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What's New In Research - April 4, 2003
04.04.03
Simultaneous occurrence of acute myeloid leukemia with multilineage dysplasia and multiple myeloma
[Article in Japanese]
Yanagimoto M, Usuki K, Iijima K, Hirai Y, Iki S, Urabe A.
Division of Hematology, NTT Kanto Medical Center.
Rinsho Ketsueki 2003 Jan;44(1):19-24

An 82-year-old woman was admitted to our hospital because of dizziness and petechiae. Peripheral blood examination showed severe anemia and thrombocytopenia. Bone marrow aspiration revealed 42% leukemic blasts positive for peroxidase with multilineage dysplasia, leading to a diagnosis of acute myeloid leukemia with multilineage dysplasia. The levels of the patient's marrow plasma cells increased to 12%, whereas serum levels of IgG, A, and M dropped. lambda type Bence Jones protein was detected on urine immunoelectrophoresis. The total urinary protein was 3, 960 mg/day. Bone scintigraphy detected multifocal uptake in the ribs. The diagnosis was multiple myeloma developing simultaneously with acute myeloid leukemia. Possible mechanisms for the occurrence of acute myeloid leukemia and multiple myeloma were discussed.


A multi-centre phase-II trial of thalidomide in relapsed/refractory multiple myeloma reveals an adverse prognostic impact of advanced age.
Mileshkin LR, Biagi JJ, Mitchell P, Underhill C, Grigg A, Bell R, McKendrick J, Briggs P, Seymour JF, Lillie K, Smith JG, Zeldis JB, Prince HM.
Department of Haematology, Peter MacCallum Cancer Institute, East Melbourne, VIC, Australia.
Blood 2003 Mar 13; [epub ahead of print]

Background: Patients with relapsed or refractory multiple myeloma have a poor outlook. Thalidomide has activity in a proportion, however criteria for predicting response have not been conclusively identified.

Methods: We initiated a prospective multi-centre Phase-II trial in patients with relapsed/refractory myeloma using thalidomide up to maximum dose 800 mg/day. Interferon-alpha-2B (1.5-3.0MU,SC,TIW) was added at week 12 if disease was responsive or stable. Patients intolerant of interferon continued thalidomide alone. Thalidomide +/- interferon was continued until disease progression. Objectives were to determine toxicity, response rate (RR), progression-free survival (PFS), overall survival (OS) and to elucidate relevant prognostic factors. Results: Seventy-five patients, with median age 64 (range 36-83), were enrolled. The median individual-maximum-tolerated dose of thalidomide was 600mg/day. 41% reached 800 mg/day. Overall RR was 28% with one complete response, and 55% stable disease (SD). The only predictor for response was age 65 (median 9.2mo v >26mo;P=0.011), raised serum LDH (P=0.002), and raised serum creatinine (P=0.007) predicted inferior outcomes. Nineteen patients received interferon. 10 discontinued due to toxicity. Four of 12 patients who received >4 weeks interferon were converted from SD to partial response.

Conclusions: Our findings confirm substantial activity of thalidomide in relapsed/refractory myeloma. Interferon may improve response in selected patients, but is often not tolerated. The inferior outcome demonstrated in those with the identified prognostic factors is important in planning management for these patients.


Prospects for CD40-directed experimental therapy of human cancer
Alex W Tong and Marvin J Stone
Cancer Immunology Research Laboratory, Baylor Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas 75246, USA
Cancer Gene Therapy (2003) 10, 1-13 doi:10.1038/sj.cgt.7700527

