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Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were down-regulated, consistent with S- phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, a well-tolerated off-patent approved drug, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.

Purpose: Patients with laparotomy-staged (PS) III 1A Hodgkin's disease confined to the upper abdomen are believed to have a favorable prognosis and require less aggressive treatment than patients with more-extensive stage III disease. We evaluated prognostic factors and outcome in 93 patients with PS III 1A Hodgkin's disease treated either with radiation therapy (RT) alone or combined RT and chemotherapy (combined modality treatment [CMT]) to determine the extent of treatment needed in this subgroup of stage IIIA patients., Materials and Methods: We retrospectively reviewed the freedom from relapse (FFR) rate, sites of recurrence, and survival rate of PS III 1A patients selected to receive extended-field irradiation (MPA, n = 27), total-nodal irradiation (TNI, n = 34), and CMT (n = 32) between 1969 and 1987. CMT consisted of six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy and MPA. Patients treated with MPA were part of a prospective trial designed to reduce treatment to patients with minimal stage III disease with very favorable characteristics., Results: Histologic subclass and treatment were the only prognostic factors for FFR and survival rates. Patients with nodular sclerosis or lymphocyte predominance histology had significantly higher FFR and survival rates compared to patients with mixed-cellularity (MC) histology. The 10-year actuarial FFR of PSIII 1A patients treated with MPA was only 39%, versus 55% for TNI (P = .02) and 94% for CMT (v MPA, P < .0001; v TNI, P = .006). The patterns of recurrence in patients who received MPA and TNI were significantly different, with MPA patients relapsing more often in untreated pelvic or inguinal nodes, and TNI patients relapsing more often in extranodal sites with or without nodal sites. The 10-year actuarial overall survival rate for patients treated with CMT was 89% versus 78% for MPA (v CMT, P = .09) and 70% for TNI (v CMT, P = .05)., Conclusion: Patients with PSIII 1A Hodgkin's disease treated with RT have a significantly higher risk of relapse and potentially a poorer survival compared with patients treated with CMT. These findings suggest that CMT should play a greater role in the treatment of this favorable substage of patients. Management with modified chemotherapy and RT in an attempt to reduce long-term treatment-induced complications may be a preferred approach for future trials.

To define the role of intensive combination chemotherapy in the treatment of low-grade or intermediate-grade lymphomas, the authors report results in 49 patients treated with intermediate-dose or high-dose methotrexate, bleomycin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cytoxan (cyclophosphamide), vincristine, and dexamethasone (m/M-BACOD) with long-term follow-up. The complete response rate was 59% (29 of 49), including 67% (eight of 12) with low-grade and 57% (21 of 37) with intermediate-grade disease. The median survival for the entire group was 81 months. The 29 complete responders had a long median survival of 131 months. Forty-five percent (13 of 29) of the complete responders, 27% of the entire group, continue in remission with a median disease-free survival of 76 months. This includes five of 19 patients with diffuse poorly differentiated lymphoma, a disease generally characterized by early relapse. Twelve patients achieved a partial response and had a shorter median survival of 53 months, whereas nonresponders survived a median of less than 5 months. Late relapse was noted in patients with low-grade and intermediate-grade disease. Age (younger than or older than 60 years) was the only predictor of long-term survival. These data indicate very long disease-free survival can be achieved in low-grade and intermediate-grade lymphomas after attaining a complete remission. Intensive doxorubicin containing chemotherapy can be considered as an option for patients with advanced low-grade lymphoma but can only be proven to be superior to single-agent chemotherapy or no initial therapy by controlled randomized trails.

Cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) is a widely used conditioning regimen in autologous bone marrow transplantation (ABMT) of patients with refractory and relapsed lymphoma. However, the maximum-tolerated dose (MTD) of these agents when used in combination has not been systematically explored. We treated 58 patients (28 with non-Hodgkin's lymphoma [NHL], 30 with Hodgkin's disease [HD]) at seven dose levels of CBV. Doses were cyclophosphamide 4,500 to 7,200 mg/m2, BCNU 450 to 600 g/m2, and VP-16 1,200 to 2,000 mg/m2. The MTD was cyclophosphamide 7,200 mg/m2, BCNU 450 mg/m2, and VP-16 2,000 mg/m2. Six hundred milligrams per square meter of BCNU was associated with five of 18 cases of interstitial pneumonitis versus two of 40 at 450 mg/m2 (P = .02). Treatment-related mortality was 5% at dose levels less than or equal to the MTD and 22% at the highest dose. In this heavily pretreated patient population, most of whom had high volume residual disease, complete responses (CRs) to CBV and ABMT occurred in 25% of assessable patients with NHL and 43% of patients with HD. Thirteen of 28 patients with NHL and 14 of 30 with HD remain free from disease progression with median follow-up of 212 and 215 days, respectively. CBV can be administered with acceptable toxicity over a wide range of doses to patients with refractory and relapsed lymphoma.

