mercaptopurine and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

Thrombocytopenia may develop in patients with acute lymphoblastic leukemia (ALL) due to myelosuppression of chemotherapy or relapse. Here we report a pediatric patient with ALL whose platelet counts decreased at the 102nd week of maintenance treatment. Thrombocytopenia was refractory to platelet infusions and bone marrow aspiration revealed remission status for ALL along with increased megakaryocytes. The cessation of chemotherapy for 2 weeks caused no increase in thrombocyte counts. The viral serology was unrevealing. A diagnosis of immune thrombocytopenic purpura (ITP) was established. After administration of intravenous immunoglobulin, the thrombocytopenia resolved. When thrombocytopenia occurs in patients with ALL in remission, ITP should be kept in mind after exclusion of the more common etiologies.. Akut lenfoblastik lösemi (ALL) tanılı hastalarda trombositopeni, kemoterapiye ikincil kemik iliği baskılanması veya hastalığın relapsı sonucu gelişebilir. Olgumuz ALL idame tedavisinin 102. haftasında gelişen trombositopeni nedeniyle incelendiği sırada immün trombositopenik purpura (İTP) tanısı almıştır. Trombositopeninin trombosit infüzyonuna rağmen dirençli olması üzerine yapılan kemik iliği aspirasyonunda löseminin remisyonda olduğu ve megakaryositlerin artmış olduğu görüldü. Kemoterapiye iki hafta ara verilmesine rağmen trombosit sayısında artma olmadı. Viral seroloji sonuçları aktif enfeksiyon ile uyumlu değildi. Hastaya İTP tanısı konuldu. İntravenöz immünoglobulin tedavisi ile trombositopeni düzeldi. Remisyondaki ALL hastalarında trombositopeni geliştiğinde, daha sık görülen nedenler dışlandıktan sonra İTP de akılda bulundurulmalıdır.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Dexamethasone; Diagnosis, Differential; Female; Humans; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Platelet Count; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Purpura, Thrombocytopenic, Idiopathic; Vincristine

Secondary malignancies are an important cause of morbidity and mortality in childhood cancer survivors. Salivary gland tumors account for about 6% of the second cancers. The majority of these are mucoepidermoid carcinomas (MEC) of the parotid gland. We report the clinical and pathological features of a rarer histological type, acinic cell carcinoma (ACC), in a childhood acute lymphoblastic leukemia (ALL) survivor. The behavior of secondary ACC appears similar to primary tumor and similar treatment may be adopted. Early recognition and complete resection is important for achieving a good outcome. Careful monitoring for recurrence or a third malignancy is needed.

Topics: Adenoma, Sweat Gland; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Carcinoma, Acinar Cell; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Epirubicin; Etoposide; Follow-Up Studies; Humans; Male; Mercaptopurine; Methotrexate; Neoplasms, Radiation-Induced; Neoplasms, Second Primary; Parotid Neoplasms; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Recurrence; Remission Induction; Survivors; Sweat Gland Neoplasms; Vincristine; Whole-Body Irradiation

Acute myelofibrosis (AMF), as defined by an acute panmyelopathy associated with marked megakaryocytic hyperplasia and marrow fibrosis, appears to be a stem cell disorder. Even though it is most difficult to distinguish from various myeloproliferative and myelodysplastic disorders as well as acute myelogenous leukemia, it has rarely been reported to terminate as acute lymphoblastic leukemia (ALL). Only five cases have been reported in the literature; two from the pediatric literature and only three from the adult literature. Of the three adult cases, two were defined by light microscopy alone. Among the cases with follow-up (3/5), all died within 2 weeks to 2 months of diagnosis. We report an additional case in an adult; the ALL was defined by morphology, flow cytometric immunophenotyping, and cytogenetic analysis. The interval from diagnosis of AMF to ALL was 3 months. Our patient was treated with standard therapy for ALL, was in complete remission at last follow-up (3 months off maintenance therapy), and represents the only reported case who attained a complete remission. There are too few cases to determine the prognostic significance of termination of AMF in an acute leukemia of lymphoid origin vs. myeloid origin.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blast Crisis; Bone Marrow; Chromosome Deletion; Chromosomes, Human, Pair 5; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Disease Progression; Flow Cytometry; Humans; Immunophenotyping; Male; Mercaptopurine; Methotrexate; Neoplastic Stem Cells; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Primary Myelofibrosis; Remission Induction; Vincristine

This study was conducted as the first clinical trial by Japan Association of Childhood Leukemia Study to improve the outcome of B-cell acute lymphoblastic leukemia and explore a less toxic reinduction block.. From 1997 to 2002, 563 patients with B-cell acute lymphoblastic leukemia aged 1 to 15 years were enrolled. The patients were assigned into 4 risk groups (standard, intermediate, high, or extremely high risk) and treated with regimens intensified according to the risk. Two randomized trials were conducted to compare 2 regimens with and without a 3-week reinduction therapy in the standard-risk group, and to compare the efficacy of pirarubicin with daunorubicin in the intermediate-risk and high-risk groups. Prophylactic cranial irradiation was restricted in patients with high or extremely high risk.. The event-free survival (EFS) rate at 10 years for all patients was 77.0%. Those in the standard-risk to extremely high-risk groups were 79.3%, 72.5%, 71.7%, and 66.3%, respectively. The 15-week induction/consolidation not followed by reinduction produced 76.4% of the EFS at 10 years comparable with the regimen with reinduction therapy. Pirarubicin at 25 mg/m administered 11 times throughout the treatment produced the EFS comparable with daunorubicin at 30 mg/m.. The trial produced high survival rates in NCI-HR patients, although the outcomes in NCI-SR patients were not satisfactory possibly due to less intensive central nervous system-directed therapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Consolidation Chemotherapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Humans; Hydrocortisone; Infant; Japan; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Risk; Survival Rate; Treatment Outcome; Vincristine

In the ALL-BFM studies for treatment of acute lymphoblastic leukemia, reduction of leukemic blasts in peripheral blood after a one-week prednisone pre-phase - the so-called prednisone response - has been used for risk stratification since the 1980s and has been one of the most relevant factors for identification of high-risk patients. In the trial ALL-BFM 95, early cytomorphological marrow response on day 15 of induction therapy was prospectively evaluated and its prognostic value was analyzed in comparison to the prednisone response and other established prognostic factors.. Compared to prednisone response, day 15 marrow response was superior in outcome prediction - yet with differential effect depending on blast lineage. Outcome was poor in T cell leukemia patients with prednisone poor-response independent of day 15 marrow response, whereas among patients with prednisone good-response different risk groups could be identified by day 15 marrow response. In contrast, prednisone response lost prognostic significance in precursor B cell leukemia when stratified by day 15 marrow response.. Selective addition of day 15 marrow response to conventional stratification criteria applied on ALL-BFM 95 may significantly improve risk-adapted treatment delivery. Even though cutting-edge trial risk stratification is meanwhile dominated by minimal residual disease evaluation, an improved conventional risk assessment, as presented here, could be of great importance to countries lacking the technical and/or financial resources associated with the application of minimal residual disease analysis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biopsy; Bone Marrow; Cell Lineage; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Infant; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Patient Outcome Assessment; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Prospective Studies; Remission Induction; Risk Assessment; Vincristine

