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BioOncology Watch Timely Information for Practicing
Physicians |
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jANUARY 2000 Highlights of the 41st Annual meeting of
the American Society of Hematology, December 3-7, 1999 Monoclonal Antibody
Therapy (MAB) of Non-Hodgkin’s Lymphoma (NHL) Rituximab first-line treatment
for follicular NHL. Ph.
Solal-Celigny et al. evaluated rituximab therapy in 50 previously untreated
follicular NHL patients with low tumor burden. Patients were treated with 4 weekly infusions of 375 mg/m2
of rituximab and an overall response rate of 69% was achieved (31% CR, 10% CR
unconfirmed, and 28% PR). Molecular
remissions occurred in 17 (57%) of 32 evaluable patients and were associated
with clinical response and absence of disease progression. Ten of 12 patients analyzed remain in
molecular remission after 12 months.
Rituximab is effective first-line therapy for follicular NHL patients
and durable molecular remissions are possible with this agent. (Solal-Celigny Ph, et al. Blood
1999; 94 (Suppl 1): abstract 2802) Radioimmunotherapy of rituximab
refractory follicular NHL. Leo Gordon and colleagues are conducting a Phase III trial of
ibritumomab tiuxetan (ZevalinÔ; IDEC
Pharmaceuticals Corp), an anti-CD20 murine monoclonal antibody radiolabelled
with 90Yttrium, for follicular NHL patients refractory to
rituximab. Interim analysis (n=24)
showed a response rate of 46%.
Toxicity was primarily hematologic: 8% of patients had grade 4
thrombocytopenia and 23% had neutropenia; median time to recovery was 15 and
14 days, respectively. This preliminary
data suggests ibritumomab tiuxetan is safe and effective therapy for
follicular NHL patients refractory to rituximab. (Gordon LI, et al. Blood
1999; 94 (Suppl 1): abstract 396) ZevalinÔ vs. rituximab. Thomas Witzig and colleagues conducted a
prospective controlled trial in which 143 relapsed/refractory low
grade/follicular B-cell NHL patients were randomized to receive Zevalin or
rituximab. The interim analysis of
the first 90 patients revealed an overall response rate of 80% for the Zevalin
group compared to 44% for the rituximab patients (P<0.001). Preliminary data indicate that
radiolabeled Zevalin therapy of relapsed/refractory low grade/follicular NHL
patients compares favorably to that of rituximab. (Witzig TE, et al. Blood 1999; 94 (Suppl 1): abstract
2805) Radiolabeled tositumomab. Trials investigating therapy of low grade
and follicular NHL patients with an I131 radiolabeled anti-CD20
murine monoclonal antibody, tositumomab (Bexxar™; Coulter Pharmaceuticals)
were reported by J.M. Vose et al. and John Leonard et al. All patients received a single dosimetric
dose followed 7-14 days later by a single therapeutic dose (450 mg
tositumomab IV followed by 35 mg tositumomab radiolabeled with an appropriate
mCi amount of I131 to deliver 75cGy). In 185 previously treated follicular NHL patients (from 5 phase
I-II studies), Vose et al. observed an overall response rate of 81% with a
median duration of 11 months and a CR rate of 38% with a median duration of
57 months. In an ongoing trial of
previously untreated low grade and follicular NHL patients, Leonard et al.
administered radiolabeled tositumomab 6-8 weeks after 3 cycles of fludarabine
(25mg/m2 x 5 days every 5 weeks).
For 14 evaluable patients, the radiolabeled tositumomab converted 4
fludarabine PRs to CRs resulting in a response rate of 93% (6CR, 7PR). No patients treated with the fludarabine
combination developed human anti-murine antibodies (HAMA) while 11% of the
single agent tositumomab patients did have a HAMA response. The principle toxicities were
hematologic. Radiolabeled tositumomab
is well tolerated, can be safely combined with fludarabine, and has activity
in low grade/follicular NHL. (Vose
JM, et al. Blood 1999; 94:
(Suppl 1) abstract 387 and Leonard JP, et al. Blood 1999; 94 (Suppl 1): abstract 393) Anti-CD22 mab therapy. John P. Leonard and coworkers are
assessing the safety and effectiviness of escalating doses of a humanized
anti-CD22 monoclonal antibody known as epratuzumab (Lympho-CideÔ;
Immunomedics, Inc.) in a phase II trial of previously treated NHL
patients. Five responses (3CRs) have
been achieved in the first 4 dose levels (n=12). Epratuzumab levels were detectable in serum for up to 3 months
and reduction of circulating CD22 positive cells have been observed. Dose limiting toxicity has not been
observed and there has been no evidence of a significant anti-human antibody
response. Although previous trials
have not shown epratuzumab to be efficacious, these results indicate that
further trials of this new agent are warranted. (Leonard JP et al. Blood 1999; 94 (Suppl 1): abstract
404) Rituximab for posttransplant
B-cell lympho-proliferative disorders (B PTLDs). N. Milpied and coworkers report their
results of rituximab therapy (MabtheraÒ; Roche) of 32 patients with B PTLDs following organ
(n=26) or bone marrow (n=6) transplantation.