Abstract : CD40, a member of the tumor necrosis factor receptor (TNF-R) family, is a surface receptor best known for its capacity to initiate multifaceted activation signals in normal B cells and dendritic cells (DCs). CD40-related treatment approaches have been considered for the experimental therapy of human leukemias, lymphomas, and multiple myeloma, based on findings that CD40 binding by its natural ligand (CD40L), CD154, led to growth modulation of malignant B cells. Recent studies also exploited the selective expression of the CD40 receptor on human epithelial and mesenchymal tumors but not on most normal, nonproliferating epithelial tissues. Ligation of CD40 on human breast, ovarian, cervical, bladder, non small cell lung, and squamous epithelial carcinoma cells was found to produce a direct growth-inhibitory effect through cell cycle blockage and/or apoptotic induction with no overt side effects on their normal counterparts. CD154 treatment also heightened tumor rejection immune responses through DC activation, and by increasing tumor immunogenicity through up-regulation of costimulatory molecule expression and cytokine production of epithelial cancer cells. These immunopotentiating features can produce a "bystander effect" through which the CD40-negative tumor subset is eliminated by activated tumor-reactive cytotoxic T cells. However, the potential risk of systemic inflammation and autoimmune consequences remains a concern for systemic CD154-based experimental therapy. The promise of CD154 as a tumor therapeutic agent to directly modulate tumor cell growth, and indirectly activate antitumor immune response, may depend on selective and/or restricted CD154 expression within the tumor microenvironment. This may be achieved by inoculating cancer vaccines of autologous cancer cells that have been transduced ex vivo with CD154, as documented by recently clinical trials. This review summarizes recent findings on CD154 recombinant protein- and gene therapy-based tumor treatment approaches, and examines our understanding of the multifaceted molecular mechanisms of CD154-CD40 interactions.


Dermatologic side effects of thalidomide in patients with multiple myeloma.
Hall VC, El-Azhary RA, Bouwhuis S, Rajkumar SV
Department of Dermatology, Mayo Clinic, Jacksonville; and the Department of Dermatology, and Division of Hematology and Internal Medicine, Mayo Clinic, Rochester.
Journal of the American Academy of Dermatology 2003 Apr;48(4):548-52

BACKGROUND: Thalidomide, an antiangiogenic agent, was approved by the Food and Drug Administration in 1998 for the treatment of erythema nodosum leprosum. Although its teratogenic and neurologic side effects are well known, its dermatologic side effects continue to be defined.

OBJECTIVE: We report the dermatologic side effects in 87 patients with multiple myeloma enrolled in a comparative, open-label, clinical trial treated with thalidomide alone (50 patients) or thalidomide and dexamethasone (37 patients).

METHOD: We reviewed the records of all patients enrolled in the clinical trial. The frequency, type, severity, and time of onset of all skin eruptions that were temporally related to thalidomide treatment were recorded.

RESULTS: Minor to moderate skin eruptions were noted in 46% of patients taking thalidomide alone and in 43% of those taking thalidomide and dexamethasone. These included morbilliform, seborrheic, maculopapular, or nonspecific dermatitis. Severe skin reactions (exfoliative erythroderma, erythema multiforme, and toxic epidermal necrolysis) that required hospitalization and withdrawal of thalidomide developed in 3 patients receiving thalidomide and dexamethasone.

CONCLUSION: The prevalence of dermatologic side effects of thalidomide appear to be higher than previously reported. Although in most patients they were minor, in a few patients they were quite severe, particularly when given in conjunction with dexamethasone for newly diagnosed myeloma. Further studies are needed to verify the extent of the interaction between thalidomide and dexamethasone in this group of patients.


Novel therapeutics represent a new paradigm for treating multiple myeloma.
Article prepared by Cancer Weekly editors from staff and other reports.
©Copyright 2003 Cancer Weekly via NewsRx.com

According to a study from the United States, "multiple myeloma (MM) cells home to and adhere to extracellular matrix proteins and to bone marrow stromal cells (BMSCs); and in the BM microenvironment, grow, survive, resist drugs, and migrate under the influence of cytokines including interleukin-6, vascular endothelial growth factor, tumor necrosis factor alpha, and insulin-like growth factor (IGF)-1."

"Proliferation is via the Ras/Raf MAPK cascade, drug resistance via P13-K/Akt signaling, and migration via PKC dependent pathways. Novel therapies that target not only the MM cell, but also the BM microenvironment, can overcome drug resistance in vitro and in vivo in murine human MM models," said K.C. Anderson and coauthors, Harvard University, School of Medicine.

"For example, immunomodulatory derivatives of thalidomide (IMiDs) and the proteasome inhibitor PS-341 both induce apoptosis of MM cell lines and patient cells refractory to melphalan, doxorubicin, and dexamethasone; abrogate MM cell binding to fibronectin and BMSCs and related protection against immune- and drug-induced apoptosis; block production of cytokines which promote MM cell growth, survival, drug resistance, and migration; inhibit angiogenesis; and stimulate host anti-tumor immunity," Anderson's team said.

