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RITUXAN™ IN THE MANAGEMENT OF MULTIPLE MYELOMA

 

    1.0 OBJECTIVES

    1.1 Primary Objectives

    1.1.1 To evaluate the role of Rituxan in inducing apoptosis of malignant plasma cells.

    1.1.2 To evaluate the role of Rituxan in improving the response rate to melphalan, and prednisone.

    1.1.3 To determine if Rituxan therapy decreases residual disease and consequently prolongs plateau phase Multiple myeloma patients.

    1.2 Secondary Objectives

      1. Safety: To evaluate the toxicity of Rituxan in Multiple Myeloma patients.

    2.0 BACKGROUND AND RATIONALE

    2.1 Multiple Myeloma

    2.1.1 Disease and Induction Therapy:

    Multiple myeloma is a fatal neoplasm of Plasma cells with a median patient survival of about 30 months1,2. The disease is regarded as responsive to alkylating agents, corticosteroids and irradiation although few patients achieve true and complete remissions. The disease is not considered curable with standard therapy. Thirty percent of patients with multiple myeloma show chemotherapy resistance to initial treatment, and all of those who initially respond will ultimately relapse after a median of 15 months3. Treatment with more aggressive Multi-agent chemotherapy has not significantly improved results over conventional therapy with an alkylating agent and corticosteroids.4,5 Patients with relapsed disease after one or more first-time therapies are a particularly difficult group to treat. Thirty to fifty percent of relapsed patients will not respond to subsequent alkylator-based chemotherapy. Occasional remissions are seen in these patients, but the duration is brief and overall survival is poor.

    2.1.2 Melphalan and Prednisone:

    Multiple myeloma (MM) is a neoplastic disease characterized by the expansion of monoclonal plasma cells that seed throughout bone marrow, causing lytic bone lesions, and introduce monoclonal immunoglobulins, hence the term monoclonal gammopathy.

    The incidence of monoclonal gammopathies in the healthy population is very high. It is rare in persons under 40 years of age, with incidence increasing to 7% to 8% in persons over 65 years of age.6,7 The majority of MM patients had a prior asymptomatic gammopathy8, however, most persons with monoclonal gammopathy of undetermined significance (MGUS) will not develop MM. It is, therefore, probable that there are two distinct types of monoclonal gammopathies, benign and malignant.

    There is currently no test that distinguishes between benign and malignant monoclonal gammopathy. Clinically, patients with MGUS can be divided into two groups, with most requiring only routine follow-up, and the remainder requiring immediate chemotherapeutic intervention owing to evidence of overt disease progression. Helpful tests, such as measures of plasma cells in S phase,9-11 b2-microglobulin serum levels,12,13 and IL-6 serum levels,14-17 may contribute to determining a diagnosis; however, disease progression is clearly defined only after precipitous increase in monoclonal immunoglobulins or appearance of lytic bone lesions.

    The choice of appropriate therapy regimen remains controversial. The efficacy of melphalan and prednisone (MP), first introduced for MM more than 25 years ago, has been compared with several alternative regimens. Other regimens are equivalent to MP, but should be employed only in special cases such as renal failure, or to prevent stem cell damage.18

    2.1.3 Multiple Myeloma and biologic therapy for maintenance:

    While many induction regimens have been well studied and some are quite effective, a long-standing problem in myeloma treatment has been what to do to maintain remissions. A variety of studies have compared chemotherapy maintenance to unmaintained remission and have failed to demonstrate any added benefit from maintenance chemotherapy as long as patients were retreated at the time they relapsed. Unmaintained remissions in stage III and Bence-Jones myeloma patients are short (6-12 months). Several studies have examined the role of alpha-interferon as maintenance therapy. An Italian study reported an improved remission duration and survival as compared to no maintenance therapy.19 Other randomized trials, including a large Southwest Oncology Group study, confirmed a prolonged remission but failed to demonstrate any survival advantage.20

    Biologic Modifier therapy may improve immune reconstitution and reduce the risk of hematologic malignancy relapse in the setting of minimal residual disease by augmenting cytotoxic effect mechanism directed at residual malignant cells. However this model has not resulted in an improvement of survival.

    2.1.4 The Role of anti CD-20 antibodies.

    Multiple myeloma is a disease characterized by the accumulation of neoplastic plasma cells in the bone marrow. Despite the predominance of myeloma cells in the bone marrow, mitotic figures are rarely observed, and kinetic studies of myeloma cells indicate that they have a low labeling index during the early and the plateau phases of the disease21,22.

    The BM is widely affected from the earliest recognizable stage of the disease, while there are very few circulating plasma cells except during the terminal phase. Thus, a proliferating compartment which is at an earlier stage of B-cell differentiation than plasma cells has been postulated to exist and searches for the clonogenic precursors which feed the non-proliferative myeloma-cell compartment have been undertaken23.

    Somatic mutations, which result in amino acid substitutes, are observed frequently in the Ig variable region genes in multiple myeloma, but there is no intraclonal variation. This fact suggests that the target cell of malignant transformation in multiple myeloma is a B-lineage cell, which already has undergone antigenic selection. This B-lineage cell probably corresponds to a pre-plasma cell or a plasma cell rather than a memory B cell. Tumor cells which share an identical third-complementary-determining -region (CDR3) sequence with the myeloma cells can be detected from the various fractions representing different stages of B-cell differentiation, such as CD34+, CD20+ CD10+, CD20+ CD21+, CD20+ CD19+ cells from the peripheral blood. Thus the tumor cell in multiple myeloma are composed of immunophenotypically heterogeneous subpopulations at various stages of differentiation, similar the normal B-lineage cells24.

    The use of Rituxan after achieving a plateau phase, could theoretically prevent the proliferative B-cell compartment from feeding the non-proliferative myeloma cell compartment, and thus relapse.

    2.1.5 Rituxan and enhancing the effects of chemotherapy:

    Sections 2.1.5.1, and 2.1.5.2, will describe the rationale for using Rituxan in enhancing the initial response to chemotherapy. In summary, the role of bcl-2 in the resistance of multiple myeloma patients to chemotherapy has been described, and hence the possible role for Rituxan in enhancing the effect of MP. Also, Rituxan induces apoptosis in lymphoid cells where the drug could work synergisticaly with chemotherapy.

    2.1.5.1 Rituxan monoclonal antibody sensitizes a b-cell lymphoma cell line to cell killing by cytotoxic drugs

    More than 50% of patients with aggressive B lymphomas and the majority of patients with low-grade lymphomas are not cured by current therapeutic strategies. The lymphomas express the B cell antigen CD20 on the cell surface and this antigen serves as target for antibody-directed therapies. Clinical studies with encouraging results have been underway with the use of a chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgGI-6 constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC-2B8. This study investigated the potential anti-tumor therapeutic value of combination treatment with anti-Rituxan and cytotoxic drugs. The in vitro study examined the sensitizing effect of Rituxan antibody on the DHL-4 B lymphoma line to various cytotoxic agents. Cytotoxicity was determined by the MTT assay. Surface and cytoplasmic proteins were determined by flow cytometry. Pretreatment of DHL-4 with Rituxan resulted in inhibition of cell proliferation and cell death and a fraction of the cells underwent apoptosis. While the DHL-4 tumor cells were relatively resistant to several cytotoxic drugs, pretreatment with Rituxan rendered the cells sensitive to TNF-a, ricin, diphtheria toxin (DTX), adriamycin and cisplatin but not to VP16. Chemosensitization of DHL-4 tumor cells was not due to down modulation of either the MDR-1 or bcl-2 gene products. However, treatment of DHL-4 with Rituxan inhibited TNF-a secretion. These findings demonstrate that Rituxan antibody potentiates the sensitivity of DHL-4 tumor cells to several cytotoxic agents. Further, the findings suggest that combination treatments with Rituxan antibody and drugs may be of clinical benefit in the treatment of patients with resistant aggressive B lymphomas.25,26

