Treatment of a case of childhood acute non-lymphocytic leukemia (ANLL) using high-dose cytosine arabinoside for intensification of early therapy

A 12-year-old girl with acute non-lymphocytic leukemia was treated with a protocol involving high-dose cytosine arabinoside (Ara-C) for intensification of early therapy. The patient, who had been revealed to have CNS infiltration on admission, achieved complete remission after receiving ACMA/BHAC combination and intrathecal MTX. As an early intensification treatment, ID/HD Ara-C was safely and effectively administered; this consisted of ADR (45 mg/m2 iv) Day 1, intermediate-dose Ara-C (0.5 g/m2, 1-h drip, q. 12 h) Days 2-4, and high-dose Ara-C (3 g/m2, 3-h drip, q. 12 h) Days 10-11, followed by L-asp (6,000 U/m2, im) on Day 12. Ten months later, the patient has been in continuous complete remission. High-dose Ara-C should be included with caution as an early intensification of treatment to improve the therapeutic results of childhood ANLL.     

Combined etoposide and 5-azacitidine in children and adolescents with refractory or relapsed acute nonlymphocytic leukemia: a Pediatric Oncology Group Study

An intensive regimen of combined etoposide (VP-16) and 5-azacitidine (5-Az) was used to treat 96 children and adolescents with refractory or relapsed acute nonlymphocytic leukemia (ANLL). Patients were given two sequential five-day courses of VP-16, 250 mg/m2 for three days, followed by 5-Az, 300 mg/m2 for two days. An additional five-day course was administered if marrow aplasia was not evident by day 13. A complete remission rate of 45% was achieved with a median of two courses of VP-16 and 5-Az. The outcome of induction therapy was not influenced by prior treatment, blast cell morphology, or disease status on study entry (refractory or relapsed). Twenty-seven patients have relapsed after remission periods of 35 to 920 days (median, 110 days); seven others are free of leukemia for up to 519 days. The effectiveness of VP-16/5-Az combination therapy in patients refractory to anthracyclines and cytarabine indicates a potential role for these compounds in first-line treatment of patients with ANLL.     

Preliminary results of consolidation therapy with high-dose cytosine arabinoside for patients with bad-risk or relapsed acute leukemia or lymphoblastic non-Hodgkin's lymphoma

High-dose Ara-C consolidation therapy for patients with primary refractory or relapsed acute leukemia (AML and ALL) or relapsed lymphoblastic non-Hodgkin's lymphoma (LNHL) was investigated. Between January 1983 and January 1986, 47 adult patients with primary refractory or relapsed AML, ALL or lymphoblastic NHL received a remission induction regimen that included intermediate-dose Ara-C (1g/m²2hr q 12hr × 12). Of the twenty-nine (61.7%) patients who achieved complete remission sixteen (AML 9, ALL 5, LNHL 2) received 1–3 consolidation courses that included high-dose Ara-C (3g/m² q 12hr × 8). Three patients died as a result of major infections during the pancytopenic phase that followed the first consolidation course and 6 relapsed at 4, 4, 6, 8, 9 and 16 months; at the moment of this report the remaining 7 patients have been in continued remission for 8 to 28 months (6 have been in continued complete remission for ⩾ 11 months). The predicted median disease-free interval for patients who survived consolidation therapy is 16 months. Of the 13 patients who did not undergo consolidation chemotherapy 2 subsequently underwent allogeneic bone marrow transplantation and 3 died as a result of major infectious complications while in complete remissiion. Eight patients received no further treatment because they refused or had previously experienced severe toxicity. The median disease-free interval for this group was only 3 months. Our preliminary data on brief intensive consolidation therapy for patients with relapsed or primary refractory leukemia or non-Hodgkin's lymphoma suggest that this kind of treatment prolongs disease-free interval.     