Flow cytometry immunophenotyping (FCM) is an undispensable tool for the diagnosis and for the treatment stratification of childhood acute lymphoblastic leukemia. The correlation of the EGIL-classification with prognostically relevant parameters like age, prednisone response and risk group is analyzed.. Between March 2000 and June 2009 12 patients less than 1 year of age, 1 836 patients with 1 to less than 6 years, 620 patients with 6 to less than 10 years, 615 patients with 10 to less than 15 years and 275 patients with 15 to less than 19 years were analyzed with a comprehensive 4-color antibody panel and classified according to the EGIL recommendations.. Bone marrow or peripheral blood mononuclear cells were isolated by ficoll gradient centrifugation, washed and stained with fluorochrome-conjugated antigen-specific monoclonal antibodies. Cell preparations were acquired and analyzed on a flow cytometer.. Centralized FCM was performed for 2 775 patients (82.6%) with B-cell precursor acute lymphoblastic leukemia, 493 patients (14.7%) with T-cell acute lymphoblastic leukemia and 90 patients (2,7%) with biphenotypic acute leukemia. There was a slight overall predominance of male (56.1%) over female (43.9%) patients. Patients with B-cell precursor ALL had a slightly more favourable outcome with a 10 y pEFS of 78 ± 1.0%, compared to patients with a T-ALL or BAL (biphenotypic acute leukemia) phenotype with a 10 y pEFS of 74 ± 1.8% (n.s.) or 69 ± 9.0% (p<0.009), respectively.. FCM according to the EGIL recommendations not only provides diagnostic lineage determination and subclassification but also enables an initial prognostic orientation before MRD (minimal residual disease)-based risk stratification becomes available.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cell Lineage; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Flow Cytometry; Humans; Immunophenotyping; Infant; Leukemia, Biphenotypic, Acute; Male; Mercaptopurine; Methotrexate; Neoplasm, Residual; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Survival Analysis; Vincristine

In the ALL-BFM 95 trial for treatment of acute lymphoblastic leukemia, response to a prednisone pre-phase (prednisone response) was used for risk stratification in combination with age and white blood cell count at diagnosis, response to induction therapy and specific genetic high-risk features.. Cytomorphological marrow response was prospectively assessed on Day 15 during induction, and its prognostic value was analyzed in 1,431 patients treated on ALL-BFM 95.. The 8-year probabilities of event-free survival were 86.1%, 74.5%, and 46.4% for patients with M1, M2, and M3 Day 15 marrows, respectively. Compared to prednisone response, Day 15 marrow response was superior in outcome prediction in precursor B-cell and T-cell leukemia with, however, a differential effect depending on blast lineage. Outcome was poor in T-cell leukemia patients with prednisone poor-response independent of Day 15 marrow response, whereas among patients with prednisone good-response different risk groups could be identified by Day 15 marrow response. In contrast, prednisone response lost prognostic significance in precursor B-cell leukemia when stratified by Day 15 marrow response. Age and white blood cell count retained their independent prognostic effect.. Selective addition of Day 15 marrow response to conventional stratification criteria applied on ALL-BFM 95 (currently in use in several countries as regular chemotherapy protocol for childhood acute lymphoblastic leukemia) may significantly improve risk-adapted treatment delivery. Even though cutting-edge trial risk stratification is meanwhile dominated by minimal residual disease evaluation, an improved conventional risk assessment, as presented here, could be of great importance to countries that lack the technical and/or financial resources associated with the application of minimal residual disease analysis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biomarkers; Bone Marrow; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Infant; Lymphocyte Count; Male; Mercaptopurine; Neoplasm, Residual; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Prognosis; Prospective Studies; Remission Induction; Risk Assessment; Treatment Outcome; Vincristine

Myelotoxicity during thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme thiopurine methyltransferase (TPMT) and thus more thiopurine converted into 6-thioguanine nucleotides. Of 601 children with acute lymphoblastic leukemia (ALL) who were treated by the NOPHO ALL-92 protocol, 117 had TPMT genotype determined, whereas for 484 patients only erythrocyte TPMT activity was available. The latter were classified as heterozygous, if TPMT activity was <14 IU/ml, or deficient (<1.0 IU/ml). 526 patients had TPMT wild type, 73 were presumed heterozygous, and two were TPMT deficient. Risk of relapse was higher for the 526 TPMT wild type patients than for the remaining 75 patients (18 vs 7%, P=0.03). In Cox multivariate regression analysis, sex (male worse; P=0.06), age (higher age worse, P=0.02), and TPMT activity (wild type worse; P=0.02) were related to risk of relapse. Despite a lower probability of relapse, patients in the low TPMT activity group did not have superior survival (P=0.82), possibly because of an excess of secondary cancers among these 75 patients (P=0.07). These data suggest that children with ALL and TPMT wild type might have their cure rate improved, if the pharmacokinetics/-dynamics of TPMT low-activity patients could be mimicked without a concurrent excessive risk of second cancers.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Child; Child, Preschool; DNA Damage; Female; Genotype; Humans; Inactivation, Metabolic; Infant; Male; Mercaptopurine; Methylation; Methyltransferases; Neoplasm Proteins; Neoplasms, Second Primary; Polymorphism, Genetic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Risk; Scandinavian and Nordic Countries; Thioguanine

