Comparison of central nervous system prophylaxis with cranial radiation and intrathecal methotrexate versus intrathecal methotrexate alone in acute lymphoblastic leukemia

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) prophylaxis with cranial irradiation plus 5 doses of intrathecal methotrexate (i.t. MTX) reduces the incidence of CNS relapse to 7%-15%. However, increased evidence of CNS delayed toxicity started to be recognized as CT scan abnormalities and neuropsychologic alterations, mainly in children. Two questions were analyzed in the present report: (1) Will further doses of i.t. methotrexate and dexamethasone (i.t. MTX- DMT) decrease the incidence of CNS relapse in patients treated early in remission with cranium irradiation plus i.t. MTX-DMT even more? (2) Is i.t. MTX-DMT given during induction and maintenance equally as effective as cranium irradiation plus i.t. MTX-DMT? A randomized study was designed to answer the first question. Incidence of primary CNS relapse in i.t. MTX-DMT-treated patients with a WBC count less than 50,000 was 11% (15 of 135 patients) and was 11% (17 of 150) in the untreated group. In patients with a WBC count greater than 50,000, it was 16% (6/37) in the treated group and 19% (6/31) in the control group. No difference was observed according to treatment in both prognostic groups. Patients in this study were retrospectively compared with a consecutive protocol in which patients received 3 doses of i.t. MTX-DMT alone during induction plus 3 doses weekly during the first month of remission and every 3 mo thereafter. The incidence of primary CNS leukemia at 60 mo in patients with a WBC count less than 50,000 was 20% in the irradiated group and 32% in the group with i.t. MTX-DMT alone. This difference was not significant. However, the relapse-free survival at 60 mo was 26% and 41%, respectively, (p less than 0.0005). The incidence of primary CNS relapse in patients with a WBC count more than 50,000 at 48 mo was 28% in the irradiated group and 42% in the nonirradiated group. The difference was not significant. The duration of complete remission was similar, remaining at 15% and 16% of patients disease-free at 48 mo, respectively. We conclude that (A) after cranial irradiation plus i.t. MTX-DMT X 5, the use of additional doses of i.t. MTX-DMT is not of further benefit in preventing CNS relapse; (B) the use of i.t. MTX-DMT alone compares similarly with cranial irradiation plus i.t. MTX-DMT in the incidence of CNS relapse; and (C) relapse-free survival and survival in patients with a WBC count less than 50,000 were significantly longer in those without cranial irradiation.     

High-dose retinol in children with acute myelogenous leukemia in remission

In a single-institution study, 23 consecutive children with acute myeloid leukemia (AML) have been treated with a protocol including doxorubicin, cytarabine and 6-thioguanine as induction therapy, followed by four courses of high-dose cytarabine as consolidation. Total duration of chemotherapy was 6-8 months from diagnosis. 21 out of the 23 children achieved complete remission. During remission, the children received 52 mumol (50,000 I.U.) retinol as retinyl palmitate per square meter daily. 14 of the 21 children are still in their first remission with a mean observation time of 36 months. In our study retinyl ester given in doses up to 30 times the recommended daily allowances has not caused any clinical or biochemical side effect for up to 4 yr of therapy.     

Marrow transplantation for children with acute lymphoblastic leukemia in second remission

Fifty-seven children between the ages of 3 and 17 years with acute lymphoblastic leukemia (ALL) in chemotherapy-induced second bone marrow remission were given cyclophosphamide, total body irradiation, and bone marrow transplants from HLA-matched donors. Sixteen died of transplant- related complications. Eighteen relapsed between 56 and 833 days after transplantation, and 16 died of leukemia. Two survive in remission off treatment following chemotherapy. Twenty-three survive in continuous remission from 1.4 to 10.4 years after transplantation and the actuarial analysis shows disease-free survival of 40% with a plateau extending from 2.5 to 10.4 years.     

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.     

Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission

Allogeneic bone marrow transplantation (BMT) may be curative for more patients than chemotherapy for the child with relapsed acute lymphoblastic leukemia. This study reviewed the outcomes of 363 children with acute lymphoblastic leukemia in second remission who received unrelated donor BMT from 1988 to 2000 in order to define prognostic factors that affect leukemia-free survival (LFS). Median patient age was 9 years (range, 0-19 years), and median follow-up 29 was months (range, 0-125 months). The median duration of first remission was 24 months (range, 0-109 months). Prognostic factors, including age, duration of first remission, HLA matching, and graft-versus-host (GVH) disease, were analyzed using both univariate and multivariate analyses. Overall survival was 38%, and LFS was 36% at 5 years. LFS was significantly worse for patients 15 years or older (log-rank, P =.009). HLA matching was associated with improved LFS. Acute GVH disease developed in 71%, with 29% having grades III-IV. The incidence of chronic GVH disease was 39% for patients who survived more than 80 days and was significantly higher for female patients receiving marrow from female donors (P =.0009). Transplantation-related mortality was 42% and was associated with HLA mismatches, age 15 years and older, and first remission less than 12 months. The 5-year estimate for relapse was 22%, with first remission at least 6 months associated with a lower risk. Results of unrelated donor BMT appear similar to multi-institutional studies of matched related donor BMT, and this approach appears to be curative for many patients. However, innovative approaches are needed for patients with initial remissions of less than 6 months and for older teenagers.     

High remission rate in acute myeloblastic leukemia in children treated with high-dose methylprednisolone.