Weekly 375mg/m2 infusions of rituximab (2-8 infusions) were
well tolerated and were utilized as first-line therapy in 30 patients and
salvage therapy in 2 patients. The
overall response rate was 69% (20CRs and 2PRs); with median follow up of 10
months (3-19 months), 22 patients are alive and 18 patients remain in
CR. These results suggest that
rituximab is a potentially effective therapy for patients who develop B PTLD. (Milpied N, et al. Blood 1999; 94 (Suppl 1): abstract
2803) Combination rituximab plus CHOP
induction therapy. O. Howard
and associates treated 40 newly diagnosed mantle cell lymphoma (MCL) patients
with rituximab 375 mg/m2 on day 1 plus standard CHOP on day 3
every 21 days for 6 cycles. Adverse
events were similar to those for CHOP alone.
39 patients were evaluable, with 19 (48%) CRs, 19 (48%) PRs, and one
stable disease. Median progression
free survival was 16.2 months and 11 (48%) of 23 patients with baseline Ig or
bcl-1 rearrangements had no evidence of disease in marrow or blood by PCR
analysis after therapy. These data
show that rituximab/CHOP treatment achieves high clinical and molecular CR
rates in MCL. This therapy may provide a means to obtain autologous stem
cells free of tumor for a high dose consolidation therapy strategy. (Howard
O, et al. Blood 1999; 94
(Suppl 1): abstract 2804) Multiple
Myeloma/Leukemia
Induction of CD20 expression in
multiple myeloma (MM). S.P. Treon
et al. discovered through experiments with the RPMI 8226 MM cell line that
interferon-g (IFN-g)
induces CD20 expression on MM cells.
The mechanism of action may be via the observed INF-g-
induced increase of Pu.1 expression, a transactivator of CD20 expression. Subsquent studies have demonstrated that
exposure of MM patient plasma cells and B-cells in culture to INF-g
increases CD20 expression and rituximab binding CD20 expression of CLL, NHL,
and normal donor B-cells as well as normal donor progenitor cells were not
affected by IFN-g. IFN-g may provide a means to develop CD-20 directed therapy for
MM. (Treon SP, et al. Blood
1999; 94 (Suppl 1): abstract 521) Targeted tyrosine kinase
inhibitor therapy for chronic myelogenous leukemia (CML). Brian Druker and coworkers utilized a
specific Bcr-Abl kinase inhibitor (STI 571; Novartis Pharmaceuticals) to
treat chronic phase CML patients who have failed interferon therapy. 54 patients at ten dose levels (25-500 mg)
completed at least 4 weeks of therapy.
Complete hematologic responses (normal WBC and platelet counts for ³ 4
weeks) were obtained in 23 of 24 patients receiving ³ 300 mg
of STI 571 for ³ 4
weeks. In addition, cytogenetic
responses developed in 33% of these patients at dose levels of ³ 300 mg
within 2 months of beginning therapy and 2 patients have achieved complete
cytogenetic remission with continued therapy. Dose limiting toxicity has not yet been encountered. Bcr-Abl tyrosine kinase activity plays an
essential role in CML transformation and STI 571 has significant activity in
chronic phase CML patients who have failed interferon treatment. (Druker BJ,
et al. Blood 1999; 94 (Suppl
1): abstract 1639) CD154 gene therapy for chronic
lymphocytic leukemia (CLL). Dr. W.G. Wterda and colleagues report preliminary data on a
phase I dose finding trial of infusion of autologous CLL cells transfected
with an adenoverous vector expressing recombinant CD154 (Ad-CD154) for the
treatment of CLL. Ad-CD154 infected
CLL-B-cells can induce autologous T-cells to generate CLL-specific cytotoxic
T lymphocytes. Thus far infusions of
3 x 108, 1 x 109, and 3 x 109 autologous
Ad-CD154 infected CLL-B-cells have been well tolerated. Absolute T cell counts increased in all
patients while absolute lymphocyte counts were reduced by a mean of 40%
+/-21% and lymph node masses decreased by a mean of 70% +/-19% within 1 to 4
weeks of treatment. A dose response
relationship has not been observed.
