Severe osteopenia in a young boy with Kostmann's congenital neutropenia treated with granulocyte colony-stimulating factor: suggested therapeutic approach.

Kostmann's syndrome is a congenital disorder that causes an impairment of myeloid differentiation in the bone marrow characterized by severe neutropenia, which can be treated with recombinant human granulocyte colony-stimulating factor (G-CSF). We present the case of a 13-year-old boy with Kostmann's syndrome who was treated with recombinant human G-CSF from age 3.5 years. His growth and development was normal, although complicated by intermittent infections. Bone mineral density (BMD) measurement revealed severe osteopenia at the spine and hips (lumbar spine BMD 0.486 g/cm(2); Z score -3.6), and he was referred to the Endocrine Service. Relevant laboratory evaluation showed a pretreatment ionized calcium level at the upper limit of normal (1.28 mmol/L; range: 1.13-1.32 mmol/L), suppressed intact parathyroid hormone (iPTH) level (12 pg/mL; range: 10-65 pg/mL), and a low 1,25-dihydroxy vitamin D level (21 pg/mL; range: 24-65 pg/mL). He had evidence of increased bone turnover evidenced by elevated urinary deoxypyridinoline (DPD) cross-links (46.9 nmol/mmol creatinine; range: 2-34 nmol/mmol creatinine) and a simultaneous increase in markers of bone formation with elevated osteocalcin level (200 ng/mL; normal: 20-80 ng/mL) and alkaline phosphatase level (236 IU/mL; normal: 38-126 IU/mL). Because of clinical concern for his skeletal health, bisphosphonate therapy with intravenous pamidronate was initiated. One month after treatment, the iPTH and DPD cross-links were in the normal range (54 pg/mL and 17.7 nmol/mmol creatinine, respectively) and the 1,25-dihydroxy vitamin D level was elevated (111 pg/mL). Four months after treatment, there was a striking increase in BMD at the lumbar spine (+30.86%), femoral necks (left, +20.02%; right, +17.98%), and total hips (left, +18.40%; right, +15.94%). Seven months after bisphosphonate therapy, his biochemical parameters showed a return toward pretreatment levels with increasing urinary DPD cross-links (28.7 nmol/mmol creatinine) and decreasing iPTH (26 pg/mL). However, the BMD continued to increase (8 months posttreatment), but the magnitude of the increment was attenuated (lumbar-spine, +4.8%; left total hip, +1.2% and right total hip +2.4%), relative to BMD at 4 months. Eight months after the initial treatment, his iPTH was suppressed at 14 pg/mL and he again received pamidronate (at a lower dose); 3 months later, he had an additional increase in BMD (lumbar spine +7.4%, left total hip +3.9%, right total hip +2.7%), relative to the previous study. We hypothesize that prolonged administration of G-CSF as treatment for Kostmann's syndrome is associated with increased bone resorption, mediated by osteoclast activation and leading to bone loss. In children, the resulting osteopenia can be successfully managed with antisreorptive bisphosphonate therapy with significant improvement in bone density. Measurements of biochemical parameters of bone turnover can be used to monitor the magnitude and duration of the therapeutic response and the need for BMD reassessment and, perhaps, retreatment.

Spontaneous remission of granulocyte colony-stimulating factor-associated leukemia in a child with severe congenital neutropenia.

Leukemia is observed with increased frequency in patients with severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy. The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period. The patient subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by polymerase chain reaction. This report provides novel insights on leukemia developing in congenital neutropenia.

Multilineage Immune-Mediated Cytopenias in Childhood: A Report of Five Patients.