One hundred thirty-four assessable patients with stage II-IV large-cell lymphoma (LCL) were treated with the combination chemotherapy regimen methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) between July 1981 and May 1986. The m-BACOD regimen substituted moderate-dose methotrexate (200 mg/m2 x 2) for the high-dose methotrexate used in the preceding M-BACOD regimen; all other drugs were administered as with m-BACOD. Eighty-two patients (61%) in the completed m-BACOD trial achieved a complete response (CR). With a median follow-up of 3.6 years, 62 patients (76%) continue in CR. Predicted survivals of 1, 3, and 5 years for the entire m-BACOD group are 80%, 63%, and 60%, respectively, with a 5-year disease-free survival (DFS) of 74% for the patients who achieve CR. The results obtained with m-BACOD are comparable with those obtained in the preceding M-BACOD trial, which now has a median follow-up of 8.0 years. The reduction in methotrexate dosage in m-BACOD patients was not associated with an increased incidence of CNS relapse. Long-term follow-up of the 215 M/m-BACOD patients indicates that the regimens are not associated with an increased incidence of secondary malignancy. Prolonged follow-up also indicates that advanced-stage patients have a persistent rate of late relapse of about 7.0% per year for years 2 to 5 of their follow-up and that stage II patients have an approximate 2.1% per year rate of late relapse. Application of the previously described prognostic factor model to the 215 M/m-BACOD patients from the completed trials identifies a high-risk group of patients with a CR rate and predicted 5-year survival (38% and 24%, respectively) that are significantly worse than those of the group as a whole (65% and 57%, respectively).

A new combination chemotherapy program (M-BACOD) was administered to 101 patients with advanced diffuse histiocytic and diffuse undifferentiated lymphoma (DHL and DUL). High dose methotrexate (M) 3 g/m2 with leucovorin factor rescue was given on day 14 between cycles of bleomycin (B), adriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D) administered every 3 weeks for 10 cycles. The complete remission rate (CR) was 72% in all 101 patients or 77% in 95 evaluable patients. The median follow-up is 3 yr 2 mo with one-third of CR patients followed beyond 4 yr. Twenty-six percent of CR patients have relapsed with a projected 5-yr survival rate of 80% (5-yr disease-free rate 65%). The overall survival of all 101 study patients reaches a plateau at 59% projected out to 5 yr. Patients with prior therapy had a significantly lower CR rate than those without prior treatment (p = 0.001); however, no other unfavorable prognostic characteristics could be identified. Relapse in the central nervous system CNS occurred in only 5.4% of CR patients. M-BACOD results in prolonged survival and possible cure in a high proportion of all patients with DHL and DUL.

A total of 464 pathologically staged IA through IIIB Hodgkin's disease patients were evaluated for the risk of developing acute nonlymphocytic leukemia, non-Hodgkin's lymphoma, or a fatal infection after treatment with radiation therapy (RT) alone, initial combined radiation therapy and chemotherapy (CMT), or RT with MOPP administered at relapse. Patients received a standard six cycles of MOPP, and additional maintenance chemotherapy was not administered. Patients receiving total nodal irradiation (TNI) and MOPP chemotherapy have an 11.9% actuarial risk of developing a fatal complication at ten years, as compared to a 0.8% risk for lesser field irradiation and MOPP (P = .005). The risk with RT alone is 0.6%. Patients 40 years of age or older have a greater risk for complications. These data report a low risk for fatal complication with CMT when less than TNI is administered and when maintenance chemotherapy is not used.

We designed a protocol (VAPA) that featured 14 mo of intensive postremission induction chemotherapy in an effort to improve remission durations for patients with acute myelogenous leukemia (AML). One hundred and seven patients under 50 yr of age were entered into this study. The rate of complete remission is 70%. A Kaplan-Meier analysis of patients entering remission predicts that 56% +/- 7% (+/-SE) of patients less than 18 yr and 45% +/- 9% of patients aged 18-50 yr will remain in remission at 3 yr (median follow-up is 43 mo). Patients with the monocytic subtype had a statistically significant shorter duration of remission (2-sided p less than 0.05). There was a high incidence of primary CNS relapse in children. Thirty-one of 41 patients who completed the regimen remain in remission without maintenance therapy. We conclude that the VAPA protocol continues to offer a promising approach to treatment of AML.

