Monosomy 7 (−7) and deletion 7q \del(7q) are rare in childhood acute myeloid leukemia (AML). We retrospectively collected data on 258 children with AML or refractory anemia with excess blasts in ...transformation (RAEB-T) and −7 or del(7q) with or without other cytogenetic aberrations \± other. Karyotypes included −7 (n = 90), −7 other (n = 82), del(7q) (n = 21), and del(7q) other (n = 65). Complete remission (CR) was achieved in fewer patients with −7 ± other compared with del(7q) ± other (61% versus 89%, P < .001). Overall, the 5-year survival rate was 39% (SE, 3%). Survival was superior in del(7q) ± other compared with −7 ± other (51% versus 30%, P < .01). Cytogenetic aberrations considered favorable in AML \t(8;21)(q22;q22), inv(16)(p13q22), t(15;17)(q22;q21), t(9;11)(p22;q23) (n = 24) were strongly associated with del(7q) and a higher 5-year survival rate compared with del(7q) without favorable cytogenetics (75% versus 46%, P = .03). Patients with −7 and inv(3),−5/del(5q), or + 21 had a 5-year survival rate of 5%. Stem cell transplantation analyzed as a time-dependent variable had no impact on overall survival. However, patients not achieving CR had a 31% survival rate after stem cell transplantation. Childhood AML with chromosome 7 aberrations represents a heterogeneous group of disorders with additional cytogenetic aberrations having a major prognostic impact which should be reflected in future risk-group stratification.
The current screening for eligibility of unrelated volunteer marrow donors comprises a complete clinical check‐up, a blood CBC and serum protein immunoelectrophoresis. This allows to eliminate acute ...leukemias, myeloproliferative and myelodysplastic disorders, myelomas and MGUS. To date, the risk of transmission of chronic lymphocytic leukemia (CLL) disease is only evaluated by the clinical evaluation and CBC. We report here the case of a CLL‐type MBL disease occurring in a 12‐year‐old boy after unrelated BMT. Deep biological investigations, as Immunophenotyping, cytogenetic and molecular biology allow us to determine the donor origin of the CLL clone. In 2010, 14.2% donor (105/737) for unrelated hematopoietic stem cell transplantation were over 45y. It is currently estimated (USA) that 1 in 210 men and women will be diagnosed with CLL during their lifetime. Given the long asymptomatic phase of CLL, this raises the case for a detection strategy analog to that used for MGUS and myeloma through serum protein electrophoresis. This case‐report, to our knowledge, of a CLL‐type MBL unrelated donor‐to‐recipient transmission through BMT raises ethical and practical questions, such as the proper information about disease transmission risk. The cost‐effectiveness of a systematic peripheral blood Immunophenotyping in donors elder than 40y at time of stem cell donation should be evaluated.
Summary
Inherited factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder mostly caused by point mutations. Large genomic re‐arrangements at F7 locus could account for a fraction ...of mutant alleles that remain unidentified after DNA sequencing, because they escape conventional polymerase chain reaction (PCR)‐based techniques. We report the first systematic screening of F7 for large re‐arrangements, by semi‐quantitative multiplex PCR of fluorescent fragments targeting the 9 exons and the promoter region. A well‐characterised cohort of 43 unrelated patients either apparently homozygous for a F7 point mutation or carrying at least one unidentified F7 mutant allele participated in this study. Two large F7 re‐arrangements were identified in two FVII‐deficient pedigrees, including a discontinuous deletion involving two distinct portions of F7 whose proximal and distal end junctions were characterised. A simple and efficient method for the routine detection of gross alterations of F7, which accounted for 2.3% of mutant alleles in our sample, is now available in inherited FVII deficiency. This test should complement conventional PCR‐based techniques not only in unsolved cases, but also where inheritance pattern analysis is not achievable.
