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Biomedical subjects

R Alexanian

Publications and source records attributed to R Alexanian.

At least 91 records · Page 5Linked to original sources
PubMed1990

Autologous bone marrow transplantation in multiple myeloma: identification of prognostic factors.

Multiple myeloma remains a universally fatal malignancy with a median survival time not exceeding 3 years. A clinical trial was undertaken to determine feasibility and efficacy of marrow-ablative chemoradiotherapy supported by unpurged autologous bone marrow (ABMT) and to define prognostic variables. Total body irradiation and either melphalan or thiotepa were administered to 55 patients (median age 53 years; range 20 to 66 years). The group of 21 patients with resistance to standard melphalan-prednisone and to continuous infusions of vincristine and Adriamycin with high dose dexamethasone (VAD) included 7 with primary unresponsive disease and 14 with resistant relapse; among the 34 patients achieving remission with the VAD regimen, 14 were in first and 20 in a subsequent remission. Marked cytoreduction by greater than or equal to 75% was observed among all 21 patients with refractory myeloma, whereas further cytoreduction of this magnitude was noted in only 56% of the 34 patients already in remission after VAD. Five of the 6 early deaths among all 55 patients occurred in the 14 patients with resistant relapse, none of whom achieved complete remission and who, as a group, had median durations of relapse-free and overall survival of only 8 and 7 months, respectively. Among the 41 remaining patients, there was only one early death, and 27% achieved complete remission including a 36% incidence among the 14 patients treated in first remission; their projected 4-year survival rate was 82% regardless of their disease status (first or later remission or primary resistance). When information about sensitivity to prior therapy is unavailable, the presence before ABMT of both high beta-2-microglobulin levels (greater than 3 mg/L) and non-IgG isotype helped identify 9 among the 55 patients with a very poor prognosis: all 8 responders relapsed within 9 months, and 8 patients died within 15 months. By contrast, a 4-year projected survival rate of over 70% for the other patients (about 80% of this series) justifies further investigation of this novel treatment approach in comparison with standard dose regimens. Our results indicate that marrow-ablative therapy cannot be recommended for myeloma patients with resistant relapse or those with a combination of risk factors (advanced tumor burden, absence of IgG isotype). The apparent lack of an adverse effect of even marked plasmacytosis in autografts (up to 30%) emphasizes the need for better cytoreduction rather than bone marrow purging.

Adult↗
PubMed1990

High-dose melphalan and granulocyte-macrophage colony-stimulating factor for refractory multiple myeloma.

High-dose melphalan has induced remissions in about 40% of patients with refractory myeloma, but the mortality has been high, at about 20%, due to complications of prolonged granulocytopenia. In an attempt to stimulate earlier granulocyte recovery, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously to 23 patients with refractory myeloma who had been treated with melphalan at a high dose of 100 mg/m2. Thirty-nine percent of patients achieved marked tumor cytoreduction by at least 75%, 2 died within 2 months from infectious complications during severe neutropenia; and median durations of relapse-free and overall survival were 7 and 10+ months, respectively. The nine patients presenting with both advanced age over 50 years and a long history of prior therapy of over 1 year required significantly longer median times of 31 days for granulocytes and of 63 days for platelets to reach safe levels of at least 500/microL and 50,000/microL, respectively, than the 14 remaining patients who had none or only one of these adverse features (21 and 26 days, respectively). In a historic control of 43 patients treated previously with high-dose melphalan but without GM-CSF, hematologic recovery to the aforementioned levels of granulocytes and platelets proceeded over almost 5 weeks, regardless of age and prior treatment exposure. Thus GM-CSF seems to hasten marrow recovery, especially in patients with adequate normal marrow stem-cell reserve as defined by younger age or less prior therapy. While not shortening the duration of neutropenia, GM-CSF dose increments (from 0.25 to 0.5 to 0.75 mg/m2) increased the incidence of severe toxicity from 0% to almost 40%, especially among older patients. These results support the usefulness of low-dose GM-CSF (0.25 mg/m2) in stimulating marrow recovery in selected patients with adequate marrow reserve treated with high-dose melphalan for refractory multiple myeloma.

Colony-Stimulating Factors↗
PubMed1990

Fludarabine therapy in macroglobulinemic lymphoma.