This study was performed to determine whether there is any distinction to be made between single and multiple-lineage cytopenias particularly with regard to natural history and prognosis. From December 1989 to May 1994, five of 50 children (median age 7 years) with chronic immune cytopenias were diagnosed with multi-lineage immune- ediated cytopenias. Two patients presented with immune thrombocytopenia (ITP) and later developed autoimmune hemolytic anemia (AIHA); one had ITP and immune eutropenia who subsequently became Coombs' positive but never developed AIHA. One child presented with ITP and immune neutropenia and later developed AIHA. The fifth child presented simultaneously with thrombocytopenia and neutropenia with positive antineutrophil antibody but without antiplatelet antibody and Coombs' positivity. Four patients were given primary therapy with IVIG and one with prednisone. One patient responded to prednisone but relapsed subsequently. Further treatment with IVIG roduced initial normalization of his counts with occasional fluctuation of the absolute neutrophil count. Two responded to IVIG and are in complete remission (CR). Of the two nonresponders to IVIG, one responded subsequently to prednisone and is in CR. The other one, after being refractory to multimodality treatment, was diagnosed with a lupus erythematosis variant and is currently on alternate day prednisone. Moderate thrombocytopenia and absolute neutropenia still persist. Multi-lineage immune-mediated cytopenias may represent a pathogenic phenomenon that is distinct from autoimmune single-lineage disease. Clinical response to treatment may correlate with these differences that may be genetic in origin. Clinical course and response to therapy are less predictable when autoimmune disease is present.

Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide.

Seventeen children with advanced myeloid malignancies (induction failure, relapse, myelodysplasia, secondary AML, or CR >1) received thiotepa 750 mg/m2 i.v., busulfan 12 mg/kg or 640 mg/m2 p.o., and cyclophosphamide 120 mg/kg i.v. as a preparative regimen for allogeneic or autologous hematopoietic stem cell (HSC) transplantation. Of the 15 allogeneic transplants, eight were from matched siblings, one was from a mismatched sibling, and six were from unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Regimen-related toxicity was common but tolerable, affecting mainly the skin and gastrointestinal tract. Three patients died early and were not evaluable for engraftment; engraftment occurred in the remaining patients. Nine patients with active disease at the time of transplant were evaluable for response; all achieved remission. With a median follow-up of 40 months (range, 10-71 months), nine patients are alive and disease-free. The 3-year actuarial event-free survival was 51% (95% confidence interval (CI) 27-76%). Seven patients died of transplant-related complications: infection (n = 4), chronic GVHD (n = 1), veno-occlusive disease, VOD, (n= 1) and pulmonary alveolar hemorrhage (n = 1). Only one patient had leukemia relapse and died. We conclude that the use of high-dose thiotepa, busulfan and cyclophosphamide is an effective conditioning regimen for childhood myeloid malignancies and may be tested in patients with less advanced disease (eg CR1).

Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients.

BACKGROUND: Fever and neutropenia (F&N) is a common complication of cancer chemotherapy. It is conveniently managed by hospitalization and empiric administration of parenteral antibiotics. This study attempted to determine whether pediatric cancer patients with F&N identified as low risk for morbidity and mortality by clinical criteria at the time of presentation could be treated safely as outpatients. METHODS: Seventy-three episodes of F&N in 41 patients were studied prospectively over 2 years. Eligibility criteria included age > or =2 years, reliable caretakers, and residence within 1 hour of the hospital. Exclusion criteria included hemodynamic instability, dehydration, severe mucositis, pneumonia, leukemia/lymphoma induction therapy, bone marrow transplantation, or other serious comorbidity. Patients were evaluated, received a single dose of intravenous ceftazidime, and were observed for 3-16 hours. They were randomized to receive either oral ciprofloxacin or intravenous ceftazidime as outpatients. Patients were seen daily until they had been afebrile for at least 48 hours and had a rising absolute phagocyte count of >500 cells/microL. RESULTS: Sixty-three of 73 episodes (86%) were successfully managed on an outpatient basis. For 31 of 33 episodes in the ceftazidime arm, the patients remained outpatients, compared with 32 of 40 in the ciprofloxacin arm; this difference was not statistically significant. On average, patients remained febrile for 2.7 days and were treated for 4.7 days. Seventy-seven percent of episodes required no modification of initial antibiotic therapy. Of the 10 patients who were hospitalized, 4 had prolonged fever and 3 had emesis. Protracted neutropenia was associated with the need for hospitalization. There were no deaths, intensive care unit transfers, or serious complications. CONCLUSIONS: Carefully selected low risk children with fever and neutropenia can be treated safely as outpatients. Close daily medical scrutiny is required.