改良FLAG方案治疗33例难治复发性急性白血病的初步分析

背景与目的:FLAG方案用于治疗难治复发性急性非淋巴细胞性白血病(acute non-lymphocytic leukemia,ANLL)已有多年,大多报道的CR率为50%～64%.本研究探讨改良FLAG方案(减少合并应用Ara-C剂量并在化疗前不用G-CSF)能否达到同样疗效,并减轻不良反应.方法:33例成人急性白血病中难治性ANLL 16例,难治性急性淋巴细胞白血病(ALL)12例,复发性ALL 5例.全部病例接受氟达拉宾30 mg@(m2@d)-1,静滴,第1～5天;其中合并Ara-C 200 mg@d-1有18例,Ara-C 500 mg@d-1有5例,Ara-C 1 000 mg@d-1有10例,全部静脉滴注5～7天为1疗程.应用Ara-C 200 mg@d-1组和ALL组化疗前不用G-CSF,ALL患者每周加用长春新碱2 mg,共2次;强的松60～80 mg@d-1,共14天.化疗后WBC＜1.0×10 9/L者加用G-CSF,剂量均为300μg@d-1,皮下注射至WBC 3.0×10 9/L以上.每疗程完成后复查骨髓.结果:16例难治性ANLL的CR率为56.3%,而12例难治性ALL的CR率为8.3%(P＜0.01);难治性ANLL患者中Ara-C 200 mg@d-1组的CR率高于500～1 000 mg@d-1组(70%:33%),但无统计学差异(P＞0.05).化疗后WBC 0.6×10 9/L和血小板15.6×10 9/L的平均持续时间分别为5天和4.3天,Ara-C 200 mg@d-1组感染发生率明显低于500～1 000 mg@d-1Ara-C组(58.0%:85.7%)(P＜0.05).结论:与经典的FLAG方案相比,改良FLAG方案的CR率有增高、感染发生率降低.     

Analysis of treatment failure in acute nonlymphocytic leukemia patients over fifty years of age. A Southwest Oncology Group study.

Fourteen participating centers registered 33 patients on a Southwest Oncology Group Study of adults with acute non-lymphocytic leukemia (ANLL). Induction consisted of cytosine arabinoside 70 mg/m2 days 1-7 by continuous intravenous (i.v.) infusion, VP-16 50 mg/m2 i.v. over 1 hour days 1-3, and daunomycin 30 mg/m2 i.v. bolus days 1-3. Twenty-five patients (median age 69 years) were evaluable for response. Eleven (44%) achieved a remission marrow but only 8 fulfilled both blood and marrow criteria for complete remission. Of the 11 patients with a remission marrow, there were no patients over 70 years of age. Major coexisting disease data were evaluated. Only 5 patients had no major coexisting disease and 4 of those 5 achieved a remission marrow. The study illustrates and underscores the following problems of remission induction in the elderly: (a) increased susceptibility to the stress of the induction period, with 6 patients (24%) dying before treatment day sixteen; (b) disease resistance to antileukemic therapy with persistent ANLL in 6 patients (24%), despite two induction courses; and (c) hematopoietic stem cell sensitivity in the elderly with marrow regeneration failure documented in 2 patients (8%) following induction. Acute nonlymphocytic leukemia in the elderly has a poor prognosis, and novel therapeutic approaches are warranted.     

Toxicity of high dose Ara-C in children and adolescents

The toxicity of high dose cytosine arabinoside (Ara-C) in 23 leukemic children aged 1.5 years to 16 years 11 months was evaluated. The group included 11 children with acute lymphoblastic leukemia (ALL), nine with acute nonlymphoblastic leukemia (ANLL), two with chronic myelocytic leukemia (CML) in blastic crisis, and one with Burkitt's lymphoma. Toxicity consisted of bone marrow suppression in all patients, with a mean nadir time of 11 days for platelets and granulocytes. All patients experienced nausea and vomiting; 12 of 23 had drug induced fever; seven of 23 conjunctivitis; five of 23 mucositis; four of 23 diarrhea, and one of 23 elevated transaminase with hyperbilirubinemia. Adverse reactions were mild and reversible in all patients. No serious neurologic toxicity was seen. The toxicity observed in four patients with prior cranial irradiation was not any different from nonirradiated patients. The only life-threatening effect was neutropenia, the consequences of which were generally well controlled with antibiotic therapy. While this agent was effective in induction of remission in AML patients resistant to standard doses of Ara-C, it had no significant effect in a very small number of patients with relapsed ALL and CML in blast crisis. Side effects of high dose Ara-C though relatively substantial are manageable enough to warrant wider scale efficacy trials of this agent in childhood leukemias and solid tumors.     

