Genetic abnormalities associated with the t(12;21) and their impact in the outcome of 56 patients with B-precursor acute lymphoblastic leukemia.

The ETV6/RUNX1 rearrangement is found in 20-30% of children with B-cell precursor acute lymphoblastic leukemia and is associated with a good outcome. To determine the cytogenetic and molecular abnormalities associated with the ETV6/RUNX1 rearrangement and the influence of this rearrangement in patients' evolution, we analyzed the molecular cytogenetic profiles of 56 children with this rearrangement and B-cell precursor acute lymphoblastic leukemia. Secondary changes detected with conventional cytogenetics and with fluorescence in situ hybridization were found in 71.4% of cases, the most frequent being the loss of the normal ETV6 allele, 12p aberrations, duplication of the fusion gene, and trisomy 21, as in replicating the results of previous studies. In this preliminary series, with a mean follow-up of 69.3 months, secondary abnormalities did not influence patients' outcome. It seems therefore that the prognostic value of the t(12;21) does not vary and that ETV6/RUNX1 rearrangement is an independent indicator of good prognosis.

Allogeneic and autologous bone marrow transplantation in AML in first remission. The Spanish experience.

From 1983 to 1994 two types of trials were performed. Between 1983 and 1987 a modified VAPA protocol (post-remission therapy with intensive sequential blocks for 12-16 months) was given to 40 patients from two institutions. CR was attained in 75% and 5-year EFS was 35%. In 1988 a post-remission protocol based on intensification chemotherapy (two high-dose Ara C treatments combined with mitoxantrone in the first and amsacrine in the second) followed by BMT was initiated. Remission induction was DAE combination (1 or 2). Patients in CR or PR with HLA-compatible donor received an allogeneic transplant (al-BMT) and those without an autologous transplant (ABMT) with "purged" marrow. Pre-BMT therapy was fractionated TBI and CYCLO in patients over 3 years and Busulfan + CYCLO + VP-16 in those under 3. Between April '88 and December '94, 51 patients (aged 3 months to 15 years) were enrolled. 80% attained CR, 14% were failures or partial responses and 6% died before the 30th day. During the intensification phase, 5 patients attained CR and one relapsed and died. 47 patients (45 in CR and 2 in PR) proceeded to the BMT phase. 16 patients (14 in CR and 2 in PR) received al-BMT and 31 (all in CR) ABMT. Both group characteristics were comparable.

AML1 amplification in a child with acute lymphoblastic leukemia.

We report a case of de novo acute lymphoblastic leukemia with tandem amplification of the AML1 gene located in a chromosome marker that originated from chromosome 21 and a long event-free survival.

ETV6/RUNX1 rearrangement in childhood B-precursor acute lymphoblastic leukemia with normal karyotypes or without cytogenetic results.

The ETV6/RUNX1 rearrangement (also known as TEL/AML1) was evaluated in 39 children with B-precursor acute lymphoblastic leukemia (ALL) who had a normal karyotype or lack of mitoses. Forty-one point six percent of patients with normal karyotypes and 66.6% of patients without mitoses presented with the ETV6/RUNX1 rearrangement. In addition to this rearrangement, eight patients showed loss of the normal ETV6 allele; of three patients without mitoses, two showed an extra signal of the RUNX1 gene and the third showed the fusion gene duplicated and loss of the normal ETV6 allele. One patient without the ETV6/RUNX1 rearrangement and without mitoses showed two extra signals of the RUNX1 gene.

[Evaluation of the efficacy of chelation therapy with deferoxamine in patients with thalassemia major]. / Valoración de la eficacia del tratamiento quelante con desferrioxamina en pacientes afectados de talasemia maior.

BACKGROUND: The current treatment of thalassaemia maior (TM) is based on a hypertransfusion regimen, with deferoxamine (DFO) chelation therapy to minimize the consequences of iron overload. To evaluate the long-term efficacy of chelation therapy, a group of 9 patients treated for a period of 9 years was studied. METHODS: The mean age of patients at the beginning of chelation therapy was 7 years. The age range at the moment of the study was 11 to 21 years. Pre-transfusion haemoglobin values were maintained above 10 gr/dl. DFO was administered by 10-hour sub-cutaneous infusion, 5 or 6 days a week at a dose of 40 mg/kg. Different iron overload parameters were considered, with special attention to cardiac function, growth and endocrinologic development. Signs of DFO toxicity were also studied. RESULTS: The final mean iron elimination rate was 72.6%. One patient died from cardiac haemosiderosis. Eight of the 9 patients showed significant growth impairment and 7, who have attained puberal or post-puberal age, suffer from one or more endocrinologic disorders (6 hypogonadism, 2 diabetes mellitus, 2 hypothyroidism and 1 hypoparathyroidism). The only toxic effect observed was transient crystalline opacity in 2 patients. CONCLUSIONS: Despite the early initiation of chelation therapy, TM patients receiving hypertransfusion regimen showed iron overload, with myocardiopathy, growth retardation and several endocrinologic disorders, mainly secondary hypogonadism, glucose metabolism disfunction and primary hypothyroidism.

Disseminated fusariosis.

