Age and treatment response in acute nonlymphoblastic leukemia.

Treatment of older acute leukemia patients has been the subject of recent debate. We treated 101 acute leukemia patients in a prospective randomized trial. Fifty-seven per cent of the population was over 50. Half were treated with a mild induction program (VAMP) and half with a vigorous program (CAT). The older patients who received vigorous treatment did better than those who received mild treatment. We suggest that patients over 50 should be regarded as a separate category in design of treatment protocols in order to further maximize the benefits of therapy.     

Mitoxantrone in combination with etoposide and cytarabine for treatment of poor prognosis acute non lymphoid leukemia patients.

BACKGROUND. The proved effectiveness and relatively low extrahematological toxicity of Mitoxantrone, Ara-C and Etoposide as single agents and in combination in the treatment of acute non lymphoid leukemia (ANLL) are well established. In a phase II study the efficacy and toxicity of an induction combination regimen with Mitoxantrone, Ara-C and Etoposide were evaluated for treatment of poor risk ANLL patients. METHODS. Twenty-seven poor prognosis ANLL patients were treated with Mitoxantrone, 7 mg/sm days 1-3; VP16, 150 mg/sm days 1-3; Ara-C, 200 mg/sm continuous infusion days 1-5. Median age of treated patients was 63 (17-78): 10 de novo leukemias (4 greater than 65 yrs 3 with cardiomyopathy); 12 secondary leukemias (5 secondary to a myelodysplastic syndrome, 5 to myeloproliferative syndrome, 2 to other neoplasias); 3 relapses; 2 refractory. RESULTS. Fifteen patients (55.5%) achieved CR (8 de novo leukemias, 3 relapses, 4 secondary leukemias); 7 died in induction, 5 progressed. Median remission duration was 27 weeks (range 5-70 wks) and overall median survival 13 weeks (range 4-80). Extraematological toxicity was low, but five patients died from infections and two from hemorrhages. CONCLUSIONS. The combination tested in this trial proved effective in the treatment of "poor risk" ANLL, but the results need to be confirmed on greater numbers of patients, mainly in the group of de novo leukemias that can't be treated with more aggressive regimens.     

Teniposide and cytarabine combination chemotherapy in the treatment of relapsed adolescent and adult acute lymphoblastic leukemia

Nineteen adolescents and adults with relapsed acute lymphoblastic leukemia (ALL) were treated with teniposide (VM-26) plus cytarabine (ara-C). Eight patients (42%) achieved complete remission. Infection and bleeding secondary to myelosuppression were the most serious complications seen. Responders received periodic reinductions with VM-26 and ara-C, but all relapsed within 16 weeks from remission. Our data demonstrate the effectiveness of combination chemotherapy with VM-26 plus ara-C in adolescent and adult ALL in relapse and suggest testing of this combination in first-line protocols. For remission maintenance, the association of other drug combinations is necessary.     

Intensive chemotherapy with daunorubicin, 5-azacytidine, 6-thioguanine, and cytarabine (DATA) for the blastic transformation of chronic granulocytic leukemia

Thirty patients with blastic transformation of chronic granulocytic leukemia were treated with a combination of daunorubicin, 5-azacytidine, 6-thioguanine, and cytarabine. Hematopoietic toxic effects were substantial and eight of 23 patients developed hepatic dysfunction (bilirubin greater than 5.5 mg/dl). Although the regimen resulted in marked decrease in peripheral blood blast cells and produced marrow hypoplasia in most of the patients (20 of 23), there was little therapeutic benefit. Seven patients died while aplastic, nine had recurrence of blastic leukemia, and only four had partial improvement in marrow function.     

Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group.