A prospective, randomized multicenter study was performed to evaluate the relative efficacy of two different concepts for early intensive therapy in a randomized trial of children with B-precursor acute lymphoblastic leukemia (ALL) at high risk (HR) for relapse. Four hundred and ninety eligible children with HR-ALL were randomized on the Pediatric Oncology Group (POG) 9006 phase III trial between 7 January 1991 and 12 January 1994. After prednisone (PDN), vincristine (VCR), asparaginase (ASP) and daunorubicin (DNR) induction, 470 patients received either 12 intensive parenteral treatments of intermediate dose (1 g/m2 each) methotrexate (MTX) and mercaptopurine (MP) over 24 weeks (regimen A) or 12 intensive course of alternating myelosuppressive drug combinations given over 30 weeks (regimen B). These drug combinations included MTX/MP, teniposide (VM-26)/cytosine arabinoside (AC) and VCR/PDN/DNR/AC/ASP. Central nervous system (CNS) prophylaxis was age-adjusted triple intrathecal chemotherapy. Patients with CNS disease at diagnosis were treated with craniospinal irradiation after the intensive phase. Continuation was standard doses of MTX and MP for 2 years. This trial was closed early because of an apparent early difference favoring regimen B. Results show that 470 patients achieved remission (97%). Two hundred and thirty two were randomized to regimen A and 238 to regimen B. The estimated 4-year event-free survival (EFS) for patients treated with regimen A is 61.6 % (s.e. = 3.3%) and with regimen B is 69.4% (s.e. = 3.1%), P = 0.091. Toxicities were more frequent on regimen B. In conclusion, for children with B-precursor ALL at high risk to relapse, early intensification with myelosuppressive combination chemotherapy was more toxic but produced no significant difference in EFS when compared to those treated with parenteral methotrexate and mercaptopurine.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain; Child; Child, Preschool; Female; Humans; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

A total of 119 children (1990-95) with acute lymphoblastic leukemia (ALL) B-lineage either CD10+ or CD10- were registered into a single non-randomized chemotherapy protocol. Only untreated patients with standard risk were included in the study. Their ages ranged from 1.8-10 years with a mean of 5.1 years. There were 82 (68%) children with early pre B-All, 35 (29%) with pre B-ALL and 2(1.6%) with transitional pre B-ALL (p < 0.00001). The patients were divided according to CD10 reactivity, either + (94 children) or -(25 patients). The event-free survival (EFS) at 60 months for the CD10+ children was of 78% (alive 73/94), while for the CD10- was 71% (alive 18/25) (p = 0.6) and 74% for both groups. The factors that influenced favorably the survival in the CD10+ group were the age between 3 to 5.99 years (p < 0.00001), sex (either male or female), leukocyte count between 10-24.9 x 10(9)/l (p < 0.00001), LDH under 300 U/I (p < 0.00001) and L1 bone marrow cytomorphology (p < 0.00001). In the CD10- patients, the EFS was favorably influenced by the female sex (p = 0.04), leukocyte count under 10 x 10(9)/l (p = 0.05) and LDH < 300 U/l (p = 0.02). CNS infiltration was documented in 4.2% (5/119). Mortality secondary to chemotherapy was seen in 7%. In conclusion, this is the first large series in Mexican children with B-lineage ALL published. Because of the relatively small number of patients in each group (pre B and transitional pre B), all the patients in the current series were treated alike. When the 119 patients were divided only on the basis of CD10 reactivity, the EFS for both groups (CD10+ and-) was similar; therefore, the reactivity to CD10 has no prognostic value in this type of ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Female; Humans; Immunophenotyping; Infant; Life Tables; Male; Mercaptopurine; Methotrexate; Neprilysin; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Risk Factors; Survival Analysis; Teniposide; Treatment Outcome; Vincristine

The Pediatric Oncology Group (POG) acute leukemia in childhood (ALinC) 13 study tested two treatment regimens that used different CNS chemoprophylaxis for children older than 12 months with non-T, non-B acute lymphoblastic leukemia (ALL) and with no demonstrable CNS disease at diagnosis.. With the first regimen, standard (S), six injections of triple intrathecal chemotherapy (TIC), consisting of methotrexate (MTX), hydrocortisone (HC), and cytarabine (ara-C), were administered during intensification treatment and at every-8-week intervals throughout the maintenance phase for 17 additional doses. The second regimen, standard and MTX pulses (SAM), also specified six TICs during intensification, but substituted every-8-week pulses of intermediate-dose parenteral methotrexate (IDM; 1 g/m2) for the 17 maintenance TIC injections, with a low-dose intrathecal (IT) MTX boost administered with the first four maintenance IDM pulses. Otherwise, systemic therapy on regimen SAM was identical to regimen S. There were 1,152 patients randomized to the S and SAM regimens after stratification by risk group (age/leukocyte count) and immunophenotype.. The 5-year probabilities (+/- SE) of an isolated CNS relapse were regimen S: good risk (n = 381), 2.8% +/- 1.3%; poor risk (n = 196), 7.7% +/- 3.2%; good + poor risk (n = 577), 4.7% +/- 1.5%; regimen SAM: good risk (n = 388), 9.6% +/- 2.2%; poor risk (n = 187), 12.7% +/- 4.2%; good + poor risk (n = 575), 10.9% +/- 2.2%. In poor-risk patients, approximately one third of the isolated CNS relapses occurred before preventive CNS therapy was begun at week 9. Hence, regimen S has provided better CNS preventive therapy for both good- and poor-risk patients (P < .001 overall). The difference is statistically significant for good-risk patients (P < .001), but not for poor-risk patients (P = .20). Neither treatment has shown a significant advantage in terms of general outcome.. TIC injections extended throughout the intensification and maintenance periods are superior to IDM pulses for prevention of CNS leukemia. Our results with TIC seem comparable with those achieved with other contemporary methods of CNS preventative therapy. Thus, extended TIC affords a reasonable alternative to CNS irradiation plus upfront IT MTX for patients with B-progenitor ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Central Nervous System Diseases; Cyclophosphamide; Cytarabine; Dose-Response Relationship, Drug; Humans; Hydrocortisone; Injections, Spinal; Leukemic Infiltration; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Risk Factors; Vincristine

From February 1986 to January 1991 the Pediatric Oncology Group (POG) treated 2404 children or adolescents with acute lymphoblastic leukemia (ALL) on immunophenotype (T-, B-, Pre-B, or Early pre-B-cell), age, and leukocyte count based treatment protocols (ALinC 14, T-cell 3, B-cell and infant leukemia studies). The immunophenotypic subgroups comprised 78.9% B-precursor cell, 15.1% T-cell, 2.0% B-cell, and 4% infant ALL. Patients with B-progenitor cell ALL were stratified by age and leukocyte count and randomized to receive induction therapy comprised of vincristine, prednisone, and asparaginase with triple intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine), followed by intensification with moderate-dose MTX (Regimen A), moderate-dose MTX plus asparaginase (Regimen B), moderate-dose MTX plus cytarabine given early (Regimen C), or moderate-dose MTX plus cytarabine given over the first 16 months of therapy (Regimen D). Continuation therapy comprised mercaptopurine and methotrexate with vincristine plus prednisone pulses. Central nervous system preventive treatment was continued for two years. Patients with T-cell or B-cell ALL or infants less than 1 yr old were treated on individual very intensive multiagent therapy protocols. The 4-year event-free survival for all patients was 66.4% +/- 2.4%; B-precursor ALL approximately 72%, T-ALL approximately 50%, B-ALL approximately 60%, and infants less than 1 yr old approximately 16.5%. We conclude that about two-thirds of newly diagnosed children with ALL can be cured with this approach which spares the majority of children exposure to alkylating agents, anthracyclines, epipodophylotoxins, and irradiation, diminishing the risks of serious acute and late effects.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Flow Cytometry; Humans; Hydrocortisone; Immunophenotyping; Infant; Infant, Newborn; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Vincristine