Economic and resource utilization analysis of outpatient management of fever and neutropenia in low-risk pediatric patients with cancer.

PURPOSE: To measure resource allocation in outpatient management of fever and neutropenia in low-risk pediatric patients with cancer and its impact on their families. PATIENTS AND METHODS: A prospective clinical trial was conducted. Eligible patients received a single dose of intravenous (IV) antibiotics and were observed for several hours in clinic. Patients were randomly assigned to continue either IV or oral antibiotics and were seen daily as outpatients. Charges were calculated based on the number of resources used and Medicare/Medicaid reimbursement schedules. A questionnaire was used to measure the impact of outpatient treatment on the family. RESULTS: Seventy-three episodes of fever and neutropenia were studied. The median duration of treatment was 4 days. Eighty-six percent of the episodes were managed without hospitalization. The median calculated charge was $1840. The median calculated charge for patients receiving oral antibiotics was $1544 and was significantly less than the $2039 median charge for outpatients treated with IV antibiotics. The estimated charge for comparable inpatient treatment was $4503. Nearly all families preferred outpatient care, and few reported a loss of work hours or increased child care expenses. CONCLUSIONS: Outpatient treatment of low-risk episodes of fever and neutropenia is substantially less costly than inpatient care and is preferred by most families.

Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study.

PURPOSE: A prospective study was conducted to assess the effects of chemotherapy for cancer on children's long-term neuropsychologic status. PATIENTS AND METHODS: Ninety-nine children who received no cranial radiation therapy (CRT) completed four annual neuropsychologic assessments. Fifty-one patients received intrathecal (IT) chemotherapy (ITC); 48 received no CNS treatment. These two groups were compared using repeated-measures analysis of variance on IQ, memory, language, freedom from distractibility, academic achievement, executive functions, and fine-motor, perceptual-motor, and tactile-spatial skills. In addition, 51 of the sample of 99 patients had been examined 5 to 11 years after diagnosis. Their data were analyzed to evaluate the longer-term effects of chemotherapy. The predictability of demographic and medical variables on neuropsychologic outcome at 3-year and long-term follow-up study were assessed using multiple regression techniques. RESULTS: Overall, the effects of chemotherapy in the absence of CRT appear to be slight. Patients who received ITC and intravenous (IV) methotrexate declined slightly on perceptual-motor skills, but were still well within the normal range. Both groups, regardless of treatment, declined on academic achievement tests, although not to a statistically significant degree. Age effects were found on performance IQ (PIQ) and perceptual-motor skills. Socioeconomic status (SES) correlated with a large number of variables. Sex effects were not significant. CONCLUSION: The present results are largely consistent with previous findings for nonirradiated groups. Treatment effects from ITC are slightly more apparent 5 to 11 years after diagnosis than at 3-year follow-up evaluation but this does not constitute a clinically meaningful difference. More noticeable are academic declines among all groups, regardless of treatment.

Ganciclovir prophylaxis for cytomegalovirus infection in pediatric allogeneic bone marrow transplant recipients.

Twenty-nine pediatric allogeneic bone marrow transplant (BMT) recipients, ages 2-17 years, were followed prospectively for cytomegalovirus (CMV) infection. Patients at risk received ganciclovir (GCV) prophylactically at a dose of 5 mg/kg/day i.v., 3 to 5 days per week, until day 100. Surveillance blood and urines were obtained weekly. Twelve patients developed DMV infection: one patient died with CMV interstitial pneumonitis on day 19 post-transplant prior to initiating GCV prophylaxis; 10 patients developed CMV viremia (n = 9) or viruria (n = 1) between day 30 and day 95 (median day 50) while receiving GCV prophylaxis; and one patient developed asymptomatic CMV viruria on day 130, 1 month after completing GCV prophylaxis. Patients with breakthrough infections on prophylaxis were treated with intensified GCV and i.v. immunoglobulin. No patient developed visceral involvement, although five patients had recurrent viremia. Six of the seven long-term survivors continued to excrete CMV in the urine intermittently for 6 to 28 months post-transplant. GCV was well tolerated with transient, mild neutropenia in five patients and thrombocytopenia in four patients. No extramedullary toxicity was encountered. GCV prophylaxis at a dose of 15-25 mg/kg/week is not adequate to prevent CMV reactivation in children receiving marrow transplants from unrelated donors and/or T cell-depleted grafts.

