S. P. Dibenedetto

Assessment of the value of treatment with granulocyte colony‐stimulating factor in children with acute lymphoblastic leukemia: a randomized clinical trial

Abstract: The present trial was designed to test the effects of G‐CSF on the duration of the second phase of induction chemotherapy in children with newly diagnosed acute lymphoblastic leukemia (ALL). A total of 32 patients were assigned randomly to a group that received (14 patients; group A) or a group that did not receive (18 patients; group B) G‐CSF (10 g/kg/day subcutaneously and daily) throughout of the second phase of induction therapy. One of 14 (7.1%) patients in group A and 2 of 18 (11.1%) patients in group B completed the course of chemotherapy within the planned time. The median length of this phase was 37 days (range, 29 to 65; mean, 40; SD, 8.6) for patients in group A and 36 days (range, from 29 to 55; mean, 38; SD, 7.4) for those in group B, and the difference was not statistically significant. The number of days during which patients had granulocyte counts of less than 2 × 109/l, the number of febrile episodes of unknown origin, the number of bacterial and fungal infections and the number of days of hospitalization did not differ in a statistically significant manner between the two groups. Our data suggest that G‐CSF supportive therapy may be unnecessary in children with neutropenia of short duration, for whom the risk of infection is low.

Growth and growth hormone in children during and after therapy for acute lymphoblastic leukaemia

Growth impairment and growth hormone (GH) deficiency have been reported in children treated for acute lymphoblastic leukaemia (ALL). We have studied growth and GH secretion in a group of 50 patients, affected by ALL, during a 2- to 5-year period after diagnosis, and in 12 “long-term-survivors”. We observed a significant decrease in growth velocity during the 1st year (in particular during the first 6 months) of therapy and a catch-up growth after the end of therapy. “Longterm survivors” did not exhibit a significant reduction of height standard deviation score (SDS), as compared to height SDS at diagnosis. None of the patients showed GH deficiency. Our data indicate that chemotherapy significantly affects growth of patients treated for ALL, whereas radiotherapy-at the doses used in this study-does not induce GH deficiency, at least not within 9 years after diagnosis.

Levels of L-asparagine in CSF after intramuscular administration of asparaginase from Erwinia in children with acute lymphoblastic leukemia.

PURPOSE As part of a study on the pharmacokinetics associated with the administration of asparaginase (ASNase) from Erwinia to the CNS, we determined the levels of asparagine in the CSF of children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Twenty children received eight standard doses of intramuscular ASNase (10,000 IU/m2) every 3 days as part of induction therapy. In the postremission phase of therapy, the children were randomized to receive either 20 courses of high-dose intramuscular ASNase (25,000 IU/m2) weekly (n = 8) or four courses of standard-dose intramuscular ASNase (10,000 IU/m2) every 3 days (n = 12). RESULTS All patients had detectable levels of L-asparagine in the CSF at the time of diagnosis. The levels of L-asparagine in CSF were undetectable in 15 of 20 (75%) and in seven of 19 (36.8%) children 3 and 5 days, respectively, after administration of standard-dose ASNase. After administration of high-dose ASNase, the levels of L-asparagine in the CSF were undetectable in five (62.5%) and two (25%) of eight children after 3 and 5 days, respectively. CONCLUSION In this study 60% to 70% and 25% to 35% of children had complete depletion of L-asparagine from the CSF after 3 and 5 days, respectively, after administration of both schedules of ASNase from Erwinia. In the remaining patients, administration of ASNase may have resulted in a suboptimal antileukemic effect at the CNS level.

Incidence and morbidity of infection by hepatitis C virus in children with acute lymphoblastic leukaemia.

A group of 90 patients with acute lymphoblastic leukaemia (ALL) in first continuous complete remission (CCR), admitted in our hospital between January 1986 and September 1992, were tested for the presence of antibodies against hepatitis C virus (HCV), antibodies against hepatitis B virus and antibodies against HIV-1 during maintenance therapy or thereafter. They were compared with a group of 71 children with other malignancies in first CCR who had been diagnosed consecutively from January 1986 to September 1992. No patient with ALL or any other malignancy was found to be positive for hepatitis B surface antigen or HIV-1. HCV-specific antibodies were detected in 28 out of 87 children (32.1%) with ALL and in 4 out of 44 patients (9%) with malignancies other than ALL who had received at least one transfusion of blood or platelets (P<0.01). HCV-specific antibodies were also detected in one out of three untransfused children with ALL but in none of the untransfused children with malignancies other than ALL. HCV-specific seropositivity influenced the management of children with ALL during maintenance therapy. In fact, as a result of abnormal liver function tests, maintenance therapy had to be suspended significantly more often in the case of HCV-seropositive patients with ALL than in HCV-seronegative ones. Despite the high morbidity during maintenance therapy, chronic liver disease (CLD) was uncommon in both groups: five children with ALL (17.2% of HCV-seropositive children) and one child with a malignancy other than ALL (25%) had CLD. If a follow up for a longer period confirms these observations the impact of HCV-related CLD on the quality of life and survival of patients with ALL or other malignancies will probably be minimal.