The clinical effect of low-dose Ara-C in patients with refractory acute nonlymphocytic leukemia and myelodysplastic syndrome

Twenty-one patients with refractory acute nonlymphocytic leukemia (ANLL) and myelodysplastic syndrome were treated with low-dose cytosine arabinoside (LDARC). LDARC was administered by subcutaneous injection every 12 hours at a dose of 10 mg/m2 (regimen A) or at a dose of 20 mg/m2 by continuous intravenous infusion (CIV) or continuous subcutaneous injection (CSC) (regimen B). Among 22 courses, two elderly patients with ANLL (M4 and M5) and one M4 patient with myelofibrosis obtained complete remission (CR) and three elderly patients with ANLL (one M1 and two M2) and one patient with ANLL developed from RAEB in transformation obtained partial remission (PR). The overall remission rate (CR + PR) was 31.8%. The CR durations were 2.5, 5 and 2 months, respectively. The plasma concentration of Ara-C determined in regimen B was 8.26 +/- 4.12 ng/ml. There was no difference in the plasma concentration of Ara-C between CIV and CSC. We consider that the major mode of action of LDARC lies in its cytotoxic effect, since all patients who obtained remission exhibited pancytopenia and bone marrow hypoplasia. However, in several patients, we observed transient monocytosis and granulocytosis which were considered to be suggestive evidence of differentiation of leukemia cells.     

Vindesine effect in myeloid leukemia

Summary Vindesine (VDS), a semisynthetic vinca alkaloid derivative, was given weekly at a dose of 3 mg/m² as single-agent chemotherapy to seven patients with chronic myeloid leukemia in blastic metamorphosis (CML/BM), and 12 patients with acute nonlymphocytic leukemia (ANLL). A substantial and rapid decrease of leukemic cells was obtained in 31 of 36 patients, and this was independent of cell phenotype and morphology. VDS may improve the results of polychemotherapy of ANLL, and is useful for palliative treatment of CML/BM.     

Low-dose cytosine arabinoside (Ara-C) therapy in the myelodysplastic syndromes and acute leukemia

Twenty-two patients with either a myelodysplastic syndrome or acute nonlymphocytic leukemia were treated with 10-21 days of subcutaneous cytosine arabinoside (Ara-C) (5-10 mg/m2 every 12 hours). There were two complete remissions and ten partial responses. Clinically significant improvements in peripheral blood counts persisted for periods of 8 weeks to greater than 21 weeks. Responses were seen even in patients who had previously proven refractory to conventional induction regimens or high-dose Ara-C. The toxicity, however, was considerable. Nearly all patients developed significant thrombocytopenia. Platelet and red cell transfusion support was required in many cases. The response to low-dose Ara-C therapy seen in patients with the leukemic and myelodysplastic disorders may be mediated by the induction of cell differentiation or a direct cytotoxic effect on a sensitive population of cells. Low-dose Ara-C may provide an alternative therapy in the selected patient with acute nonlymphocytic leukemia or a myelodysplastic syndrome.     

Intermediate-dose cytosine arabinoside and amsacrine. An effective regimen with low toxicity in refractory acute nonlymphocytic leukemia

Results of remission induction therapy in refractory acute nonlymphocytic leukemia (ANLL) has been improved since the introduction of high-dose cytosine arabinoside. However, the toxicity of these regimens attributes to an early death rate of about 20% to 30%. The authors treated 37 poor-risk patients with ANLL with intermediate-dose cytosine arabinoside and amsacrine for remission induction. One consolidation course and no maintenance therapy was given. Eleven of 19 patients with a first relapse entered complete remission (58%); ten of 15 patients in this group older than 50 years were complete responders (67%). Median duration of second remission was 8.2 months (range, 2-14). Three of 13 patients with primarily resistant disease had a complete remission (23%), but there was no response in five patients with a myeloid blastic phase of chronic myelogenous leukemia. Side effects of this remission induction regimen were mild; no cardiac, pulmonary, or central nervous system toxicity was observed. Five patients (14%) died during the remission induction phase, three from complications during aplasia and two from refractory leukemia.     