Topics: Abnormal Karyotype; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biomarkers, Tumor; Biopsy; Cyclophosphamide; Disease Progression; DNA Nucleotidylexotransferase; Doxorubicin; Fatal Outcome; Female; Humans; Lymphoma, Follicular; Mercaptopurine; Methotrexate; Middle Aged; Pancytopenia; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Rituximab; Salvage Therapy; Splenic Rupture; Splenomegaly; Stomach; Vincristine

Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph

Topics: Animals; Antimetabolites, Antineoplastic; Cell Cycle; Cell Line, Tumor; Disease Models, Animal; DNA Damage; Drug Resistance, Neoplasm; Female; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mercaptopurine; Methotrexate; Mice; Mice, Knockout; Models, Biological; Philadelphia Chromosome; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays

Childhood adrenocortical carcinoma (ACC) is a rare tumor and its association with acute lymphoblastic leukemia (ALL) is even rarer. One such case is discussed in this case report. A 3-year-old patient was concomitantly diagnosed with ALL and an initially nonmetastatic ACC. Management started by following the Total XV protocol without a window phase. Left adrenalectomy was conducted after the consolidation phase. Recurrence of a mass at the tumor bed was discovered at week 33 of the continuation phase. Reexcision was conducted, followed by the administration of an ACC protocol including cisplatin, etoposide, and doxirubicin. Mitotane was added when a pulmonary metastasis was discovered and then stopped after the patient suffered from an arachnoid cyst and speech difficulties. The ALL protocol was resumed from week 34 of the continuation phase. Progression of pulmonary nodules was noted after week 45. A pulmonary metastectomy was performed. The ALL protocol was resumed up to week 51 with a good response as proven by assessment of minimal residual disease. A further recurrence was diagnosed at the abdominal tumor bed with a paravertebral mass and a pulmonary nodule. The patient was assigned to palliative treatment and died after a 32-month survival. Such rare associations need more extensive discussions of the best possible management in scientific literature.

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Combined Modality Therapy; Doxorubicin; Etoposide; Fatal Outcome; Humans; Language Development Disorders; Lung Neoplasms; Mercaptopurine; Methotrexate; Mitoxantrone; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Nephrectomy; Pneumonectomy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

Topics: Aged, 80 and over; Antibodies, Bispecific; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Breast Neoplasms; Carcinoma, Transitional Cell; Cytarabine; Female; Humans; Lymphoma, B-Cell; Mercaptopurine; Methotrexate; Neoplasms, Second Primary; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Salvage Therapy; Urinary Bladder Neoplasms; Vincristine

Topics: Adult; Amino Acid Substitution; Antineoplastic Combined Chemotherapy Protocols; Female; GTP Phosphohydrolases; Histiocytic Sarcoma; Humans; Membrane Proteins; Mercaptopurine; Methotrexate; Mutation, Missense; Neoplasms, Second Primary; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Tumor Suppressor Protein p53; Vincristine

Both tumour suppressor and oncogenic functions have been ascribed to the atypical zeta isoform of protein kinase C (PKCζ), whereas its constitutively active form PKMζ is almost exclusively expressed in the brain where it has a role in long-term memory. Using primers unique for either isoform, we found that both PKCζ and PKMζ were expressed in a subset of paediatric acute lymphoblastic leukaemia (ALL) cases carrying a TCF3 (E2A) chromosomal rearrangement. Combined PKCζ and PKMζ (PKC/Mζ) protein as well as phosphorylation levels were elevated in ALL cases, especially TCF3-rearranged precursor B-ALL cases, compared with normal bone marrow (P<0.01). Furthermore, high PKC/Mζ expression in primary ALL cells was associated with increased sensitivity to 6-thioguanine and 6-mercaptopurine (P<0.01), thiopurines used in ALL treatment. PKCζ is believed to stabilize mismatch-repair protein MSH2, facilitating thiopurine responsiveness in T-ALL. However, PKC/Mζ knockdown in a TCF3-rearranged cell line model decreased MSH2 expression but did not induce thiopurine resistance, indicative that the link between high PKC/Mζ levels and thiopurine sensitivity in paediatric precursor B-ALL is not directly causal. Collectively, our data indicate that thiopurine treatment may be effective, especially in paediatric TCF3-rearranged ALL and other patients with a high expression of PKC/Mζ.

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Leukemic; HEK293 Cells; Humans; Isoenzymes; Lentivirus; Leukocytes, Mononuclear; Mercaptopurine; Phosphorylation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase C; Thioguanine

We describe the case of an 8-year-old girl with common precursor B-cell acute lymphoblastic leukemia who presented with severe pancytopenia during maintenance therapy with methotrexate and 6-mercaptopurine. The bone marrow smear showed moderate hypocellularity and trilinear dysplastic changes consistent with a diagnosis of drug toxicity, with no evidence of lymphoblasts. Flow cytometric immunophenotyping was negative for leukemic cells. Blood cell counts normalized after treatment with folinic acid. Maintenance therapy was gradually restarted and she remained well at follow-up visits. Myelotoxicity from methotrexate and 6-mercaptopurine may represent an unpredictable incident during an otherwise uneventful maintenance therapy, and may occur independently of other organ toxicities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Child; Disease Management; Female; Follow-Up Studies; Humans; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis

Symptomatic fasting hypoglycemia has been reported as an unusual side effect in patients with acute lymphoblastic leukemia (ALL) on maintenance therapy. We evaluated the relation of the red cell 6-mercaptopurine (6-MP) metabolite 6-methyl-mercaptopurine (6MMP) with hypoglycemia.. We retrospectively reviewed charts of three patients with ALL and symptomatic hypoglycemia while fasting who were noted to have high levels of 6MMP. All patients had an empiric trial of switching from evening to morning 6-MP administration, and two patients were subsequently switched to twice daily dosing. Patients also received complex carbohydrates at bedtime.. Switching 6-MP from evening to morning administration reduced 6MMP levels yet preserved adequate levels of the active metabolite red cell 6-thioguanine nucleotide (6TGN). All patients had decreased hypoglycemic events when changed from evening to morning dosing. Two patients showed a rebound in 6MMP levels with return of hypoglycemic symptoms. Both were then switched to twice daily 6-MP dosing with one having a decrease in 6MMP and hypoglycemic symptoms.. High levels of 6MMP are associated with symptomatic hypoglycemia which may be mitigated by switching to morning or twice daily 6-MP dose administration.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Blood Glucose; Child; Child, Preschool; Dexamethasone; Dietary Carbohydrates; Drug Administration Schedule; Fasting; Female; Guanine Nucleotides; Humans; Hyperglycemia; Hypoglycemia; Hypoxanthine Phosphoribosyltransferase; Infant; Liver Glycogen; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Methylation; Methyltransferases; Polymorphism, Genetic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Retrospective Studies; Thionucleotides

