response (6 CRs and 8 PRs) to DLI
treatments. In 5 patients the
response was induced following T-cell dose escalation in subsequent
DLIs. Five patients remained in
remission for more than 30 months after DLI and the median survival for all
patients was 18 months. Factors that
were identified as predictors for response to DLI were chemotherapy-sensitive
disease prior to transplantation, response to reinduction chemotherapy, and a
T-cell dose >1 x 108 cells/kg. Acute and chronic
graft-versus-host disease occurred in 15 (56%) and 7 (26%) patients,
respectively, and 2 patients died from bone marrow aplasia. DLI is effective treatment for patients
with relapsed multiple myeloma after allogeneic stem-cell transplantation and
may induce long-term remissions in some patients. (Lokhorst HM, et al. J Clin Oncol 2000;18:3031-3037) Leukemia
Gemtuzumab zogamicin.
K. Naito and colleagues investigated the mechanism of action of
gemtuzumab zogamicin (CMA-676; Wyeth Lederle, Japan), a
calicheamicin-conjugated humanized anti-CD33 murine monoclonal antibody, in
several myeloid leukemia cell lines.
A selective cytotoxic effect was seen in cell lines that expressed
CD33. The cytotoxic effect was dependent
on the gemtuzumab zogamicin dose, the degree of CD33 expression, and the rate
of proliferation of the leukemic cells.
P-gp-expressing multidrug-resistant sublines were refractory to
gemtuzumab zogamicin. In the presence
of MDR modifiers (eg. MS209 and PSC833) these resistant leukemic cells became
sensitive to the cytotoxic effects of gemtuzumab zogamicin. The combination of gemtuzumab zogamicin
and MDR modifiers is a potential therapeutic modality for patients with
multidrug-resistant acute myeloid leukemia.
(Naito K, et al. Leukemia 2000;14:1436-1443) |
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