High‐dose methotrexate improves clinical outcome in children with acute lymphoblastic leukemia: St. Jude total therapy study X
Minnie AbromowitchJudith OchsChing‐Hon PuiDavid K. KalwinskyGaston K. RiveraDiane FaircloughA. Thomas LookH. Omar HustuSharon B. MurphyWilliam E. EvansGary V. DahlW. Paul Bowman
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Abstract High‐dose methotrexate (HDMTX, 1,000 mg/m 2 ) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard‐risk ALL: a leukocyte count < 100 × 10 9 /L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone‐vin‐cristine‐asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow‐up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC ( P = .049) or historical institutional control regimens ( P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar ( P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.Keywords:
Teniposide
Acute lymphocytic leukemia
Mercaptopurine
Regimen
Seventy-eight children with acute leukemia who had failed to undergo remission with prednisone therapy were treated with vincristine. Those who again failed to respond adequately were treated with combined 6-mercaptopurine and methotrexate. Seventy patients in the vincristine-treated group were evaluated and 42 of these (60.0%) had complete or good partial remission. Complete bone marrow remission was achieved in 33 of these subjects (47.1%). Thirty-three children were entered on the combined 6-mercaptopurine—methotrexate regimen, all but one of whom were evaluated. Fifteen of 29 patients having an adequate trial (51.7%) attained complete or good partial remissions in this group and complete marrow remission was seen in six (20.7%).
Mercaptopurine
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Spontaneous remission
Acute lymphocytic leukemia
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A total of 180 children with acute leukemia was randomized to one of two induction regimens: vincristine plus prednisone, or 6-mercaptopurine plus prednisone. Of 170 patients evaluable for induction therapy, a hematologic remission was achieved in 83% (72/87) on vincristine plus prednisone, and in 93% (77/83) on 6-mercaptopurine plus prednisone. When hematologic remission was achieved, patients were randomized to one of three maintenance schedules: 6-mercaptopurine alone, 6-mercaptopurine plus prednisone for 4 weeks every 3 months, or 6-mercaptopurine plus prednisone plus vincristine for 4 weeks every 3 months. The durations of hematologic remission were compared from the achievement of hematologic remission to bone marrow relapse. The survival data were presented as an overview of the effect of this initial therapy on duration of survival. There was no statistical difference between the two induction regimens. The most important finding in the comparison of the three maintenance schedules was that reinforcement of 6-mercaptopurine maintenance therapy with either prednisone or prednisone plus vincristine resulted in significantly longer durations of remission. Vincristine added to prednisone for reinforcement after induction of remission by vincristine plus prednisone did not increase the duration of hematologic remission or survival over prednisone reinforcement alone.
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Abstract Eighteen (72%) of 25 evaluable and previously untreated patients with adult acute lymphoblastic leukemia entered complete remission (CR) following induction therapy with Adriamycin, vincristine, and prednisone in a Southwest Oncology Group study. Remission maintenance therapy with methotrexate and 6‐mercaptopurine resulted in a median duration of CR of 10.2 months. The addition of Adriamycin to prednisone and vincristine may be beneficial in slow responders or nonresponders to these two drugs and in patients with initially high peripheral blood blast counts.
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Acute lymphocytic leukemia
Induction chemotherapy
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The case of a patient with Charcot-Marie-Tooth syndrome and diffuse large-cell lymphoma, in whom a severe generalized weakness developed after the intravenous administration of vincristine (2 mg) during combination chemotherapy, is reported. Spontaneous resolution of the severe weakness occurred when teniposide was substituted for vincristine in the chemotherapy regimen.
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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).
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Seventeen children with acute myelocytic leukemia were treated with a combination of 6-azauridine, 6-mercaptopurine, and vincristine. Twelve attained complete bone marrow remission, and 2 achieved good partial remissions. For maintenance therapy, patients who attained remission were randomized into 2 groups: one received 6-mercaptopurine alone; the other received a combination of 6-mercaptopurine, 6-azauridine, and vincristine. The median duration of hematologic remission in these groups was 7 and 6 months, respectively. Meningeal leukemia developed in 8 of 15 patients. The overall median survival time was 8 months; for those who attained remission it was 10.5 months. The combination of 6-azauridine, 6-mercaptopurine, and vincristine was effective for remission induction of acute myelocytic leukemia in children.