To evaluate the prognostic significance of blasts in the CSF at diagnosis in children with ALL, 2049 patients (pts) enrolled from 1989 to 1996 in EORTC 58881 trial were retrospectively studied. ...Treatment design was according to BFM. Central nervous system (CNS)-directed therapy consisted in i.v. methotrexate (MTX) (5 g/sqm over 4 hours) in 4 to 10 courses, according to grade of initial CNS involvement, and intrathecal MTX. No radiotherapy was used. Three randomizations were programmed: Erwinia vs Medac E.coli asparaginase (all pts); addition or not of i.v. Ara-C to i.v. MTX (for increased-risk pts); addition of monthly courses of i.v. 6-MP in maintenance therapy (all pts). According to CNS status, pts were classified in 4 groups: 1) CNS-1: <6 WBC/μl, RBC<100/μl, no blasts; 2) dubious CNS-2: presence of blasts, RBC>100/μl; 3) surreptitious CNS-2: presence of blasts, <6 WBC/μl, RBC<100/μl; 4) CNS-3: presence of blasts, >5 WBC/μl, RBC<100/μl. Only CNS-3 pts were to receive 10 courses of i.v. MTX, but some of dubious (N=21) and surreptitious CNS-2 pts (N=19) did eventually receive 10 courses as well. Dubious CNS-2 (n=53), surreptitious CNS-2 (n=52), and CNS-3 (n=54) contained a higher rate of pts with unfavourable features than CNS-1 pts: WBC > 100000/μl; T-lineage; NCI high risk; very high risk (VHR) features (≥1000 peripheral blasts/μl post prephase, high-risk cytogenetics). Median follow-up was 7.5 years. The 5-yr overall event-free survival (EFS) and overall survival (OS) rates (SE%) were 71.6 % (1.0 %) and 82.6 % (0.8%) respectively. The 5-yr EFS rate (SE%) was 72.1 % (1.0%) for CNS-1, 62.2 % (6.6%) for dubious CNS-2, 64.7 % (6.7%) for surreptitious CNS-2, and 70.3 % (6.2%) for CNS-3 group. Overall, pts with blasts in the CSF (dubious CNS-2, surreptitious CNS-2 or CNS-3) had a significantly (p=0.02) shorter EFS than those in the CNS-1 group: 5-yr EFS rate 65.6% (3.8%) vs 72.1%. Multivariate analysis indicated that low WBC, Medac E-Coli asparaginase, absence of VHR features, middle age group were, together, predictive for longer EFS, whereas CNS involvement (CNS-2/-3 vs CNS-1) lost its prognostic value (p=0.87). Out of 2018 pts who reached CR, a total of 71 isolated and 78 combined CNS relapses were reported. The 5-yr isolated CNS relapse rate was 3.8%: 3.5% in CNS-1, 6.7% in dubious CNS-2, 10.5% in surreptitious CNS-2 and 7.1% in CNS-3 group. The 5-yr isolated or combined CNS relapse rate was 7.9%; in the 4 CNS-groups it was 7.6%, 11.1%, 14.7% and 9.2% respectively. The 5-yr OS rate (SE%) was 83.5% (0.9%) in CNS-1 vs 72.4% (3.9%) in CNS-2/-3: p=0.0003. Prognostic importance was lost (p=0.23) in multivariate analysis. Conclusion: the presence of blasts in the CSF, with or without pleiocytosis, is associated with unfavorable prognostic features and with worse outcome. Intensification of CNS-directed chemotherapy, without CNS radiation, is an effective treatment of initial meningeal leukemic involvement.
Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and ...adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.
The purpose of this study was to determine the clinical and biological characteristics at diagnosis in children and adolescents with chronic myelogenous leukemia (CML) in contemporary practice.
...Analysis was conducted on data from 3 prospective trials conducted in children and adolescents with CML. Forty pediatric patients were evaluated in 16 French pediatric oncology units between 1991 and 2003.
The disease predominately affected children who were older than 10 years (67% of the patients), with a higher prevalence in boys than girls (gender ratio: 1.5). Approximately 20% of cases were diagnosed incidentally. The main presenting symptoms were asthenia, weight loss, and complaints related to splenomegaly. Occasional patients presented with signs evocative of leukostasis. Symptoms were more common in patients with splenic enlargement, which was present in 70% of patients, and higher leukocyte counts. Markedly raised leukocyte counts were common (median white blood cell count: 242 x 10(9)/L). The age and the gender of the patients had no effect on the leukocyte count, the hemoglobin level, or the platelet count. A predominance of b3a2 transcript was observed in the 16 children who were studied for the type of chimeric BCR-ABL mRNA.
This is largest reported series of CML at diagnosis in children and adolescents. It shows that the characteristics of CML seem to differ in children compared with previously published adult series; in particular, the presenting leukocyte counts are often higher in children.
Out of 744 newly diagnosed ALL children under the age of 18 years treated according to the EORTC-CLCG protocols 58831 and 58832, 28 (4%) were infants less than 1 year of age. An elevated risk factor, ...which takes into account the sizes of the liver and spleen and the number of circulating blasts, was present in 25 cases. Most patients had non-common ALL. Among 15 patients studied by cytogenetics, nine present chromosomal abnormalities, six of them having a t(4;11) translocation. Complete remission was achieved in 86% of cases. One patient died in complete remission of therapy-related infection. The overall EFS is 43%. It is not statistically different in very young infants as compared to infants older than 6 months. Except for patients with AUL or with t(4;11) translocation, a continuous complete remission rate above 50% can be achieved with a median follow-up of 4 years. The results obtained in infant ALL with EORTC-CLCG protocols are currently better than those obtained with some other protocols, but remains inferior when compared to the ones obtained in older children. Thus, further improvements are needed and should be evaluated in large cooperative trials.
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