mitoguazone and Lymphoma

Results of a salvage combination regimen, MIME (methyl-glyoxal-bis-guanylhydrazone [methyl-GAG], ifosfamide, methotrexate, etoposide), as well as a front-line study, both containing ifosfamide, are described. The MIME regimen is associated with an overall response rate of 60% and a complete response (CR) rate of 24% in 208 patients. Twenty-five percent of complete responders with aggressive lymphomas have had sustained remissions longer than 2 years. The long-term survival of the whole group of patients with intermediate-grade lymphoma is 15%. Complete responders with low-grade lymphoma, in contrast, show an initially favorable relapse pattern, but a plateau has not been observed in the relapse-free survival curve. In view of the activity observed with ifosfamide as a single agent, a front-line regimen was devised that was aimed at maximizing the CR rate by changing the chemotherapy according to the response obtained after every three courses. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was administered initially, and if CR was not obtained, a second regimen, HOAP-Bleo (doxorubicin, vincristine, cytarabine, prednisone, bleomycin), was given. Again if after three courses CR was not attained, IMVP-16 (ifosfamide, methotrexate, etoposide) was administered. The CR rate was 81% and the long-term survival (at 10 years) was 62%, which compares favorably with other third-generation regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Etoposide; Humans; Ifosfamide; Lymphoma; Methotrexate; Mitoguazone

In this study we explored whether a standard chemotherapy regimen consisting of mitoguazone, ifosfamide, methotrexate and etoposide (MIME) combined with 5 micrograms/kg or 10 micrograms/kg G-CSF was capable of mobilizing peripheral blood progenitor cells (PBPC) in lymphoma patients. Thirty-three patients with Hodgkin's disease (HD) and 108 patients with non-Hodgkin's lymphoma (NHL) were mobilized with MIME/G-CSF. Most patients were heavily treated with different chemotherapy regimens receiving a median of 11 cycles (range 3-40) of chemotherapy prior to mobilization. Eight of 141 patients failed to mobilize PBPC and bone marrow was harvested. In addition, 10 patients obtained a harvest of < 2.0 x 10(6) CD34+ cells/kg. More than 2.0 x 10(6) CD34+ cells/kg were achieved in all HD patients and in 83% of the NHL patients. Fifty-eight per cent of the patients harvested > or = 5 x 10(6) CD34+ cells/kg. Eleven per cent of the patients developed neutropenic fever during the mobilization and 3% had nadir platelet values below 20 x 10(9)/L. An inverse correlation was observed in high-grade NHL (H-NHL) patients between the number of chemotherapy cycles given before mobilization and yield of CD34+ cells. Such an association was not seen among patients with HD, transformed and low-grade NHL. When G-CSF 10 micrograms/kg was used in combination with MIME, this correlation was no longer seen in patients with H-NHL. There was also association between CD34+ cell yield and prior radiotherapy in patients with HD or transformed NHL or low-grade NHL. These results demonstrate that an ordinary salvage chemotherapy regimen, such as MIME combined with G-CSF, can be successfully used to mobilize PBPC. Although no significant effect of increased dose of G-CSF was found, our data suggest that MIME/G-CSF 10 micrograms/kg should preferentially be used to mobilize PBPC in H-NHL patients pre-treated with > or = 12 cycles of chemotherapy, in irradiated HD patients and in all low-grade and transformed lymphomas.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Component Removal; Etoposide; Graft Survival; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Lymphoma; Methotrexate; Middle Aged; Mitoguazone; Premedication; Recurrence; Transplantation, Autologous

A new regimen not cross-resistant with standard regimens was developed for patients with relapsed or refractory Hodgkin's disease and non-Hodgkin's lymphoma. The regimen consisted of cisplatin, 70 mg/M2 given intravenously on day 1, vindesine, 3 mg/M2 given intravenously on days 1 and 8 (and also on day 15 of the first cycle only), and methylguazone, 600 mg/M2 given intravenously on days 8 and 15. Courses were repeated every 21 days. Thirty-nine patients (35 with non-Hodgkin's and 4 with Hodgkin's lymphoma) were treated and all were evaluable for response and toxicity. There were 5 complete and 14 partial responses for a total response rate of 49% (C.I. = 35%-63%). The median durations of partial and complete response were only 2.8 and 4.2 months, respectively. Only one patient remained in complete response for more than a year. There was one treatment-related death from renal failure on the study. Although this regimen was, in general. well tolerated the results are disappointing and seem no better than those obtained with many other salvage regimens for lymphoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Lymphoma; Male; Middle Aged; Mitoguazone; Survival Analysis; Treatment Outcome; Vindesine