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 9; Combined Modality Therapy; Cranial Irradiation; Cytarabine; Daunorubicin; Erythropoiesis; Etoposide; Female; Humans; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms, Second Primary; Oncogene Proteins, Fusion; Pancytopenia; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Translocation, Genetic; Vincristine

Topics: Antimetabolites, Antineoplastic; Brain Ischemia; Cytarabine; Deglutition Disorders; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Doxorubicin; Dysarthria; Hemiplegia; Humans; Hydrocortisone; Injections; Leukoencephalopathies; Magnetic Resonance Angiography; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Young Adult

Acute B-cell leukemia (B-ALL) is a rare form of pediatric leukemia characterized by a very high-proliferation index, rapid clinical progression, and a high frequency of central nervous system (CNS) involvement. Commonly, it is treated in the clinical trials for Burkitt lymphoma, of which it represents the leukemic counterpart.. Children with B-ALL diagnosed between 1988 and 1999 were enrolled in the AIEOP-8805 protocol. Treatment included six high-dose chemotherapy courses. No prophylactic CNS irradiation was administered.. Sixty-five consecutive patients were enrolled in the study. L3 morphology was observed in 57 of 65 patients (88%). Twenty-five children (38%) had tumor mass in addition to massive bone marrow infiltration; 11 children (17%) had CNS disease at diagnosis. Sixty-two patients obtained complete morphological remission of which 13 suffered a relapse, including 3 with initial CNS involvement. Ten-year overall survival and event-free survival were 77% and 75%, respectively. Neither relevant long-term toxicity nor second malignancies were observed.. The AIEOP-8805 confirmed that short high-dose chemotherapy is highly effective for the treatment of B-ALL without significant long-term adverse sequelae. Therapy modifications to reduce relapse rate, such as the use of anti-CD20 monoclonal antibody and more effective CNS treatment, are being tested.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; L-Lactate Dehydrogenase; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Vincristine

Functional polymorphisms in the thiopurine methyl transferase (TPMT) gene have been associated with varying levels of enzyme activity and the occurrence of toxicity related to thiopurines. A total of 98 patients (66 pediatric and 32 adults) with precursor B acute lymphoblastic leukemia (Pre-B ALL) were evaluated for TPMT gene polymorphisms. The inability to tolerate 6-mercaptopurine (6-MP) at conventional doses was considered as a surrogate marker of hematologic toxicity. The allele frequency of TPMT*2, *3A, *3B and *3C in the study population was 0.5, 0, 0 and 2.6%, respectively, similar to the frequency observed in other Asian populations. Five patients were heterozygous for TPMT*3C variant allele, and one of these patient's was compound heterozygous with TPMT*2 variant as the other allele. The impact of TPMT polymorphisms on the toxicity and treatment outcome was assessed in 66 pediatric patients only, as there was no variant TPMT detected in the adult patients. Three of the 5 patients (60%) heterozygous for TPMT*2 or TPMT*3C polymorphisms and 12/61 patients (20%) with wild type TPMT genotype had more than 10% of reduction of 6-MP dose (P=0.07). The presence of TPMT polymorphisms did not seem to completely explain the variation in 6-MP toxicity in this small group of patients. Other novel variants in TPMT or variations in the genes involved in transport and biotransformation of 6-MP need to be evaluated in the Indian population.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Child, Preschool; Female; Humans; India; Male; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Survival Rate; Young Adult

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (>or=10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 x 10(9)/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS(12y):0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r(S)=0.36, P=0.02), which became nonsignificant for those who relapsed (r(S)=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r(S)=0.38, P=0.02), which was not the case for those who developed a relapse (r(S)=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Child; Child, Preschool; Female; Humans; Infant; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Methyltransferases; Neoplasm Recurrence, Local; Neutrophils; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Survival Rate; Treatment Outcome

Immunophenotypic classification of acute lymphoblastic leukemia (ALL) has well-recognized prognostic implications. The significance of CD20 expression has been evaluated in childhood precursor B-lineage ALL with conflicting results. We retrospectively analyzed the influence of CD20 expression on outcome in 253 adults with de novo precursor B-lineage ALL treated with either conventional (VAD/CVAD) or intensive (hyper-CVAD) frontline chemotherapy regimens in the pre-rituximab era. Overall, CD20 positivity of at least 20% was associated with lower 3-year rates of complete remission duration (CRD; 20% vs 55%, P < .001) and overall survival (OS; 27% vs 40%, p = .03). In the CD20 negative subset, the 3-year rates for CRD (58% vs 42%, p = .04) and OS (60% vs 28%, P < .001) were superior for hyper-CVAD compared with VAD/CVAD; rates were particularly favorable for the CD20 negative younger age group (68% and 85%, respectively). In contrast, 3-year CRD and OS rates were uniformly poor for the CD20-positive group regardless of therapy (27% or less). Multivariate analysis for event-free survival identified older age, leukocyte count higher than 30 x 10(9)/L, presence of Philadelphia chromosome, high systemic risk classification, and CD20 positivity as independent predictors of worse outcome. In conclusion, CD20 expression in de novo adult precursor B-lineage ALL appears to be associated with a poor prognosis. Incorporation of monoclonal antibodies directed against CD20 into frontline chemotherapy regimens warrants investigation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD20; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Cranial Irradiation; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Proportional Hazards Models; Remission Induction; Vincristine; Young Adult

The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ALL, we used human 500K single-nucleotide polymorphism arrays to identify somatic copy number alterations (CNAs) in 20 diagnosis/relapse pairs relative to germ line. We identified 758 CNAs, 66.4% of which were less than 1 Mb, and deletions outnumbered amplifications by approximately 2.5:1. Although CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. In addition, we noted concordance in global gene expression and DNA copy number changes (P = 2.2 x 10(-16)). Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Child; Child, Preschool; Cohort Studies; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Leukemic; Humans; Ikaros Transcription Factor; Male; Mercaptopurine; Mutation; Neoplasm Proteins; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Recurrence; Trans-Activators

We report a 13-year-old male patient with Charcot-Marie-Tooth disease (CMT) type 2 who developed severe neuropathy because of vincristine (VCR) for his acute lymphoblastic leukemia. A clumsy gait, muscle weakness in his fingers, and inverted champagne bottlelike muscle in the lower limbs were noticed after remission induction treatment for acute lymphoblastic leukemia, which included VCR at a total dose of 8 mg/m. An electrophysiologic study showed an almost normal median motor nerve conduction velocity (approximately 50 m/s), markedly reduced M-wave amplitude and sensory disturbance. He was diagnosed as CMT type 2 based on his symptoms and electrophysiologic findings. His symptoms gradually worsened, and even after VCR was discontinued, he could not walk alone for 7 months. VCR has previously been considered to be relatively safe in CMT type 2, however, some patients with CMT type 2 might show severe neurologic toxicities, as seen in patients with CMT type 1.

