Adverse prognostic features in 251 children treated for acute myeloid leukemia.

Potential predictors of event-free survival (EFS) were assessed in 251 consecutively diagnosed children treated for acute myeloid leukemia (AML) on three successive clinical trials. The lack of significant differences in 4-year EFS for these studies (20% +/- 4%, 29% +/- 4%, and 20% +/- 7%) permitted combined analysis of presenting features. Splenomegaly (P = .002), coagulation abnormalities (P = .001), leukocyte count > or = 10 x 10(9)/L (P = .002), and age > 14 years (P = .01) were statistically significant predictors of a poorer EFS by univariate analysis and retained significance in multivariate analysis. Age < 2 years and monocytic leukemias (often cited as adverse factors in AML) showed no prognostic influence in this study. The estimated relative risk of failure for a child with a single adverse feature at diagnosis was at least 1.4 times greater than that for a patient with no adverse features. For children with two or more adverse features, the relative risk increased by more than threefold. These clinical variables, alone or in combination, may identify important subgroups of patients with AML at high risk for failure and for whom improved or alternative therapies are especially important.

High-dose cyclophosphamide-high-dose methotrexate with coordinated intrathecal therapy for advanced nonlymphoblastic lymphoma of childhood: results of a Pediatric Oncology Group study.

The Pediatric Oncology Group (POG) investigated a high-dose cyclophosphamide (CPM) high-dose methotrexate (MTX) regimen to determine therapeutic efficacy in confirmed advanced nonlymphoblastic non-Hodgkin's lymphoma (NHL) (stages III and IV) and B-cell acute lymphatic leukemia (B-ALL) in children. Another goal was to determine the comparative effectiveness of shortened maintenance treatment (2 versus 6 courses) in the study population. Systemic induction therapy included vincristine, prednisone, cyclophosphamide, and intermediate-dose MTX with leucovorin rescue. Superimposed intrathecal (IT) therapy included cytosine arabinoside for 2 successive days followed on day 3 by MTX. Intrathecal MTX was given 3 times during induction. At the end of induction, 2 days of triple (hydrocortisone, MTX, and cytosine arabinoside) therapy were given intrathecally (TIT). All patients then received a consolidation course of 4 doses of TIT, 2 doses of cyclophosphamide, and 4 more courses of vincristine and MTX with leucovorin rescue. Patients were then randomized to receive either 2 or 6 cycles of vincristine plus MTX with leucovorin rescue. The TIT was given with each cycle. Complete response rates by histology and Murphy stage (1) were as follows: undifferentiated lymphoma (DUL) stage III, 84/105 (80%): stage IV, 5/12 (42%); and other NHL [primarily large cell lymphoma (LCL)] stage III, 21/28 (75%); stage IV, 2/3 (67%). Event-free survival (EFS) at greater than 2 years was similar for patients with DUL and LCL, i.e., 65 and 61%, respectively. No significant difference in outcome was noted between patient groups receiving 2 or 6 maintenance treatments (p = .76). Treatment was notable for its modest toxicity following the early change to single-dose CPM therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Teniposide (VM-26) and continuous infusion cytosine arabinoside for initial induction failure in childhood acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study.