Fractionated high-dose cyclophosphamide for advanced pediatric solid tumors.

PURPOSE: The objective of this study was to determine the tolerance and toxicities of high-dose cyclophosphamide (CPA) at 7 g/m2 given in four fractions over 8 h in children with advanced solid tumors. PATIENTS AND METHODS: Twenty children aged 1 1/2-19 years (median, 12 years) received 24 courses of high-dose CPA at 7 g/m2 for the treatment of advanced malignant solid tumor. CPA was given in four 1-h infusions of 1.75 g/m2 each, with 1 h of rest between each dose. MESNA was used as a uroprotective agent and was continued for 24 h after the final dose of CPA. With only one exception, all patients were discharged at the end of MESNA infusion and received granulocyte colony-stimulating factor, prophylactic ciprofloxacin, and co-trimoxazole. RESULTS: Severe but transient myelosuppression was observed. The median time to neutrophil and platelet recovery was 17 and 19 days, respectively. Fever developed after 13 of the 24 courses, and hospitalization was required. Extramedullary toxicities were mild. No patient showed cardiomyopathy or hemorrhagic cystitis. Forty-six percent of the courses were managed entirely on an outpatient basis. Objective tumor response was seen in five patients. CONCLUSIONS: CPA at 7 g/m2 is well tolerated by children with advanced malignancies and should be considered in earlier phases of antineoplastic therapy.

Ethnicity and cure rates of Texas children with acute lymphoid leukemia.

BACKGROUND: Ethnic differences in the survival of children treated for acute lymphoid leukemia (ALL) have been described in several locations. Children of African, Polynesian, Native American, and Mexican ancestry had a less favorable outcome than children of European ancestry when treated in a similar manner by the same physicians and nurses. METHODS: We reviewed the medical records of the 94 European-American (E-A) and 84 Mexican-American (M-A) Texas children registered and treated in national collaborative ALL therapy trials at the M. D. Anderson Cancer Center in Houston between 1974 and 1985 and followed through June 1994. Information was collected regarding age, sex, presenting clinical features, risk for relapse grouping, protocol assignment, event free survival, and the financial status of their families. Cure was defined as initial continuous complete remission for more than seven years and cessation of therapy for more than four years. Presenting characteristics of E-A and M-A children were compared, and then related to cure rates by univariate and multivariate analyses. Event free survival rates of E-A and M-A children were determined together and by sex. RESULTS: Comparing presenting features, financial status as identified by pay code was significantly less for M-A children. Other features were not significantly different. By univariate analysis, an age of 2 to 6 years, female sex, initial white blood cell count below 10,000/microL, low risk grouping, registration on the most recent protocol, and full pay status were significantly associated with higher cure rates. By multivariate analysis, male gender, high risk group, and registration on earlier protocols were found to be significantly associated with a low cure rate. Event free survival and cure rate were lower for M-A children, but the differences were not statistically significant. CONCLUSIONS: Further study of larger numbers of patients, including contemporary immunophenotypic and genotypic characterization of ALL, is needed for better definition of possible ethnic differences. Ethnicity and financial status should be included in the analysis of clinical trials of ALL therapy.

Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B.

