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What's New In Research - December 19, 2002
Epoetin Alfa Treatment Improves Quality of Life and Increases Hemoglobin Levels during Chemotherapy for Lymphoma, Chronic Lymphocytic Leukemia (CLL), and Multiple Myeloma (MM) Patients with Mild-to-Moderate Anemia.
David J. Straus, Ralph R. Turner, Marcia A. Testa, Johanna F. Hayes, Brenda J. Sarokhan, the Procrit Hematologic Malignancies Study Group. Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; PHASE V Technologies, Inc., Wellesley Hills, MA, USA; Biostatistics, Harvard School of Public Health, Boston, MA, USA; Clinical Affairs, Ortho Biotech Products, L.P., Bridgewater, NJ, USA

While the effects of severe anemia in cancer patients are well known, those of more common mild-to-moderate anemia are often overlooked, in part because of other more debilitating symptoms. Recombinant human erythropoietin (r-HuEPO, epoetin alfa, EPO) increases hemoglobin (Hb) levels and reduces transfusion requirements in patients with anemia. This report describes interim results (data from 179 patients of the 260 enrolled) from a randomized, open-label, multicenter, 16-week trial that assessed the effect of once-weekly (QW) EPO in patients with mild-to-moderate anemia (baseline Hb 10 and 12 g/dL) and lymphoma (92%), CLL (4%), or MM (5%) receiving chemotherapy. Mean age was 57 years (±15), 53% were male, and 78% Caucasian. Hb, disease status, quality of life (FACT-An, LASA), and health care resource use were assessed monthly. In total, 77 patients were randomized to receive EPO (40,000 U SC QW) immediately, while 102 were observed (OBS) during chemotherapy unless Hb fell to <9 g/dL (at which time EPO was administered 40,000 U SC QW). Baseline Hb (12.4 ± 1.4 g/dL) increased significantly in the EPO group (0.8 ± 2.5, P=.007) and decreased significantly in the OBS group (-0.8 ± 1.0, P<.001; between-group P=.005). Hb fell below 9 g/dL in only 4 (4%) OBS patients. EPO patients reported a significant improvement (P=.036) in total FACT-An, in addition to the anemia (P=.047), physical well being (P=.003), and fatigue (P=.032) subscales. Progressive disease status, but not EPO treatment, was associated with decline in LASA daily activities (P=.041) and energy scores (P=.047). EPO treatment and low baseline Hb were associated with Hb change (P<.001). Changes in total FACT-An and anemia subscale scores were significantly correlated with change in Hb (r=0.20, P<.05), despite small Hb changes. From baseline to end of treatment, the EPO group, compared to the OBS group, had a significantly greater decrease in clinic visits (P=.002) and days requiring general assistance with usual daily activities (P<.001). This interim report suggests that epoetin alfa administered QW improves the sense of well-being and ability to function in patients with mild to moderate anemia receiving chemotherapy for lymphoma, CLL, or MM.

A pilot study on feasibility and efficacy of amifostine preceding high-dose melphalan with autologous stem cell support in myeloma patients.
Jantunen E, Kuittinen T, Nousiainen T.
Department of Medicine, Kuopio University Hospital, P.O. Box 1777, 70211 Kuopio, Finland.
Leuk Lymphoma 2002 Oct;43(10):1961-5

To evaluate feasibility and potential efficacy of amifostine (AMI) in the prevention of toxicities associated with high-dose melphalan (MEL), ten myeloma patients received AMI 910 mg/m2 in 15 min infusion preceding MEL 200 mg/m2 followed by stem cell infusion (AMI group). Hematologic and extra-hematologic toxicities as well as the need for supportive care observed in the AMI group were compared with ten myeloma patients treated in an identical protocol but without AMI. Hypotension was the most important adverse event of AMI infusion. No differences were observed in the time of engraftment between the AMI group and the control group neither was there any difference in the need for supportive care. Oral mucositis grade >2 was observed in 30% of the patients in both groups. Diarrhea grade >2 occurred only in two AMI patients but in five control patients. AMI preceding high-dose MEL is feasible, although adverse events are observed in some patients. Whether AMI could reduce the gastrointestinal toxicity associated with high-dose MEL can be reliably assessed only in prospective randomized trials.