    2.1.5.2 Overexpression of Bcl-2 family proteins and chemoresistance:

    Bcl-2 overexpression can render cells markedly more resistant to the cytotoxic effects of essentially all currently available anticancer drugs.28 While cytotoxic drugs damage tumor cells by a variety of mechanisms (e.g., DNA cleavage, DNA alkylation, microtubule aggregation, nucleotide precursor inhibition), ultimately the damage induced must somehow be translated into signals for apoptosis. In this regard, overexpression of Bcl-2 or its antiapoptotic homolog Bcl-XL has been shown to prevent proteolytic processing and activation of caspases in response to chemotherapy-induced damage.29-32 The predicted consequence of the cytoprotection provided by Bcl-2 is that damaged malignant cells remain viable and may be able to repair drug-induced injury and resume proliferation. Overexpression of Bcl-2 or Bcl-XL has been shown to create a cellular environment that is permissive for accumulation of mutations and aberrant chromosomal segregation.33-34 This presumably occurs because cells with genetic defects and chromosomal damage would otherwise be eliminated by apoptosis. Thus, damaged tumor cells that overexpress Bcl-2 or Bcl-XL may survive and acquire additional secondary mutations that can lead to the emergence of other mechanisms of drug resistance (e.g., overexpression of MDR-1; amplification of dihydrofolate reductase, loss of glucocorticoid receptors) and tumor progression via oncogene activation or tumor suppressor gene inactivation. Bcl-2 has been experimentally shown to render cells more resistant to killing by dexamethasone, cytosine arabinoside (Ara-C), methotrexate, cyclophosphamide, Adriamycin, daunomycin, 5-fluoro-deoxyuridine, 2-chlorodeoxyadenosine, fludarabine, taxol, etoposide (VP-16), camptothecin, nitrogen mustards, mitoxantrone, cisplatin, vincristine, and some retinoids. The extent to which gene transfer-mediated elevations in Bcl-2 protein levels provide protection from the cytotoxic effects of these drugs varies, depending on the particular drug and the cell line, but it can be as much as 4 or more logs (10,000 x) or as little as half a log (5 X).2.1.5.2 Overexpression of Bcl-2 family proteins and chemoresistance:

    Bcl-2 overexpression can render cells markedly more resistant to the cytotoxic effects of essentially all currently available anticancer drugs.28 While cytotoxic drugs damage tumor cells by a variety of mechanisms (e.g., DNA cleavage, DNA alkylation, microtubule aggregation, nucleotide precursor inhibition), ultimately the damage induced must somehow be translated into signals for apoptosis. In this regard, overexpression of Bcl-2 or its antiapoptotic homolog Bcl-XL has been shown to prevent proteolytic processing and activation of caspases in response to chemotherapy-induced damage.29-32 The predicted consequence of the cytoprotection provided by Bcl-2 is that damaged malignant cells remain viable and may be able to repair drug-induced injury and resume proliferation. Overexpression of Bcl-2 or Bcl-XL has been shown to create a cellular environment that is permissive for accumulation of mutations and aberrant chromosomal segregation.33-34 This presumably occurs because cells with genetic defects and chromosomal damage would otherwise be eliminated by apoptosis. Thus, damaged tumor cells that overexpress Bcl-2 or Bcl-XL may survive and acquire additional secondary mutations that can lead to the emergence of other mechanisms of drug resistance (e.g., overexpression of MDR-1; amplification of dihydrofolate reductase, loss of glucocorticoid receptors) and tumor progression via oncogene activation or tumor suppressor gene inactivation. Bcl-2 has been experimentally shown to render cells more resistant to killing by dexamethasone, cytosine arabinoside (Ara-C), methotrexate, cyclophosphamide, Adriamycin, daunomycin, 5-fluoro-deoxyuridine, 2-chlorodeoxyadenosine, fludarabine, taxol, etoposide (VP-16), camptothecin, nitrogen mustards, mitoxantrone, cisplatin, vincristine, and some retinoids. The extent to which gene transfer-mediated elevations in Bcl-2 protein levels provide protection from the cytotoxic effects of these drugs varies, depending on the particular drug and the cell line, but it can be as much as 4 or more logs (10,000 x) or as little as half a log (5 X).

    3.0 TREATMENT PLAN

    3.1 Patients will be treated with Rituxan, intravenously every week for a total of 4 weeks. This will be repeated every 6 months, for a total of 6 cycles. If uncontrollable recurrent infectious process occurs, the drug will be discontinued after 4 cycles.

    3.2 Melphalan, will be administered in the standard fashion . This will be repeated every 4-6 weeks as allowed by counts for a minimum of 9 cycles, and two cycles after best response.

    3.3 Prednisone will be given 1-4. This will be repeated every 4-6 weeks with the melphalan, for a minimum of 9 cycles, and two cycles after best response.

    3.4 The combination of chemotherapy will start after the first 4 treatments of Rituxan have been administered, i.e., day 35 of therapy.

    4.0 PATIENT SELECTION

    4.1 Inclusion Criteria:


    Each patient must meet these criteria to be considered for enrollment.

    4.1.1 Newly diagnosed Patients with multiple myeloma

    4.1.2 Patients with pancytopenia related to multiple myeloma will be eligible for treatment i.e. patients with > 50% plasma cells in the BM, or have splenomegaly, or have plasma cell leukemia.

    4.1.3 Patients must have an Eastern Cooperative Group (ECOG) Performance Status of 0-2.

    4.1.4 Organ function permitted:

    4.1.4.1 If bone marrow is occupied by <50% plasma cells: WBC > 2500/µl or Absolute Neutrophil Count > 1000/µl, however if the platelet count is > 75,000/m l, a neutrophil count of > 500/m l will be allowed.

    4.1.4.2 Platelets > 45,000/µl. Patients with Thrombocytopenia related to ITP, B12 or folate deficiency will be eligible.

    4.1.4.3 Bilirubin < 2x institutional upper limits of normal

    4.1.4.4 Liver enzymes (ALT or AST) < 2 x normal (unless >1/3 of liver is involved by tumor, in which case ALT or AST must be < 5 x normal)

    4.1.4.5 Creatinine £ 2.0 mg/dl

    4.2 Ineligibility Criteria:

    4.2.1 The patient will be evaluated within three weeks prior to entry. Any one of the following conditions eliminates a patient from participating in this protocol.

    4.2.2 Concurrent involvement in any other clinical trial using an investigational drug or device, or participation in any investigational drug study within 4 weeks prior to study registration. Exceptions may be made by the study investigators for participation in certain studies (e.g. antimicrobial studies) on a case by case basis.

    4.2.3 Severe infection requiring intravenous antibiotic treatment.

    4.2.4 Severe hepatic disease (e.g. SGOT or SGPT, bilirubin, alkaline phosphatase more than 2.5 times the normal laboratory range).

    4.2.5 Patients with previous bone marrow transplantation as part of their previous treatment regimen.

    4.2.6 Patients with a life expectancy of less than 3 months will be ineligible.

    4.2.7 Pregnant or lactating patients will be ineligible. Men or women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

    4.2.8 No prior malignancy is allowed, except for adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the patient has been disease-free for at least 5 years.

    4.2.9 Patients with solitary bone or solitary Extramedullary plasmacytoma as the only evidence of Plasma cell dyscrasia.

     5.0 STUDY PARAMETERS

    5.1 Allowable Concomitant Therapy

    • Erythropoietin for anemia, GM-CSF for severe, symptomatic neutropenia.
    • Aredia and immunoglobulin therapy will be allowed at any stage of therapy.
    • Plasmapheresis at the initiation of therapy to treat renal failure will be allowed.