"In the setting of relapsed refractory MM, a phase I trial of the IMiD CC5013 shows stable paraprotein or better in 20 of 24 (79%) patients, with a favorable toxicity profile. In this same patient population 85% of 54 patients treated in a Phase II trial of PS-341 achieved either paraprotein response (50%) or stable disease (35%)."

"Cellular and gene microarray studies comparing PS-341 and an IkappaB kinase inhibitor, PS-1145, suggest that selective NF-kappaB blockade cannot account for all the anti-MM activity of PS-341."

"Finally, cellular and signaling studies provide the preclinical rationale for combining these novel agents with conventional therapies, or with each other, to enhance efficacy. These novel therapeutics therefore represent a new treatment paradigm in MM targeting the tumor cell in its microenvironment to overcome classical drug resistance and improve patient outcome. Future studies should define the utility of these agents as primary therapy, treatment for first relapse, and maintenance therapy," study authors contend.

Anderson and colleagues published the results of their study in Cancer (Moving disease biology from the lab to the clinic. Cancer, 2003;97(3 Suppl. S):796-801).


Tandem stem cell transplants may improve the chances of complete remission for multiple myeloma patients.
Article prepared by Cancer Weekly editors from staff and other reports.
©Copyright 2003 Cancer Weekly via NewsRx.com

"Between 1994 and 1999, 88 multiple myeloma (MM) patients were included in a phase II study to evaluate a tandem autologous stem cell transplantation (ASCT) program," according to researchers in Spain.

"The first was conditioned with melphalan 200 mg/m2 (MEL200-ASCT1), and the second with cyclophosphamide, etoposide and BCNU (CBV-ASCT2)," wrote J. J. Lahuerta and colleagues at Hospital Universitario 12 de Octubre.

"All patients were in response after MEL200-ASCT1. A control group of MM patients with response to a single ASCT was selected to compare outcomes," they said. "After MEL200-ASCT1, 26 patients (30%) achieved complete remission (CR). Of the remaining 48 evaluable patients, 16 (33%) achieved CR with CBV-ASCT2."

"The final CR rate was 48%," study data showed. "The 5-year overall survival (OS) was 55% [95% confidence interval (CI) 43-67%] while the event-free survival (EFS) was 28% (95% CI 15-39%)."

"CR status after CBV-ASCT2 was the most important prognostic factor for OS and EFS (P = 0.00001)," Lahuerta and coworkers reported, "although no differences in outcomes were detected when the patients in CR after MEL200-ASCT1 were compared with those who obtained CR after CBV-ASCT2."

"Univariate and multivariate analyses showed improved OS and EFS for the tandem series as compared with the control series treated with a single MEL200-ASCT. However, in a stratified comparison by response, there were no prognostic differences between tandem patients and control patients treated with a single ASCT," the researchers noted.

They concluded that "the benefit of a second high-dose therapy course depends on its capacity to result in CR for MM patients who have not attained CR after ASCT1."

Lahuerta and coauthors published their study in the British Journal of Haematology (Tandem transplants with different high-dose regimens improve the complete remission rates in multiple myeloma. Results of a Grupo Espanol de Sindromes Linfoproliferativos/Trasplante Autologo de Medula Osea phase II trial. Br J Haematol, 2003;120(2):296-303).


The nitric oxide synthase inhibitor L-NAME stalls angiogenesis in plasmacytoma.
Article prepared by Cancer Weekly editors from staff and other reports.
©Copyright 2003 Cancer Weekly via NewsRx.com

"Angiogenesis is a critical factors in sustaining the growth, invasion and metastasis of certain solid tumors and hematological malignancies such as multiple myeloma (MM)," researchers in Japan report.

"In the present study, we examined the anticancer potential of an inhibitor of nitric oxide synthase (NOS), N-G -nitro-l-arginine methyl ester (L-NAME), in a novel severe combined immunodeficient mouse model (KHM mouse) that harbors the highly sanguineous plasmacytoma cell line KHM-4, derived from a patient with highly chemoresistant MM," wrote S. Uneda and colleagues, Kumamoto University, School of Medicine.

"KHM mice were intraperitoneally administered with either L-NAME, doxorubicin, melphalan, or paclitaxel," they said.

"A significant reduction in tumor sizes was noted in L-NAME-administered KHM mice while no significant reduction was observed in melphalan- or doxorubicin-administered mice. A profound decrease in angiogenesis was observed in tumor tissues from L-NAME- and paclitaxel-administered KHM mice."

