G. Schaison

Subacute and chronic myelomonocytic leukemia in children (juvenile CML). Clinical and hematologic observations, and identification of prognostic factors

The clinical and hematologic characteristics of 38 children with subacute and chronic myelomonocytic leukemia (S & CMMOL) are described, and the prognostic significance of these characteristics as recorded at diagnosis is reported. The common and distinctive feature of these children was the excessive proliferation of cells of neutrophilic and monocytic series. The disease predominated in younger children, 95% were younger than 4 years, and boys were more affected than girls (22/16). The onset of the disease was heralded most often by acute or subacute symptoms. Splenomegaly was the most common physical finding at diagnosis. Leukocytosis was usually under 100 × 109/I. Monocytosis and granulocytosis were often associated with normoblastosis, and, in some cases, with moderate blastosis (≦30%). Severe anemia and marked thrombocytopenia were found in about one third of patients, increased fetal hemoglobin levels in 53%, and increased γ‐globulin levels in 50% of cases. The Philadelphia chromosome was absent in all blood and marrow cell karyotypes. Thirty‐three of 38 patients were treated with moderate or intensive chemotherapy, and in all cases treatment never resulted in a complete remission. Terminal acute leukemia occurred in 11 cases. Of the 38 patients, 29 have died (median survival time, 16 months). Initial characteristics predicting a short survival (log‐rank test) included: older age (≦2 years) (P < 0.001), hepatomegaly (P < 0.05), bleeding (P < 0.001), thrombocytopenia (P < 0.01), high counts of blasts and normoblasts in peripheral blood (P < 0.01, P < 0.01). Sex, infections, cutaneous manifestations, lymphadenopathy, degree of splenomegaly, hemoglobin levels, fetal hemoglobin, leukocyte counts, percent of blasts in bone marrow, and serum γ‐globulin levels were of no prognostic value. When survival was plotted on a semilogarithmic scale, a change in death rate was evident at the second year of survival suggesting that there may be two subgroups of patients with myelomonocytic picture, one with very rapid, and another with a much slower rate of mortality. A stepwise discriminant‐function analysis was performed in an attempt to distinguish between those children who lived ≦2 years and those who lived longer. A linear combination of variables which best discriminated between these two subgroups was found. Nearly all patients could be classified as a short‐survivor or long‐survivor on the basis of age and platelet, blast, and normoblast counts in peripheral blood. This discriminant function may be used for the estimation of prognosis and, accordingly, for the selection of the appropriate therapy of new cases.

Bone Marrow Transplantation in Fanconi Anaemia

Summary Five patients with Fanconi anaemia have been treated by bone marrow transplantation from HLA identical donors. Only one patient survived for more than 3 years. She is now perfectly healthy with complete haematological reconstitution with chimaerism and disparition of chromosomal abnormalities. In contrast, four patients died of acute severe GVHD soon after grafting. In addition, all had signs of severe cyclophosphamide toxicity. This evolution could be explained by a special sensitivity of FA cells to alkylating agents and may indicate the need to modify the conditioning regimen in FA patients.

Critical study of prognostic factors in childhood acute lymphoblastic leukaemia: differences in outcome are poorly explained by the most significant prognostic variables. Fralle group. French Acute Lymphoblastic Leukaemia study group.

We determined the proportion of survival variability explained by the usual prognostic factors in childhood acute lymphoblastic leukaemia (ALL) during a prognostic study of 1552 patients enrolled in three consecutive Fralle group protocols (Fralle 83, Fralle 87 and Fralle 89). The event‐free survival rates at 5 years were 54.8% (SD 1.9), 43.1% (SD 2.7) and 55.6% (SD 2.2), respectively. In the univariate analysis the following variables were predictive of poor outcome: male gender, elevated leucocytosis (> 50 × 109/l), circulating blastosis, haemoglobin >12 g/dl, platelet count <100 × 109/l, age under 1 year or over 9 years, enlarged mediastinum, nodes, spleen and liver, T phenotype, absence of CD10+ cells; testicular and meningeal involvement, poor response to induction therapy (CCSG M3), and LDH >400 U/l. Among the cytogenetic features, hyperdiploidy had a protective effect, whereas hypodiploidy, translocation and other structural abnormalities had a negative influence, particularly in cases of t(9;22) or t(4;11). Multivariate analysis summarized the prognostic information in terms of four variables: age, gender, leucocytosis and cytogenetic features. Missing data had little influence on the results. However, despite their significance in the multivariate analysis, these four variables each had very low predictive power (1.1% for gender, 2.0% for age, 3.5% for leucocytosis, and 1.6% for cytogenetic features). Thus, the most significant prognostic factors in childhood ALL each explain no more than 4% of the variability in prognosis. This may explain the disappointing practical value of these factors and underlines the need for prognostic tools in childhood ALL.

