melphalan and Burkitt-Lymphoma

Although cytotoxic immunosuppressive agents play an unquestionably useful role in treating many neoplastic and non-neoplastic disorders, there is accumulating evidence that the toxicity associated with their use is considerable. The therapeutic successes obtained with antitumor agents have led to increases in the life span of cancer patients, but have also provided the opportunity for this toxicity to become manifest. A search of the available literature was carried out, with emphasis on cases in which a malignancy developed in patients following chemotherapy for either neoplastic or non-neoplastic (e.g., renal transplantation, psoriasis) conditions; particular focus was given to the incidence of acute myelogenous leukemia in various groups of Hodgkin's disease and multiple myeloma patients. That patients with nonmalignant conditions treated with cytotoxic immunosuppressive agents are also at increased risk of developing a malignancy raises the possibility that these agents may have oncogenic potential. Therefore, one may be faced with the paradox that the patients benefiting most from chemotherapy may be at highest risk of suffering its consequences.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azathioprine; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia, Myeloid, Acute; Lymphoma; Mechlorethamine; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Prednisone; Pregnancy; Procarbazine; Time Factors; Vincristine

Topics: Acute Disease; Animals; Asparaginase; Burkitt Lymphoma; Child; Cyclophosphamide; Cytarabine; Dactinomycin; Daunorubicin; Fluorouracil; Humans; Leukemia; Melphalan; Mercaptopurine; Methotrexate; Mice; Oncogenic Viruses; Prednisolone; Prednisone; Vincristine

Topics: Africa, Central; Burkitt Lymphoma; Fluorescent Antibody Technique; Humans; Immunization, Passive; Melphalan; Methods; Prognosis

A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Burkitt Lymphoma; Carmustine; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; HIV Infections; Humans; Lymphoma, B-Cell; Male; Melphalan; Middle Aged; Transplantation, Autologous

Attempts to improve the efficacy of pretransplant conditioning regimens have been published, the potential of a better antileukemic effect being impaired by more frequent and severe toxicities. The efficacy of an intensified regimen, TAM (TBI, high-dose cytosine arabinoside and melphalan), is evaluated by analyzing long-term follow-up of a homogenous group of 42 high-risk ALL patients allografted in first CR. Age at time of BMT was 25.9 +/- 10.4 years (3-41). Twenty-two patients had more than three adverse prognostic factors. Ten patients had a Ph chromosome. Probability of overall survival was 45 +/- 9%, and for all surviving patients median follow-up time was 66 months. Event-free survival was 40 +/- 8% at 7 years after transplantation and the expected relapse rate reached 31%. Twenty-two deaths occurred, six after a relapse but 16 appeared to be directly due to the BMT procedure. None of the pretransplant characteristics significantly affected outcome after BMT. TAM appeared to be an efficient antileukemic therapy for conditioning high-risk ALL patients before allogeneic transplantation, but was still very toxic. The use of TAM in adult ALL patients in first CR is not recommended and the real role of intensified conditioning regimens remains to be demonstrated.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Burkitt Lymphoma; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Female; Follow-Up Studies; Humans; Leukemia-Lymphoma, Adult T-Cell; Male; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Whole-Body Irradiation

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Carmustine; Cost-Benefit Analysis; Cyclophosphamide; Cytarabine; Etoposide; Female; HIV Infections; Humans; Ifosfamide; Male; Melphalan; Methotrexate; Middle Aged; Neoplasm Staging; Retrospective Studies; Rituximab; Survival Analysis

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Carmustine; Cytarabine; Female; HIV Seropositivity; Humans; Male; Melphalan; Middle Aged; Podophyllotoxin; Stem Cell Transplantation; Transplantation, Autologous

Together with tolerance to killing induced by methylating agents, loss of mismatch repair (MMR) has previously been found to be associated with hypersensitivity to the DNAcross-linking agent 1-(2-chloroethyl)-3-cyclohexyl-nitrosourea(CCNU) in several human tumor cell lines (Aquilina et al., 1998). Here, we have investigated whether MMR might act as an efficient repair pathway and provide protection against the clastogenicity induced by CCNU and whether the hypersensitivity of MMR-defective cells is extended to other cross-linking agents. An increase in cell killing and in the frequency of micronuclei was observed after CCNU exposure in 2 hPMS2-defective clones (clones 6 and 7) compared with the parental HeLa cells. Introduction of a wild-type copy of chromosome 7 in clone 7 led to re-expression of the hPMS2 protein and brought survival and chromosomal damage upon CCNU exposure to parental levels. Our data indicate that MMR protects against the clastogenic damage induced by this drug. The hPMS2-defective HeLa cells were also hypersensitive to killing by mitomycin C. Mitomycin C sensitivity was confirmed in an hMLH1-defective clone derived from Raji cells and in msh2-defective mouse embryo fibroblasts derived from knock-out mice. hPMS2-defective and parental HeLa cells were transplanted into nude mice, and the animals were treated with mitomycin C. While parental cell growth rate was unaffected, the growth of MMR-defective tumor was significantly reduced. Our results indicate that the in vitro hypersensitivity to mitomycin C conferred by loss of MMR is paralleled in vivo and may have implications for the chemotherapy of MMR-defective tumors.