As part of a program to develop less leukemogenic chemotherapy regimens for the treatment of favorable prognosis Hodgkin's disease, a phase I-II trial of mitoxantrone, etoposide, mitoguazone, and vinblastine was used to treat patients with relapsed and refractory malignant lymphoma and Hodgkin's disease. An overall partial response rate of 41% was observed. Although useful responses were seen, the absence of complete remissions is disappointing.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Etoposide; Hodgkin Disease; Humans; Lymphoma; Middle Aged; Mitoguazone; Mitoxantrone; Prognosis; Prospective Studies; Recurrence; Remission Induction; Vinblastine

Seventy-two patients with recurrent or refractory malignant lymphoproliferative diseases were treated with MIME combination chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) and concurrent mesna to prevent urothelial toxicity; 41 patients had high/intermediate-grade non-Hodgkin's lymphoma (NHL), 18 low-grade NHL/chronic lymphocytic leukemia (CLL), and 13 Hodgkin's disease (HD). The overall response rates were 56% in high/intermediate-grade NHL, 11% in low-grade NHL/CLL, and 69% in HD respectively. Median survival in the same 3 groups was 7, 2 and 10 months respectively. Neither previous type of response to chemotherapy nor previous amount of treatment predicted the outcome of MIME chemotherapy. Toxicity was modest, hemorrhagic cystitis did not occur, and only one therapy-related death occurred. Although MIME appears to be a safe treatment with considerable activity in recurrent or refractory lymphoproliferative disease very few patients become long-term survivors. However, MIME is well suited for remission induction in patients intended for subsequent autologous bone-marrow transplantation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Hodgkin Disease; Humans; Ifosfamide; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoma, Non-Hodgkin; Methotrexate; Middle Aged; Mitoguazone; Prognosis

Topics: Child; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Humans; Leukemia; Lymphoma; Mitoguazone

We treated 45 patients with advanced malignant lymphoma, using a combination of methyl-GAG and teniposide (VM-26). All patients had received extensive prior treatment with combination chemotherapy with or without irradiation. Both methyl-GAG (600 mg/m2) and VM-26 (100 mg/m2) were administered on Days 1 and 8 of the treatment protocol and, in responding patients, every 2 weeks thereafter. Partial responses occurred in six of 12 patients with Hodgkin's disease and in ten of 31 patients with non-Hodgkin's lymphoma. The median duration of response for all patients was 3 1/2 months (range, 1 1/2-11). There were moderate toxic effects, including nausea, myalgia, weakness, and myelosuppression. Relative to our recent experience with methyl-GAG as a single agent, the addition of VM-26 to methyl-GAG did not produce a superior rate or duration of response in similar, heavily pretreated patient populations with malignant lymphoma; however, the combination caused considerably more myelotoxicity. We conclude that the use of VM-26 with methyl-GAG in this dose schedule offers no advantage over single-agent therapy. Methyl-GAG, when administered on a biweekly schedule, is effective and well-tolerated. This agent should be considered for incorporation into chemotherapy protocols for the therapy of previously untreated patients with malignant lymphoma.

Topics: Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Guanidines; Humans; Lymphoma; Mitoguazone; Podophyllotoxin; Teniposide

Broad phase II trial of methylglyoxal-bi (guanylhydrazone) (MGBG) is under way at the Memorial Sloan-Kettering Cancer Center. Studies in renal cell carcinoma, lymphomas, and non-small-cell lung cancer are completed, and substantial numbers of patients with esophageal and head and neck cancer have been treated. Small numbers of patients with other solid tumors have also been entered into the study. MGBG has significant antineoplastic activity against lymphomas, with 16/40 heavily pretreated patients (40%) having partial remissions (PR) lasting 1 to 8+ months. MGBG has also demonstrated more modest activity in non-small-cell lung cancer, esophageal, and head and neck carcinoma; it appears to have little or no therapeutic value in renal cell cancer. Toxicities have been manageable, and included mild nausea and vomiting, diarrhea, mucositis, and myelosuppression. The dose-limiting toxicity, seen most frequently in those patients with impaired renal function, was lethargy and fatigue. MGBG has demonstrated activity in lymphomas, lung, esophageal, and head and neck cancer. Further trials of this agent are indicated, both alone and in combination.