    5.2 Treatment and Dose Modifications

    5.2.1Melphalan:
    The dose of melphalan will be reduced by 25% if the neutrophil count persists at < 1000/m l after a two-week delay. This dose reduction will not apply if the neutrophil count at the initiation of therapy was < 1,500/m l, and the platelet count at the initiation of the chemotherapy cycle is > 100,000/m l. Melphalan will be given every 4-6 weeks if the neutrophil count is > 1,000/m l and/or platelet count > 75,000/m l, or at least 75% of baseline WBC and platelets. Therapy can be delayed up to 4 weeks for counts to recover. 5.2.1Melphalan:
    The dose of melphalan will be reduced by 25% if the neutrophil count persists at < 1000/m l after a two-week delay. This dose reduction will not apply if the neutrophil count at the initiation of therapy was < 1,500/m l, and the platelet count at the initiation of the chemotherapy cycle is > 100,000/m l. Melphalan will be given every 4-6 weeks if the neutrophil count is > 1,000/m l and/or platelet count > 75,000/m l, or at least 75% of baseline WBC and platelets. Therapy can be delayed up to 4 weeks for counts to recover.

    5.2.2Prednisone:
    The dose of prednisone will be reduced by up to 50% if uncontrollable diabetes mellitus results from the therapy.
    5.2.2Prednisone:
    The dose of prednisone will be reduced by up to 50% if uncontrollable diabetes mellitus results from the therapy.

    5.2.3 Rituxan:

    No dose modifications are necessary. However, in-patients who experience a gram positive infectious process requiring IV antibiotics following the use of Rituxan, therapy with IVIG will be instituted at a loading dose of 1.0gm/kg, then 0.4gm/kgm every 4-6 weeks or oral Bactrim DS TIW at the discretion of the PI, and the infectious disease faculty. Patients who experience at least two episodes of infections in areas traditionally caused by gram positive organisms, will also, be prophylaxed in the same manner as listed above. If the prophylaxis procedure does not result in a change in the infectious trend, Rituxan will be discontinued after only 4 cycles.

    6.0 Drug Information:

    6.1 MELPHALAN

    6.1.1 GENERAL

    The alkylating agents are antitumor drugs that act through the covalent bonding of alkyl groups (one or more saturated carbon atoms) to cellular molecules. Historically, the alkylating agents have played an important role in the development of cancer chemotherapy. The nitrogen mustards, mechlorethamine (HN2, nitrogen mustard) and tris (b -chlorethyl) amine (HN3), were the first non hormonal agents to show significant antitumor activity in humans.35-37 The clinical trials of nitrogen mustards in patients with lymphomas evolved from clinical observations of the effects of sulfur mustard gas used in World War I. This compound was found to produce lymphoid aplasia in addition to the expected irritation of the lungs and mucous membranes and was evaluated as an antitumor agent.38 The related, but less reactive, bischloroethylamines (nitrogen mustards) were found to be less toxic and to cause regressions of lymphoid tumors in mice. The first clinical studies produced some dramatic tumor regressions in lymphoma patients, and the antitumor effects were confirmed by an organized multi-institution study.35-37 The demonstration of the clinical utility of the nitrogen mustards encouraged further efforts to find chemical agents with antitumor activity, leading to the wide variety of antitumor agents in use today. At present, alkylating agents occupy a central position in cancer chemotherapy, both in conventional combination regimens and in high-dose protocols with bone marrow transplantation. Because of their linear dose-response curve in cell culture experiments, these drugs [particularly cyclophosphamide, melphalan, and carmustine (BCNU)] have become the primary tools used in allogeneic transplantation protocols for acute leukemia and in autologous transplantation for lymphomas and breast cancer.

    6.1.2 CHEMISTRY

    Mechanisms of Alkylating Reactions

    Traditionally, alkylating reactions have been classified as SN1 (nucleophilic substitution, first-order) or SN2 (nucleophilic substitution, second-order). In the SN1 reaction there is an initial formation of a highly reactive intermediate, followed by the rapid reaction of this intermediate with a nucleophile to produce the alkylated product. In this reaction, the rate-limiting step is the initial formation of the reactive intermediate. Thus the reaction exhibits first-order kinetics with regard to the concentration of the original alkylating agent, and the rate is essentially independent of the concentration of the substrate, hence the designation SN1.

    The SN2 alkylation reaction represents a bimolecular nucleophilic displacement. The rate of this reaction is dependent on the concentration of both the alkylating agent and the target nucleophile. Therefore, the reaction follows second-order kinetics. The terms SN1 and SN2 are defined kinetically but normally are used in reference to the mechanism of action.

    Melphalan is transported into several cell types by at least two active transport systems, which also carry leucine and other neutral amino acids across the cell membrane.39-41 High levels of leucine in the medium will protect cells from the cytotoxic effects of melphalan by competing with melphalan for transport into the target cells.42 Because appreciable levels of leucine are present in plasma and extracellular fluid, this competition may have pharmacologic significance. Although murine leukemia cells contain at least two transport systems for melphalan and L-leucine, one of these systems is lacking in murine granulocyte precursors (CFU-Cs).43 This system, missing in CFU-Cs but present in leukemia cells, is identified by its capacity to transport the amino acid analogue 2-amino-bicyclo [2,2,] heptane-2-carboxylic acid (BCH). These unexpected findings have prompted a search for cytotoxic analogues of BCH that might be taken up by tumor cells but not by normal granulocyte precursors. In contrast to the active transport systems for mechlorethamine and melphalan, the highly lipid-soluble nitrosoureas BCNU and CCNU enter cells by passive diffusion.44

    6.1.3 TUMOR RESISTANCE

    The emergence of alkylating agent-resistant tumor cells is a major problem that limits the clinical effectiveness of these drugs. One mechanism for drug resistance is that of decreased drug entry into the cell. Numerous studies have shown that L5178Y lymphoblast cells resistant to mechlorethamine may have decreased uptake of the drug.45-49 Murine L1210 leukemia cells that are resistant to melphalan have a specific mutation in the lower-affinity, higher-velocity L-transport system, which results in a decreased affinity of the carrier protein for leucine and melphalan.

    6.1.4 Melphalan Clinical Pharmacology

    The clinical pharmacology of melphalan has been examined by several groups. Alberts and colleagues50 studied the pharmacokinetics of melphalan in patients who received 0.6 mg of the drug per kilogram intravenously. the peak levels of melphalan, as measured by HPLC, were 4.5 to 13 mM (1.4 to 4.1 mg/ml), and the mean half-life (t1/2b) of the drug in the plasma was 1.8 hours. The 24-hour urinary excretion of the parent drug averaged 13% of the administered dose. Inactive mono- and dihydroxy metabolites appear in plasma within minutes of drug administration.

    Other studies have shown that there is low and variable systemic availability of the drug after oral dosing.51-52 Food slows its absorption. After oral administration of melphalan, 0.6 mg/kg, much lower peak levels of drug of about 1 mM (0.3 mg/ml) were seen. The time to achieve peak plasma levels varies considerably and occurs as late as 6 hours after dosing. The low bioavailability was due to incomplete absorption of the drug from the gastrointestinal tract, because 20% to 50% of an oral dose could be recovered in the feces.52 No drug or drug products were found in the feces after intravenous administration. In addition to its unpredictable bioavailability, oral melphalan AUC is reduced one-third by concomitant cimetidine administration.53

    After conventional oral doses of 0.15 to 0.25 mg/kg,54 peak plasma levels of 0.16 to 0.625 mM (50 to 190 ng/ml) occurred 0.7 to 2.3 hours after drug administration. The same plasma levels were found after the initial dose of drug or after the second dose in a 5-day schedule, indicating that no accumulation of plasma levels of the drug occurs with daily administration. In this study the magnitude and time of peak plasma levels appear to be more consistent than was seen with the higher doses reported by Alberts et al.50 Cornwell and colleagues55 pointed out that for patients receiving intravenous melphalan, the incidence of severe myelosuppression is increased in patients with a blood urea nitrogren (BUN) greater than 30 mg/dl, suggesting that these patients have altered drug excretion. The half-life of melphalan in plasma is significantly prolonged in anephric dogs.56 Thus, as an approximation, intravenous doses of this agent should be reduced by 50% in patients with an elevated BUN.