The toxicity of MOPP chemotherapy, including nausea, vomiting, hair loss, and neuropathy, can limit patient compliance. Alternative regimens employing oral alkylating agents and vinblastine have been designed to ameliorate these toxicities. The authors reviewed their experience in 24 patients with advanced-stage Hodgkin's disease who were treated with chlorambucil, vinblastine, procarbazine, and prednisone (ChlVPP). Complete responses were obtained in 92% (11/12) of previously untreated patients and in 92% (11/12) of patients who relapsed after radiation (10/10) or chemotherapy (one of two). Overall, relapse-free survival is 82% with a median duration of follow-up of 5.5 years. Toxicity was minimal with myelosuppression being the dose-limiting toxicity. Severe nausea and vomiting occurred in only two patients and was considered secondary to procarbazine. Mild nausea occurred in six other patients. Minimal alopecia was seen in three patients and only two patients developed a mild peripheral neuropathy. The authors conclude that ChlVPP appears as effective as MOPP chemotherapy for Hodgkin's disease in comparable presentations but is a less toxic regimen. Thus, it may be useful in situations where poor compliance and patient acceptance may compromise optimal dose and frequency of drug administration.

A combination chemotherapy program using methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M-BACOD), which resulted in a high complete response rate and prolonged disease-free survival in lymphomas of the unfavorable diffuse histiocytic and diffuse undifferentiated histopathologic subgroups, was administered to 44 patients with advanced favorable and intermediate-prognosis non-Hodgkin's lymphomas, including nodular lymphoma of the poorly differentiated lymphocytic, mixed, and histiocytic subtypes, and diffuse lymphoma of the poorly differentiated lymphocytic or mixed histologic subtypes. High-dose methotrexate (3 g/m2) was given on Day 14 between cycles of bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone, administered every 3 weeks for ten cycles. Leucovorin factor (10 mg/m2) was given iv 24 hours after the methotrexate infusion was completed, and was continued at 10 mg/m2 by mouth every 6 hours for 72 hours. Therapy was well-tolerated, with predictable myelosuppression in the majority of patients. The complete response rate was 57% (25 of 44 patients), including ten of 18 (56%) patients with nodular and 15 of 26 (58%) patients with diffuse lymphomas. Median overall follow-up among living patients is 65 months, 58 months for patients with nodular and 69 months for patients with diffuse histologic subgroups. Overall survival at 5 years was 64% for patients who achieved complete response, 32% for partial responders, and 0% for those patients who did not respond. Disease-free survival of complete responders was 43% at 5 years, with only one disease-related death noted after 36 months. The nodular and diffuse patient subgroups had similar overall and disease-free survivals. Although initial bone marrow involvement was documented in nine of 18 (50%) nodular patients and in 13 of 26 (50%) diffuse patients, CNS relapse occurred in only one complete and two partial responders. The prolonged disease-free survival observed after M-BACOD therapy demonstrates that durable responses can be achieved with intensive chemotherapy.

The m-BACOD regimen attempted to lower the dose of methotrexate in the M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) program. Between July 1981 and January 1985, 87 previously untreated or minimally treated patients with diffuse large cell lymphoma were treated with the m-BACOD regimen (methotrexate 200 mg/m2 on days 8 and 15, bleomycin 4.0 mg/m2 on day 1, doxorubicin 45 mg/m2 on day 1, cyclophosphamide 600 mg/m2 on day 1, vincristine 1.0 mg/m2 on day 1, and dexamethasone 6 mg/m2 on days 1 to 5; leucovorin was given 24 hours after methotrexate at 10 mg/m2 every six hours for eight doses orally). Of 86 evaluable patients, 59 (68.5%) had a complete remission (CR). Partial response was seen in 21 patients with six still surviving (5 to over 15 months). Of the seven patients who had no change, all have died. The median duration of follow-up for the entire series was 30 months (range, 2 to 61). Relapse from CR occurred in 15 of 59 (25%). Currently, 56 of 87 patients (64%) survive; all but 12 are in their first remission. Overall survival was 84% for those achieving an apparent CR. The major toxic effect of the m-BACOD regimen was myelosuppression with severe leukopenia and fever, which required hospitalization for about 33% of patients. Mucositis occurred in 39 patients; 19 had severe mucositis. No significant difference in overall survival was seen between the high-dose methotrexate M-BACOD and the low-dose m-BACOD regimens.

