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The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50 mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261).

Chronic myeloid leukaemia (CML) is a malignant disease of the bone marrow characterised by the presence of the Philadelphia (Ph) chromosome. About 20% of acute lymphoblastic leukaemia (ALL) patients also show this genetic abnormality. A new drug, imatinib (Glivec, Novartis Pharma AG, Basel, Switzerland, and formerly STI571) is having a profound effect on the treatment and management of all stages of CML and Philadelphia chromosome positive (Ph+) ALL. New treatment algorithms are being developed. Should imatinib replace or be combined with existing therapies? To address this question, we review the pros and cons of therapy with interferon-alpha (IFN-alpha), allogeneic transplantation, autologous transplantation, imatinib, and in the case of Ph+ ALL, chemotherapy and experimental approaches. Conservative and aggressive treatments will be discussed and new molecular methods of monitoring cytogenetic response and their significance will also be reviewed.

Background: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase., Methods: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated., Results: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred., Conclusions: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.

The development of the targeted signal transduction inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) has prompted new ways of thinking about the treatment of chronic myeloid leukemia, other sensitive solid tumors such as gastrointestinal stromal tumors, and malignancies in general. The stresses associated with the extraordinary pace of testing and approval of imatinib mesylate provide lessons to government regulatory agencies, pharmaceutical companies, university researchers, professional societies, and the media in terms of their approach to cancer care, drug development, and dissemination of information. Such medical breakthroughs can generate an enormous, and occasionally overwhelming, volume of new information to be assimilated; misinformation and exaggeration should be avoided. Furthermore, in today's Internet age of information, a large fraction of a patient's medical knowledge and/or opinions may have been obtained and forged online, with input from other patients, and patients are clearly more informed about their illnesses and their options than in the past. The availability of imatinib mesylate has already profoundly changed the nature and sequence of treatment recommendations for patients with chronic myeloid leukemia, but a great deal still remains to be learned and new clinical trials must be designed to address numerous questions about the optimal use of this powerful new medication., (Copyright 2001 by W.B. Saunders Company.)

Background: Fludarabine is an effective treatment for chronic lymphocytic leukemia that does not respond to initial treatment with chlorambucil. We compared the efficacy of fludarabine with that of chlorambucil in the primary treatment of chronic lymphocytic leukemia., Methods: Between 1990 and 1994, we randomly assigned 509 previously untreated patients with chronic lymphocytic leukemia to one of the following treatments: fludarabine (25 mg per square meter of body-surface area, administered intravenously daily for 5 days every 28 days), chlorambucil (40 mg per square meter, given orally every 28 days), or fludarabine (20 mg per square meter per day for 5 days every 28 days) plus chlorambucil (20 mg per square meter every 28 days). Patients with an additional response at each monthly evaluation continued to receive the assigned treatment for a maximum of 12 cycles., Results: Assignment of patients to the fludarabine-plus-chlorambucil group was stopped when a planned interim analysis revealed excessive toxicity and a response rate that was not better than the rate with fludarabine alone. Among the other two groups, the response rate was significantly higher for fludarabine alone than for chlorambucil alone. Among 170 patients treated with fludarabine, 20 percent had a complete remission, and 43 percent had a partial remission. The corresponding values for 181 patients treated with chlorambucil were 4 percent and 33 percent (P< 0.001 for both comparisons). The median duration of remission and the median progression-free survival in the fludarabine group were 25 months and 20 months, respectively, whereas both values were 14 months in the chlorambucil group (P<0.001 for both comparisons). The median overall survival among patients treated with fludarabine was 66 months, which was not significantly different from the overall survival in the other two groups (56 months with chlorambucil and 55 months with combined treatment). Severe infections and neutropenia were more frequent with fludarabine than with chlorambucil (P=0.08), although, overall, toxic effects were tolerable with the two single-drug regimens., Conclusions: When used as the initial treatment for chronic lymphocytic leukemia, fludarabine yields higher response rates and a longer duration of remission and progression-free survival than chlorambucil.

We examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1,450/microL at diagnosis and was 31,000/microL (range, 6,800-72,000/microL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95)

Background: It is uncertain which people with chronic myelogenous leukemia (CML) in chronic phase should receive conventional treatment (interferon and/or chemotherapy) versus high-dose therapy and a bone marrow transplant. There are no randomized trials comparing these approaches and analyses of data from non-randomized studies are complex, contradictory without sufficient detail to allow subject-level treatment decisions., Objective: Determine appropriateness of high-dose therapy and bone marrow transplants in persons with CML in chronic phase with specific features. Develop a treatment algorithm. PANELISTS: nine leukemia experts from diverse geographic sites and practice settings., Evidence: Boolean MEDLINE searches of chronic myelogenous leukemia and chemotherapy and/or transplants., Consensus Process: We used a modified Delphi-panel group judgment process. Age, prognostic score, disease duration, and type of conventional therapy and response were permuted to define 90 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional therapy on a 9-point ordinal scale (1, most inappropriate, 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors (HLA-matched related or unrelated people other than an HLA-identical sibling); and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of similar settings and a treatment algorithm developed., Conclusions: In people with CML in chronic phase and an HLA-identical sibling donor and in those with an alternative donor (but no HLA-identical sibling), a transplant was rated appropriate in those with a < or = partial cytogenetic response to interferon and uncertain or inappropriate in all other settings. Autotransplants were rated uncertain or inappropriate in all settings. Most of the variance in appropriateness ratings between different clinical settings was accounted for by response to interferon: complete versus < or = partial response. An HLA-identical sibling donor, when available, was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling, an alternative donor was favored over an autotransplant at higher appropriateness indices and the converse at lower appropriateness indices.

Background: Despite considerable data, there is still controversy over which adults with acute myelogenous leukemia (AML) in 1st remission should receive high-dose therapy and a bone marrow transplant rather than conventional-dose chemotherapy. Analyses of data from randomized trials are complex, conclusions sometimes contradictory and results not sufficiently detailed to allow subject-level decisions., Objective: To determine appropriate use of high-dose therapy and bone marrow transplants in persons with AML in 1st remission with specific features. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings., Evidence: Boolean MEDLINE searches of acute myelogenous leukemia and chemotherapy and/or transplants., Consensus Process: We used a modified Delphi-panel group judgment process. Age, WBC, cytogenetics and FAB-type were permuted to define 72 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a nine-point ordinal scale (1, most inappropriate, 9, most appropriate) considering 3 types of donors: (1) HLA-identical siblings; (2) alternative donors (HLA-matched related or unrelated people other than an HLA-identical sibling); and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm developed., Conclusions: In people with an HLA-identical sibling, this type of transplant was rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. In people without an HLA-identical sibling, an alternative donor transplant was rated appropriate in those < 30 years with unfavorable cytogenetics, uncertain in those > 30 years and unfavorable cytogenetics and inappropriate in all other settings. Autotransplants were rated appropriate in people with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor, when available, was always preferred to an alternative donor transplant or autotransplant. In people without an HLA-identical sibling, an autotransplant was almost always favored over an alternative donor transplant with the magnitude of preference inversely correlated with transplant appropriateness.

Background: There is controversy over whether high-dose therapy and a bone marrow transplant is better than conventional-dose chemotherapy in adults with acute lymphoblastic leukemia (ALL) in first remission. This decision may depend on which type of donor is available: an HLA-identical sibling, an alternative donor transplant (HLA-matched related or unrelated people other than HLA-identical siblings), or autotransplant., Objective: To determine the appropriate use of high-dose therapy and bone marrow transplants in ALL in first remission. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings., Evidence: Boolean MEDLINE searches of acute lymphoblastic leukemia and chemotherapy and/or transplants., Consensus Process: We used a modified Delphi-panel group judgment process. Age, white blood cell (WBC) count, cytogenetics and immune type were permuted to define 48 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate; 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors; and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm was developed., Conclusions: In people with an HLA-identical sibling donor, transplants were rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling but with an alternative donor, this type of transplant was rated appropriate in those with unfavorable cytogenetics. However, an autotransplant was preferred over an alternative donor transplant in all other settings where a transplant was rated uncertain. In people without an HLA-identical sibling or alternative donor, autotransplants were rated uncertain in all settings except in those with not unfavorable cytogenetics, WBC < 100 x 10(9) l(-1) and T- or pre-B-cell type where they were rated inappropriate.