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Clinical Trials as Topic; Drug Evaluation; Esophageal Neoplasms; Female; Guanidines; Head and Neck Neoplasms; Humans; Kidney; Lung Neoplasms; Lymphoma; Male; Middle Aged; Mitoguazone; Skin Diseases; Ulcer

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Agents; Humans; Lymphoma; Mitoguazone; Remission Induction; Treatment Outcome

With the intent of using active regimens in the front-line setting, new combinations of chemotherapy have been tested as salvage treatment in lymphoma patients at M.D. Anderson Hospital. Combinations based on ifosfamide plus etoposide, including IMVP-16 (ifosfamide/methotrexate/etoposide) and MIME (methyl-GAG/ifosfamide/methotrexate/etoposide) resulted in overall and complete responses (CRs) of 60 and 25%, respectively. Long-term follow-up of MIME indicates a 25% cure rate in intermediate-grade lymphoma patients who achieve CR. The in vitro synergism of platinum and high-dose cytarabine recently has been confirmed clinically. A study is currently under way to evaluate the effect of integrating MINE (mesna/ifosfamide/mitoxantrone/etoposide) and ESHAP (etoposide/methyl prednisolone/cytarabine/platinum) into one protocol.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cytarabine; Drug Evaluation; Etoposide; Follow-Up Studies; Humans; Ifosfamide; Lymphoma; Lymphoma, Non-Hodgkin; Mesna; Methotrexate; Methylprednisolone; Methylprednisolone Hemisuccinate; Mitoguazone; Mitoxantrone; Remission Induction; Survival Rate

Thirty adult patients with relapsed or refractory malignant lymphoma underwent a Phase I-II trial of salvage chemotherapy combining methyl-gag, high-dose Ara-C, M-Amsa, and ifosfamide (MAMI protocol). All patients had been extensively pretreated. At the time of salvage therapy, 21 patients had visceral involvement and 23 patients were refractory. The overall response rate was 50% (11 patients in complete remission and 3 patients in partial remission). The main toxicity was myelosuppression; 4 treatment-related deaths occurred and 17 patients died of tumor progression with a median of 5 months. The MAMI protocol showed similar antitumoral efficacy to that of other salvage chemotherapy regimens used for poor prognosis malignant lymphoma but was more toxic. However, a response rate of 45% in refractory patients should be taken into account and this drug association deserves further investigation with regard to the selection of patients for bone marrow transplants.

Topics: Adolescent; Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Dose-Response Relationship, Drug; Female; Humans; Ifosfamide; Lymphoma; Male; Middle Aged; Mitoguazone; Pilot Projects

A phase II trial of combination chemotherapy with mitoxantrone, cisplatin, and methyl-glyoxal bix-guanylhydrazone (MGBG) was conducted in 32 patients with unfavorable histology malignant lymphoma. All patients had relapsed after only one prior chemotherapy regimen (CHOP--56%; mBACOD--28%). There were three complete and eight partial responses (overall response rate--34%) among 32 eligible patients. The median duration of remission was 6.0 months. Severe granulocytopenia was common, with 19/32 patients (63%) suffering life-threatening, and 1/32 (3%) suffering fatal, granulocytopenia. We conclude that mitoxantrone-cisplatin-MGBG has modest activity as salvage treatment in malignant lymphoma patients, but produces severe toxicity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Evaluation; Female; Humans; Lymphoma; Male; Middle Aged; Mitoguazone; Mitoxantrone

