Fludarabine and cytarabine as a sequential infusion regimen for treatment of adults with recurrent, refractory or poor prognosis acute leukemia.

We did a retrospective analysis on the safety and efficacy of sequential infusion fludarabine and cytosine arabinoside (ara-C) in treating refractory, recurrent or poor prognosis acute leukemia in adult patients. Forty-five adult patients with acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) received a total of 68 courses of sequential continuous infusion of fludarabine for 2 days (total dose 71.5 mg/m(2) ) followed by 3 days of ara-C (total dose 7590 mg/m(2) ). Thirty-nine patients had refractory or recurrent disease, and six had other adverse prognostic features. Thirty-six patients had AML, seven had ALL, and two had CML in blastic phase. Complete remission was seen in 20 patients (44%), and partial remission in 5 patients (11%), giving a total response rate of 56%, similar for both AML and ALL. Duration of response to prior therapy did not affect the response rate. All 3 patients with Philadelphia chromosome positive ALL obtained complete remission. Median remission duration was 4.7 months (range 0.6-36.6), and median overall survival was 5.0 months (0.7-40+). Median overall survival was 10.1 months in responders. Pulmonary toxicity was seen in 8 patients, of whom 2 died from adult respiratory distress syndrome. No cardiac toxicity was observed, but 3 patients had transient cerebellar toxicity. Profound myelosuppression was seen in all patients. We conclude that the sequential infusion of fludarabine and ara-C is an effective non-cardiotoxic regimen for adults with refractory, recurrent or poor prognosis acute leukemia, may be particularly useful for resistant Philadelphia chromosome positive ALL, and may warrant further investigation in this subset. Pulmonary rather than neurological toxicity may be a unique side effect of the regimen.

Addition of high-dose Ara-C to the BMT conditioning regimen reduces leukemia relapse without an increase in toxicity.

The optimal conditioning regimen for allogeneic BMT for hematological malignancies is still to be determined. We used a conditioning regimen including high-dose Ara-C (HDAC)/CY/TBI for patients at high risk for leukemic relapse (regimen A, Ara-C 3 g/m2 every 12 h for six doses followed by CY 45 mg/kg for 2 days and TBI 13.2 Gy in eight fractions) and a standard CY/TBI conditioning regimen for patients at low risk (regimen B, CY 60 mg/kg for 2 days and TBI 13.2 Gy in eight fractions). We analyzed 55 patients treated with regimen A (group A) and 36 patients with regimen B (group B). Relapse rates (10.9% in group A, 2.9% in group B, P = 0.23), 5-year overall (53.2% in group A and 60.8% in group B, P = 0.26) and disease-free (47.7% in group A and 60.8% in group B, P = 0.11) survival rates were not significantly different between these groups, although group A consisted of high-risk patients. Regimen-related toxicities were not significantly different between the two groups. This result suggests that adding HDAC to CY/TBI conditioning regimen may reduce leukemic relapse and improve survival without increasing regimen-related toxicities.

Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1.

BACKGROUND: Children with neurofibromatosis type 1 (NF1) are at increased risk of developing benign and malignant solid tumors as well as hematologic malignancies, including de novo juvenile chronic myelogenous leukemia, monosomy 7 syndrome, and acute myelogenous leukemia. The normal NF1 allele is frequently deleted in the bone marrow cells from NF1 patients with hematologic malignancies, suggesting a pathogenic role in primary leukemogenesis. The authors report monosomy 7 myelodysplastic syndrome (MDS) as a second malignant neoplasm (SMN) in five children with sporadic NF1, the results of molecular analysis for NF1 and ras alterations in their bone marrow, and summarize their experience with SMNs in pediatric patients with NF1. METHODS: Monosomy 7 MDS was diagnosed as an SMN in five children with NF1 by morphologic and cytogenetic studies of bone marrow specimens. DNA extracted from these malignant bone marrows was analyzed for allelic loss at the NF1 locus and for the presence of ras mutations. The Children's Hospital of Philadelphia (CHOP) Tumor Registry was also reviewed to estimate the incidence of SMNs in pediatric NF1 patients. RESULTS: Bone marrow specimens from four patients retained constitutional heterozygosity at the NF1 locus; one specimen was uninformative. There was no evidence of activating ras mutations. The risk of an SMN was approximately 11% among the 64 NF1 registrants with primary malignancies in the CHOP registry, but was 75% (6 of 8) among patients treated for a pediatric embryonal cancer. CONCLUSIONS: Children with NF1 are susceptible to the development of malignant myeloid disorders both as a primary event and as an SMN. Additional molecular genetic analysis is necessary to determine if the NF1 gene is inactivated by somatic mutation in these secondary leukemias.