One hundred twenty-one patients with diffuse large-cell lymphoma treated with m- or M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) were evaluated for pretreatment characteristics predictive for response and survival. Two characteristics, poor performance status and massive bulky disease, were negatively associated with response rate in a multivariate analysis. These two characteristics were also negatively associated with survival in multivariate analysis, as was another factor, an increased number of extranodal sites of disease. These three pretreatment characteristics were used to construct a model containing 12 categories of patients at increasing risk for relapse and shortened survival. These categories divided naturally into three broad groups of patients with respective 5-year survival rates of 68%, 55%, and 24%.

Thirty-four patients with acute promyelocytic leukemia (APL) (median age 37 years, range 20 to 69 years) received induction treatment between 1974 and 1985 with cytosine arabinoside (ara-C) and an anthracycline. Bone marrow hypercellularity was present at the time of diagnosis in all patients, although the median peripheral leukocyte count was 2,600/microL. A second course of induction therapy consisting of further ara-C and anthracycline was initiated 15 days after the start of treatment if bone marrow hypocellularity could not be documented. Karyotypic analysis of bone marrow blasts was performed on 15 of 34 patients; 11 of 15 had abnormalities in chromosomes 15 and/or 17. Twenty-nine of 34 (85%) patients had laboratory evidence of disseminated intravascular coagulopathy. Of the 29 patients surviving 14 days, 24 (83%) received a second course of induction therapy. Complete remission was achieved in 25 of 34 (74%) patients, with four of 25 (16%) requiring one course of induction chemotherapy and 21 of 25 (84%) receiving two courses. Bone marrow specimens obtained 15 days after the start of therapy from the 25 patients who eventually attained complete remission showed the continued presence of dysplastic promyelocytes in 21 cases; three specimens were technically inadequate and only one was truly devoid of promyelocytes. Seventeen of 25 (68%) patients still had persistence of abnormal bone marrow promyelocytes seven or more days after the second course of therapy. Patients in complete remission received various forms of postremission therapy. Ten of the 25 (40%) completely responding patients remain alive in continuous complete remission. Neither the absence of bone marrow hypocellularity nor the persistence of dysplastic promyelocytes during induction exerted any influence on the probability for survival. These findings confirm and extend prior reports that complete remission in APL, in contrast to other subtypes of acute nonlymphocytic leukemia (ANLL), can frequently be achieved without bone marrow aplasia. Whether this observation signifies that complete remission in APL is due to leukemic cell differentiation or selective cytotoxicity is unknown. The absence of therapy-induced bone marrow hypoplasia in APL is not an absolute indication of induction failure or a poor ultimate prognosis.

From 1970 to 1982, remission rates from large series of patients with a median age of approximately 50 years continue to exceed 50% and in series of younger patients may be as high as 75%. These improved results have been due to the combination of cytosar and an anthracycline in RI programs. The current major question is whether or not "consolidation" therapy has improved long-term disease-free survival. Our current results, covering the decade 1970-1980 and using more and more intensive RC programs, do not demonstrate an increase in the percentage of long-term survivors. The results from 1980 to 1982 are encouraging, but must be tempered by the fact that late relapses of adult ANLL are becoming more frequent and 2-year follow-up is much too short an evaluation period. In addition, the prolonged survival in program D may be due to the more intensive RI program and not at all related to the RC. At the present time, our experience lends no support to the theory that more intensive RC programs meaningfully prolong long-term survival.

A small group of patients (22) with metastatic breast cancer, most of whom had advanced visceral disease, have been treated since 1973 with low-dose, multiple-drug chemotherapy: vinblastine, 0.05 mg/kg, I.V.; cyclophosphamide, 6 mg/kg P.O.; 5-fluorouracil, 500 mg. P.O., and methotrexate, 0.3 mg/kg P.O. The schedule includes the use of one drug on each of four days every week. The drugs were taken in the sequence listed on alternate days, except that dosages of methotrexate and vinblastine were consecutive. The remission rate was 68% (15/22). The median duration of remission was 30 months. The median survival time of responding patients exceeds 40 months. Of the 15 responding patients, six (40%) remain alive with a mean survival time of more than 46 months. The regimen causes minimal toxicity and has been willingly accepted by patients for as long a period as 54 months. A therapeutic advantage appears to have been achieved by this high-frequency, low-dose schedule.