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Neuroblastoma is one of common solid tumors in children. The major treatment modality for neuroblastoma (NB) is chemotherapy combined with operation or irradiation. But the survival rate is still low for advanced patients. Further study is needed for improving cure rate of neuroblastoma. This study was designed to evaluate the efficacy of children with neuroblastoma treated in Cancer Center, Sun Yat-sen University, and to explore reasonable therapy strategy.The clinical data of 30 children with NB aged from 7 months to 13 years were analyzed retrospectively. These patients were treated with chemotherapy plus operation or radiation. The stages were as follow: II, n=2; III, n=12; IV, n=15; IVS, n=1. Chemotherapy regimen was CAV (cyclophosphamide 750 mg/m(2) d1, vincristine 1.5 mg/m(2), d1, Adriamycin 50 mg/m(2) d1) alternated with EP (teniposide or etoposide 60 mg/m(2) d1-d5, cisplatin 20 mg/m(2) d1-d5). The resection would be done after 4 to 6 cycles of chemotherapy if possible. The chemotherapy or radiation would be done after resection. If operation was not available, the patients continued to receive the chemotherapy. The patients with stage IVS only received cyclophosphamide plus vincristine.Among 30 patients, 2 cases achieved complete remission (CR 6.7%) by chemotherapy alone; 21 cases achieved partial remission (PR 70%); 6 cases showed no change (NC 20%); 1 cases showed progressive diseases (3.3%). Overall response rate (CR+PR) were 76.7% by chemotherapy alone. Of 21 PR patients, 9 cases could be resected;4 cases achieved CR after operation; 1 case achieved CR after radiation. The 2-year overall survival rate was 47.8% for all patients; 100% for Stage II/IVS, 34% for stage III, 22% for stage IV, respectively. Grade III/IV hematological toxicity occurred in 41.2% of the CAV regimen and 26.6% of the EP regimen.Chemotherapy plus operation or radiation is the major treatment for neuroblastoma. CAV/EP alternative chemotherapy is the active regimen for NB. The toxicity is tolerable. Advance stage NB needs further study for improving the prognosis.
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Combination chemotherapy
Chemotherapy regimen
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A high incidence of severe peripheral neuropathy occurred during the pilot study of a new regimen for the treatment of non-Hodgkin's lymphoma. The clinically observed incidence and severity of vincristine-induced peripheral neuropathy was considerably enhanced by the sequential use of vincristine and teniposide in this combination chemotherapy.
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Two hundred forty-seven patients with non-Hodgkin's lymphoma were randomized to receive doxorubicin, cyclophosphamide, and prednisolone in combination with vincristine (ACVP) or teniposide (ACTP) or both vincristine and teniposide (ACTVP). ACVP produced 44% complete remissions (CRs) and 32% partial remissions (PRs), whereas ACTP produced 46% CRs and 33% PRs and ACTVP produced 47% CRs and 36% PRs. Survival and relapse-free survival were also comparable for the three arms. The majority (59%) of patients had diffuse large cell lymphoma. Within this group, CR was achieved in 52% and no significant difference was observed in the response rates, survival, or relapse-free survival for the three treatment arms. Toxic effects occurred with equivalent frequency in the three regimens, except for neurotoxicity and myelosuppression. Moderate to severe neurotoxicity occurred in 20% of ACTVP-treated patients and in 8% of ACVP-treated patients but was not seen in any of the ACTP-treated patients (P = 0.0004). Severe myelosuppression occurred in 27% of ACTVP-treated patients and in 22% of ACTP-treated patients but only in 8% of ACVP-treated patients (P = 0.02), indicating an increased risk of myelosuppression for the combinations including teniposide. These results confirm our previous findings that teniposide can replace vincristine in the treatment of non-Hodgkin's lymphoma, with freedom from neurotoxicity and comparable survival and response rates. However, the combined use of teniposide and vincristine in the schedule as described has not increased response rates or survival but has instead added to neurotoxicity.
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