Myelodysplastic syndromes in childhood: report of 49 patients from a French multicentre study

We describe the clinical, cytological and cytogenetic features of 49 cases of myelodysplastic syndromes (MDS) in childhood. Three children had received prior cytotoxic treatment (group 1); all of these had cytogenetic abnormalities and died shortly after diagnosis. 22 children had constitutional anomalies (group 2). The remaining 24 MDS were considered as ‘primary’ (group 3). Hypoplastic marrow was found in nine cases, and only 53% of the MDS fitted the adult FAB classification. Transformation to AML occurred in 11 cases, development of aplastic anaemia in three cases, and spontaneous remission in one case each of RA and RAEB. Differences were observed between groups 2 and 3 in terms of mean age at diagnosis (11.1 months v 5 years), rate of cytogenetic anomalies (15% v 38%) and rate of progression towards acute leukaemia (13% v 29%). In group 2, all the four girls studied exhibited a polyclonal pattern of X‐inactivation, which suggests that MDS may be only the haematological expression of an embryological defect with different target tissues.

Impact of Addition of Maintenance Therapy to Intensive Induction and Consolidation Chemotherapy for Childhood Acute Myeloblastic Leukemia: Results of a Prospective Randomized Trial, LAME 89/91

PURPOSE To determine whether the use of maintenance therapy (MT) delivered after intensive induction and consolidation therapy confers any advantage in childhood acute myeloid leukemia (AML). PATIENTS AND METHODS A total of 268 children with AML were registered in the Leucámie Aiquë Myéloïde Enfant (LAME) 89/91 protocol. This regimen included an intensive induction phase (mitoxantrone plus cytarabine) and, for patients without allograft, two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase, and amsacrine. In the LAME 89 pilot study, patients were given an additional MT consisting of mercaptopurine and cytarabine for 18 months. In the LAME 91 trial, patients were randomized to receive or not receive MT. RESULTS A total of 241 (90%) of 268 patients achieved a complete remission. The overall survival and event-free survival at 6 years were 60% +/- 6% and 48% +/- 6%, respectively. For the complete responders after consolidation therapy, the 5-year disease-free survival was not significantly different in MT-negative and in MT-positive randomized patients (respectively, 60% +/- 19% v 50% +/- 15%; P =.25), whereas the 5-year overall survival was significantly better in MT-negative randomized patients (81% +/- 13% v 58% +/- 15%; P =.04) due to a higher salvage rate after relapse. CONCLUSION More than 50% of patients can be cured of AML in childhood. Either drug intensity or each of the induction and postremission phases may have contributed to the outstanding improvement in outcome. Low-dose MT is not recommended. Exposure to this low-dose MT may contribute to clinical drug resistance and treatment failure in patients who experience relapse.

Use of Recombinant Human Granulocyte Colony-Stimulating Factor to Increase Chemotherapy Dose-Intensity: A Randomized Trial in Very High-Risk Childhood Acute Lymphoblastic Leukemia

PURPOSE To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.