Among its multiple toxic effects, L-asparaginase induces allergic reactions that may reduce its biological effect. The impact of hypersensitivity reactions on the duration of leukemia-free survival (LFS) was assessed in adults with newly diagnosed acute lymphoblastic leukemia (ALL) receiving intensive multi-agent chemotherapy. In CALGB study 8811 (Blood 1995; 85: 2025-2037), 197 adults were scheduled to receive 14 doses of Escherichia coil L-asparaginase (6000 U/m2 SC) during 7 of the first 12 weeks of chemotherapy. No further L-asparaginase was given. Chemotherapy was given for 24 months. The median follow-up time has been 5.7 years. Of the 141 patients who remained on study after 12 weeks, 82 (58%) had received all 14 planned doses; 38 (27%) had 12-13 L-asparaginase doses documented in their treatment record; 21 (15%) patients had received < or =11 doses due to a variety of toxic effects. The mean number of doses received prior to experiencing any hypersensitivity reaction was seven (range 1-11). Seven patients had mild hypersensitivity reactions, but all seven eventually received 12-14 doses of E. coil L-asparaginase. Twenty-one other patients had severe hypersensitivity reactions that required discontinuation of E. coil L-asparaginase; 20 of these patients were switched to Erwinia L-asparaginase to complete their treatment. Ultimately, 12 of these 20 patients received 14 doses of L-asparaginase in total, and six received 12-13 doses. Thus, only three of the 21 patients who had severe hypersensitivity reactions received < or =11 total L-asparaginase doses. Other L-asparaginase-related complications included pancreatitis (15 patients), hypofibrinogenemia <100mg/dl (29 patients), and deep venous thrombosis or pulmonary embolism (eight patients); some of these patients had L-asparaginase discontinued after these complications. The estimates for LFS at 3 years were 55% (95% confidence interval, 44-65%) for the patients who received all 14 L-asparaginase doses (median LFS, 5.1 years), 47% (95% CI, 33-62%) for those who received 12-13 doses, and 48% (95% CI, 29-67%) for those who received < or =11 doses. There were no significant differences between these three groups in the length of LFS (P=0.68). LFS did not correlate with a history of severe hypersensitivity reaction (P=0.67). In general, E. coil L-asparaginase was well tolerated in these adult patients, and most patients received all of the planned therapy. Patients who had mild L-asparaginase hypersensitivity reactions and patients who switched to Erwinia L-asparaginase because of more severe allergic reactions did not have significantly shorter LFS than the remaining adults treated on this ALL protocol. The possibility that E. coli L-asparaginase is inactivated or destroyed in those individuals who have become hypersensitive to it becomes less important when allergic patients are secondarily treated with Erwinia L-asparaginase.

Background: All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with all-trans-retinoic acid improves outcome., Methods: Three hundred forty-six patients with previously untreated acute promyelocytic leukemia were randomly assigned to receive all-trans-retinoic acid or daunorubicin plus cytarabine as induction treatment. Patients who had a complete remission received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy, then high-dose cytarabine plus daunorubicin. Patients still in complete remission after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with all-trans-retinoic acid or to observation., Results: Of the 174 patients treated with chemotherapy, 120 (69 percent) had a complete remission, as did 124 of the 172 (72 percent) given all-trans-retinoic acid (P=0.56). When both induction and maintenance treatments were taken into account, the estimated rates of disease-free survival at one, two, and three years were 77, 61, and 55 percent, respectively, for patients assigned to chemotherapy then all-trans-retinoic acid; 86, 75, and 75 percent for all-trans-retinoic acid then all-trans-retinoic acid; 75, 60, and 60 percent for all-trans-retinoic acid then observation; and 29, 18, and 18 percent for chemotherapy then observation. By intention-to-treat analysis, the rates of overall survival at one, two, and three years after entry into the study were 75, 57, and 50 percent, respectively, among patients assigned to chemotherapy, and 82, 72, and 67 percent among those assigned to all-trans-retinoic acid (P= 0.003)., Conclusions: All-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia.

Didemnin B is a member of a class of compounds, derived from a marine source, undergoing phase II study. Twenty-two patients with relapsed myeloma were treated with didemnin B at an initial dose of 4.9 mg/m2, given once every 28 days. All were evaluable for toxicity, and 15 were evaluable for myeloma response. No tumor regressions occurred in the 15 patients evaluable for response. Vomiting was the major toxicity, occurring in 73% of patients despite vigorous pre- and post-treatment medication with at least three intravenous antiemetics. Two instances of grade 4 hypersensitivity reaction occurred. We conclude that didemnin B has no activity at this dose and schedule in myeloma that has relapsed after one or two prior therapeutic regimens.

