Haematologica 2003 - Supplements

P12.2.5
MONOCLONAL ANTIBODY THERAPY FOR THE
PLASMA CELL MALIGNANCIES
Steven P. Treon M.D., M.A., Ph.D.
Dana Farber Cancer Institute, Harvard Medical School, Boston,
MA, USA
Monoclonal antibody therapy, particularly with rituximab
(Rituxan, MabThera) has been successfully used in the treatment
of B-cell malignancies. In an effort to extend the activity of
rituximab, we conducted studies using rituximab alone and in
combination therapy in Waldenstrom’s macroglobulinemia (WM)
and multiple myeloma (MM). In studies examining extended
dose (i.e. 8 infusions) rituximab, we observed an overall response
rate (ORR) of 73% (69% PR; 4% MR) and an estimated median
time to treatment failure of 20+ months, which compared
favorably to those reported by us and others (6-9 months) using
standard dose (i.e. 4 infusions) rituximab. Significant
improvements in hematological function were also observed in
patients receiving extended dose rituximab. Pre-rituximab
therapy, 35% of patients were anemic and 28% were
thrombocytopenic which decreased to 5% and 9%, respectively
following therapy. Interestingly, response to extended dose
rituximab was correlated with pre-therapy IgM levels, but not
BM tumor cell burden. Eighteen of 20 patients (90%) with an
IgM level of 6,000 mg/dL responded (p=0.002).
The reason for this finding remains under active investigation. In
an effort to further extend the activity of rituximab in WM
patients, we also examined in a multicenter trial combination
therapy with extended dose rituximab and 6 cycles of fludarabine.
Interim analysis of the first 23 patients on this study showed that
90% (15% CR; 61% PR; 14% MR) of patients attained a
response. Unlike in WM, a role for rituximab in MM appears
particularly limited to those patients whose BM plasma cells
(BMPC) express CD20. In a multicenter study, we treated 19
MM patients with extended dose rituximab, regardless of their
CD20 status. Six of 19 (32%) patients demonstrated either a PR
(n=1) or SD (n=5), with a median time to treatment failure of 5.5
(range 3-21+) months. 5/6 of these patients had CD20 + BMPC,
while CD20 status could not be determined in one patient. In an
effort to advance the use of monoclonal antibody therapy in WM
and MM, we have sought to define mechanism(s) by which
rituximab facilitates tumor cell killing. As part of these efforts,
we conducted studies to determine a role for antibody dependent
cell mediated cytotoxicity (ADCC) by evaluating polymorphisms
in position 158 of the Fc gammaRIIIa (CD16) receptor. The Fc
gammaRIIIa receptor has previously been reported to modulate
human immunoglobulin G1 binding, and antibody dependent cell
mediated cytotoxicity (ADCC). Genetic dimorphisms at position
158 result in expression of either the valine (V), or phenylalanine
(F) amino acids which may be expressed either in a homozygous
(V/V; F/F) or heterozygous (V/F) phenotype. In these studies, we
used allele specific PCR analysis to determine position 158
polymorphisms for 58 patients with Waldenstrom’s
macroglobulinemia for whom clinical responses to rituximab
therapy were known. PCR amplifications of exon 4, intron 4 and
most of intron 5 were performed using primers which specifically
amplified Fc gamma RIIIa but not Fc gamma RIIIb. Each end of
the PCR product was then sequenced, and sequence information
from exon 4 was used to provide genotype information for codon
158, while the sequence information from exon 5 end was used to
confirm that the PCR product was specifically from the Fc
gamma RIIIa gene. Of the 58 WM patients examined, 10/58
(17%) were homozygous for V (Fc gammaRIIIa-V/V); 26/58
(45%)were heterozygous (Fc gamma RIIIa-V/F); and 22/58
(38%) were homozygous for F (Fc gamma RIIIa-F/F). No
significant differences in sex, age, baseline IgM levels, number of
prior therapies, and number of rituximab infusions received was
seen among the three allotype groups. The overall response rate
(major, i.e. >50% decline in IgM and minor, i.e. >25% decline in
IgM responses) for the three allotype groups were as follows:
6/10 (60%) Fc gamma RIIIa V/V; 13/26 (50%) Fc gamma RIIIa
V/F; and 8/22 (36%) Fc gamma RIIIa F/F (V/V and V/F vs. F/F
p=0.28). Comparison of major RR among the V carriers vs. F/F
revealed even greater differences: 4/10 (40%) Fc gamma RIIIa
V/V; 9/26 (36%) Fc gamma RIIIa V/F (13/36 for V carriers
combined), and 2/22 (9.0%) for Fc gamma RIIIa F/F (V/V and
V/F vs. F/F p=0.03) The results of these studies support an
association between V carrier status and higher response rates
(particularly for major responses) to rituximab among patients
with WM. Moreover, the results of these studies may have
implications for the development and use of monoclonal
antibodies in B-cell malignancies. Given these results, as well as
those by other investigators suggesting a primary role for ADCC
function in mediating rituximab clinical activity, we have
performed studies using immunomodulators to enhance the
ADCC function of rituximab. Thalidomide and its analogue
Revamid were previously shown by us to enhance myeloma cell
lysis by natural killer cells. As a follow-up to these studies, we
recently demonstrated that both Thalidomide and Revamid
significantly enhanced rituximab mediated ADCC of CD20 +
ARH-77 lymphoplasmacytic cells. In view of these results, a
clinical trial combining Thalidomide and Rituximab is
contemplated. Lastly, ongoing pre-clinical and clinical studies are
underway to develop monoclonal antibody therapy targeting
CD20 using yttrium 90 conjugated Zevalin, as well as
unconjugated monoclonal antibodies targeting CD22, CD40, and
CD52.
These studies were funded through generous grants or gifts from
the Research Fund for Waldenstrom’s at the Dana Farber Cancer
Institute, the International Waldenstrom’s Macroglobulinemia
Foundation, the International Myeloma Foundation, the Multiple
Myeloma Research Foundation, the American Society of Clinical
Oncology Young Investigator Award, a National Institutes of
Health Career Development Award, the Peter and Helen Bing
Fund, the Bailey Family Fund, Genentech Bio-Oncology Inc.,
IDEC Pharmaceuticals Inc., Celgene Corporation, and Berlex
Oncology Inc.
References
1. Treon SP, Shima Y, Preffer FI, Doss DS, Ellman L,
Schlossman RL, Grossbard ML, Belch AR, Pilarski LM,
Anderson KC. Treatment of plasma cell dyscrasias by antibody
immunotherapy. Sem Oncol 1999; 26: 97-106.
2. Treon SP, Shima Y, Grossbard ML, Preffer FI, Belch
AR, Pilarski LM, Anderson KC. Treatment of multiple myeloma
by antibody mediated immunotherapy and induction of myeloma
selective antigens. Ann Oncol 2000; 11:107-111.
3. Treon SP, Anderson KC. The use of rituximab in the
treatment of malignant and non-malignant plasma cell disorders.
Sem Oncol 2000; 27:79-85.
4. Treon SP, Raje N, Anderson KC: Immunotherapeutic
strategies for the treatment of plasma cell malignancies. Sem
Oncol 2000; 27:598-613.
5. Davies FE, Raje N, Hideshima T, Lentzsc S, Young G,
Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP,
Richardson PG, Schlossman RD, Morgan GJ, Muller GW,
Stirling DI, Anderson KC: Thalidomide and immunomodulatory
derivatives augment natural killer cell cytotoxicity in multiple
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