Nasrollah Hakami

Vincristine, prednisone and L-asparaginase in the induction of remission in children with acute lymphoblastic leukemia following relapse.

Two hundred and twenty‐seven children with recurrent acute lymphoblastic leukemia were treated with various combinations of vincristine, prednisone, cyclophosphamide and L‐asparaginase in an approach to the induction of remission. The combination of L‐asparaginase 1,000 μ/kg iv q.d. X 10, vincristine 2.0 mg/m2iv q.w. X 4 and prednisone 40 mg/m2 p.o.q.d. X 28 days was found to be highly effective. The incidence of remission was 73%. No significant improvement was achieved when cyclophosphamide was added to this regimen. Various combinations of cytosine arabinoside, cyclophosphamide, vincristine, prednisone, BCNU or CCNU failed to maintain remission duration for more than two to three months. Neither BCNU nor CCNU prevented the development of CNS leukemia.

Alterations of HLe-1 (T200) fluorescence intensity on acute lymphoblastic leukemia cells may relate to therapeutic outcome.

Quantitative differences in HLe-1 expression were studied on normal lymphocytes and lymphoblasts of patients with acute lymphoblastic leukemia (ALL). A relationship was found between quantitative antigen expression and therapeutic outcome. Alterations in fluorescence intensity (FI) were demonstrated using quantitative flow cytometric methods and the monoclonal antibody (MoAb) anti HLe-1 (T200). Lymphoblasts from patients with ALL produced FI peaks ranging form channel 17 to 112 (mean 68; n = 28), while normal lymphoid cells were at FI channel 127 +/- 3 (n = 121). Patients with the dimmest-staining lymphoblasts (channels 17-50) responded better to therapy than those with brighter-staining cells (channels 50-100). Data from this pilot study suggests that the FI of malignant lymphoblasts has implications in the clinical response to therapy.

Translocation (4;11) in acute myelogenous leukemia

A child with acute myelogenous leukemia is presented. Cytogenetic analysis of her leukemic cells revealed a (4;11)(q12;q23) translocation. The slight difference in the breakpoint on chromosome #4 from previously reported cases of t(4;11) may account for the degree of myeloid differentiation expressed. Acute leukemia associated with t(4;11) is a unique subgroup that originates in an early myeloid stem cell and carries a poor prognosis.

Sequential oral hydroxyurea and intravenous cytosine arabinoside in refractory childhood acute leukemia: a pediatric oncology group phase 1 study.

At concentrations >0.1 mM, hydroxyurea (HU) enhances the accumulation of cytosine arabinoside (ara-C) in leukemia cells in vitro. This study of children with refractory acute leukemia was designed to take advantage of this biochemical modulation. A fixed dose of HU and an escalating dose of ara-C were used. Oral HU (1200 mg/m2) was followed 2 hours later by ara-C (250–3100 mg/m2) intravenously in 15 minutes. The combination was given on days 1, 2, 3 and 8, 9, 10. Thirty-three children [26 acute lymphocytic leukemia (ALL), 7 acute nonlymphocytic leukemia] were treated; 29 received at least 1 full course. All patients developed grade 4 cytopenias. Other grade 3 to 4 toxicities included hyperbilirubinemia (2), elevated transaminases (3), transient gait disturbance (1), stomatitis (3), typhlitis (1), nausea/vomiting (9), and marrow aplasia >4 weeks (1). Three patients had intracranial bleeds while thrombocytopenic. Only liver toxicities and nausea/vomiting exhibited any dosage effect. The maximum tolerated dose of ara-C was 2400 mg/m2. There were 6 complete responses (5 ALL), 5 partial responses (3 ALL), and 19 patients with no response or progressive disease. There was no dosage effect for response with 2 complete responses occurring at the lowest ara-C level. Responses were transient (1 to 3 mo). Twenty of twenty-six patients achieved a peak serum HU level >0.5 mM by 2 hours after the HU dose. The mean level at 2 hours was 0.57 mM (range: 0.21 to 0.99 mM). This combination of HU and ara-C is tolerable and has efficacy in refractory leukemias. Responses at the lowest ara-C dose level suggests synergism.

Osteogenic sarcoma following Hodgkin's disease

The cases of two children who developed osteogenic sarcoma of the distal femur following prolonged remission of Hodgkins disease are reported. These cases are unique in that the sarcoma developed in an area not previously irradiated. This occurrence suggests the possibility of genetic susceptibility to primary cancers in certain individuals, although prior chemotherapy may have contributed to this occurrence.

ELEVATED PLASMA RENIN ACTIVITY AND “BIG RENIN” IN MESOBLASTIC NEPHROMA

Elevation of plasma renin activity (PRA) has been reported with several kidney tumors, but not with mesoblastic nephroma (MN), a common renal tumor of early infancy. We have studied a 3 month old infant with a large intrarenal mass, histologically characterized as MN. Prior to removal of the tumor, the infant exhibited severe hypertension, and moderate hypokalemia. PRA from peripheral veins, aorta, and inferior vena cava, below the renal vein were markedly elevated to greater than 300 ng/ml/hour. Massive amounts of “Big Renin”, greater than 1000 ng/ml/3 hour were also demonstrated. Normalization of blood pressure and serum potassium occurred shortly after removal of the renal mass, and PRA and “Big Renin” returned to basal levels. There is no evidence of tumor recurrence and serial measurements of PRA over a 12 month period shows levels below 5 ng/ml/hour and “Big Renin” remains undetectable. Also, in repeated studies, expansion of plasma volume resulted in suppression of PRA, demonstrating normal regulation of renin release. These observations suggest: (1) Mesoblastic nephroma may be associated with autonomous production of PRA, producing hypertension and hypokalemia; and (2) Serial measurements of PRA may be a useful biologic marker for detection of early recurrence of the tumor.