Topics: Adolescent; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Charcot-Marie-Tooth Disease; Contraindications; Cytarabine; Daunorubicin; Etoposide; Gait Disorders, Neurologic; Humans; Male; Mercaptopurine; Methotrexate; Muscle Weakness; Neural Conduction; Peripheral Nervous System Diseases; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Vincristine

Disseminated adenoviral infection with hepatitis is rare in children undergoing standard chemotherapy. We report on a 3(1/2)-year-old male with fatal adenovirus hepatitis receiving maintenance chemotherapy for acute lymphoblastic leukemia (ALL). Adenoviral hepatitis was proven by histology, viral culture, and PCR in a liver biopsy. Quantitative real-time PCR in the peripheral blood showed adenoviral DNA copy number >10(9)/ml. Despite aggressive supportive care and antiviral treatment with cidofovir, the patient died rapidly due to fulminant liver failure. Diagnostic and treatment options for adenovirus infection remain unsatisfactory for these patients. We propose suggestions for diagnosis and therapy.

Topics: Adenovirus Infections, Human; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Asparaginase; Child, Preschool; Cidofovir; Computer Systems; Cytosine; DNA, Viral; Fatal Outcome; Hepatitis, Viral, Human; Humans; Immunocompromised Host; Male; Mercaptopurine; Methotrexate; Multiple Organ Failure; Organophosphonates; Polymerase Chain Reaction; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Vincristine; Viremia

Ondansetron is a commonly used medication in the treatment of nausea and vomiting arising from many etiologies, including chemotherapy. Although it is a highly safe drug, ondansetron use has been associated, rarely, with hypokalemia. However, it is unknown whether hypokalemia is due to the medication itself or to an underlying potassium disturbance caused by prior metabolic derangements, including vomiting. We relate a patient who presents with hypokalemia of unknown etiology, with evidence suggesting a possible relationship to ondansetron. We also present a proposed mechanism for this phenomenon.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cytarabine; Dexamethasone; Female; Humans; Hypokalemia; Mercaptopurine; Methotrexate; Nausea; Ondansetron; Polyethylene Glycols; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

Environmental agents have long been thought to be linked to the development of malignancies. Due to the difficulty in identifying and verifying exposures to such agents, only a few chemical compounds are clearly linked to malignancies. We report here the case of a 36-year-old man with pre-B cell acute lymphoblastic leukemia. This patient was using industrial strength glue to reattach a chipped tooth for approximately 1 year, and such use was associated with chronic exposure of his oral mucosa to this glue. This case raises the possibility that chronic exposure to cyanoacrylates, the adhesive agents in industrial strength glue, may be associated with the development of acute lymphoblastic leukemia in humans.

Topics: Adhesives; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyanoacrylates; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Doxorubicin; Humans; Male; Mercaptopurine; Methotrexate; Mouth Mucosa; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Remission Induction; Salvage Therapy; Self Care; Tooth Fractures; Vincristine

Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT), but membranous glomerulopathy (MG) has rarely been described as a manifestation of chronic GVHD. We report two cases of MG in children who underwent allogeneic HSCT. The clinical findings were characterized by edema of the lower extremities and nephrotic proteinuria in one case and hypertension, hematuria and edema with non-nephrotic proteinuria in the other one. Renal biopsy was consistent with MG and appropriate immunosuppressive therapy was prescribed. Both patients achieved complete remission and are alive without renal disease 4 and 2 years after the diagnosis of MG. The normal levels of albumin and non-nephrotic proteinuria in one of the two cases raise the question of whether the real incidence of MG after HSCT is underestimated. Therefore, we strongly suggest regular urine analysis during the follow-up of children undergoing HSCT in order to diagnose MG early.

Topics: Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Edema; Glomerulonephritis, Membranous; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Transplantation Conditioning; Transplantation, Homologous; Vincristine

We evaluated the incidence of MTS1/p16 deletions by loss of heterozygosity (LOH) analysis in 36 non-high risk B-cell precursor childhood acute lymphoblastic leukemia (BCP-ALL) and correlated these results with clinical features and with the presence of minimal residual disease (MRD) at the end of induction therapy. LOH was analyzed using three microsatellite markers flanking the p16 gene. MRD was studied by the polymerase chain reaction (PCR) for IgH and TCRdelta genes. All patients were classified and treated according to the BFM-86 protocol. A slower response to the induction treatment (MRD) was associated with LOH of p16 and worse clinical outcome. Thus, LOH of p16 may be a marker of chemotherapy resistance among the children classified as non-high risk BCP-ALL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cyclin-Dependent Kinase Inhibitor p16; Cyclophosphamide; Cytarabine; Drug Resistance, Neoplasm; Female; Gene Deletion; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; Genes, p16; Humans; Infant; Life Tables; Loss of Heterozygosity; Male; Mercaptopurine; Methotrexate; Microsatellite Repeats; Neoplasm, Residual; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Receptors, Antigen, T-Cell, gamma-delta; Remission Induction; Retrospective Studies; Survival Analysis; Treatment Outcome; Vincristine

The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).. The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG(3-7)) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 micromol/L [(3)H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance.. Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 +/- 896.3 vs. 640 +/- 472.5 pmol/10 cells) or of accumulated MTXPG (1450.0 +/- 919.4 vs. 617.4 +/- 482.7 pmol/10(9) cells) (median +/- semi-interquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG(3-7)/10(9) cells was 80.0% +/- 7.3% versus 90.5% +/- 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG(3-7)/10(9) cells.. In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Child; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Female; Humans; Hydrocortisone; Injections, Spinal; Karyotyping; Leucovorin; Life Tables; Lymphocytes; Male; Mercaptopurine; Methotrexate; Neoplastic Stem Cells; Polyglutamic Acid; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Pteroylpolyglutamic Acids; Recurrence; Remission Induction; Survival Analysis; Tumor Cells, Cultured; Vincristine