    6.2 GLUCOCORTICOIDS

    The physiologic effects of the glucocorticoids are many and protean. Insight into the role of glucocorticoid hormones in maintaining homeostasis was gained early with recognition of the pathologic conditions of glucocorticoid deficiency and excess. In 1855, Addison57 provided the classic description of the wasting disease associated with the destruction of the suprarenal glands and shortly thereafter, Brown-Sequard58 demonstrated the essential role of the adrenal gland in sustaining life in dogs. The syndrome of glucocorticoid excess was characterized in 1932 by Cushing.59

    It is now known that adrenal function is regulated in a circadian fashion by the pituitary gland. In 1926, Foster and Smith60 established that hypophysectomy resulted in adrenal atrophy, which, in 1932, was shown by several groups 61-63 to be reversed by treatment with extracts of the pituitary. The agent in these extracts, adrenocorticotropic hormone (ACTH) was purified by 1943,64-65 chemically and structurally identified by 1956,66 and synthesized by 1963.67

    Under the negative-feedback mechanisms governing the release of ACTH, the glucocorticoids are synthesized in the fascinculata zone of the adrenal cortex from cholesterol upon binding of ACTH to the steroid synthesizing cells. The rate-limiting step is generally considered to be the conversion of cholesterol to 5-pregnenolone by a mechanism mediated by cyclic adenosine monophosphate (AMP) and calcium ions, possibly requiring the synthesis of a short-lived protein.68 The capability of the adrenal gland for upregulating steroidogenesis is rapid (taking place within minutes) and great; the daily production of cortisol can be increased up to 10-fold in periods of stress.

    Once synthesized in the adrenal gland, cortisol enters the circulation and reaches the periphery mostly bound to plasma proteins including albumin, orosomucoid (a-acidic glycoprotein), and CBG or transcortin.69 These proteins differ in their binding affinities for the corticoids (CBG having the highest and albumin the lowest) and in their plasma concentrations. At physiologic concentrations of cortisol in human plasma (approximately 10mg/dl), 76% of cortisol is bound to CBG, 13.5% is bound to albumin, 10.5% is unbound, and negligible amounts are bound to orosomucoid. Certain changes in endocrine status can alter the binding capacity of CBG and therefore the total blood levels of the steroids (although the amount of free hormone does not change drastically because of normal feedback control of pituitary ACTH secretion). Estrogens stimulate CBG synthesis in the liver, and as a result, total cortisol levels are markedly elevated during pregnancy. However, hypercortisolism is not evident clinically because the transcortin-bound steroid is not biologically active. 70,71 Corticosteroids also affect CBG levels; adrenalectomy causes a decrease in plasma CBG that is reversible with cortisol replacement.72 Finally, thyroidectomy decreases and thyroxine administration increases CBG activity in rats.73

    Although it was thought initially that steroid binding to plasma proteins served a transport function, it now seems that protein binding provides a storage or buffer function. Thus large quantities of hormone circulate in a biologically inert reservoir, from which the active agent is readily available by dissociation. An additional advantage of protein binding is protection from degradation and excretion, which decreases the metabolic clearance rate. Furthermore, protein binding decreases the accumulation of highly lipophilic steroids in adipose tissue, where they would be relatively inaccessible to the bloodstream and ultimately to the target tissues.

    Free cortisol, upon dissociation from the plasma binders, exerts its effects by entering cells and binding to an intracellular receptor. Although glucocorticoid-responsive tissues may respond in a highly tissue-specific fashion, these actions all seem to be mediated by the glucorcorticoid receptor. The specificity of the response is probably accounted for by differences in specific gene activation within each tissue. The physiologic actions of glucocorticoids include the following: (1) metabolic effects - a permissive role in epinephrine and glucagon-stimulated lipolysis, gluconeogenesis, and glycogenolysis; (2) catabolic effects - increased protein degradation and decreased protein synthesis in muscle, adipose, lymphoid, and connective tissue to provide increased amino acids for hepatic protein synthesis and gluconeogenesis; (3) cardiac effects - increased contractility, cardiac output, and sensitivity to catecholamines; and (4) musculoskeletal effects - increased capacity for muscular work.74 Another major glucocorticoid effect is the anti-inflammatory action that provides the basis for much of the therapeutic usefulness of the glucocorticoids.

    Glucocorticoids in pharmacologic concentrations produce marked lymphocytopenia and thymic atrophy in experimental animals.75 Thus these steroids were used initially with great enthusiasm when it was discovered that they also could kill some leukemic lymphoblasts in humans.76 Glucocorticoid receptors can be demonstrated in normal peripheral blood lymphocytes as well as in partially purified subpopulations of lymphocytes as well as in partially purified subpopulations of lymphocytes and monocytes 77,78 and in leukemia cells.79-81 These receptor proteins are similar to the glucocorticoid receptors more extensively characterized in liver and rat thymocytes.

    Many protocols utilize vastly suprapharamcologic concentrations of glucorcorticoid such as 1 g of prednisolone per square meter of body surface area. Plasma concentrations with these doses approach 1000 times those required to saturate receptor and induce killing of sensitive cells in vitro. However, on a once-daily dosage, 20 or more half-lives may elapse before the next dose of drug is administered, so there is a rationale for using such large doses. Also, it is possible that at least some effects of glucocorticoids may not require receptor. There are no data, however, to suggest that such massive doses have any benefit over conventional regimens.

    Glucocorticoid effects at normal physiologic levels are short-lived, with a rapid metabolic clearance of cortisol (plasma half-life of about 60 minutes). Other steroids are cleared from the plasma at rates of about 2000 liters/day, which correspond to a plasma half-life of 20 minutes.74 The half-lives of several synthetic steroids in dog plasma are as follows: prednisone, 33 minutes; dexamethasone, 60 minutes; prednisolone, 60 to 71 minutes; 6a -methylprednisolone, 81 minutes; and triamcinolone, 116 minutes. 82 Cortisol is extensively metabolized to inactive glucuronides, sulfates, and other forms in a number of tissues such that only 1% to 2% of the unaltered steroid actually ends up in the urine. 83 By far the most important organ for metabolism is the liver. The liver also plays a crucial role in activating certain synthetic 11-keto glucocorticoids such as cortisone and prednisone, which must be converted to 11-hydroxymetabolites to exert activity.

    Thus patients with compromised hepatic function may not respond to these agents because of decreased ability to convert to the 11b -OH steroid by the 11-keto reductase system. Hyperthyroidism markedly shifts the equilibrium of this reaction in favor of the inactive oxidized forms, whereas hypothyroidism does the reverse.73 Anorexia nervosa and other malnourished states favor the 11b -OH steroids in a manner similar to the effect of hypothyroidism.84 Drugs that induce hepatic enzymes may increase metabolism of glucocorticoids. These include barbiturates, phenytoin, and rifampin.85

    At least seven enzymatic reactions that occur predominantly in the liver contribute to the metabolism of cortisol; of these, tetrahydroreduction of a ring alone provides nearly half the total urinary metabolites. 86,87 Synthetic glucocorticoids, having a ketone group at C-11 (cortisone, prednisone, prednisolone), must be reduced to their hydroxy analogues to become active. One example is prednisone, which is rapidly converted to prednisolone.85 In children, a considerable proportion of the urinary steroids are excreated unconjugated or free, whereas in adults, most of the steroids are conjugated to form glucuronides and, to a lesser degree, sulfates. These modifications either decrease or abolish glucocorticoid activity. Inactive metabolites are excreted by the kidney with small amounts of unmetabolized drug. Only negligible amounts are excreted in the bile, with no enterohepatic circulation.85 Because the metabolic clearance rate of cortisol is quite similar among most people, the replacement dose of hydrocortisone (12 to 15 mg/m2/day) is fairly uniform. There is systemic absorption from the skin and mucous membranes; therefore, topical preparations containing triamcinolone or other potent fluorinated glucocorticoids analogues also may have cushinoid consequences.