"A marked decrease in human vascular endothelial cell growth factor (VEGF) levels was identified in tumor tissues from L-NAME-administered KHM mice, strongly suggesting that L-NAME suppressed VEGF production by tumor cells through its inhibition of NOS in tumor cells, resulting in reduced neovascularization in mice leading to the regression of tumor sizes," researchers indicated.

"The present data represent the first observations that certain NOS inhibitors potentially serve as experimental agents for the treatment of chemoresistant MM and plasmacytoma," they concluded.

Uneda and colleagues published their study in British Journal of Haematology (A nitric oxide synthase inhibitor, N-G-nitro-L-arginine-methyl-ester, exerts potent antiangiogenic effects on plasmacytoma in a newly established multiple myeloma severe combined immunodeficient mouse model. Br J Haematol, 2003;120(3):396-404).


Molecular testing of stem cell autografts for contamination with malignant cells fails to predict the outcome of treatment in multiple myeloma patients.
Article prepared by Cancer Weekly editors from staff and other reports.
©Copyright 2003 Cancer Weekly via NewsRx.com

"To evaluate the clinical impact of minimal residual disease in multiple myeloma, apheretic products from 51 autotransplanted patients were tested by fluorescent (GeneScan) polymerase chain reaction (PCR)" in a recent study from Italy.

"Sixty-nine per cent of harvests were contaminated when evaluated for IgH rearrangement," reported S. Galimberti and colleagues at the University of Pisa. "Forty-six patients responded to transplant, with 52.9% achieving complete response (CR)."

"The clinical response of patients was significantly influenced by the number of re-infused CD34+ cells," but "positive PCR results of re-infused harvests were not significantly related to patient outcome," Galimberti and coworkers found. "Median overall survival (OS) was 33 months, and a significant advantage for patients transplanted by 12 months from diagnosis was observed."

While "OS was longer for patients receiving PCR-negative stem cells, with 72% of patients surviving to 70 months in the group receiving PCR-negative harvests vs. 48% in the group transplanted with contaminated precursors," this discrepancy was "not statistically significant," study data indicated. "Ex vivo purging caused a reduction of contamination of up to 3 logs; nevertheless, 80% of purged harvests remained PCR-positive and the purging procedure did not alter response or survival rates."

"Thus, the failure of a predictive role for this highly sensitive molecular method could be explained by the assumption that in vivo persisting malignant cells are the true source of relapse in MM," the researchers concluded.

Galimberti and coauthors published the results of their study in the British Journal of Haematology (Peripheral blood stem cell contamination evaluated by a highly sensitive molecular method fails to predict outcome of autotransplanted multiple myeloma patients. Br J Haematol, 2003;120(3):405-412).


The novel synthetic retinoid AHPN/CD437 triggers a rapid, but incomplete apoptotic response in human myeloma cells.
Article prepared by Cancer Weekly editors from staff and other reports.
©Copyright 2003 Cancer Weekly via NewsRx.com

According to a recent study from France, AHPN/CD437 "appears to possess an apoptotic activity superior to classical retinoids in vitro as in vivo."

"Numerous studies have shown that CD437-induced apoptosis is independent of its nuclear receptor activity, suggesting that CD437 might have a unique mechanism of action," explained B. Joseph and coauthors at the Institut de Recherches sur le Cancer, who conducted a study to "compare CD437- and all-trans retinoic acid (atRA)-induced cell death."

"CD437 provoked a rapid apoptotic phenotype immediately followed by secondary necrosis in RPMI 8226, U266 and L363 human myeloma cell lines," they found. "Nuclear apoptotic features were observed upon both CD437 and atRA treatments."

However, "membrane blebbing and the subsequent formation of apoptotic bodies, a classical apoptotic event, was only observed upon atRA treatment," study results indicated. "In addition, CD437, contrary to atRA, was unable to induce tissue transglutaminase (tTG), an intracellular enzyme involved in the formation of cross-linked protein polymers contributing to apoptotic morphological changes."

"Taken together, these data suggest that CD437 induces rapid but incomplete apoptotic phenotype in human myeloma cells," the researchers concluded.

Joseph and colleagues published their study in Biochimica Et Biophysica Acta - Molecular Cell Research (The novel retinoid AHPN/CD437 induces a rapid but incomplete apoptotic response in human myeloma cells. Bba-mol Cell Res, 2003;1593(2-3):277-282).


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