Correlation of sera TNF-alpha with percentage of bone marrow plasma cells, LDH, beta2-microglobulin, and clinical stage in multiple myeloma.
Jurisic V, Colovic M.
Pathophysiology Departmnet, School of Medicine, University of Kragujevac, Serbia.
Med Oncol 2002;19(3):133-9

Tumor necrosis factor-alpha (TNF-alpha) is important for function, differentiation, and transformation of B-lymphocytes in multiple myeloma (MM) but can also induce apoptosis of myeloma cells. Based on this opposite effect, it is very crucial to analyze the correlation of the serum level of TNF-alpha with clinical parameters of the patients. In this article, we analyzed 18 MM patients, 48% male and 52% female, with a mean age of 52 yr (range: 35-81 yr), clinical stage I in 21.4%, stage II in 26.4%, and stage III in 52.2% of patients. Patients with advanced clinical stage, presence of osteolysis, and elevated lactate dehydrogenase (LDH) had a significant difference (Mann-Whitney U-test, p < 0.05) in the serum level of TNF-alpha in comparison with those in the early stage, without osteolysis, and normal LDH. The correlation of individual values of TNF-alpha with the percentage of plasma cells in the bone marrow, LDH, beta2-microglobulin, fibrinogen, and sedimentation rate was significant (p < 0.05). However, we have not found a significant correlation between TNF-alpha and concentration of hemoglobin, the number of white blood cells or platelets (p > 0.05). We concluded that our data indicate determination of TNF-alpha as a good parameter for estimation of tumor mass presence, among individual patients with MM, and may by used for monitoring during application of different therapy protocols.

The Role of SDF1a/CXCR4 in Promoting the Growth of Human Myeloma Cells.
Cai-Xia Li, Yue-Dan Wang, De-Pei Wu, Xue-Guang Zhang. Department of Hematology, 1st Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Department of Immunology, Soochow University, Suzhou, Jiangsu, China; Department of Immunology, Centre of Medical Sciences, Peking University, Beijing, Beijing, China

Interleukin-6 (IL-6) is reported as a major survival and proliferation factor of human multiple myeloma cells and IL-6-dependent myeloma cell lines can be obtained from patients with terminal disease. We show that stromal cell-derived factor 1 (SDF-1), an alpha chemokine that binds to the CXCR4 receptor, promotes the growth of myeloma cell lines and fresh myeloma cells from patients with multiple myeloma. The overexpression of CXCR4 could be detected on human IL-6-dependent myeloma cell lines (XG-1, XG-6, XG-7, and XG-2) and fresh myeloma cells from patients with MM by using gene macroarrays FACS analysis. We demonstrated that SDF-1a supported the long-term growth of myeloma cells as did IL-6 besides induced migration of myeloma cells. An up-regulation of autocrine IL-6 (from 5.1pg/105 cells/24 hours to 60.3pg/105 cells/24 hours) by XG-1 cells was found in culture supernatant when SDF-1a was added in the culture system. The myeloma cell growth factor activity of SDF-1a was due to up-regulation of autocrine IL-6 by myeloma cells partially. The proliferation of myeloma cells induced by SDF-1a could be blocked by additional anti-CXCR4 monoclonal antibody (12G5) or anti-IL-6 monoclonal antibody (B-E8). These data indicate that, in the IL-6-dependent myeloma cell lines or fresh myeloma samples, SDF-1a triggers myeloma cell growth. They suggest that the expression of CXCR4 may have an essential role in the proliferation and migration of myeloma cells in the patients with multiple myeloma.

Promising preclinical activity of 2-methoxyestradiol in multiple myeloma.
Dingli D, Timm M, Russell SJ, Witzig TE, Rajkumar SV.
Molecular Medicine Program [D. D., S. J. R.] and Division of Hematology [M.T., T. E. W., S. V. R.], Mayo Clinic and Foundation, Rochester, Minnesota 55905.

PURPOSE: 2-Methoxyestradiol (2ME2), a natural endogenous product of estradiol metabolism, has demonstrated activity against tumor cell lines and can inhibit angiogenesis. There are limited treatment options for patients with multiple myeloma (MM) who relapse after high-dose therapy and stem cell transplantation. We studied the preclinical activity of 2ME2 as a therapeutic agent for myeloma. Experimental Design: Five established myeloma cell lines as well as primary plasma cells from patients with MM were exposed to 2ME2 at various concentrations. We evaluated the activity of the drug to inhibit cell replication and induction of apoptosis in vitro as well as the ability of the drug to inhibit myeloma tumor xenograft growth in severe combined immunodeficient mice.

RESULTS: 2ME2 inhibited tritiated thymidine uptake in all myeloma cell lines tested in a dose-dependent fashion and induced G(2)-M phase cell cycle arrest. The drug induced apoptosis in all cell lines tested and in half of the primary plasma cells evaluated in a dose-response manner. Forty-eight hours after drug exposure, a large proportion of the cells were dead by propidium iodide staining. Injection of the drug i.p. suppressed myeloma tumor xenograft growth, and the effect was sustained after cessation of therapy.

CONCLUSIONS: 2ME2 has significant activity against myeloma cell lines and primary myeloma cells both in vitro and in an animal model. Clinical trials are required to evaluate its activity in patients with MM.

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