    The dosages of drugs used can be described ad physiologic or that which is normally secreted by the adrenal gland (equivalent to 20 mg daily of hydrocortisone). Pharmacological doses are greater than physiologic doses. Approximate equivalent oral dosages are cortisone, 25 mg; hydrocortisone, 20 mg; prednisolone, 5 mg; prednisone, 5 mg; methylprednisone, 4 mg; triamcinolone, 4mg; dexamethasone, 0.75 mg; and betamethasone, 0.6 mg.85

    The duration of hypothalamic-pituitary axis suppression with a single oral dose of glucocorticoids is 1.25 to 1.5 days with 250 mg of hydrocortisone, 250 mg of cortisone, 50 mg of prednisolone, 40 mg of methylprednisolone, and 50 mg of prednisone.85 Suppression is 2.25 days with 40 mg of triamcinolone, 2.75 days with 5 mg of dexamethasone, and 3.25 days with 6 mg of betamethasone.85

    Deleterious effects produced by pharmacological amounts of glucocorticoids are listed in Table 5-3. These include immunosuppression with concomitant nosocomial infections, Cushing syndrome, diabetes mellitus, poor wound healing, psychosis, posterior subcapsular cataracts, osteoporosis, and alterations in mentation including euphoria and psychosis.

    Utilization of glucocorticoids with no mineralocorticoid activity may reduce toxicity. Synthetic steroids with very little mineralocorticoid activity include dexamethasone, methylprednisone, prednisolone, prednisone, and triamcinolone.

      6.3 RituxanTM

    6.3.1 Rituxan

    DESCRIPTION

    The Rituxan (Rituximab) antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD2O antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA analysis) and has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD2O antigen of approximately 8.0 nM.

    The chimeric anti-CD2O antibody is produced by mammalian cell (Chinese Hamster ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. The anti-CD2O antibody is purified by affinity and ion exchange chromatography. The purification process includes specific viral inactivation and removal procedures.

    Rituxan is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) administration. Rituxan is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The product is formulated for intravenous administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5.

    6.3.2 CLINICAL PHARMACOLOGY

    6.3.2.1 General

    Rituximab binds specifically to the antigen CD2O (human B-lymphocyte-restricted differentiation antigen, Bp3 5), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes. 88, 89 The antigen is also expressed on> 90% of B-cell non-Hodgkin’s lymphomas (NHL)90 but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissues.91 CD2O regulates an early step(s) in the activation process for cell cycle initiation and differentiation,91 and possibly functions as a calcium ion channel.92 CD2O is not shed from the cell surface and does not internalize upon antibody binding.93 Free CD2O antigen is not found in the circulation.89

     

     6.3.2.2 Pre-clinical Pharmacology and Toxicology

    Mechanism of Action: The Fab domain of Rituximab binds to the CD2O antigen on B-lymphocytes and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC)94 and antibody-dependent cellular cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line.95

    Normal Tissue Cross-reactivity: Rituximab binding was observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B-lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in non-lymphoid tissues examined.

    Human Pharmacokinetics/Pharmacodynamics

    In patients given single doses at 10, 50, 100, 250 or 500 mg/m2 as an IV infusion, serum levels and the half-life of Rituximab were proportional to dose. In 9 patients given 375 mg/m2 as an IV infusion for four doses, the mean serum half-life was 59.8 hours (range 11.1 to 104.6 hours) after the first infusion and 174 hours (range 26 to 442 hours) after the fourth infusion. The wide range of half-lives may reflect the variable tumor burden among patients and the changes in CD2O positive (normal and malignant) B-cell populations upon repeated administrations.

    Rituximab at a dose of 375 mg/m2 was administered as an IV infusion at weekly intervals for four doses to 166 patients. The peak and trough serum levels of Rituximab were inversely correlated with baseline values for the number of circulating CD2O positive B cells and measures of disease burden. Median steady-state serum levels were higher for responders compared to nonresponders; however, no difference was found in the rate of elimination as measured by serum half-life. Serum levels were higher in patients with International Working Formulation (IWF) subtypes B, C, and D as compared to those with subtype A. Rituximab was detectable in the serum of patients three to six months after completion of treatment.

    The pharmacokinetic profile of Rituximab when administered as six infusions of 375 mg/m2 in combination with six cycles of CHOP chemotherapy was similar to that seen with Rituximab alone.

    Administration of Rituxan™ resulted in a rapid and sustained depletion of circulating and tissue-based B cells. Lymph node biopsies performed 14 days after therapy showed a decrease in the percentage of B-cells in seven of eight patients who had received single29 doses of Rituximab ³ 100 mg/in . Among the 166 patients in the pivotal study, circulating B-cells (measured as CD 19+ cells) were depleted within the first three doses with sustained depletion for up to 6 to 9 months post-treatment in 83% of patients. One of the responding patients (1%), failed to show significant depletion of CDl9+ cells after the third infusion of Rituximab as compared to 19% of the nonresponding patients. B-cell recovery began at approximately six months following completion of treatment. Median B-cell levels returned to normal by twelve months following completion of treatment.

    There were sustained and statistically significant reductions in both 1gM and IgG serum levels observed from 5 through 11 months following Rituximab administration. However, only 14% of patients had reductions in IgG and/or 1gM serum levels, resulting in values below the normal range.

    the full course of therapy. (See DOSAGE and ADMINISTRATION.) Medications for the treatment of hypersensitivity reactions, e.g., epinephrine, antihistamines and corticosteroids should be available for immediate use in the event of a reaction during administration.

    Infusions should be discontinued in the event of serious or life-threatening cardiac arrhythmias. Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during and after subsequent infusions of Rituxan™. Patients with preexisting cardiac conditions including arrhythmias and angina have had recurrences of these events during Rituxan™ therapy and should be monitored throughout the infusion and immediate post-infusion period.

    .

    6.3.5.1 Infusion-Related Events: An infusion-related symptom complex consisting of fever and chills/rigors occurred in the majority of patients during the first Rituxan infusion. Other frequent infusion-related symptoms included nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, sensation of tongue or throat swelling (angioedema), rhinitis, vomiting, hypotension, flushing, and pain at disease sites. These reactions generally occurred within 30 minutes to 2 hours of beginning the first infusion, and resolved with slowing or interruption of the Rituxan infusion and with supportive care (IV saline, diphenhydramine, and acetaminophen). The incidence of infusion-related events decreased from 80% (7% Grade 3/4) during the first infusion to approximately 40% (5% to 10% Grade 3/4) with subsequent infusions. Mild to moderate hypotension requiring interruption of Rituxan infusion with or without the administration of IV saline occurred in 32 (10%) patients. Isolated occurrences of severe reactions requiring epinephrine have been reported in patients receiving Rituxan for other indications. Angioedema was reported in 41(13%) patients and was serious in one patient. Bronchospasm occurred in 25 (8%) patients; one-quarter of these patients were treated with bronchodilators. A single report of bronchiolitis obliterans was noted. 6.3.5.1 Infusion-Related Events: An infusion-related symptom complex consisting of fever and chills/rigors occurred in the majority of patients during the first Rituxan infusion. Other frequent infusion-related symptoms included nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, sensation of tongue or throat swelling (angioedema), rhinitis, vomiting, hypotension, flushing, and pain at disease sites. These reactions generally occurred within 30 minutes to 2 hours of beginning the first infusion, and resolved with slowing or interruption of the Rituxan infusion and with supportive care (IV saline, diphenhydramine, and acetaminophen). The incidence of infusion-related events decreased from 80% (7% Grade 3/4) during the first infusion to approximately 40% (5% to 10% Grade 3/4) with subsequent infusions. Mild to moderate hypotension requiring interruption of Rituxan infusion with or without the administration of IV saline occurred in 32 (10%) patients. Isolated occurrences of severe reactions requiring epinephrine have been reported in patients receiving Rituxan for other indications. Angioedema was reported in 41(13%) patients and was serious in one patient. Bronchospasm occurred in 25 (8%) patients; one-quarter of these patients were treated with bronchodilators. A single report of bronchiolitis obliterans was noted.