Hepatic dysfunction is a rare presentation of leukemia in children. Because most chemotherapy agents are metabolized by the liver, this complication may have major adverse consequences and effective treatment could be compromised.. The MEDLINE database and current management guidelines from the United States Pediatric Cooperative Cancer Groups were reviewed and analyzed. Data from two institutional cases are described.. Although previous literature is not informative, our experience suggests that children with leukemia and moderate hepatic dysfunction may tolerate aggressive chemotherapy.. Current protocol guidelines for dose modification for liver disease may be overly stringent and modification may be beneficial.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biopsy; Child, Preschool; Cholestasis, Intrahepatic; Chromosome Deletion; Daunorubicin; Hepatomegaly; Humans; Liver; Liver Function Tests; Male; Mercaptopurine; Methotrexate; Practice Guidelines as Topic; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Prognosis; Remission Induction; Thrombocytopenia; Ultrasonography; Vincristine

Topics: Anemia, Refractory, with Excess of Blasts; Aneuploidy; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Chromosome Aberrations; Chromosomes, Human, Pair 8; Cladribine; Combined Modality Therapy; Cranial Irradiation; Cytarabine; Daunorubicin; Fatal Outcome; Female; Gene Amplification; Genes, myc; Humans; Hydrocortisone; Karyotyping; Mercaptopurine; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

The difference in the current cure rates between adult and childhood acute lymphoblastic leukaemia (ALL) may be caused by differences in drug resistance. Earlier studies showed that in vitro cellular drug resistance is a strong independent adverse risk factor in childhood ALL. Knowledge about cellular drug resistance in adult ALL is still limited. The present study compared the in vitro drug resistance profiles of 23 adult ALL patients with that of 395 childhood ALL patients. The lymphoblasts were tested by the MTT assay. The group of adult ALL samples was significantly more resistant to cytosine arabinoside, L-asparaginase, daunorubicin, dexamethasone and prednisolone. The resistance ratio (RR) was highest for prednisolone (31.7-fold) followed by dexamethasone (6.9-fold), L-asparaginase (6. 1-fold), cytosine arabinoside (2.9-fold), daunorubicin (2.5-fold) and vincristine (2.2-fold). Lymphoblasts from adult patients were not more resistant to mercaptopurine, thioguanine, 4-HOO-ifosfamide, mitoxantrone and teniposide. There were no significant differences in drug resistance between adult T-cell (T-) ALL (n = 11) and adult common/pre-B-cell (B-) ALL (n = 10). Additionally, adult T-ALL did not differ from childhood T-ALL (n = 69). There were significant differences between adult common/pre-B-ALL and childhood common/pre-B-ALL (n = 310) for prednisolone (RR = 302, P = 0.008), dexamethasone (RR = 20.9, P = 0.017) and daunorubicin (RR = 2.7, P = 0.009). Lymphoblasts from adults proved to be relatively resistant to drugs commonly used in therapy. This might contribute to the difference in outcome between children and adults with ALL.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Agents; Asparaginase; Bone Marrow Cells; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Idarubicin; Ifosfamide; Infant; Leukemia, Prolymphocytic; Leukemia, T-Cell; Male; Mercaptopurine; Middle Aged; Mitoxantrone; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prognosis; Statistics, Nonparametric; Teniposide; Thioguanine; Vincristine

The use of anthracycline antibiotics in adult acute lymphoblastic leukemia (ALL) has resulted in an improved outcome to remission induction therapy. However,the exact role of these drugs in consolidation therapy is less clear, especially in specific ALL subsets.. A retrospective analysis was conducted on the outcome of 308 patients (median age 35 years, range 13-75) with the most frequent subtype, early-B ALL, treated between 1974 and 1998 on eight consecutive protocols. Anthracycline-related effects were assessed by evaluating the impact of planned anthracycline dose-intensity (A-DI) on long-term outcome. A-DI (in mg/m(2)/week) during the first twelve weeks of consolidation therapy was classified as either "high" (doxorubicin>20, idarubicin>7) or "low".. Complete remission was achieved in 78% of cases. With a median follow-up of 6.5 years, on multivariate analysis, disease-free survival (DFS) correlated only with expression of the Philadelphia (Ph) chromosome and/or associated BCR-ABL rearrangements (Ph/BCR(+)) (P=0.0001) and planned A-DI (P<0.0001). On this basis, four major prognostic groups with significantly different DFS could be identified: (1) Ph/BCR(-), "high" A-DI (n=102), median 3.5 years and 41% at five years, respectively; (2) Ph/BCR(-), "low" A-DI (n=64), 1.3 years and 16%; (3) Ph/BCR(+), "high" A-DI (n=35), 1.7 years and 20%; (4) Ph/BCR(+), "low" A-DI (n=39), 0.75 years and 0%. When analyzed separately for Ph/BCR(-) (n=166) and Ph/BCR(+) (n=74) patients, the A-DI effect on DFS was preserved in the former (P=0.018) whereas, in Ph/BCR(+) patients, only age <50 years (P=0.004) and blast count <25 x 10(9)/l (P=0.02) correlated with better DFS. However, Ph/BCR(+) patients with the best prognostic profile (age <50 years and blast count <25 x 10(9)/l; n=21) who were treated on "high" A-DI regimens experienced a median DFS of 2.2 years with DFS 21% at five years, compared to 0.67-1 years and 0-10% in other cases (n=53, P<0.01).. A "high" A-DI may act as a positive treatment-related prognostic factor in early B-lineage ALL. Although mainly restricted to patients with Ph/BCR(-) ALL, A-DI could also influence the outcome in Ph/BCR(+) patients with other favorable prognostic factors.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Etoposide; Female; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Humans; Idarubicin; Life Tables; Male; Melphalan; Mercaptopurine; Middle Aged; Neoplasm Proteins; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Retrospective Studies; Teniposide; Transplantation, Autologous; Treatment Outcome; Vincristine

Two cases of young patients, Jehova Witnesses (JW), diagnosed as having acute lymphoblastic leukaemia are presented. In one case a complete remission (CR) was obtained, lasting until now, 20 months after diagnosis; the other one died 11 months after diagnosis without achieving a CR. Three important questions can be raised in JW: 1) the absolute respect to patients' wishes; 2) to treat or not to treat; and 3) the pertinent therapy. The answer is yes to 1) and 2), and a slight myelotoxic therapy for the last one.