To evaluate the incidence of thrombocytopenia and bleeding among patients with solid tumors treated intensively with chemotherapy, the records of 1274 patients treated between 1972 and 1980 on protocols known to produce significant myelosuppression were reviewed. Three hundred one patients with solid tumors (breast, lung, melanoma, sarcoma, primary brain, testicular, hypernephroma and others) experienced 5063 days of thrombocytopenia (platelet count less than 50,000/microliters) and 670 days of severe thrombocytopenia (platelet count less than 20,000/microliters). The median number of days thrombocytopenia was 6 (range, 1-250). There were only 44 episodes of clinically detectable serious bleeding, primarily gastrointestinal (26/44), during thrombocytopenia and all but seven episodes first occurred at platelet counts between 20,000-50,000/microliters. Fifteen of the 44 bleeding episodes were associated with coagulation abnormalities, 24 occurred during serious infection, and 12 occurred at sites of tumors. One hundred forty-seven of the 301 patients (49%) received platelet transfusions. In 86 thrombocytopenic patients with central nervous system (CNS) tumors, there was no evidence of CNS bleeding during thrombocytopenia. Hemorrhagic deaths were uncommon, and of the 12 patients who died of bleeding, 7 had normal counts. There is a very low incidence of significant thrombocytopenia or bleeding among patients with solid tumors treated with combination chemotherapy or experimental agents escalated to maximally tolerated doses. These data suggest that with respect to thrombocytopenic bleeding intensive treatment of patients with solid tumors can be pursued with relative safety utilizing the standard transfusion supportive measures now widely available.

Thirty-two patients with advanced gynecologic malignancies were treated with m-AMSA, 120 mg/m2 intravenously every 3 weeks. Seventeen patients with advanced carcinoma of the cervix who were treated with m-AMSA had a median performance status (CALGB scale) of 2. There were two partial responses (PR) (14%) in 16 evaluable patients. The median duration of survival was 76 days following the initiation of m-AMSA treatment. In ovarian carcinoma, none of the nine evaluable patients who were treated responded. One PR occurred among four treated patients with endometrial adenocarcinoma. Toxicity was limited to myelosuppression (WBC greater than 2500/micrograms in 29/77 courses, WBC greater than 1500/micrograms in 16/77 courses, platelets greater than 100,000/micrograms in 10/77 courses, and drug-induced anemia in 7/77 courses) and mild to moderate nausea and vomiting (10/31 patients). Three patients required hospitalization for fever and granulocytopenia, and one patient died from drug-induced sepsis. Although toxicity was acceptable in this group of heavily pretreated patients, m-AMSA has limited activity in patients with advanced carcinoma of the cervix and no apparent activity in patients with advanced epithelial ovarian carcinomas. Continued trials are indicated in patients with adenocarcinoma of the endometrium.

Sixty-six newly diagnosed patients with acute nonlymphocytic leukemia received either daunorubicin alone or a combination of daunorubicin, cytosine arabinoside, 6-thioguanine, and pyrimethamine for remission-induction therapy. The two treatment groups were comparable with respect to the two major prognostic factors in this disease, which were age and presence or absence of infection on admission. The two therapies produced similar results with respect to CR rate and median survival results. Single-agent therapy was associated with less frequent utilization of hospital inpatient facilities and fewer platelet transfusions. The four-drug combination did not decrease the incidence of meningeal leukemia. Patients who achieved CR were treated with two half-dose consolidation courses of the successful remission-induction regimen. Subsequently, all patients received cyclophosphamide and guanazole monthly for maintenance therapy. Median durations of remission for both induction-treatment groups were similar (6.8 and 5.6 mos). The therapeutic results with the single agent in this study were not inferior to those obtained with the drug combination tested, as well as most other previously reported combinations of antileukemic drugs.