    6.3.5.2 Immunologic Events: Rituxan™ induced B-cell depletion in 70 to 80% of patients and was associated with decreased serum immunoglobulins in a minority of patients. The incidence of infection does not appear to be increased. During the treatment period, 50 patients in the pivotal trial developed 68 infectious events; 6 (9%) were Grade 3 in severity and none were Grade 4 events. Of the 6 serious infectious events, none were associated with neutropenia. The serious bacterial events included sepsis due to Listeria (n= 1), Staphylococcal bacteremia (n1) and polymicrobial sepsis (n1). In the post-treatment period (30 days to 11 months following the last dose), bacterial infections included sepsis (n1); significant viral infections included herpes simplex infections (n=2) and herpes zoster (n3). Rituxan™ induced B-cell depletion in 70 to 80% of patients and was associated with decreased serum immunoglobulins in a minority of patients. The incidence of infection does not appear to be increased. During the treatment period, 50 patients in the pivotal trial developed 68 infectious events; 6 (9%) were Grade 3 in severity and none were Grade 4 events. Of the 6 serious infectious events, none were associated with neutropenia. The serious bacterial events included sepsis due to Listeria (n= 1), Staphylococcal bacteremia (n1) and polymicrobial sepsis (n1). In the post-treatment period (30 days to 11 months following the last dose), bacterial infections included sepsis (n1); significant viral infections included herpes simplex infections (n=2) and herpes zoster (n3).

    6.3.5.3 Retreatment Events: Twenty-one patients have received more than one course of Rituxan™. The percentage of patients reporting any adverse event upon retreatment was similar to the percentage of patients reporting adverse events upon initial exposure. The following adverse events were reported more frequently in retreated subjects: asthenia, throat irritation, flushing, tachycardia, anorexia, leukopenia, thrombocytopenia, anemia, peripheral edema, dizziness, depression, respiratory symptoms, night sweats, and pruritus. Twenty-one patients have received more than one course of Rituxan™. The percentage of patients reporting any adverse event upon retreatment was similar to the percentage of patients reporting adverse events upon initial exposure. The following adverse events were reported more frequently in retreated subjects: asthenia, throat irritation, flushing, tachycardia, anorexia, leukopenia, thrombocytopenia, anemia, peripheral edema, dizziness, depression, respiratory symptoms, night sweats, and pruritus.

    6.3.5.4 Hematologic Events: During the treatment period (up to 30 days following last dose)

    Severe thrombocytopenia occurred in 1.3% of patients, severe neutropenia occurred in 1.9% of patients, and severe anemia occurred in 1.0% of patients. A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy were reported.

    6.3.5.5 Cardiac Events: Four patients developed arrhythmias during Rituxan infusion. One of the four discontinued treatment because of ventricular tachycardia and supraventricular tachycardias. The other three patients experienced trigeminy (1) and irregular pulse (2) and did not require discontinuation of therapy. Angina was reported during infusion and myocardial infarction occurred 4 days post-infusion in one subject with a prior history of myocardial infarction. 6.3.5.5 Cardiac Events: Four patients developed arrhythmias during Rituxan infusion. One of the four discontinued treatment because of ventricular tachycardia and supraventricular tachycardias. The other three patients experienced trigeminy (1) and irregular pulse (2) and did not require discontinuation of therapy. Angina was reported during infusion and myocardial infarction occurred 4 days post-infusion in one subject with a prior history of myocardial infarction.

     

    Adverse Events ³ 5% of Patients (N=315)

    Severe and life-threatening (Grade 3 and 4) events were reported in 10% (32/315) of patients. The following Grade 3 and 4 adverse events were reported: neutropenia (1.9%), chills (1.6%), leukopenia and thrombocytopenia (1.3% for each), hypotension, anemia, bronchospasin, and urticaria (1.0% for each), headache, abdominal pain, arrhythmia (0.6% for each), and asthenia, hypertension, nausea, vomiting, coagulation disorder, angioedema, arthralgia, pain, rhinitis, increased cough, dyspnea, bronchiolitis obliterans, hypoxia, asthma, pruritus, and rash (one patient each, 0.3%).

    The following adverse events occurred in ³ 1.0% but < 5.0% of patients, in order of decreasing incidence: flushing, arthralgia, diarrhea, anemia, cough increase, hypertension, lacrimation disorder, pain, hyperglycemia, back pain, peripheral edema, paresthesia, dyspepsia, chest pain, anorexia, anxiety, malaise, tachycardia, agitation, insomnia, sinusitis, conjuctivitis, abdominal enlargement, postural hypotension, LDH increase, hypocalcemia, hypesthesia, respiratory disorder, tumor pain, pain at injection site, bradycardia, hypertonia, nervousness, bronchitis, and taste perversion.

    The proportion of patients reporting any adverse event was similar in patients with bulky disease and those with lesions <10 cm in diameter. However, the incidence of dizziness, neutropenia, thrombocytopenia, myalgia, anemia and chest pain was higher in patients with lesions >10 cm. The incidence of any Grade 3 and 4 event was higher (31% vs. 13%) and the incidence of Grade 3 or 4 neutropenia, anemia, hypotension, and dyspnea was also higher in patients with bulky disease compared with patients with lesions <10 cm.

    6.3.5.6 OVERDOSAGE

    There has been no experience with overdosage in human clinical trials. Single doses higher than 500 mg/m2 have not been tested.