High-dose cytarabine treatment in acute leukemias and leukemic meningiosis: clinical aspects and pharmacokinetics

Clinical reports concerning the therapeutic effects of high dose Cytosine arabinoside (HD Ara-C) in meningeal leukemia are relatively rare. Pharmacokinetic studies, however, have indicated potentially effective concentrations of Ara-C in cerebrospinal fluid (CSF) during and after high-dose infusions of the drug given intravenously. In this report, the treatment results of HD Ara-C in 14 patients with refractory or relapsed acute leukemia are presented including those of 2 patients with meningeal leukemia. In these 2 patients as well as in 1 patient without central nervous system (CNS) leukemia, Ara-C and Ara-U concentrations in CSF and plasma were measured during a 6-day therapy with HD Ara-C (3 g/m2 q 12h 12 X). Ara-C and Ara-U levels were determined on Days 3 and 6 of therapy, each at the end of a 3-h i.v. infusion of the drug. In the 14 patients (8 with AML, 6 with ALL) treated, a total number of 17 treatment cycles were given for remission induction with doses of Ara-C ranging from 1-3 g/m2 q 12 h 6-12 X. A complete remission rate of 47% was achieved. The duration of remission ranged from 1 to 6 months. Of the 2 patients with CNS leukemia, 1 patient achieved complete remission both in CSF and in bone marrow, the other patient only in CSF. The mean concentration of Ara-C in CSF was 903 ng/ml with a ratio of 0.38 to that in plasma. Ara-C and Ara-U did not appear to accumulate in CSF or in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of phorbol esters on normal myeloid precursors and leukemic cells: basis for autologous bone marrow reconstitution in acute nonlymphocytic leukemia using phorbol ester-treated bone marrow from patients in remission

The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces macrophage-like differentiation of HL60 cells and cells from patients with acute nonlymphocytic leukemia (ANLL). We assessed the use of TPA as a means of eradicating residual leukemia from remission bone marrow prior to autologous bone marrow reconstitution. A 30-min incubation with TPA led to marked growth arrest in HL60 cells and in cells from most patients with acute myelogenous leukemia and acute myelomonocytic leukemia, whereas cells from most patients with acute promyelocytic leukemia and acute undifferentiated leukemia demonstrated a lesser degree of growth arrest. Freezing and thawing, a necessary step in autologous reconstitution, had no effect on the cessation of proliferation induced in HL60 or ANLL cells preincubated with TPA for 30 min. Virtually normal myeloid precursor growth occurred in normal or remission bone marrow cells preincubated with TPA and then frozen and thawed. Based on these observations, two patients with advanced ANLL in remission underwent marrow ablative therapy followed by autologous reconstitution using TPA-treated bone marrow. Limited normal hematopoiesis was reestablished in both patients, although they subsequently experienced leukemic relapse. These studies demonstrate that in ANLL cells, TPA stimulates growth arrest; in contrast, hematopoiesis is able to proceed both in vitro and in vivo.     

Abnormalities of chromosome 16 in association with acute myelomonocytic leukemia and dysplastic bone marrow eosinophils

Six patients with M4 acute myelomonocytic leukemia ( AMMoL ) were identified who had abnormalities of chromosome 16 in bone marrow cells. Five had a pericentric inversion, inv(16)( p13q22 ), and a sixth patient had a translocation, t(16;16)(p13.1;q22). Each of these six patients had bone marrow eosinophils that were abnormal in morphology on light and/or electron microscopy and by cytochemical stains. The eosinophils constituted 1%-24% of nucleated marrow cells. Of 61 acute nonlymphocytic leukemia (ANLL) patients, all those with AMMoL and abnormal bone marrow eosinophils had an inv(16) or a t(16;16). One other patient in this group had a rearrangement of chromosome 16 (with a break in the short arm at band p13); however, the ANLL type was M1 and no abnormal eosinophils were present. Four patients with ANLL types other than M4 had an increase in marrow eosinophils; three in whom the eosinophils appeared normal and one with ANLL-M2 and bizarre eosinophils morphologically distinct from those seen in AMMoL . Chromosome pair 16 was normal in the latter four patients. AMMoL with dysplastic bone marrow eosinophils appears to represent a unique clinicopathologic entity associated with several related abnormalities affecting 16q . The morphologic features of both blasts and eosinophils may be more important than the absolute number of eosinophils in the marrow in identifying this group of patients. This may have prognostic importance as five of six patients achieved complete remission with standard antileukemic therapy and are still alive.     