Since the differentiating effect of high-dose methylprednisolone (HDMP) on myeloid leukemic cells has been shown in one of our patients with acute myeloblastic leukemia (AML-M4), 27 previously untreated children with AML were given HDMP (20-30 mg/kg per day) combined with cytosine arabinoside (Ara-C; 3 mg/kg) for the first 2 weeks of induction therapy. Marked clinical improvement was observed in all patients with the exception of one who died within 24 hours of the treatment. Enlarged liver and spleen (greater than 5 cm) became nonpalpable in 3 (37%) out of 8 and 5 (100%) out of 5 patients, respectively, and bone marrow blasts decreased below 5% in 7 patients (27%) within 2 wk of HDMP and Ara-C treatment. Adriamycin (1 mg/kg) was added 2 wk after initiation of induction therapy. Twenty-two (84.6%) of the 26 patients achieved complete remission, 3 (11.5%) had partial remission and no response was obtained in one. Treatment was well tolerated. The addition of HDMP as a differentiating and/or cytolytic agent to conventional anti-leukemic chemotherapy increased the complete remission rate and prolonged the duration of remission of our AML patients.     

High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia

High-dose methotrexate (MTX) has been extensively used for treatment of acute lymphoblastic leukemia (ALL). To determine the optimal dose of MTX in childhood relapsed ALL, the ALL Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group performed this prospective randomized study. A total of 269 children with a first early/late isolated (n = 156) or combined (n = 68) bone marrow or any isolated extramedullary relapse (n = 45) of precursor B-cell (PBC) ALL (excluding very early marrow relapse within 18 months after initial diagnosis) were registered at the ALL-REZ BFM90 trial and randomized to receive methotrexate infusions at either 1 g/m(2) over 36 hours (intermediate dose, ID) or 5 g/m(2) over 24 hours (high dose, HD) during 6 (or 4) intensive polychemotherapy courses. Intensive induction/consolidation therapy was followed by cranial irradiation, and by conventional-dose maintenance therapy. Fifty-five children received stem-cell transplants. At a median follow-up of 14.1 years, the 10-year event-free survival probability was .36 (+/- .04) for the ID group (n = 141), and .38 (+/- .04) for the HD group (n = 128, P = .919). The 2 groups did not differ in terms of prognostic factors and other therapeutic parameters. In conclusion, methotrexate infusions at 5 g/m(2) per 24 hours, compared with 1 g/m(2) per 36 hours, are not associated with increased disease control in relapsed childhood PBC acute lymphoblastic leukemia.     

Recovery of megakaryocytopoiesis in vitro in children with acute lymphoblastic leukemia during induction of remission

In children with acute lymphoblastic leukemia (ALL), megakaryocytopoiesis was investigated in vitro by the semisolid agar culture technique. In untreated ALL the median number of committed megakaryocyte progenitor cells (CFU-Mk) in the bone marrow was 2 (range less than 0.1-8) per 10(5) bone marrow cells instead of 30 (range 14-93) in controls, the impairment being dependent on the degree of leukemic bone marrow infiltration. However, if the number of CFU-Mk was related to residual nonleukemic bone marrow cells only, two-thirds of the children investigated had a frequency of CFU-Mk within the normal range. After 2 weeks of induction therapy the majority of the children had a low number of CFU-Mk in the bone marrow (median 6, range 0.5-40), a fact that could no longer be explained by a dilution of CFU-Mk by leukemic cells. After 4 weeks of chemotherapy (day 29) the frequency of CFU-Mk had risen to 18 (range 3-67) per 10(5) bone marrow cells, a value still significantly (p less than 0.01) below the normal range. In contrast to the changes in the number of CFU-Mk the median cell number per megakaryocyte colony remained constant during induction of remission. After cessation of long-term chemotherapy all children investigated had a normal number of CFU-Mk, suggesting that no permanent chemotherapy-related damage to committed megakaryocyte progenitor cells was induced.     

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.     

Spontaneous remission of acute myeloid leukemia

Summary A patient with acute myelomonocytic leukemia who experienced a spontaneous remission, is reported. He had precedent and concurrent bacterial infections as most of these cases described. Low peripheral WBC and myeloblasts, Auer-rod positive blasts, bone marrow eosinophilia with atypical eosinophils, and a partial deletion of chromosome 16 were favorable prognostic parameters. A brief review of the literature and possible explanations for the regulation of granulopoiesis are presented.     

High-dose methotrexate in acute lymphocytic leukemia.

A pharmacokinetic study of methotrexate (MTX) was performed in 60 patients who received high-dose MTX at 500 mg/m2 infused over 24 hours. MTX levels reached 1.2 X 10(-7) M in the cerebrospinal fluid (CSF) within 10 minutes and remained constant at that level for 24 hours. Forty of these 60 patients were children with acute lymphocytic leukemia. In these 40 patients, simultaneous intrathecal MTX was given along with high-dose MTX. The resultant CSF levels (lumbar area) were higher than those obtained with either high-dose MTX alone or simultaneous intrathecal MTX alone. To date, there have been one systemic and one central nervous system relapse in these 40 children, and the treatment program appears safe to administer.     

Spontaneous complete remission in a patient with acute monocytic leukemia

A spontaneous complete remission was observed in a 47-year-old female with acute monocytic leukemia. Resolution of all abnormalities, including systemic papule, thrombocytopenia, increased numbers of immature monocytoid cells in the peripheral blood and bone marrow, elevation of serum lysozyme and LDH, and trisomy 8 on chromosome analysis, occurred without any treatment. Moreover, the remission was not associated with any infection or blood transfusion, and is persistent for 12-month duration.