    7.0 REFERENCES:

      1. Gobbi M, Cavo M, Savelli GA, et al. Prognostic factors and survival in multiple myeloma: Analysis of 91 cases treated by melphalan and prednisone. Haematologica 1980, 65:437-445.
  1. Hansen OP, Galton DAG. Classification and prognostic variables in myelomatosis. Scand J Haematol 1985,35:10-19.
  2. Woodruff R. Treatment of multiple myeloma. Cancer Treat Rev 1981, 8:225-270.
  3. Alexanian R. Treatment of multiple myeloma. Rev Acta Haematol 1980, 63:237-240.
  4. Ahre A, Bjorkholm M, Mellstodt H, et al. Intermittent high dose melphalan/prednisone Vs continuous low dose melphalan treatment in multiple myeloma. Eur J Cancer Clin Oncol 1983, 19:499-506.
  5. Aguzzi F, Bergami MR, Gasparro C, et al: Occurrence of monoclonal components in general practice: Clinical implications. Eur J Haematol 48:192-195, 1992.
  6. Papadopoulos NM, Elin RJ, Wilson DM: Incidence of gamma-globulin banding in a healthy population by high resolution electrophoresis. Clinical Chemistry 28:707-708, 1982.
  7. Kyle RA, Beard CM, O’Fallon WM, Kurland LT: Incidence of multiple myeloma in Olmsted County, Minnesota: 1978 through 1990, with a review of the trend since 1945. J Clin Oncol 12:1577-1583, 1994.
  8. Boccadoro M, Pileri A: Cell kinetics of multiple myeloma. Hematol Pathol 1:137-142, 1987.
  9. Durie BGM, Salmon SE, Moon TE: Pretreatment tumor mass, cell kinetics and prognosis in multiple myeloma. Blood 59:43-51, 1982.
  10. Greipp PR, Kyle RA: Clinical, morphological, and cell kinetic differences among multiple myeloma, monoclonal gammopathy of undetermined significance, and, and smoldering myeloma. Blood 62:166-171, 1983.
  11. Bataille R, Grenier J, Sany J: Beta-2-microglobulin in myeloma: Optimal use for staging, prognosis and treatment. A prospective study of 160 patients. Blood 63:468-476, 1984.
  12. Durie BGM, Stock-Novack D, Salmon SE, et al: Prognostic value of pretreatment serum $2 microglobulin in myeloma: A Southwest Oncology Group Study. Blood 75:823-830, 1990.
  13. Klein B, Zhang XG, Lu ZY, Bataille R: Interleukin-6 in human multiple myeloma. Blood 85:863-872, 1995.
  14. Lu ZY, Brailly H, Wijdenes J, et al: Measurement of whole body interleukin-6 (IL-6) production: Prediction of the efficacy of anti-IL-6 treatments. Blood 86:3123-3131, 1995.
  15. Ludwig H, Nachbaur DM, Fritz E: Interleukin-6 is a prognostic factor in multiple myeloma. Blood 77:2794-2795, 1991.
  16. Pulkki K, Pelliniemi TT, Rajamaky A, et al: Soluble interleukin-6 receptor as a prognostic factor in multiple myeloma. Finnish Leukaemia Group. Br J Haematol 92:370-374, 1996.
  17. Boccardo M, Marmount F, Tribalto M, et al. Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high risk patients. J Clin Oncol 9:444, 1991.
  18. Palumbo A, Boccadoro M, Garino LA, et al. Interferon plus glucocorticoids as intensified maintenance therapy prolong tumor control in relapsed myeloma. Acta Haematologica 1993, 90:71-76
  19. Salmon SE, Crowley JJ, Grogan TM et al. Combination chemotherapy glucocorticoids and interferon-alpha in the treatment of multiple myeloma. A SWOG study. J Clin Onc 1994, 12:2405-2414.
  20. Greipp PR and Kyle RA. Clinical, morphological and cell kinetic differences among multiple myeloma, monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Blood 1983, 62:166-71.
  21. Boccadoro, M, Durie BGM, Frutiger Y et al. Lack of correlation between plasma cell labeling index and serum beta-2-microglobulin in monoclonal gammopathies. Acta Haemtol 1987, 78:239-42.
  22. Buchsbaum RJ and Schwartz RS. Cellular origins of hematologic neoplasms. N. Eng. J. Med. 1990, 322:694-96.
  23. Takishita M and Kosaka, M. Multiple myeloma: new evidence and insights from the immunoglobulin heavy chain gene and phenotypes. Leukemia and Lymphoma.1995, 19:395-400.
  24. Demiden, A, Lam, T, Alas, S, Hariharan, K, Hanna, N, Bonavida, B. Chimeric Anti-CD20 (IDEC-C2B8) Monoclonal Antibody Sensitizes a B Cell Lymphoma Cell Line to Cell Killing by Cytotoxic Drugs. Cancer Biotherapy & Radiopharmaceuticals 1997; 12(3):177-11896.
  25. Safrit JT, Belldegrum A, Bonavida B. Sensitivity of human renal cell carcinoma lines to TNF, adriamycin and combination: Role of TNF-mRNA induction in overcoming resistance. J Urology 1993; 149:1202-1208.
  26. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bc1-2 is an inner mitochondrial.
  27. Reed JC: Bc1-2: Prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 9:451-473, 1995.
  28. Boulakia CA, Chen G, Ng FW, et al: Bc1-2 and adenovirus E1B 19kDA protein prevent E1A-induced processing of CPP32 and cleavage of poly (ADP-ribose) polymerase. Oncogene 12:529-535, 1996.
  29. Datta R, Banach D, Kojima H, et al: Activation of the CPP32 protease in apoptosis induced by 1-betaD-arabinofuranosylcytosine and other DNA-damaging agents. Blood 88:1936-1943, 1966.
  30. Ibrado AM, Huang Y, Fang G, et al: Bc1-xL overexpression inhibits Taxol-induced Yama protease activity and apoptosis . Cell Growth Differ 7:1087-1094, 1996.
  31. Ibrado AM, Huang Y, Fang G, et al: Overexpression of Bc1-2 or Bc1-xL inhibits Ara-C-induced CPP32/Yama protease activity and apoptosis of human acute myelogenous leukemia HL-60 cells. Cancer Res 56:4743-4748, 1996.
  32. Cherbonnel-Lasserre C, Gauny S, Kroneneberg A: Suppression of apoptosis by Bc1-2 or Bc1-xL promotes susceptibility to mutagenesis. Oncogene 13:1489-1497, 1996.
  33. Minn AJ, Boise LH, Thompson CB: Expression of Bc1-xL and loss of p53 can cooperate to overcome a cell cycle checkpoint induced by mitotic spindle damage. Genes Dev 10:2621-2631, 1996.
  34. Rhoads CP. Nitrogen mustards in treatment of neoplastic disease. JAMA 131:656, 1946.
  35. Jacobson LP, Spurr CL, Barron ESQ, et al. Studies on the effect of methyl-bis (beta-chloroethyl) amine hydrochloride on neoplastic diseases and allied disorders of the hemapoietic system. JAMA 132:263, 1946.
  36. Goodman LS, Wintrobe MM, Dameshek W, et al. Use of methyl-bis (beta-chloroethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia. JAMA 132:126, 1946.
  37. Adair CPJ, Bagg HJ. Experimental and clinical studies on the treatment of cancer by dichloroethylsulphide (mustard gas). Ann Surg 93:190, 1931.
  38. Goldenberg GJ, Lee M, Lam H-YP, et al. Evidence for carrier-mediated transport of melphalan by L5178Y lymphoblasts in vitro. Cancer Res 37:755, 1977.
  39. Vistica DT, Rabon A, Rabinowitz M. Effect of L-alpha-amino-gamma-guanidinobutyric acid on melphalan therapy of the L1210 murine leukemia. Cancer Lett 6(6):345, 1979.
  40. Begleiter A, Lam H-YP, Grover J, et al. Evidence for active transport of melphalan by two amino acid carriers in L5178Y lymphoblasts in vitro. Cancer Res 39:353, 1979.
  41. Vistica DT, Toal JN, Rabinowitz M. Amino acid conferred protection against melphalan: characterization of melphalan transport and correlation of uptake with cytotoxicity in cultured L1210 murine leukemia cells. Bicochem Pharmacol 27:2865, 1978.
  42. Vistica DT. Cytotoxicity as an indicator for transport mechanism: evidence that murine bone marrow progenitor cells lack a high affinity leucine carrier that transports melphalan in murine L1210 leukemia cells. Blood 56:427, 1980.
  43. Begleiter A, Lam H-YP, Goldenberg GJ. Mechanism of uptake of nitrosourea by L5178Y lymphoblasts in vitro. Cancer Res 37:1022, 1977.
  44. Klatt P, Stehlin JS Jr, McBride C, et al. The effect of nitrogen mustard treatment on the DNA of sensitive and resistant Ehrlich tumor cells. Cancer Res 29:286, 1969.
  45. Wolpert MK, Ruddon RW. A study on the mechanisms of resistance to nitrogen mustard (HN2) in Ehrlich ascites tumor cells: comparison of uptake of HN2-14C into sensitive and resistant cells. Cancer Res 29:873, 1969.
