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Targeted Therapies Timely
Information for Practicing Hematologists and Oncologists www.tgt-therapies.com |
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NOVEMBER 2005 CASTLEMAN DISEASE Anti–interleukin (IL)-6 receptor
antibody therapy. Castleman disease is a lymphoproliferative
disorder characterized by lymphadenopathy, systemic constitutional symptoms, and
severe wasting as the illness progresses. A dysregulated overproduction of
IL-6 in patients with Castleman disease led Nishimoto and colleagues to
investigate the effectiveness of therapy with a humanized anti–IL-6 receptor
monoclonal antibody (MRA). Twenty-eight patients have been enrolled in this
ongoing study and were treated with infusions of MRA 8 mg/kg given biweekly
over 16 weeks. Therapy with MRA was found to alleviate lymphadenopathy,
relieve constitutional symptoms, improve biochemical parameters, and increase
body weight. Furthermore, 11 of 15 patients treated with oral corticosteroids
were able to reduce their corticosteroid dose during MRA therapy. Adverse
events were mild to moderate. These findings indicate that MRA therapy over
16 weeks improves the symptoms and biochemical abnormalities associated with
Castleman disease. Further follow-up is ongoing. (Nishimoto N, et al. Blood. 2005;106:2627–2632.) NON-SMALL CELL LUNG CANCER (NSCLC) Epidermal growth factor receptor
(EGFR) gene copy number and mutations and increased sensitivity to gefitinib.
Bronchoalveolar carcinomas (BACs) and lung
adenocarcinomas with bronchoalveolar features have previously been reported
to be sensitive to EGFR tyrosine kinase inhibitors. Hirsch and others report
an analysis of archival tumor tissue collected during a Southwest Oncology
Group clinical trial of patients with advanced-stage BAC treated with
gefitinib. Fluorescent in situ hybridization (FISH) was used to detect EGFR,
and HER2 genes and gene copy number was correlated with clinical outcome (n =
81). Median overall survival was greater in EGFR/FISH-positive patients than
EGFR/FISH-negative patients (not reached vs. 8 months; P = 0.042). EGFR copy number was also identified as a significant
predictor for survival by multivariate analysis. No association between HER2
gene copy number and survival was found. In a second study, Takano and associates extracted DNA from surgical
specimens of 66 patients with NSCLC who had experienced relapse after
surgery. Pyrosequencing and quantitative real-time
polymerase chain reaction were used to analyze the allelic pattern and EGFR
and ErbB2 copy numbers. No ErbB2 mutations were identified; however 39
patients (59%) had EGFR mutations. Following subsequent therapy with gefitinib,
patients with EGFR mutations had a higher response rate (P <0.0001), longer median time to progression (P <0.0001), and greater median
survival time (P = 0.0001) than
patients without EGFR mutations. In addition, increased EGFR copy number (≥3/cell)
was found in 29 patients and was associated with a higher response rate (P = 0.005) and longer median time to
progression (P = 0.038). These two
studies demonstrated that increased EGFR copy number and EGFR mutations are
associated with improved clinical outcomes in patients with NSCLC. (Hirsch
FR, et al. J Clin
Oncol. 2005;23:6838–6845; Takano
T, et al. J Clin
Oncol. 2005;23:6829–6837.) MANTLE-CELL LYMPHOMA (MCL) Rituximab plus alternating
chemotherapy results in durable remissions. Hyper-CVAD
(cyclophosphamide-vincristine-doxorubicin-dexamethasone) chemotherapy
alternating with high-dose methotrexate and cytarabine has been shown to be
effective in patients with aggressive MCL. Romaguera
and coworkers treated patients who had newly diagnosed aggressive histopathologic
variants of MCL with rituximab plus hyper-CVAD (cycles 1, 3, 5, and 7)
chemotherapy alternating with rituximab plus high-dose methotrexate and
cytarabine (cycles 2, 4, 6, and 8). Rituximab 375 mg/m2 was
administered on the first day of each cycle. Among 97 evaluable patients, the
response rate was 97%, and 87% of patients achieved a complete response (CR)
or an unconfirmed CR. The 3-year failure-free survival rate for patients ≤65
years of age was 73% compared with 50% for patients aged >65 years (P = 0.02). The 3-year overall survival
rate was 82% (median follow-up, 40 months). The principal toxicity was
hematologic, and five patients died of acute toxicity. Four patients
developed treatment-related myelodysplasia or acute myelogenous leukemias.
These data suggest that rituximab plus alternating hyper-CVAD chemotherapy is
an effective therapy for patients with previously untreated aggressive MCL.
However, this regimen is not recommended as standard therapy for patients
aged >65 years. Randomized phase III studies are needed to more clearly
define the role of this regimen. (Romaguera JE, et
al. J Clin Oncol. 2005;23:7013–7023.) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Fludarabine plus alemtuzumab. Elter and others conducted a phase II study of 36 patients
with relapsed or refractory B-cell CLL treated with fludarabine plus
alemtuzumab (FluCam). The alemtuzumab dose was
escalated on 3 consecutive days from 3 to 10 to 30 mg at the start of each
cycle. FluCam (fludarabine 30 mg/m2 and
alemtuzumab 30 mg) was given on the next 3 consecutive days. Treatment was
administered every 28 days for up to six cycles. The response rate was 83%
(11 CRs and 19 partial responses [PRs]). Two patients developed fungal pneumonias, two
patients experienced subclinical reactivation of cytomegalovirus, and one
patient died of Escherichia coli
sepsis. This study demonstrated that FluCam therapy
is effective in patients with relapsed or refractory B-cell CLL and has
acceptable toxicity. (Elter T, et al. J Clin Oncol. 2005;23:7024–7031.) HEPATOCELLULAR
CARCINOMA (HCC) Erlotinib therapy. Philip
and associates treated 38 patients with unresectable or metastatic HCC (one
prior systemic or locoregional therapy was allowed) with erlotinib, an
EGFR/HER1 tyrosine kinase inhibitor. EGFR/HER1 expression was detected in the
tumors of 88% of the patients. Disease control was observed in 59% of the
patients, and three patients had a partial radiologic response. Median
overall survival was 13 months. Grade 3 or 4 skin toxicity or diarrhea occurred
in five and three patients, respectively. Additional studies of erlotinib in
patients with advanced HCC are warranted. (Philip PA, et al. J Clin Oncol. 2005;23:6657–6663.) |
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