Topics: Adenosine Triphosphatases; Animals; Base Pair Mismatch; Burkitt Lymphoma; Cell Division; Cross-Linking Reagents; DNA Repair Enzymes; DNA-Binding Proteins; HeLa Cells; Humans; Lomustine; Melphalan; Mice; Mice, Knockout; Mice, Nude; Micronucleus Tests; Mismatch Repair Endonuclease PMS2; Mitomycin; MutS Homolog 2 Protein; Proteins; Proto-Oncogene Proteins; Transplantation, Heterologous; Tumor Cells, Cultured

The cytotoxicity of bifunctional alkylating agents is generally attributed to DNA damage, especially DNA-DNA crosslinking activity. It is unclear how crosslinks or other cellular damage result in cell death. Studies of drug effects at the level of expression of specific gene products may help elucidate the mechanism of cell killing. We examined proteins synthesized in L-phenylalanine mustard treated human lymphoma cells by [35S]methionine labeling and SDS-PAGE. Drug-treated cells showed decreased labeling of proteins in two molecular weight bands of 17 kDa (a doublet) and 12 kDa at 6, 18 and 24 hours after drug removal. One of the components of the 17 kDa doublet has been identified as calmodulin, a calcium binding protein essential to cell cycle progression and survival.

Topics: Antineoplastic Agents; Burkitt Lymphoma; Calmodulin; Cell Survival; Cross-Linking Reagents; DNA; Humans; Melphalan; Molecular Weight; Neoplasm Proteins; Tumor Cells, Cultured

Topics: Antimetabolites; Blastomeres; Burkitt Lymphoma; Buthionine Sulfoximine; Cell Line; Etoposide; Humans; Lymphocytes; Melphalan; Methionine Sulfoximine; Verapamil

The human Burkitt's lymphoma cell line BHM fails to show synergistic killing by alkylating agents in the presence of theophylline. Nitrosoureas (BCNU and CNU), a mustard agent (L-phenylalanine mustard), and a platinum coordination complex (cis-diamminedichloroplatinum-II) did not show increased cytotoxicity when cells were treated in the presence of theophylline. Despite varying abilities of the drugs to induce DNA damage in BHM cells (no DNA interstrand cross-linking with nitrosoureas or platinum and significant interstrand cross-linking following L-PAM treatment) theophylline did not alter the pattern of DNA damage. DNA interstrand cross-linking following treatment by L-PAM with theophylline was slightly decreased from that seen with L-PAM alone. All three drugs induced DNA replicon initiation inhibition in BHM cells as measured both by alkaline sucrose gradient sedimentation and pH step alkaline elution. As opposed to cell lines where methylxanthines increase alkylating agent cytotoxicity, theophylline and caffeine failed to reverse the drug-induced replicon initiation inhibition seen in BHM cells. These findings support the hypothesis that the synergistic killing seen in some cell lines with alkylating agents and methylxanthines is due to the reversal of replicon initiation inhibition by the methylxanthines.

Topics: Alkylating Agents; Burkitt Lymphoma; Carmustine; Cell Line; Cell Survival; Cisplatin; Cross-Linking Reagents; DNA, Neoplasm; Drug Resistance; Drug Synergism; Ethylnitrosourea; Humans; Melphalan; Replicon; Theophylline

Three Burkitt's lymphoma cell lines were studied for their response to cis-diamminedichloroplatinum(II) (cis-DDP) and L-phenylalanine mustard (L-PAM) with the objective of relating cytotoxicity to DNA cross-linking in human cells. Cytotoxicity was measured by cell proliferation and colony formation assays. DNA interstrand and DNA-protein cross-linking were measured by alkaline elution. Two of the cell lines showed quantitative agreement between cytotoxicity and DNA cross-linking assays following treatment with cis-DDP or L-PAM. The correlation with DNA-protein cross-linking was not as good as with interstrand cross-linking. With the third cell line, cytotoxicity and interstrand cross-linking were correlated in response to L-PAM but not in response to cis-DDP. When this line was treated with cis-DDP, cross-linking was low, but cytotoxicity was high. This line differed from the other two lines in that, following treatment with either cis-DDP or L-PAM, substantial cell lysis or disruption occurred 12 to 14 hr following treatment. The results are consistent with a general correlation between DNA cross-linking and cytotoxicity in human cells treated with bifunctional agents. An exceptional cell type, however, is described which appears to have a reduced tolerance to certain types of DNA damage, the reduced tolerance being expressed by early cell lysis or disruption.

Topics: Burkitt Lymphoma; Cell Division; Cell Line; Cell Survival; Cisplatin; Colony-Forming Units Assay; DNA; Humans; Melphalan; Proteins; Time Factors

Topics: Alkylating Agents; Burkitt Lymphoma; DNA, Neoplasm; Melphalan; Models, Chemical; Neoplasms, Experimental; Nitrogen Mustard Compounds

Topics: Antineoplastic Agents; Asparaginase; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Cytarabine; Dactinomycin; Daunorubicin; Female; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Melphalan; Mercaptopurine; Methotrexate; Prednisone; Pregnancy; Vincristine; Wilms Tumor

Topics: Adolescent; Antineoplastic Agents; Burkitt Lymphoma; Busulfan; Child; Child, Preschool; Chlorambucil; Cyclophosphamide; Cytarabine; Female; Humans; Immunotherapy; Infant; Kenya; Male; Mannitol; Melphalan; Methotrexate; Nitrogen Mustard Compounds; Nitroso Compounds; Urea

Topics: Antineoplastic Agents; Burkitt Lymphoma; Cyclophosphamide; Follow-Up Studies; Humans; Lymphoma; Melphalan; Vinblastine

Topics: Adolescent; Alkylating Agents; Antineoplastic Agents; Aziridines; Black People; Burkitt Lymphoma; Child; Cyclophosphamide; Dactinomycin; Epidemiology; Humans; Kenya; Lymphoma; Mandibular Neoplasms; Maxillary Neoplasms; Melphalan; Neoplasms; Oncogenic Viruses