  46. Goldenberg GJ, Vanstone CL, Israels LG, et al. Evidence for a transport carrier of nitrogen mustard in nitrogen mustard-sensitive and-resistant L5178Y lymphoblasts. Cancer Res 30:2285, 1970.
  47. Rutman RJ, Chun EHL, Lewis FA. Permeability differences as a source of resistance to alkylating agents in Ehrlich tumor cells. Biochem Biophys Res Commun 32:650, 1968.
  48. Redwood WR, Colvin M. Transport of melphalan by sensitive and resistant L1210 cells. Cancer Res 40:1144, 1980.
  49. Alberts DS, Chang SY, Chen H-SG, et al. Kinetics of intravenous melphalan. Clin Pharmacol Ther 26:73, 1979.
  50. Alberts DS, Chang SY, Chen H-SG, et al. Comparative pharmacokinetics of chlorambucil and melphalan in man. Recent Results Cancer Res 74:124, 1980.
  51. Tattersall MHN, Weinberg A. Pharmacokinetics of melphalan following oral or intravenous administration in patients with malignant disease. Eur J Cancer 14:507, 1978.
  52. Sviland L, Robinson A, Proctor SJ, Bateman DN. Interaction of cimetidine with oral melphalan. A pharmacokinetic study. Cancer Chemother Pharmacol 20:173, 1987.
  53. Pallante SL, Fenselau C, Mennel RG, et al. Quantitation by gas chromatography-chemical ionization-mass spectrometry of phenylalanine mustard in plasma of patients. Cancer Res 40:2268, 1980.
  54. Cornwell GG III, Pajak TF, McIntyre OR, et al. Influence of renal failure on myelosuppressive effects of melphalan: cancer and leukemia group B experience. Cancer Treat Rep 66:475, 1982.
  55. Alberts DS, Chen HSG, Benz D, et al. Effect of renal dysfunction in dogs on the disposition and marrow toxicity of melphalan. Br J Cancer 43:330, 1981.
  56. Addison T. On the constitutional and local effects of disease of the superenal capsules. London: Samuel Highley, 1855.
  57. Brown-Sequard GG. Researches experimental sur la physiologic et la pathologic descapsule surrencle. CR Acad Sci (D) (Paris) 3:422, 1856.
  58. Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations. Bull Johns Hopkins Hosp 50:137, 1932.
  59. Foster GL, Smith PE. hypophysectomy and replacement therapy in relation to basal metabolism and specific dynamic action in the rat. JAMA 87:2151, 1926.
  60. Collip JB, Anderson EM, Thompson DL. The adrenotropic hormone of the anterior pituitary lobe, Lancet 2:347, 1933.
  61. Evans HM. Present position of our knowledge of anterior pituitary function. JAMA 101:425, 1933.
  62. Houssay BA, Biasotti A, Mazzoco P, et al. Accion del exracto anterohipofisario sobre las glandulas adrenales. Rev Soc Argent Biol 9:262, 1933.
  63. Li CH, Evans HM, Simpson ME. Adrenocorticotrophic hormone. J Biol Chem 149:413, 1943.
  64. Sayers G, White A, Long CNH. Preparation and properties of pituitary adrenocorticotrophic hormone. J Biol Chem 149:425, 1943.
  65. Bell PH, Howard KS, Shepherd RG, et al. Studies with corticotrophin: II. Pepsin degradation of b -corticotrophin. J Am Chem Soc 78:5059, 1956.
  66. Schwyzer R, Sieber P. Total synthesis of adrenocorticotrophic hormone. Nature 199:172, 1963.
  67. Ontjes DA. Minireview: the pharmacologic control of adrenal steroidogenesis. Life Sci 86:2023, 1980.
  68. Westphal U. Binding of corticosteroids by plasma In: Greep RO, Astwood EB, Blaschko H, et al, eds. Handbook of physiology section I: endocrinology, vol. VI, Adrenal gland. Washington: American Physiological Society, 1975:117.
  69. Slaunwhite WR, Sandberg AA. Transcortin: a corticosteroid-protein of plasma. J Clin Invest 38:384, 1959.
  70. Sandberg AA, Slaunwhite WR Jr. Transcortin: a corticosteroid-binding protein of plasma: II. Levels in various conditions and the effects of estrogens. J. Clin Invest 38:1290, 1959.
  71. Westphal U, Williaams WC JR, Ashley BD, et al. Steroid protein interactions X. Protein binding der corticosteroide in serum adrenalekromierter und hypophyektomierter Ratten. Z Physiol Chem 332:54, 1963.
  72. Gordon GG, Southren AL. Thyroid-hormone effects on steroid hormone metabolism. Bull NY Acad Med 53:241, 1977.
  73. Loriaux DL, Cutler GB Jr. Diseases of the adrenal glands. In: Kohler PO, ed. Basic clinical endocrinology. New York: Wiley, 1981.
  74. Claman HN. Corticosteroids and lymphoid cells. N Engl J Med 267:388, 1972.
  75. Goldin A, Sandberg JS, Henderson ES, et al. The chemotherapy of human and animal acute leukemia. Cancer Chemother Rep 55:309, 1971.
  76. Neifeld JP, Lippman ME, Tormey DC. Steroid hormone receptors in normal human lymphocytes: induction of glucocorticoid receptor activity by PHA stimulation. J Biol Chem 252:2972, 1977.
  77. Lippman ME, Barr R. Glucocorticoid receptors in purified subpopulations of human peripheral blood lymphocytes J Immunol 118:1977, 19777.
  78. Lippman ME, Yarbo ME, Leventhal BG. Clinical implications of glucocorticoid receptors in human leukemia. Cancer Res 38:4251, 1978.
  79. Crabtree GR, Smith KA, Munck A. Glucocorticoid receptors and sensitivity of isolated human leukemia and lymphoma cells. Cancer Res 36:4268, 1978.
  80. Lippman ME, Halterman RH, Leventhal BG, et al. Glucocorticoid binding proteins in acute lymphoblastic leukemic blast Cells. J Clin Invest 52:1715, 1973.
  81. Fortheby K, James F. Metabolism of synthetic steroids. Adv Steroid Biochem Pharmacol 3:67, 1972.
  82. Peterson RE. Metabolism of adrenal cortical steroids. In: Christy NP, ed. The human adrenal cortex. New York: Harper & Row, 1971:87.
  83. Boyar RM, Hellman LD, Roffwarg H, et al. Cortisol secretion and metabolism in anorexia nervosa. N Engl J Med 296:190-193, 1977.
  84. McEvoy GK, ed. Adrenals. In: Drug information 88. Bethesda: American Society of Hoapital Pharmacists, 1986:1706.
  85. Bradlow HL, Zumoff E, Monder C, et al. Isolation and identification of four new carboxylic acid metabolites of cortisol in man. J Clin Endocrinol Metab 37:811-818, 1973.
  86. Peterson RE. Metabolism of adrenal cortical steroids. In: Christy NP, ed. The human adrenal cortex New York: Harper & Row, 1971:87.
  87. Valentine MA, Meier KE, Rossie 5, et al. Phosphorylation of the CD20 phosphoprotein in resting B lymphocytes. J. Biol. Chem. 1989 264(19): 11282-11287.
  88. Einfeld DA, Brown JP, Valentine MA, et al. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J. 1988 7(3):711-717.
  89. Anderson KC, Bates MP, Slaughenhoupt BL, et al. Expression of human B cell-associated antigens on leukemias and lymphomas: A model of human B cell differentiation. Blood 1984 63(6): 1424-1433.
  90. Tedder TR, Boyd AW, Freedman AS, et al. The B cell surface molecule Bi is functionally linked with B cell activation and differentiation. J. Immunol. 1985 1 35(2):973-979.
  91. Tedder TF, Zhou U, Bell PD, et al. The CD20 surface molecule of B lymphocytes functions as a calcium channel. J. Cell. Biochem. 1990 14D:195.
  92. Press OW, Applebaum F, Ledbetter JA, Martin PJ, Zarling J, Kidd P, et al. Monoclonal antibody iFS (anti-CD20) serotherapy of human B-cell lymphomas. Blood 1987 69(2):584-591.
  93. Reff ME, Carner C, Chambers KS, Chin PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994 83(2):435-445.
  94. Deinidem A, Lain T, Alas 5, Hariharan K, Hanna N, and Bonavida B. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Chemotherapy & Radiopharmaceuticals 1997 12(3):177-86.
  95. Maloney DG, Grillo-Lopez AJ, Bodkin D, White CA, Liles T-M, Royston I, et al. IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed nonHodgkin’s lymphoma. J. Clin. Oncol. 1997 15(10):3266-3274.
  96. Maloney DG, Grillo-Lopez AJ,White CA, Bodkin D, Schilder RJ, Neidhart JA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 1997 90(6):2188-2195.
  97. Maloney DG, Liles TM, Czerwinski C, Waldichuk J, Rosenberg J, Grillo-Lopez A, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994 84(8):2457-2466.

     

 
 
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