Infusions of autologous Ad-CD154 transduced CLL B-cells are well
tolerated and may have activity in CLL.
(Wterda WG, et al. Blood
1999; 94 (Suppl 1): abstract 2681) Campath-1H treatment of CLL. M.J. Keating et al. conducted a phase II
study of therapy with Campath-1H, a humanized anti-CD52 monoclonal antibody,
for CLL patients refractory to fludarabine (n=92). Campath-1H was administered as a 30 mg infusion 3 x weekly x
4-12 weeks. The overall response rate
was 33% (2 CRs and 29 PRs) and 59% (55 patients) had stable disease. The median time to progression for
responders was 9 + months.
Neutropenia and thrombocytopenia occurred in half the patients and
improved within 1-2 months after therapy was stopped. Infections developed in 56% of patients. Other adverse events were mild to moderate
in severity. These results indicate
that Campath-1H is an effective and relatively well-tolerated therapy for
advanced CLL patients refractory to fludarabine. (Keating MJ, et al. Blood
1999; 94 (Suppl 1): abstract 3118) Gemtuzumab zogamicin treatment
in AML. Eric L. Sievers
and colleagues studied gemtuzumab zogamicin (CMA-676; Wyeth-Ayerst Research),
a humanized anti-CD33 antibody linked to the cytoxic agent calicheamicin, in
a phase II trial of AML patients in first relapse (n=59). CMA-676 was given as an IV infusion (9
mg/m2) every 2 weeks x 2 doses.
20 (34%) patients achieved a remission (<5% marrow blasts, ³ 1500/ul
ANC, and platelet transfusion independence).
12 patients remain in remission with a median follow-up of 238 days
(21-608 days) and the median survival for all patients was 161 days. Severe mucositis did not develop in any
patient while all patients experienced grade 4 neutropenia and
thrombocytopenia and 9 patients had transient grade 3-4 evaluations of serum
bilirubin and/or transaminas levels.
These results show that Cam-676 has activity in AML in first relapse
and has an acceptable safety profile. (Sievers EL, et al. Blood 1999;
94 (Suppl 1): abstract 3079) Transplantation Nonmyeloablative allogeneic
peripheral blood stem cells (PBSC) transplantation. R Childs et al. studied 50 consecutive
patients (25 hematologic, 25 solid tumor) with a median age of 51 years
(23-68 years) who underwent nonmyeloablative conditioning followed by
allogeneic PBSC transplantation.
Early engraftment was detected in 49 patients (2 patients rejected the
allograft), neutrophil recovery occurred at a median of 11 days (7-19 days),
and responses were achieved in 20 patients.
3 patients died from GVHD and transplant related mortality at 100 and
200 days was 7.6% and 11.8%, respectively.
In a second study, Dr. P. McSweeney et al studied whether allogeneic
hematopoietic engraftment would take place when a nonlethal dose (200 cGy) of
TBI was used during conditioning for PBSC grafts in conjunction with
postgrafting cyclosporine (CSP) and mycophenolate mofetil (MMF)
immunosuppression. 44 patients
(median age 56 years: range 31-72) with hematopoietic malignancies entered
this trial and tolerated the transplants with mild myelosuppression. At 2 months, all of 42 evaluable patients
had donor engraftment, however, subsequently graft rejection occurred in 9
(20%) patients. These data indicate
that nonmyeloablative transplants have reduced acute toxicities, even in
older patients, and that modifications of immunosuppression may enhance
engraftment. (McSweeney P, et al. Blood
1999; 94 (Suppl 1): abstract 1742 and Childs R, et al. Blood 1999; 94 (Suppl 1): abstract
1743) |
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