Diaziquone given as a bolus has not been effective in patients with relapsed or refractory leukemia. Because of in vitro data suggesting enhancement of diaziquone-induced cytotoxicity for human and murine leukemia cells with increased duration of drug exposure and the relatively short terminal plasma half-life of diaziquone, 49 patients (34 acute nonlymphocytic leukemia [ANLL], six chronic myelogenous leukemia in blast crisis [CML-B], five acute lymphocytic leukemia [ALL], four 2 degrees ANLL) with leukemia were given diaziquone as a continuous infusion for seven days. The maximum tolerated dose was 28 mg/m2/d for seven days. The dose-limiting toxicity was the duration of bone marrow aplasia (median, 49 days to greater than 500 PMNs in responders; range, 28 to 101 days). Nonhematologic toxicity was minimal. Responses occurred only in patients with relapsed ANLL, of whom 26 were treated at effective doses. There were six complete responses (CR) (23%) and two partial responses (PR) (8%), although five of eight responders never achieved platelet counts greater than 100,000/microL. Thrombocytopenia in these patients was felt to be a manifestation of diaziquone effect, not persistence of leukemia. The median duration of CR was 195 days (range, 88 to 860+). One patient had active CNS leukemia at the start of treatment and has had a durable (28+ month) CR in both sites of disease. Diaziquone produced prolonged aplasia in patients with secondary ANLL and CML-B (five of ten patients died aplastic), whereas patients with ALL all had regrowth of leukemia and two failed to become aplastic. The lack of significant nonhematologic toxicity and the activity in patients with relapsed ANLL render diaziquone of interest as second-line therapy or consolidation therapy in first remission for patients with ANLL.

Levamisole is a synthetic, orally administered, relatively nontoxic compound with immunorestorative ability. Levamisole was tested in this study of 60 adults with acute nonlymphocytic leukemia (ANLL) to determine if augmentation of response rate or duration, or survival over that obtained with a standard chemotherapy regimen alone would result. The chemotherapy regimens for all patients consisted of daunorubicin and cytosine arabinoside for induction and consolidation, methotrexate with citrovorum factor reversal in a cytoreductive phase, and late intensification with thioguanine and cytosine arabinoside. The first 30 patients received chemotherapy alone; a second group of 30 patients were scheduled to receive levamisole in addition to chemotherapy. Levamisole, 45 mg/m2, was administered orally twice daily for three consecutive days each week beginning one week after the initiation of induction chemotherapy and continuing until relapse. No significant difference emerged between the two groups with respect to remission rate, time to achieve remission, postrelapse survival, or total survival. However, a trend towards improved postcomplete remission survival (P = 0.072) was noted in the levamisole group, and patients who received levamisole had a significantly greater reinduction rate after relapse (P = 0.019).

Sixteen patients [13 acute nonlymphocytic leukemia (ANLL), 2 acute lymphocytic leukemia, 1 chronic myelogenous leukemia in a blast crisis; median age, 40 yr; range, 25-78 yr; 9 male, 7 female] received 23 courses of carboplatin given as a bolus on a daily X 5 schedule. Six patients were given 7 courses of carboplatin at 200 mg/m2/day; 3 patients received 5 courses at 250 mg/m2; 9 patients received 11 courses at 300 mg/m2; 2 patients initially treated at 200 mg/m2 were given their 2nd course at 300 mg/m2. Significant hearing loss documented by audiometry occurred in five patients, including three of nine treated at 300 mg/m2. All five had prior or recent exposure to aminoglycoside antibiotics. Three patients developed cancer and acute leukemia group B grade 3 or 4 mucositis, and 18 of 23 courses were complicated by nausea and vomiting. Marrows were hypocellular or aplastic in all patients treated at the highest dose. No complete responses occurred, although two patients with ANLL treated at 300 mg/m2 achieved partial responses lasting 71 and 138 days. The t1/2 alpha [half-life (t1/2)], t1/2 beta, and total body clearance of ultrafilterable platinum were comparable to those previously described by us in patients receiving bolus doses of carboplatin of 22-77 mg/m2/day X 5. Carboplatin has activity in ANLL.

A phase II trial was conducted to determine which of the three possible two-drug combinations of diaziquone, etoposide and mitoxantrone was associated with the highest response rate in patients with relapsed or refractory acute myeloid leukemia (AML). Of the 167 patients (median age 55) with AML who entered the trial, 123 were in first relapse, 22 were in second relapse and 22 had failed to achieve complete remission (CR). CR rates were 30% for diaziquone and mitoxantrone, and 23% for the other two combinations (mitoxantrone/etoposide and diaziquone/etoposide), NS. Patients in first relapse had higher CR rates (40%) than other patients. Of the 166 patients who actually received treatment, 43 died before having either a CR or persistent leukemia. Non-hematologic toxicity was primarily mucosal with 24% of patients experiencing grade 3 or greater stomatitis on the two diaziquone arms, and 43% on the mitoxantrone/etoposide arm. The combination of diaziquone and mitoxantrone was selected for further testing in patients with AML. [ABSTRACT FROM AUTHOR]