From 1981 to 1983, 208 patients with recurrent or refractory lymphoma were treated with methylglyoxal-bis-guanylhydrazone (methyl-GAG), ifosfamide, methotrexate, etoposide (MIME). The complete remission (CR) rate was 24% and CR plus partial remission (PR) was 60%. Response was higher for aggressive than for indolent cell types. Median duration of CRs was 16.5 months and median survival of all patients was 9 months. In view of the in vitro synergism between cisplatin and high-dose cytarabine, we recently designed the DHAP regimen, which consists of cisplatin, 100 mg/m2 IV over 24 hours; cytarabine, 2 g/m2 IV over two hours every 12 hours for two doses; and dexamethasone, 40 mg orally daily for 4 days. There were 28 of 90 (31%) CRs and 22 of 90 (24%) PRs. Median duration of CR is 15 months; median survival of all patients is 6 months. The major toxicities have been infection (31%) and moderate to severe renal dysfunction (20%). In contrast to MIME, response rates did not differ significantly between aggressive and indolent cell types. A high-dose regimen (CBV) consisting of cyclophosphamide, 6 g/m2; carmustine, 300 mg/m2; and etoposide, 250 mg/m2 daily for 3 days followed by autologous bone marrow transplant (ABMT) has been successfully used to treat 62 patients with Hodgkin's disease recurrent or refractory after mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (MOPP/ABVD)-like regimens. A CR rate (47%) has been observed; 83% of these CRs remain alive and free of disease with a median follow-up of 19 months. This regimen appears to have curative potential in 40% of all cases and in 60% of cases treated after the first or second relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Drug Evaluation; Etoposide; Humans; Ifosfamide; Lymphoma; Methotrexate; Methylprednisolone; Mitoguazone; Transplantation, Autologous

Eighteen patients with high-grade malignant lymphoma were treated with ifosfamide-VP16213 combinations after failing to respond completely or after relapsing on CHOP-like therapy. Responders to the salvage therapy were subsequently treated with ablative chemotherapy (BCNU, VP-16213, Ara-C and melfalan) and autografted. Of these 18 patients six were in relapse, six were partial responders and six failed CHOP-like therapy. There were two complete remissions and seven partial responses to the ifosfamide-VP-16213 combinations. Of them, eight patients were transplanted, together with one non-responder. Four of these nine patients were disease-free survivors 18-34 months after autografting. There were two early deaths: one before and one during the autografting procedure. Using one of the best salvage therapy combinations followed by high-dose chemotherapy and autografting is feasible. The results in this pilot study suggest that an appreciable number of patients may be cured by this procedure.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cytarabine; Etoposide; Humans; Ifosfamide; Lymphoma; Melphalan; Methotrexate; Middle Aged; Mitoguazone; Podophyllotoxin

Three spontaneous lymphomas of 23- to 24-month-old (AB/Jena X DBA/2 Jena)F1 females were serially transplanted into syngeneic hosts. They were histologically classified as malignant lymphoblastic lymphomas (ABDt2 and ABDt5) and as a malignant lymphoma of histiocytic type (ABDt6). All lymphomas disseminated into the liver, spleen, and pancreas, whereas ABDt2 and ABDt5 additionally infiltrated the bone marrow and leptomeninx. None of the tumors showed a leukemic growth form, but extreme granulocytosis was observed in leukemia P388-bearing mice. Since the lymphomas ABDt2 and ABDt5 expressed T-cell differentiation antigens Ly-1, Ly-2, and Ly-3, they are thought to be of T-cell origin. On the contrary to the lymphocytes of parental mouse strain ABDt2 and ABDt5 cells reacted with anti H-2.23 allosera. All tumors have been found to be sensitive to at least 5/7 clinically used anticancer drugs. But only ABDt2- and P388-bearing mice survived longer than 60 days after treatment with the potent anticancer drug 1,4-benzoquinone-guanylhydrazone-thiosemicarbazone (ambazone). Successful chemotherapy of both tumors was accompanied with resistance of the hosts against the second transplant of the same tumor. Summarizing the characteristics of the newly established transplantation tumors it is concluded that they can be recommended as screening models in the search for new antineoplastic agents.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Female; Leukemia P388; Leukemia, Experimental; Lymphoma; Mice; Mitoguazone; Neoplasm Transplantation

Patients with advanced lymphoma who relapse from intensive first-line combination chemotherapy generally have a very poor prognosis. The use of investigational drugs which lack cross-resistance to agents commonly used for initial therapy represents an important approach to the management of such patients. Based upon our prior experience, we developed a protocol which employed a combination of three new agents. Mitoguazone (600 mg/m2) was administered on Days 1 and 10; etoposide (100-125 mg/m2) was administered on Days 2, 3, and 4; and gallium nitrate (300 mg/m2/day) was administered as a continuous iv infusion over 24 hours on Days 1-7. Treatment cycles were repeated every 3-4 weeks pending tolerance to toxic reactions. Forty-two patients are evaluable for response (35 with non-Hodgkin's lymphoma and seven with Hodgkin's disease). All patients had received extensive prior treatment (median of two previous chemotherapy regimens). Less than one-half of patients had achieved complete remission (CR) with previous therapy. Twenty-two patients (52%) showed major antitumor responses (five CR, 17 partial). All patients who achieved CR had diffuse large cell lymphoma. Two patients in CR relapsed in the CNS. The median duration of response for patients who achieved partial response was 4 months (range, 1-11+). Major toxic reactions included myelosuppression, optic neuritis, mucositis, and corneal keratitis or conjunctivitis. This combination of experimental agents has major therapeutic activity in patients with advanced, resistant lymphoma. Optimal application of these drugs may be obtained by use as one arm of an intensive program of alternating non-cross-resistant regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Gallium; Humans; Lymphoma; Middle Aged; Mitoguazone