Progressive Langerhans cell histiocytosis in an infant with Klinefelter syndrome successfully treated with allogeneic bone marrow transplantation.

PURPOSE: We describe successful treatment of an infant with progressive Langerhans cell histiocytosis (LCH) with allogeneic bone marrow transplantation (BMT), and discuss a chromosomal abnormality discovered in his LCH-affected tissue. PATIENTS AND METHODS: A 4-month-old male infant with a seborrheic-appearing rash, respiratory collapse, and spontaneous pneumothorax is presented. LCH was diagnosed with primary involvement of skin and lungs. His disease progressed despite aggressive multiagent chemotherapy that included high-dose methylprednisolone, vinblastine, cyclophosphamide, methotrexate, 2-chlorodeoxyadenosine, and etoposide. RESULTS: The patient was successfully treated with myeloblative therapy and low-dose total body irradiation followed by allogeneic BMT at the age of 16 months, at which time he had multisystem involvement. One hundred percent 47XXY/14p+ cells were identified from a lung biopsy; peripheral blood chromosomal analysis demonstrated mosaic 47XXY/14p+, and normal 46XY. CONCLUSIONS: Allogeneic BMT may be used successfully in the treatment of refractory, progressive LCH in infants, who are at highest risk of mortality. The cytogenetic association between Klinefelter syndrome and LCH has not been described previously. Cytogenetic analysis of other patients with LCH may be beneficial in determining a genetic association between LCH and Klinefelter syndrome and/or abnormalities of chromosome 14.

Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Childrens Cancer Group.

The purposes of this report are to reaffirm concordance difficulties with the acute myeloid leukemia (AML) French-American-British (FAB) classification, to present the frequency of previously delineated AML syndromes in pediatric patients and to describe additional characteristic AML profiles utilizing composite morphologic, cytogenetic and immunophenotypic data. Profiles of 124 children with acute myeloid leukemia (AML) and 13 children with myelodysplastic syndrome entered on the Childrens Cancer Group (CCG) pilot study CCG-2861 were examined. Concordance between institutions and reviewers for FAB designation was 65%. Discordance was found principally between M1 and M2, M2 and M4, and M4 and M5. In 49% of marrow specimens, leukemic blasts expressed at least one T lineage-related antigen; 24% expressed the B lineage-related antigen CD19. CDw14 correlated with FAB M4 or M5 morphology and was the only surface antigen associated with a specific FAB subtype. Normal karyotypes were found for 15% of the 75 children with satisfactory karyotype preparations. Recurring aberrations, found in 76% of children, included t(15;17)(q22;q11), t(8;21)(q22;q22), inv(16)(p13q22), rearrangements of band 11q23, t(6;9) (p23;q34), trisomy 8 and monosomy 7. Results from this pilot study and from the current CCG randomized trial correlating morphology, immunophenotyping and cytogenetics, will help to classify AML into unique subgroups with differing clinical consequences or therapy requirements.

Musculoskeletal neoplasms: preoperative evaluation with MR angiography.