Phase I study of high-dose cytosine arabinoside and etoposide in patients with advanced malignancies

Summary Cytosine arabinsodie (ara-C) and etoposide (VP-16) display synergy in the laboratory. Twenty-six patients participated in a phase I study of high-dose ara-C in combination with VP-16. The dose of VP-16 was held constant at 50 mg/m² as an intermittent infusion over 33 h; escalating doses of ara-C were given as infusions during hours 9–12 and 21–24. Myelosuppression was the dose-limiting toxicity and occurred with doses considerably less than those expected from studies of the two drugs as single agents. The suggested initial doses for phase II trials with this schedule are 750 mg/m²×2 doses of ara-C and 50 mg/m² of VP-16. Nonhematologic toxicity was minimal; therefore, further dose escalation is feasible in patients in whom myelosuppression is acceptable.Supported in part by grants from the National Cancer Institute (CA-12197 and CA-09422) and the American Cancer Society CF-85-182     

Comparative trial of cytarabine and thioguanine in combination with amsacrine or daunorubicin in patients with untreated acute nonlymphocytic leukemia: results of the L-16M protocol

Ninety-six patients with de novo acute nonlymphocytic leukemia (ANLL) were randomized to receive either daunorubicin (50 mg/m2, IV) on days 1-3; cytarabine (Ara-C) (25 mg/m2, IV) bolus, followed by 160 mg/m2 as a continuous IV infusion daily for 5 days and 6-thioguanine (6-TG) (100 mg/m2 po) every 12 hr daily for 5 days (DAT); or amsacrine (190 mg/m2, IV) on days 1-3 with Ara-C and 6-TG at the above doses (AAT). Patients achieving complete remission (CR) then received two courses of consolidation therapy with the same combination that had induced remission but at slightly reduced total doses. Patients less than or equal to age 40 with an HLA-identical sibling donor underwent allogeneic transplantation, usually after consolidation therapy. The remaining patients were then randomized to receive either maintenance therapy (alternating cycles of vincristine/methotrexate, cyclophosphamide/6-TG, daunorubicin/hydroxyurea and Ara-C/6-TG) or no further treatment. Ninety-two patients were evaluable for response. Twenty-five of the 46 patients (54%) who received DAT and 32 of the 46 patients (70%) who received AAT achieved CR (p = 0.13). When patients were stratified by age, however, remission induction advantage with AAT became statistically significant (p = 0.03). Additionally, more patients achieved CR following one course of AAT than following one course of DAT (48% vs 28%, p = 0.03). Overall survival in the AAT group was improved as well (p = 0.01). Too few patients were randomized on the maintenance arm of the protocol to make interpretation meaningful. Non-hematologic toxicity was generally comparable in both arms. In conclusion, patients with de novo ANLL who received AAT had a higher remission incidence and slightly longer survival compared to patients who received DAT. Further investigation of this drug combination in untreated patients with ANLL is warranted.     

Phase I and Preliminary Phase II Studies on Aclacinomycin A in Patients with Acute Leukemia

Eight patients with acute nonlymphocytic leukemia (ANLL) andfive patients with acute lymphocytic leukemia were treated withaclacinomycin A. It was given daily by one-hour infusion indoses ranging from 0.33 to 0.70 mg/kg for seven to 20 days withoutother antileukemic agents. Two patients with ANLL achieved completeremission and one with ANLL achieved partial remission. Itsmajor toxic effects were myelosuppression and gastrointestinalsymptoms.     

Low-dose cytosine arabinoside in acute non-lymphoblastic leukemia

Eighteen previously untreated patients with acute non-lymphoblastic leukemia (ANLL) were treated with cytosine arabinoside (Ara-C) in low doses (10 mg/m2 every 12 hours) subcutaneously for 3 weeks. Complete remission (CR) was achieved in four patients (22.2%), and myelosuppression was observed in nearly all of them. Thrombocytopenia (20 X 10(3)/microliters) was pronounced in the third week of treatment and six patients (33.3%) needed platelet support. Contrary to earlier claims, our experience suggests that treatment with low-dose Ara-C is associated with significant cytopenias. Ara-C does not obviate the need for intensive supportive care and CR rates are no longer better. Low-dose Ara-C does not seem to be a choice in previously untreated ANLL patients who otherwise have a high probability of achieving a CR with standard multidrug chemotherapy protocols.     