Based on encouraging results of two previous ifosfamide-VP-16 salvage combinations, methyl-gag was added to ifosfamide, methotrexate, and etoposide (VP-16). This combination is called MIME. A total of 208 patients with recurrent lymphoma were treated with this regimen. Response rates were 24% for complete remission and 36% for partial remission. The MIME regimen was more effective in patients who were treated after being off front-line therapy for longer than 6 months. However, responses were also seen in patients with disease clearly resistant to front-line therapy, suggesting that MIME was at least partially non-cross-resistant with front-line doxorubicin-containing regimens. The 15-month median relapse-free survival of complete responders and the 9-month overall median survival time for all patients treated were both similar to results from previous ifosfamide-VP-16 combination use. This regimen has been effective in the treatment of patients with recurrent or refractory lymphoma, but cannot be considered curative in the majority of cases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Resistance; Etoposide; Humans; Ifosfamide; Lymphoma; Methotrexate; Mitoguazone; Prognosis; Remission Induction

We tested the combination of cisplatin, amsacrine, and mitoguazone as salvage treatment for patients with advanced unfavorable non-Hodgkin's lymphomas. An objective response rate of 43% was noted in 30 evaluable patients, but all responses were partial and the median duration of response was only 2 months. Toxicity included life-threatening and fatal leukopenia and severe gastrointestinal intolerance. We conclude that this combination chemotherapy regimen is not a valuable salvage treatment for patients with non-Hodgkin's lymphoma.

Topics: Adult; Aged; Aminoacridines; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Digestive System; Female; Humans; Leukopenia; Lymphoma; Male; Middle Aged; Mitoguazone

The mitogenic action of prolactin in Nb 2 node lymphoma cells was inhibited by two drugs which interfere with polyamine biosynthesis. At concentrations of 0.5 mM and above alpha-difluoromethyl ornithine (DFMO), which inhibits ornithine decarboxylase and the conversion of ornithine to putrescine, significantly attenuated the mitogenic effect of prolactin. This inhibition was prevented by the addition of putrescine, spermidine, or spermine to the culture medium. At concentrations of 1 microM and above methylglyoxal bis(guanylhydrazone) (MGBG), which inhibits S-adenosylmethionine decarboxylase and hence the conversion of putrescine to spermidine and spermine, abolished the mitogenic action of prolactin. This inhibition was prevented by the addition of spermidine or spermine, but not putrescine, to the culture medium. These studies show that ongoing polyamine biosynthesis is essential for prolactin to express its mitogenic effect in this lymphoma cell line.

Topics: Adenosylmethionine Decarboxylase; Animals; Cell Division; Cell Line; Drug Interactions; Eflornithine; Lymphoma; Mitoguazone; Ornithine; Ornithine Decarboxylase Inhibitors; Polyamines; Prolactin; Rats

The Southwest Oncology Group has evaluated methyl-GAG on a weekly schedule among patients with lymphoma and Hodgkin's disease. Among 56 fully and partially evaluable patients responses were seen in 3 of 10 patients with Hodgkin's disease and 11 of 46 patients with lymphoma. Toxicity was acceptable. Methyl-GAG has significant antitumor activity among this group of heavily pretreated patients. Additional trials of methyl-GAG in combination with other agents are underway.

Topics: Adolescent; Adult; Aged; Drug Evaluation; Female; Guanidines; Hodgkin Disease; Humans; Lymphoma; Male; Middle Aged; Mitoguazone

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl-GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.

Topics: Adult; Aged; Bone Marrow; Digestive System; Guanidines; Hodgkin Disease; Humans; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Mitoguazone; Time Factors