PURPOSE: To assess the ability of magnetic resonance (MR) angiography to depict vascularity of musculoskeletal neoplasms. MATERIALS AND METHODS: Two-dimensional (2D) time-of-flight (TOF) MR angiography was compared with conventional arteriography during staging of musculoskeletal tumors in 23 prospective examinations. Phase-contrast (PC) MR angiography was also performed in 19 cases and evaluated as a possible supplement to 2D TOF imaging. RESULTS: Of named vessels, 92% in proximity to tumor were noted by blinded readers. The PC technique provided supplemental data in 47% of cases, usually related to better delineation of in-plane feeder vessels and areas with pulsatile blood flow. Of the 28 branch feeder vessels, 23 were noted on both conventional arteriograms and MR angiograms in a nonblinded review, but 16 were difficult to distinguish as feeders because of lack of associated tumor blush. CONCLUSION: MR angiography has promise to replace conventional arteriography for orthopedic preoperative planning.

Treatment of Wilms' tumour. Current recommendations.

Wilms' tumour (nephroblastoma, renal embryoma) is the fifth most common paediatric malignancy, arising from the embryonal tissue of kidneys and first formally described by Max Wilms in his classic 1899 monograph. Until the early part of this century, Wilms' tumour was associated with a less than 20% survival rate. The current survival rate exceeds 80%, primarily due to large multi-institutional trials such as the National Wilms' Tumor Study (NWTS). These studies have refined and defined the roles of surgery, chemotherapy, and radiation in treating Wilms' tumour, based on staging and histology. The dramatic improvement in the prognosis for children with Wilms' tumour, especially over the past 20 years, represents a landmark achievement in the history of paediatric oncology. Specific treatment recommendations are based on the current National Wilms' Tumor Study IV schema. Stages I and II favourable histology patients do not receive radiotherapy, but are treated postoperatively with 'pulsed' or 'conventional' dactinomycin and vincristine; stage III favourable histology requires postoperative abdominal radiotherapy followed by triple agent, 'conventional' or 'pulsed' chemotherapy (dactinomycin, doxorubicin and vincristine). Patients with stage IV favourable histology, stages II to IV anaplastic, clear cell or rhabdoid histology, are treated similarly with aggressive triple-agent chemotherapy, with the addition of radiotherapy to selected sites. Recurrent and adult Wilms' tumours have poor prognoses and are treated with aggressive surgery, radiotherapy and chemotherapy.

Clinical importance of myeloid-antigen expression in acute lymphoblastic leukemia of childhood.

BACKGROUND: Leukemic cells in 15 to 25 percent of patients with acute lymphoblastic leukemia (ALL) express myeloid antigens as well as lymphoid antigens (the latter reflecting B-cell or T-cell lineage). The relations of myeloid-antigen expression to other features of ALL and to prognosis have been controversial. METHODS: We analyzed clinical and laboratory features present at diagnosis in 236 consecutive cases of ALL in children. Immunophenotyping, including single- and dual-fluorescence analyses, was used to classify leukemic cells as B or T lymphoblasts and also to identify myeloid-antigen expression--the simultaneous expression of lymphoid-associated antigens and at least one of three myeloid-associated antigens (CD33, CD13, and CD14) on cells classified as L1 or L2 according to the French-American-British system. RESULTS: Forty-five of 185 patients with B-lineage ALL had myeloid-antigen expression, as did 8 of 41 patients with T-lineage ALL. In 10 patients, the lineage could not be determined. Myeloid-antigen expression was associated with L2 morphology (P less than 0.05), but it did not correlate with other prognostic features recognized previously. Multivariate analysis showed that myeloid-antigen expression was an important predictor of relapse in childhood ALL and the most significant prognostic factor statistically (P less than 0.0001). A white-cell count greater than or equal to 50 x 10(9) per liter at diagnosis was also an important and highly significant prognostic feature (P less than 0.001). After 40 months, the estimated disease-free survival for patients with ALL was 84 percent for those without myeloid-antigen expression and with a low white-cell count, 57 percent for those without myeloid-antigen expression and with a high white-cell count, 47 percent for those with myeloid-antigen expression and a low white-cell count, and 26 percent for those with myeloid-antigen expression and a high white-cell count (P less than 0.00001). CONCLUSIONS: Myeloid-antigen expression is an important independent predictor of a poor response to chemotherapy in childhood ALL.