Clinical and cell kinetic studies of the effects of the epipodophyllotoxin VP16-213 during therapy of refractory acute nonlymphocytic leukemia

Summary After induction failure or relapse on primary therapy, acute nonlymphocytic leukemia (ANLL) has historically been highly resistant to reinduction chemotherapy. In order to evaluate a new drug combination for this condition, 24 children and young adults with ANLL failing to attain first remission [5] or in relapse [19] were treated with VP16-213 plus 5-azacytidine (5AZ). Each patient had previously received combination chemotherapy with several antileukemic agents, including anthracyclines and cytosine arabinoside. These patients received 5-day courses of VP16-213 (200 mg/m²) daily x 3 days, followed immediately by 5AZ (300 mg/m²) daily x 2 days, repeated every 1–2 days until the bone marrow became hypoplastic. After 2–4 courses, 19 patients demonstrated an objective anti-leukemic effect by achieving marrow hipoplasia without evidence of blasts. Eleven of these (11/24=46%) achieved complete remission after a median time of 45 days from the initiation of therapy, making this combination of VP16-213 and 5AZ the most active regiment we have tested for ANLL in relapse. In order to determine the effects of VP16-213 on leukemic blast proliferation in vivo, serial bone marrow aspirates were studied in eight of these children. VP16-213 200 mg/m² IV was given daily x 3 days, and the mitotic index, labeling index and fractions of cells in G₀/G₁, S and G₂+M by flow cytometric measurement of DNA content were determined. Bone marrow samples were obtained before, 4 h and 20–24 h after the third dose in all patients, and 20–24 h after the third dose in six of the patients. The cytokinetic studies 4 h after the first dose of VP16-213 consistently showed a G₂ phase arrest of the bone marrow myeloblasts, indicating uptake of the drug and production of the same cell kinetic lesion which has been shown for cells treated with VP16-213 in vitro. In each patient studied 24 h after the third drug dose, there was a decrease in the fraction of cells in S phase compared to the pretreatment study (median decrease 56%, range 24–67%). The blast count per ml of marrow decreased by a median of 84% (range 72–91%) over this same interval. The observed decrease of fraction of cells in S phase after three doses of the drug suggests selective kill of cells in S compared to G₀/G₁. We conclude that the activity of VP16-213 against ANLL blasts can be demonstrated in vivo by the production of G₂ phase arrest and reduction of marrow blast count with findings consistent with increased cytotoxicity for cells in S and G₂ phase of the cell cycle. In addition, this intensive combination of VP16-213 and 5AZ has shown clear evidence of effectiveness in patients with refractory ANLL, and thus may be useful during initial therapy.Supported in part by Public Health Service grants CA-21765, CA-20180, and CA-15956 from the National Cancer Institute, National Institutes of Health, and Department of Health, Education and Welfare, and by ALSAC     

THA方案治疗急性非淋巴细胞白血病28例临床观察

目的观察THA方案治疗成人初治急性非淋巴细胞白血病28例的临床疗效.方法THA组(治疗组)28例,THP20mg/d+HHT4mg/d+Ara-c200mg/d,静脉滴注,7天为一疗程,疗程间歇14至21天.HA组(对照组)27例,HHT和Ara-c剂量、用法及疗程时间同治疗组.结果治疗组的总有效率92.3%(26/28),明显高于对照组的74%(20/27),P<0.05.结论THA方案治疗成人初治急性非淋巴细胞白血病疗效满意.     

High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup Study

Sixty-seven patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) who were considered to be poor candidates for treatment with cytosine arabinoside (ara-C)/anthracycline antibiotic therapy were treated with high-dose ara-C (HDara-C) remission induction therapy. Thirty-four of the 67 patients had a hematologic disorder before developing acute leukemia or had a history of exposure to marrow toxins, 23 patients were greater than 70 years old, and 10 patients had medical problems that were felt to be a contraindication to therapy with an anthracycline antibiotic. Forty-two percent of patients entered complete remission (CR), whereas 22% failed to enter remission because of persistent leukemia. Treatment was associated with substantial toxicity varying from nausea and vomiting to irreversible cerebellar toxicity. Thirty-four percent of patients died during therapy. Poor performance status, a low serum albumin, and a low platelet count were associated with death during remission induction therapy, whereas a high pretherapy leukemic cell mass and a large number of residual leukemic cells in the marrow after six days of therapy were associated with treatment failure due to persistent leukemia.