Twenty-six evaluable children with newly diagnosed acute lymphoblastic leukemia (ALL) who failed to achieve initial remission after receiving two to seven drugs for at least a 4-week period were given teniposide (VM-26) and continuous infusion cytosine arabinoside (Ara-C). Twenty-two received 150 mg/m2 of VM-26 on days 1 and 2 with 100 mg/2 of Ara-C as a continuous infusion on days 1 through 5; a second shortened course was given on day 14 to eight patients who had evidence of some antileukemic effect or were clinically judged able to tolerate a second course. The last four patients received three daily doses of VM-26 and a 7-day infusion of Ara-C at the same daily dosages. Twelve (48%) achieved complete remission (CR) of ALL. There was a trend toward decreasing response rates with an increasing number of drugs used in the initial induction regimen, i.e., five CR among seven patients with a prior two-drug induction attempt, six CR among 14 patients with a prior three- to four-drug induction attempt, and one CR among four patients with a prior five- to seven-drug induction attempt (P = 0.14). Ten of 17 non-T-cell patients and two of nine T-cell patients achieved remission (P = 0.10). The median time required to achieve a complete remission from the initiation of treatment was 26 days (range, 14-72 days). This period was shorter in those who required one course compared with those who required two induction courses, i.e., 25 days median vs. 44 days median. Toxicity was significant and due mainly to marrow aplasia and infection; one patient had severe prolonged VM-26-induced hypotension. Of the 12 patients entering remission, two were removed for marrow transplant and one was removed due to parental request. In the remaining nine patients, median remission duration was only 2 months (range, 1-18 months). All nine patients relapsed in the marrow. Among the entire group of 26 patients, only one patient is alive and a long-term event-free survivor (after allogeneic marrow transplant). Due to the current use of more aggressive initial induction regimens and the extremely poor prognosis in children who fail to achieve initial remission, more intensive regimens of continuation therapy or alternative therapies, such as bone marrow transplant, should be considered.

Intranuclear crystalloids associated with abnormal granules in eosinophilic leukocytes.

Ultrastructural evaluation of eosinophilic leukocytes from a 2-yr-old asymptomatic girl with chronic benign neutropenia (CBN) revealed a variety of morphological abnormalities. All eosinophils obtained from blood and marrow specimens contained multipole microcrystalloids in most of the mature cytoplasmic granules. An increase in crystalloid-free, immature granules in late (bilobed nuclei) eosinophils suggested a delay in granule maturation. The eosinophil granules appeared to be of normal size and demonstrated normal acid phosphatase reactivity. Eosinophilic myelocytes contained abnormal cisternae of rough endoplasmic reticulum (RER) and lacked abundant elongated RER cisternae seen in normal cells. A few eosinophilic myelocytes in specimens of bone marrow from the child contained large intranuclear crystalloids measuring up to 3 mu in length. The intranuclear crystalloid contained as cubic lattice of dense material with a periodicity similar to that described for cytoplasmic crystalloids. The ultrastructural morphology of marrow neutrophils was normal, as described in other cases of CBN. Ultrastructural examination of blood eosinophils from the father demonstrated microcrystalloids in cytoplasmic granules identical to those seen in the child. The father was asymptomatic and had normal leukocyte counts. Thus, anomalous crystalloid granule genesis occurred in the father and daughter and was not necessarily associated with neutropenia or clinical symptomatology. This anomaly is associated with the accumulation of intranuclear crystalloid material in eosinophilic myelocytes, which do not appear to be released from the marrow compartment.

Milk fever in dairy cows. VIII. Effect of injected vitamin D3 and calcium and phosphorus intake on incidence.

In a field trial, effects of prepartal intermuscular injection of 10 million units of vitamin D3 on incidence of milk fever were examined both in relation to intake of calcium and phosphorous during the dry period and previous history of milk fever. Based upon intake of calcium and phosphorus cooperating herds were grouped as feeding: 1) greater than .53% of the total ration dry matter as calcium and greater than .28% as phosphorus: 2) less than .47% as calcium and greater than .28% as phosphorus; 3) greater than .47% to less than .53% as calcium and greater than .22% to less than .28% as phosphorus. Injections of vitamin D3 given approximately 1 wk prepartum reduced incidence of milk fever in cows with previous history of milk fever in all three groups but had no effect in cows with no previous milk fever. Incidence of milk fever was lower in group 3 than for cows of groups 1 and 2 with previous milk fever and than for cows of group 1 with no previous history. The results indicate that careful control of calcium and phosphorus intake during the dry period at .5% calcium and .25% phosphorus of the dry matter of the total ration will limit milk fever incidence to about 10%. Injections of vitamin D3 as described will reduce inicidence of milk fever further in cows with previous milk fever but not in cows with no previous milk fever.