Fludarabine, a fluorinated analogue of adenine, was given to 11 patients with macroglobulinemic lymphoma, all but one having failed prior standard chemotherapy. Five patients (45%) responded with more than a 50% reduction of immunoglobulin M (IgM) tumor mass for a projected median duration of longer than 1 year. The onset of remission was usually slow, with a median tumor halving time of 5.2 months in responding patients, emphasizing the importance of repeated courses of treatment. Fludarabine is an important new agent effective against macroglobulinemic lymphoma, and should be evaluated further in combination with other active modalities.

Adult↗
PubMed1990

VAD-based regimens as primary treatment for multiple myeloma.

An alternating VCAD-VAD regimen, combining vincristine-doxorubicin by continuous infusion with cyclophosphamide and pulse dexamethasone, or VAD alone, was given to 175 previously untreated patients with multiple myeloma. The response rate with primary VAD-based regimens of 55% was virtually identical to the 54% in comparable patients treated previously with similar programs by using bolus vincristine-doxorubicin. Despite responses to VAD that were more rapid in onset than any previous treatment, remission and survival times were similar. This may be due to major differences in drug sensitivity between progenitor and differentiated plasma cells. A VAD-based regimen seems better for newly diagnosed patients when rapid control of multiple myeloma is necessary.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

New treatment strategies for multiple myeloma.

During the past 5 years, several new treatments and strategies have been developed for patients with multiple myeloma. For patients with disease resistant to standard therapies, these include the VAD regimen, dexamethasone alone, high-dose melphalan, and intensive chemoradiotherapy with bone marrow transplantation. Alpha interferon appears to have its greatest potential as part of early induction therapy or during remission maintenance. The role of hemopoietic growth factors or blood stem cells in support of high-dose therapy and drugs that may overcome multiple drug resistance continues under study. A sequence of non-cross resistant therapies early in the disease course seems worthy of investigation, especially in patients at high risk for early relapse.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

High dose cyclophosphamide, BCNU and VP-16 with autologous blood stem cell support for refractory multiple myeloma.

Eleven patients with advanced multiple myeloma refractory to standard doses of alkylating agents and salvage therapy with vincristine, adriamycin and dexamethasone (VAD) were treated with high dose cyclophosphamide, BCNU and VP-16 (CBV) with autologous blood stem cell support. Seven patients had marked marrow plasmacytosis (greater than 30%) and four had extensive pelvic bone disease precluding autologous marrow harvest. Four patients responded with a median remission duration of 7 months. Recovery of granulocytes and platelets occurred promptly in 10 evaluable patients with complete hematologic recovery. Autologous blood stem cells can provide safe and effective support for high dose CBV treatment of myeloma patients with extensive marrow plasmacytosis. The short remissions call for better cytoreductive regimens with consideration for earlier use when the myeloma may be more responsive to therapy.

Blood Transfusion, Autologous↗
PubMed1990

Renal failure in multiple myeloma. Pathogenesis and prognostic implications.

The pathogenesis, prognosis, and reversibility of renal failure were assessed in 494 consecutive, previously untreated patients with multiple myeloma. For patients with a similar extent of disease, the presence or degree of azotemia did not adversely affect prognosis. Hypercalcemia and/or Bence Jones proteinuria explained the renal failure in 97% of patients. After treatment with a combination of hydration and chemotherapy, normal renal function was achieved in 51% of patients, reversibility usually being rapid and occurring more often in those with slight elevation of serum creatinine. Myeloma control was much more important for survival prolongation than reversal of renal failure, supporting the prompt institution of effective therapy for the underlying malignancy.

Acute Kidney Injury↗
PubMed1989

High serum levels of lactic dehydrogenase identify a high-grade lymphoma-like myeloma.