Nitrogen mustard-induced chromosome breakage: A tool for Fanconi's anemia diagnosis

Abstract Chromosome studies were performed on phytohemagglutinin-stimulated lymphocytes from 9 Fanconis anemia (FA) patients, 6 of their parents, 7 controls, 2 children with aplastic anemia of unknown etiology, and one child with Zinsser-Cole-Engman syndrome. The addition of low doses (0.0085 μg/ml) of nitrogen mustard to cultures dramatically increased the chromosome breakage level in FA, the increase evaluated from means of chromosome anomalies per cell was highly significant (p

Complete correction of Glanzmann's thrombasthenia by allogeneic bone‐marrow transplantation

Summary Allogeneic bone marrow transplantation (BMT) successfully corrected type I thrombasthenia in a 4‐year‐old boy. The donor was his HLA‐A, B and D identical 14‐year‐old brother who was heterozygous for thrombasthenia. A first transplant after conditioning with cyclophosphamide and thoracoabdominal irradiation was rejected, but a second transplant using CCNU, cyclophosphamide, procarbazine and horse antihuman thymocyte globulin in the preparative regimen was successful. Engraftment was proven by studies of platelet membrane antigens, PLA1 and glycoprotein IIb/IIIa complex and by platelet function studies. Haemor‐rhagic manifestations completely disappeared; platelet membrane markers and clot retraction returned promptly to normal values, and platelet aggregation tests more slowly. Twenty‐four months after bone‐marrow transplant, the patient was well with mild chronic hepatic graft versus host disease. BMT therefore appears to be a possible treatment for severe inherited platelet disorders.

Philadelphia chromosome‐positive chronic myelocytic leukemia in children survival and prognostic factors

The survival and the prognostic significance of the diagnostic characteristics of 39 children with Philadelphia chromosome‐positive chronic myelocytic leukemia (Ph1‐positive CML), seen between 1963–1976 at the Hǒpital Saint‐Louis of Paris, have been analyzed. The disease predominated in children older than age 4 years (95%), with girls being more affected than boys (24 versus 15). The clinical and hematological picture at presentation was similar to that observed in adults with Ph1‐positive CML. Most children of this series were treated with busulfan which, as in adults, led to reduction of leucocytosis and organomegaly but did not prevent the occurrence of blastic crisis. Well‐documented blastic crisis was observed in 78% of cases. Of 39 children, 12 were still alive, all in the chronic phase. Twenty‐seven have died, 21 of them after blastic crisis, 4–156 months after diagnosis (median survival, 53 months). The effect of each diagnostic characteristic on survival was evaluated using the log‐rank test. Of the 14 characteristics studied, only the degree of blood and marrow blastosis was associated with a shorter survival. Age, sex, bleeding, lymphadenopathy, hepatomegaly, degree of splenomegaly, hemoglobin level, total leucocyte, immature granulocyte (promyelocytes + myelocytes + metamyelocytes), eosinophil, basophil, and platelet counts in the peripheral blood were of no prognostic significance. The failure to attain a level of statistical significance for some characteristics found to be of prognostic value for adults, could be due to the small sample size and/or to the disease homogeneity. The results of this study, however, stress the importance of the initial blastic infiltration in determining the duration of survival, which is ultimately determined by the occurrence of terminal acute leukemia. In conclusion, this study shows that the Ph1‐positive CML of childhood exhibits the same course, incidence of blastic crisis, and survival as the disease of adults. It also indicates that treatment with moderate chemotherapy, such as busulfan, has no effect on the duration of survival. Therefore, new therapeutic approaches are urgently needed for the treatment of this disorder in children.

Evaluation of 216 four-year survivors of acute leukemia

Analyses of records of 216 long‐term leukemia survivors disclose two types of patients‐those in whom survival does not appear heavily dependent on the type of therapy or its duration and those in whom survival depends heavily on the therapeutic program of periodic reinductions. Prognosis significance of hematologic relapse and of meningeal relapse was evaluated. Early hematologic relapses because of inadequate initial therapy may leave place for hope if patients are correctly treated afterwards; late hematologic relapses in patients correctly treated from the onset of their disease are of poor prognosis. A group of nine children who developed meningeal disease during the first 2 years of their disease and are still enjoying complete hematologic remission 4 to 7 years later. Meningeal relapses occurring after the third year have a uniformly bad prognosis. Long‐term survivals probably do possess, at least in the first group, host properties which we are unable to recognize and unable to take advantage of.