Early intensification of chemotherapy with high-dose cytarabine either in the postremission or remission induction phase has recently been shown to improve long-term relapse-free survival (RFS) in patients with acute myeloid leukemia (AML). Comparable results have been produced with the double induction strategy. The present trial evaluated the contribution of high-dose versus standard-dose cytarabine to this strategy. Between March 1985 and November 1992, 725 eligible patients 16 to 60 years of age with newly diagnosed primary AML entered the trial. Before treatment started, patients were randomized between two versions of double induction: 2 courses of standard-dose cytarabine (ara-C) with daunorubicin and 6-thioguanine (TAD) were compared with 1 course of TAD followed by high-dose cytarabine (3 g/m2 every 12 hours for 6 times) with mitoxantrone (HAM). Second courses started on day 21 before remission criteria were reached, regardless of the presence or absence of blast cells in the bone marrow. Patients in remission received consolidation by TAD and monthly maintenance with reduced TAD courses for 3 years. The complete remission (CR) rate in the TAD-TAD compared with the TAD-HAM arm was 65% versus 71% (not significant [NS]), and the early and hypoplastic death rate was 18% versus 14% (NS). The corresponding RFS after 5 years was 29% versus 35% (NS). An explorative analysis identified a subgroup of 286 patients with a poor prognosis representing 39% of the entire population; they included patients with more than 40% residual blasts in the day-16 bone marrow, patients with unfavorable karyotype, and those with high levels of serum lactate dehydrogenase. Their CR rate was 65% versus 49% (p =.004) in favor of TAD-HAM and was associated with a superior event-free survival (median, 7 v 3 months; 5 years, 17% v 12%; P =.012) and overall survival (median, 13 v 8 months; 5 years, 24% v 18%; P =.009). This suggests that the incorporation of high-dose cytarabine with mitoxantrone may contribute a specific benefit to poor-risk patients that, however, requires further substantiation. Double induction, followed by consolidation and maintenance, proved a safe and effective strategy and a new way of delivering early intensification treatment for AML.     

Homoharringtonine in combination with cytarabine and aclarubicin in the treatment of refractory/relapsed acute myeloid leukemia: a single-center experience

To assess the efficacy and toxicity of HAA regimen (Homoharringtonine 4 mg/m²/day, days 1–3; cytarabine 150 mg/m²/day, days 1–7; aclarubicin 12 mg/m²/day, days 1–7) as a salvage therapy in the treatment of refractory and/or relapsed acute myeloid leukemia (AML), 46 patients with refractory and/or relapsed AML, median age 37 (16–65) years, participated in this clinical study. The median follow-up was 41 (10–86) months. Eighty percent of patients achieved complete remission (CR), and the first single course of re-induction HAA regimen resulted in CR rate of 76.1 %. The study protocol allowed two courses of induction. The CR rates of patients with favorable, intermediate and unfavorable cytogenetics were 90 %, 88.9 %, and 37.5 %, respectively. For all patients, the estimated 3-year overall survival (OS) rate was 42 %, and the estimated relapse free survival (RFS) at 3 years for the 36 CR cases was 49 %. The toxicities associated with HAA regimen were acceptable. HAA is a good choice in cases with refractory/relapsing AML for salvage chemotherapy, preferably with a high-efficacy and low-toxicity profile.     

High-dose methylprednisolone for remission induction in children with acute nonlymphoblastic leukemia

The effectiveness of high-dose intravenous methylprednisolone (HIVMP) in inducing an initial remission was examined in a child with acute nonlymphoblastic leukemia (ANLL). Dramatic clinical and hematological improvement with 7% marrow blasts was obtained in 3 weeks with HIVMP treatment without giving any other antileukemic drugs. Based on the results of this preliminary observation we suggest that high-dose methylprednisolone (20-30 mg/kg) might be a useful approach when applied as an initial short treatment in childhood ANLL.     

Treatment of recurrent promyelocytic leukemia with a combination regimen utilizing amsacrine, cytosine arabinoside and 6-thioguanine (AAT)

Nine patients with recurrent acute promyelocytic leukemia have been treated between July, 1984 and November, 1987 with a combination therapeutic regimen consisting of amsacrine, cytosine arabinoside and thioguanine (AAT). Complete remission was achieved in 5/9 patients, one person died in aplasia of hepatic failure, and the remaining 3 died from heart failure with resistant disease. The 5 patients who achieved CR were successively treated with allogeneic (n = 2) or autologous bone marrow transplantation (n = 3). As of December, 1988 there were only 2 patients still alive and in CR, both underwent autologous bone marrow transplantation. The duration of the second complete remission in these two patients is 48+ and 29+ months, respectively. Moreover the overall survival duration for these two patients is 88+ and 41+ months, respectively. These data confirm that the AAT regimen is useful in treating recurrent acute promyelocytic leukemia, a disease otherwise characterized by a catastrophic clinical course during the recurrent phase.     