Although conferring a grave prognosis in patients with malignant lymphoma, high levels of serum lactic dehydrogenase (LDH) are usually not seen in patients with multiple myeloma, a more indolent tumor composed mainly of B cells in their terminal stage of differentiation. Thus, only 2 of 118 patients in earlier phases of myeloma showed marked LDH elevations to more than 500 U/L, whereas such abnormalities were present in 12 of 64 patients with advanced disease progressing despite treatment with vincristine, doxorubicin (Adriamycin), dexamethasone (VAD) (median LDH level, 700 U/L). High LDH levels were associated with high serum levels of beta-2-microglobulin, hypercalcemia, extraosseous disease features, a short preceding clinical course as well as a short subsequent survival time. A poor prognosis was also noted in patients with lower LDH in whom marked increments were induced by high-dose chemotherapy; thus, LDH elevations to greater than 300 U/L present before or found after high-dose cytotoxic therapy were observed in about 50% of patients with VAD-resistant myeloma and define a new clinical entity with features of extraosseous disease and an unusually aggressive course ("high-grade myeloma"). The shorter survival of newly diagnosed patients with high-normal compared with those with low-normal LDH levels (less than 200 U/L), regardless of tumor mass, suggests the presence in some patients of a tumor subpopulation with high LDH production that escapes growth control with standard treatment. Staging of multiple myeloma should therefore include measurements of serum LDH levels in addition to beta-2-microglobulin analysis and tumor mass estimation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Chemotherapy for resistant and relapsing multiple myeloma.

This report summarizes a broad experience in the treatment of patients with multiple myeloma resistant to standard chemotherapy. The VAD regimen has induced remissions in about 50% of relapsing patients but in only about 25% of previously unresponsive patients. In patients resistant to VAD, high-dose therapies with intravenous melphalan, a CBV combination (cyclophosphamide-BCNU-VP-16) or an EDAP regimen (VP-16 -platinum) produced responses in about 40% of patients. However, these treatments usually required autologous bone marrow or blood stem cell support and the median duration of control was only 6 months. With an even more intensive program using high-dose melphalan and total body irradiation supported by autologous bone marrow, all patients who survived the early treatment period responded for a median duration of about 1 year. Results indicated a dose-response effect of chemoradiotherapy on VAD-resistant myeloma with the potential that such intensive regimens will prolong disease-free survival time.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Etoposide, dexamethasone, cytarabine, and cisplatin in vincristine, doxorubicin, and dexamethasone-refractory myeloma.

Based on remarkable activity in refractory lymphomas, a combination of etoposide, cisplatin (both administered by 4-day continuous infusions), cytarabine (Ara-C), and dexamethasone (EDAP) was evaluated in 20 patients with advanced myeloma refractory to standard melphalan and prednisone (MP) and/or vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dexamethasone (VAD) and even to high doses of melphalan (HDM) (seven patients). Forty percent of patients responded regardless of previously recognized risk factors (eg, duration of drug resistance, tumor mass, and serum lactic dehydrogenase [LDH] level). While the median survival was only 4.5 months, patients with good performance (Zubrod less than 2) and low or intermediate tumor stage survived more than 14 months compared with only 2 months for the remaining group. EDAP could be readily administered in the outpatient clinic, but neutropenic fever prompted hospital admission in 80% of patients, half of whom developed penumonia and sepsis, a fatal outcome in four patients. Severe myelosuppression was of short duration, so that subsequent cycles could be administered every 3 to 4 weeks. No serious extramedullary toxicity, including renal toxicity, was encountered. Marrow toxicity and hence infectious complications may be reduced by elimination of Ara-C without compromising treatment efficacy. We conclude that the lack of cross-resistance with VAD and even HDM makes EDAP or a similar combination an attractive regiment to be formally explored in an alternating sequence with VAD in high-risk myeloma.

Aged↗
PubMed1989

Plasma cell myeloma--new biological insights and advances in therapy.