6-Mercaptopurine Cumulative Dose: A Critical Factor of Maintenance Therapy in Average Risk Childhood Acute Lymphoblastic Leukemia

A multivariate survival analysis including gender, age, log white blood cell (WBC) count, liver and spleen size at diagnosis, mean log WBC count during maintenance therapy, and the prescribed cumulative doses of 6-mercaptopurine (6-MP), methotrexate (MTX), vincristine (VCR), and prednisone (PDN) during maintenance therapy was performed on 53 children with average-risk acute lymphoblastic leukemia (ALL). The 6-MP cumulative dose prescribed during maintenance therapy resulted in the most important statistically significant independent prognostic factor. Patients who received less than the median cumulative dose of 6-MP (86% of planned protocol dose) fared significantly worse than the other patients, regardless of WBC count at diagnosis, gender, age, and other factors studied. Therefore, 6-MP cumulative dose during maintenance therapy may be the critical factor for effective maintenance therapy in childhood ALL.

Dissection of the association status of two polymorphisms in the β-globin gene cluster with variations in F-cell number in non-anemic individuals

Expression of fetal hemoglobin (Hb F) is under polygenic control involving determinants both linked and unlinked to the β‐globin gene cluster on chromosome 11. Variations in the DNase I‐hypersensitive site 2 of the locus control region (LCR‐HS2) and a C → T change at position −158 from the Gγ‐gene (detected as an XmnI polymorphism) correlate with the high level of Hb F expression in patients with sickle‐cell anemia and β‐thalassemia. Interpretation of data under these conditions of anemic stress is difficult because the preferential survival of Hb F‐containing erythrocytes (F‐cells) may not reflect the true status of Hb F expression. We investigated the relationship between these markers and Hb F expression in terms of F‐cell levels in 48 unrelated non‐anemic AS heterozygotes from Sicily. The βS‐chromosome of all these individuals was of the Benin haplotype and they differed only by their βA chromosomes. We demonstrate that F‐cell expression is more strongly associated with LCR‐HS2 polymorphism than with XmnI polymorphism. The observed association between XmnI polymorphism and Hb F expression is very likely to be due to linkage disequilibrium with LCR‐HS2 sequences. Am. J. Hematol. 56:239–243, 1997.

Presence of hemoglobinopathies in Sicily: a historic perspective.

Sicily, at the center of the Mediterranean, has been the meeting place of Eastern and Western civilizations, and in the Sicilian population the presence of many different alterations in the globin gene clusters can surely be considered testimony of past colonizations. From 1975 to 1994, 100,000 Sicilian subjects were screened by us to monitor the presence of hemoglobin (Hb) structural variants. In this paper we present the data gathered, emphasizing the high incidence (2.5%) of carriers of at least one abnormal Hb, and the great heterogeneity of globin molecular defects on the island. Twenty-six different mutations were identified: the most common occur in the beta-globin gene (beta(S), beta(C), deltabeta(Lepore), beta(G-San José), beta(O-Arab), but also quite frequent is the mutated allele alpha(J-Oxford). The chromosome haplotypes associated with some of them were characterized. Two uncommon Hbs, Copenhagen and D Punjab, and some 18 rare variants complete the wide spectrum of structural alterations of globin genes in Sicily. We think they are de novo mutations prevalently. It is not possible to exclude that the presence of a few of them is related to migratory phenomena, particularly from North Africa and East Asia. Numerous thalassemic alleles complete the picture of globin gene mutations in Silicy.

Hb Agenogi [β90(F6)Glu → Lys] and β°-Thalassa in A Sicilian Family

The propositus, a 40-year-old married woman with two children, came to our attention because of mild chronic anemia and biliary colic due to the presence of gallstones. Her case history did not reveal any important previous illnesses

Detection of minimal residual disease: methods and relationship to outcome in T-lineage acute lymphoblastic leukemia.

The molecular basis of acute lymphoblastic leukemia (ALL) of both B-cell and T-cell lineages seems better understood using polymerase chain reaction (PCR) methods. The analysis of clone-specific junctional regions of rearranged genes for both Immunoglobulin (Ig H) and T-cell receptor (TcR) is the most sensitive tool for detection of minimal residual disease (MRD) in ALL. Because of the heterogeneity of all ALL patients examined in several studies, the detection of MRD at different times of treatment has not as yet been correlated with disease outcome. In contrast, T-ALL is a homogeneous disease characterized by expansion of a single clone showing a specific Rearranged junctional region of TcR delta and/or gamma genes. The use of a clone-specific probe allows detection of residual leukemia throughout treatment. However, 60 % of patients with T-ALL relapse during treatment or towards the end of therapy, with resurgence of the original leukemic clone. It is possible that the detection of MRD at a specific time-point after diagnosis, as well as at the beginning of maintenance, may help to identify a group of T-ALL patients at high risk of relapse. The correlation between detection of MRD and treatment phase may be used in the future to evaluate whether treatment regimens can be improved allowing for stratification, based on PCR-mediated detection of MRD.

Diabetes Insipidus 9 Years after Cessation of Therapy for Acute Lymphoblastic Leukemia

A case of a 16-year-old who developed diabetes insipidus (DI) 9 years after cessation of therapy for ALL is reported. Because hereditary and traumatic factors are excluded as a cause of DI in this patient, possible explanations may be leukemic CNS relapse, secondary brain tumor, primitive idiopathic DI, and late sequelae of CNS radiochemotherapy.