Chemotherapy of acute leukemia: a comparison of vincristine, cytarabine, and prednisone alone and in combination with cyclophosphamide or daunorubicin

Adults (274) with acute leukemia (AML) were randomly assigned to one of three treatment regimens: vincristine, prednisone, cytarabine--(1) 100 mg/sq m/day with cyclophosphamide (COAP); (2) 100 mg/sq m/day with daunorubicin (DOAP); and 200 mg/sq m/day (OAP). Cytarabine was infused continuously for five days. Patients entering complete remission randomly received maintenance treatment with COAP or OAP. For 197 previously untreated AML patients given COAP, DOAP, or OAP, remission rates were 37%, 35%, and 43%, respectively; median lengths, 40, 45, and 90 weeks; median survival, 7, 11, and 8 weeks. No statistically significant difference was found among treatments. Therefore, adding cyclophosphamide or daunorubicin, or using the COAP regimen with continuously infused cytarabine, produced no significant improvement over previously reported regimens. There was no significant difference in remission lengths in previously untreated AML patients maintained on OAP (median 81 weeks) or COAP (median 65 weeks).     

Molecular response in two children with relapsed acute myeloid leukemia treated with a combination of gemtuzumab ozogamicin and cytarabine

Phase I/II studies of gemtuzumab ozogamicin (GO) in pediatric refractory/relapsed acute myeloid leukemia (AML) have been reported. We present the cases of two children with relapsed AML who were treated with GO plus cytarabine, leading to a decrease of minimal residual disease down to levels not previously obtained. The toxicity profile of this treatment was relatively mild, except for severe but manageable myelosuppression.     

Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia

Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and cytarabine on alternating courses. Liposomal cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal cytarabine. Toxicities usually manifested after the MTX and cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and cytarabine can result in significant neurotoxicity.     

Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older

Outcome of patients with acute myeloid leukemia (AML) who are older than 60 years of age remains unsatisfactory, with low remission rates and poor overall survival. We have previously established the activity of clofarabine plus cytarabine in AML relapse. We have now conducted a phase 2 study of clofarabine plus cytarabine in patients aged 50 years or older with previously untreated AML. Clofarabine was given at 40 mg/m2 as a 1-hour intravenous infusion for 5 days (days 2 to 6) followed 4 hours later by cytarabine at 1 g/m2/d as a 2-hour intravenous infusion for 5 days (days 1 to 5). Of 60 patients, 29 (48%) had secondary AML, 30 (50%) had abnormal karyotypes (monosomy 5 and/or 7 in 15 [25%]), and 11 (21%) showed FLT3 abnormalities. The overall response (OR) rate was 60% (52% CR, 8% CRp). Four patients (7%) died during induction. Adverse events were mainly grade 2 or lower and included diarrhea, nausea, vomiting, mucositis, skin reactions, liver test abnormalities, and infusion-related facial flushing and headaches. Myelosuppression was common. Clofarabine plus cytarabine has activity in adult AML, achieving a good CR rate. However, survival does not appear to be improved compared with other regimens. Modifications of this combination in AML therapy of older patients warrant further evaluation.     

Drug-induced kinetic perturbations of the marrow blasts in acute leukemia. Effects of the daunorubicin, cytosine arabinoside and 6-thioguanine combination.

Cell kinetic changes induced in the marrow blasts by treatment with a triple cytotoxic regimen including daunorubicin, cytosine arabinoside and 6-thioguanine (DAT) were investigated in 6 previously untreated acute nonlymphocytic leukemia patients. A decrease in the labeling and mitotic indices was consistently observed 24 h after administration of daunorubicin, suggesting a G2 block and a preferential lytic effect on the S-phase cells operated by the drug. Conversely, cytosine arabinoside and 6-thioguanine in combination induced a series of kinetic perturbations variable from case to case; however, three principal patterns of kinetic response were recogized and discussed in detail. Useful information for the planning of a more rational antileukemic therapy can be drawn from a systematic study of the kinetic effects induced by drug combinations.