Plasma cell myeloma is a more complex neoplasm than suggested by the relative uniformity of its dominant plasma cells, which represent the terminal stage of normal B-cell differentiation. Phenotypic, molecular, and cellular genetic data favor the presence of a myeloma stem cell early in hematopoietic development so that, as in chronic myelogenous leukemia (CML), a far distance exists between the primordial malignant cell that was the target of malignant transformation and the dominant clinical phenotype. Traces of pre-B, myeloid, and T cells are coexpressed with the mature B-cell phenotype, an occurrence unknown in normal B-cell differentiation. Analogous to CML, disease progression is marked by disease dedifferentiation, occasionally with cessation of myeloma protein production and development instead of extramedullary lymphomalike features with high LDH or myelodysplasia/acute myelogenous leukemia (AML) syndromes. The prognostic importance of serum LDH levels even in newly diagnosed myeloma suggests the early presence of tumor cells with "LDH phenotype," which, as a result of drug resistance and proliferative advantage, expand preferentially during disease progression. Further characterization of these cells may provide important clues about the ontogeny of multiple myeloma. Myeloma cells express many receptors for different biological signals that might be exploitable for therapy with immunotoxins or radioisotopes. Plasma cells and their precursors also produce a variety of cytokines, some of which have putatively autostimulatory functions (eg, IL-1, IL-5, IL-6) and/or are related to disease manifestations (eg, IL-1 and TNF-beta as OAF). The wealth of cellular expression by plasma cells provides clues for understanding the mechanisms of gene activation and the nature of abnormal growth and differentiation. The accuracy of prognostically relevant staging systems has been refined with the use of new quantitative parameters that reflect tumor mass (ie, serum B2M levels) and biology. Further studies of cellular and molecular biology (ie, CAL-LA, H-ras) may reveal those tumor cell features that define clinical entities, response to therapy, and long-term prognosis. The lack of a major advance in prognosis despite the use of more drugs and more intensive regimens justifies the continued use of standard melphalan-prednisone for patients with a highly favorable prognosis, for the very aged, and for those with a short life expectancy due to other major medical problems. However, a radical departure from standard practice is required to improve the prognosis for younger patients with poor risk features.(ABSTRACT TRUNCATED AT 400 WORDS)

B-Lymphocytes↗
PubMed1988

Recombinant interferon gamma in hairy cell leukemia, multiple myeloma, and Waldenstrom's macroglobulinemia.

Fifteen patients with multiple myeloma, five with hairy cell leukemia, and five with Waldenstrom's macroglobulinemia were treated with recombinant interferon gamma (rINF-gamma) to determine the antitumor activity of this agent. The rIFN-gamma was administered by daily intramuscular injection at doses ranging from 0.125 to 0.5 mg/m2. No responses were observed in patients with multiple myeloma, although in one patient the disease has remained stable for over 16 months. Minimal improvement in some hematologic indexes were observed in three of five patients with hairy cell leukemia. One partial remission and one minor response were documented in two of the five patients with Waldenstrom's macroglobulinemia. In five patients, an increase in normal serum immunoglobulins was observed. These results suggest that there is only minimal activity of rIFN-gamma as a single agent in neoplasms of B-cell origin.

Adult↗
PubMed1988

Phenotypic heterogeneity in aneuploid multiple myeloma indicates pre-B cell involvement.

The expression of early and mature B cell markers, surface beta 2-microglobulin (B2M) and cytoplasmic immunoglobulin (clg) by aneuploid tumor cells in bone marrow aspirates from 44 patients with multiple myeloma was evaluated by correlated DNA immunofluorescence flow cytometry. Myeloma tumor cells of almost 90% of the patients contained monoclonal clg and expressed the mature plasma cell antigen R1-3 as well as surface B2M; common acute lymphoblastic leukemia antigen (CALLA) was present in 55%, B2 in 17%, and B4 in 23% of samples studied. Coexpression of CALLA and clg in 46% of all patients identified a novel myeloma phenotype without known counterpart in the normal differentiation of B cells. CALLA and clg were independently expressed and gave rise to CALLA+/clg-, CALLA+/clg+, and CALLA-/clg+ cells. The association of CALLA and mature plasma cell markers may define discrete stages of neoplastic plasma cell differentiation.

Aneuploidy↗
PubMed1988

Prognosis of asymptomatic multiple myeloma.

Prognostic factors were assessed in 35 consecutive, asymptomatic patients with multiple myeloma. The presence of any lytic bone lesion or a serum myeloma protein concentration of at least 3.0 g/dL was followed by early disease progression and the need for chemotherapy within two years. Such patients require frequent monitoring of electrophoretic data. In patients without these features, the myeloma did not progress for a median of three years and the subsequent median survival time was seven years, identifying those likely to live for ten years after diagnosis. Because the treatment of myeloma remains palliative, chemotherapy should be withheld until symptoms develop or complications are imminent.

Actuarial Analysis↗