Topics: Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Blood Transfusion; Christianity; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Fatal Outcome; Female; Humans; Male; Mercaptopurine; Methotrexate; Personnel, Hospital; Physician-Patient Relations; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Refusal to Treat; Remission Induction; Right to Die; Treatment Refusal; Vincristine

The early toxicity, incidence of graft-versus-host disease (GVHD) and long-term follow-up were evaluated in two children with Down syndrome (DS) treated for acute lymphoblastic leukemia (ALL) in second complete remission by HLA-matched sibling allogeneic bone marrow transplantation (BMT). Preparative conditioning therapy consisted of cytosine arabinoside (Ara-C) and fractionated total body irradiation (F-TBI) and GVHD prophylaxis of cyclosporin A. The conditioning regimen was well tolerated, the only acute complication being mild mucositis. Engraftment (polymorphonuclear cells >500/microliter) was documented by day +17 in both patients. One child remains in continuous complete remission, without medical problems, 60 months after BMT. The second patient died from complications associated with chronic GVHD 21 months following BMT. Ara-C and F-TBI is a well-tolerated preparative regimen for children with DS undergoing allogeneic BMT.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cytarabine; Daunorubicin; Down Syndrome; Fatal Outcome; Graft vs Host Disease; Humans; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Salvage Therapy; Transplantation, Homologous; Vincristine; Whole-Body Irradiation

True histiocytic lymphomas (THLs) are rare tumors in which the malignant cells show morphologic and immunophenotypic evidence of histiocytic differentiation. We describe THLs that arose after therapy for one case of T-lineage lymphoblastic lymphoma (LyL) and two cases of acute lymphoblastic leukemia (ALL) (both CD10+, one pre-B phenotype). The lymphoblastic neoplasms were not unusual in any way, and responded well to standard therapy. The THLs arose 10 to 20 months after complete remission was achieved for the lymphoblastic neoplasms, at which time there was still no clinical or pathologic evidence of the lymphoblastic neoplasms. All three THLs exhibited clinical and morphologic features of malignancy. Neoplastic cells in the THLs had abundant eosinophilic vacuolated cytoplasm and pleomorphic nuclei, and expressed histiocytic antigens in the absence of lymphocyte-specific lineage markers. Because THLs are rare neoplasms, their occurrence after otherwise successful therapy for lymphoblastic neoplasms in these three cases may constitute a distinct clinicopathologic entity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Neoplasms; Child; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Etoposide; Fatal Outcome; Humans; Ifosfamide; Lymphoma, Large B-Cell, Diffuse; Male; Mediastinal Neoplasms; Mercaptopurine; Methotrexate; Methylprednisolone; Neoplasms, Second Primary; Neoplastic Stem Cells; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Prednisone; Remission Induction; Scapula; Spinal Neoplasms; Vincristine

The use of peripheral blood as a source of hematopoietic precursors is an alternative to the bone marrow in allogeneic transplantation. Although pediatric allogeneic PBPC experience is limited, there is no reason to believe that the outcome and benefit with PBPC should be different than adults. We describe our initial experience in two children who received PBPC allogeneic transplantation in whom the donors were mobilized with filgrastim. Hematopoietic recovery was achieved on days 14 and 16, and the patients did not develop severe GVHD.

Topics: Adolescent; Bone Marrow; Bone Marrow Cells; Child; Combined Modality Therapy; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Infant; Leukapheresis; Leukemia, Myelomonocytic, Chronic; Male; Mercaptopurine; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins; Remission Induction; Salvage Therapy; Transplantation Conditioning; Transplantation, Homologous

To describe the use of combination chemotherapy, including divided-dose oral methotrexate (dMTX), for children with B-precursor acute lymphoblastic leukemia (ALL). dMTX produced prolonged MTX exposure on an outpatient basis.. Two hundred forty-three patients were treated from January 1986 to May 1992. dMTX was given weekly during consolidation and biweekly for the first 16 months of continuation therapy with mercaptopurine (6-MP) and asparaginase (L-ASP). Initially, etoposide (VP-16) and cytarabine (Ara-C) pulses were included. Treatment continued for 30 months with single-dose weekly MTX replacing dMTX during continuation, part 2. Unexpected acute neurotoxicity was eliminated by the addition of leucovorin. VP-16 and Ara-C were omitted in the face of acute myelogenous leukemia (AML).. Two hundred thirty-nine patients entered remission: 16 had a lymphoid marrow relapse, two each with testicular or CNS relapse; 19 a CNS relapse; 16 secondary AML; three other second malignancies; two withdrew for transplant; three died in remission; 16 withdrew because of noncompliance, and nine withdrew with toxicity. Event-free survival (EFS) at 4 years was 73 +/- 4%; 81 +/- 4% for 150 patients with better risk features and 60 +/- 7% for 93 with high-risk features. Lymphoid marrow relapse-free survival in the standard- and high-risk patients was 94 +/- 3% and 86% +/- 6%, respectively. The most common adverse event was secondary AML in the standard-risk group and isolated CNS relapse in the high-risk group.. This therapy produced an overall EFS similar to other published regimens, but the pattern of failures is very different, with few patients having a lymphoid marrow relapse. These data suggest that highly effective therapy for children with ALL can be delivered on an outpatient basis using a regimen featuring repetitive dMTX.

Topics: Administration, Oral; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Cytarabine; Drug Administration Schedule; Etoposide; Female; Humans; Infant; Male; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

A 3 1/2 year old girl with cystic fibrosis who underwent successful treatment for acute lymphoblastic leukemia remains in complete remission 36 months after diagnosis. We also report high clearance rates of three antineoplastic agents in this patient. Drug doses were adjusted to achieve optimal systemic exposure.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cystic Fibrosis; Cytarabine; Daunorubicin; Female; Humans; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Teniposide; Vincristine

Topics: Carbon Radioisotopes; Cell Division; Cell Line; Drug Screening Assays, Antitumor; Drug Synergism; Glycine; Humans; Kinetics; Leukemia-Lymphoma, Adult T-Cell; Mercaptopurine; Methotrexate; Phosphates; Phosphorus Radioisotopes; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Purines; Tetrahydrofolate Dehydrogenase; Thymidine Monophosphate

In the group of 75 ALL patients treated between 1980 and 1989, two women (ages 25 and 17, both FAB-L2 and CALLA +, after 56 and 34 months of continuous CR, respectively) were found to have a relapse manifested as a local infiltration of skin, with involvement of the adjacent lymph nodes in one patient. The leukaemic character of the skin infiltration was confirmed by skin needle aspiration and tissue biopsy expressing CD10 and CD24. Both patients were given intensified systemic chemotherapy and local X-ray irradiation. Complete remission was obtained with the disappearance of the skin infiltrations followed after 13 and 8 months, respectively, followed by a marrow relapse with symptoms of CNS involvement in one case. Both patients died because of treatment resistance (the overall survival time equalled 70 and 44 months, respectively).

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cyclophosphamide; Cytarabine; Doxorubicin; Female; Humans; Immunotherapy; Leukemic Infiltration; Mercaptopurine; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Radiotherapy; Recurrence; Remission Induction; Skin; Vincristine