A 7-year-old boy with T cell acute lymphoblastic leukemia developed disseminated hyalohyphomycosis due to Fusarium solani. The clinical features included fever, severe myalgia, documented fungemia with F. solani, an ecthyma gangrenosum-like lesion next to a peripheral venous catheter, and disseminated pustules. Severe neutropenia due to chemotherapy was the most relevant risk factor. Histopathologic study of the ecthyma gangrenosum-like lesion, as well as pustular lesions, revealed epidermal necrosis and an inflammatory infiltrate in the upper dermis, with numerous septate hyphae demonstrated by periodic acid-Schiff stain. Clinical resolution was achieved with granulocyte colony-stimulating factor and amphotericin B administration. Our case suggests that the peripheral venous access was probably the portal of entry of the fungus.

Results of intensive chemotherapy in children with juvenile chronic myelomonocytic leukemia: a pilot study.

BACKGROUND: The use of chemotherapy in juvenile chronic myelomonocytic leukemia (J-CMML) has not generally been successful. Our previous experience in 11 patients demonstrated that chemotherapy with low doses of daunorubicin or cytarabine resulted in a 90% fatal outcome and a median survival rate of only 7 months. PROCEDURE AND RESULTS: Between 1985 and 1997, six children (five boys and one girl) aged 3-67 months (median age: 20.5) were diagnosed with J-CMML and underwent intensive combination chemotherapy similar to that used for acute myeloblastic leukemia. Two patients with high-risk factors developed progressive disease with fatal outcome at 5 and 18 months postdiagnosis, respectively. However, four patients without poor prognosis indices responded and were alive 145, 82, 51, and 6 months after diagnosis. Overall survival in this small series at 7 years from diagnosis is 60% (CI: 17-100). CONCLUSIONS: The use of intensive combination chemotherapy in children with J-CMML can result in long-term survival in some patients.

Childhood calcinosis cutis.

Calcinosis cutis, an uncommon disorder characterized by hydroxyapatite crystals of calcium phosphate deposited in the skin, has been described infrequently in childhood. Classically, it is divided into dystrophic, metastatic, and idiopathic types. We report an 8-year-old girl with hyperphosphatemia secondary to a tumor lysis syndrome, who developed a localized soft tissue calcification over a previous lesion of ecthyma gangrenosum. Intravenous infusion of calcium gluconate was probably the precipitating factor. Our case illustrates that several etiopathogenic mechanisms may be simultaneously involved in calcinosis cutis.

Early and delayed consolidation chemotherapy significantly improves the outcome of children with intermediate risk acute lymphoblastic leukemia. Final results of the prospective randomized PETHEMA ALL-89 TRIAL.

BACKGROUND AND OBJECTIVES: To evaluate the impact of early and delayed consolidation chemotherapy on the outcome of children with acute lymphoblastic leukemia (ALL) stratified according to risk groups. DESIGN AND METHODS: From 1989 to 1994, 195 children (< or = 15 years old) diagnosed as having ALL (ALL-L3 excluded) in 15 Spanish hospitals entered the prospective, randomized PETHEMA ALL-89 trial. Patients were stratified into low-risk (LR), intermediate-risk (IR) and high-risk (HR) groups according to their initial features and the rate of response to induction therapy. LR-ALL patients were randomized to receive or not early consolidation chemotherapy (C-1). After receiving C-1, IR patients were randomized to receive or not delayed consolidation chemotherapy (C-2). HR patients received C-1 and C-2 chemotherapy. Standard maintenance chemotherapy was administered to all patients for 2 years. High doses of intravenous methotrexate and 12 triple intrathecal doses were given as prophylaxis against central nervous system (CNS) disease. RESULTS: The mean (and standard deviation) age was 6 (4) years and 120 patients were males. Fourteen patients had early pre-B-ALL, 149 common or pre-B-ALL, and 32 T-ALL. Complete remission (CR) was attained in 189 patients (97%), 11 of whom (6%) had a slow response. Risk group stratification after CR was: LR 89, IR 50 and HR 56 patients (including a subset of 26 patients at very high risk). Ten-year event-free survival (EFS) and overall survival (OS) probabilities for the whole series were 58% (95% CI: 52-64%) and 69% (61-77), respectively, with a median follow-up of 8.7 years. Dividing the patients according to risk group, the 10-year EFS and OS probabilities in the LR group were 71% (63-79) and 86% (80-92), respectively; in the IR group 69% (57-81) and 76% (64-88), respectively, and in the HR group 30% (18-42) and 44% (32-57), respectively. For LR patients receiving C-1, EFS and OS were 79% (57-92) and 90% (82-98), respectively, versus 62% (48-76) and 66% (51-81) in patients not receiving C-1 (p= 0.06). For IR patients, EFS and OS were significantly improved in those receiving early and delayed consolidation (EFS 87% (74-88) vs. 52% (41-70), and OS 92% (87-97) vs. 61% (51-71)(p=0.036). Prognostic factors for EFS identified in multivariable analyses were: age >10 years in the LR group (OR 3.5, 95% CI 1.3-9.5, p=0.01), and treatment with C-2 in IR patients (OR 5.0, 95% CI 1.4-17.8, p=0.01). The CNS relapse rate was 4% for all the series (including the HR subset). Tolerance to treatment was good. INTERPRETATION AND CONCLUSIONS: In this study, early consolidation seemed to improve the prognosis of children with LR-ALL, but differences in EFS were not significant. Delayed consolidation had a favorable influence on the outcome of IR-ALL. CNS preventive treatment without cranial irradiation was effective in all the groups of ALL patients.