The safety and efficacy of a monoclonal antibody purified factor IX concentrate were evaluated in two continuing trials of 32 previously untreated patients with mild, moderate, or severe hemophilia B. Patients were evaluated every 2 weeks for 24 weeks and every 3 months thereafter for at least 1 year. No patients became positive for human immunodeficiency virus antibody or hepatitis C virus antibody during the trial. Two patients developed a false-positive hepatitis B core antibody, one transiently, but neither had elevated levels of alanine aminotransferase (ALT). None of the 25 patients evaluable for non-A, non-B, non-C hepatitis by strict International Society of Thrombosis and Hemostasis criteria developed elevated levels of ALT indicative of posttransfusion infection. Anaphylaxis occurred in one subject who also developed an inhibitor to factor IX (19.3 Bethesda units). Five of the eight adverse events reported (63%) were mild in severity, and the relationship of three of these to therapy was considered remote. Hemostasis with monoclonal antibody purified factor IX concentrate was excellent in all patients.

Prevention of graft-versus-host disease with anti-CD5 ricin A chain immunotoxin after CD3-depleted HLA-nonidentical marrow transplantation in pediatric leukemia patients.

To determine if partial T cell depletion and intensive post-transplant immunosuppression is effective for the prevention of graft-versus-host disease (GVHD) in pediatric recipients of HLA-non-identical marrow transplants, 10 children with leukemia received high-dose thiotepa, cyclophosphamide and total body irradiation followed by transplantation of CD3-depleted marrow from matched unrelated or one-antigen mismatched related adult donors. To maximize the number of stem cells infused, a large volume (1-1.51) of marrow was harvested from the donors. After immunopurging, the marrow infused contained a median of 3.7 x 10(6) CD34+ cells/kg, 1.4 x 10(6) CD3+ cells/kg, and 1.6 x 10(6) CD5+ cells/kg as assessed by flow cytometry. Cyclosporine, methylprednisolone and anti-CD4 ricin A chain immunotoxin (XZ-CD5) were used for prevention of GVHD post-transplant. All patients achieved an ANC > 0.5 x 10(9)/l. No patient developed capillary leak syndrome or renal failure from XZ-CD5. Five developed grade 2-4 acute GVHD, and all responded to treatment with steroids. Five of nine evaluable patients developed chronic GVHD. Two patients relapsed, but the most common cause of death was infection with or without chronic GVHD. Four patients survive 10+ to 27+ months post-transplant. XZ-CD5 is well-tolerated in T cell-depleted marrow transplant recipients. However, partial T cell depletion and intensive post-transplant immunosuppression did not prevent moderate acute GVHD or chronic GVHD. This may have been due to the high number of T cells infused with the marrow.

Apparatus to measure the step and frequency responses of gas analysis instruments.

The dynamic characteristics of gas analysers are often assessed by measuring the step response. It is difficult to generate a verifiable instantaneous step change in gas composition. We constructed a 0.06 ml measurement chamber connected via high-speed valves (0.5 ms response time) to two 31 reservoirs pressurized to 50 kPa with gases containing different concentrations of CO2. An electronic system opens the valves alternately depending on the polarity of a control voltage Vc. Two walls of the chamber contain narrow-band infra-red filters centered at 4.24 microns (50% transmission points at 4.16 and 4.32 microns) where CO2 absorption is high. A photoconductive infra-red sensor and an infra-red source are positioned on either side of the chamber. The output of the sensor is amplified by an instrumentation amplifier. Signal averaging of the sensor output in either the time or frequency domain was used to overcome the noise of the infra-red sensor. Step changes in Vc yielded exponentially changing outputs with a time constant of 1.1 ms. A quadrupole mass spectrometer's response to step changes in CO2 concentration generated in the measurement chamber fitted single exponential curves well with a maximum time constant of 37.7 ms and transport delay of 194 ms. The frequency response of the infra-red system, from Vc to the sensor output, fell by 0.7 dB with a phase lag of 30 degrees between 1 and 50 Hz. Using the infra-red system to measure the true input to the mass spectrometer, the frequency response of the mass spectrometer was found to fall by 35 dB with a phase lag of over 3000 degrees between 0.2 and 50 Hz. A first-order model with delay fitted to the step response predicted the mass spectrometer frequency response well below 10 Hz but overestimated the response above 10 Hz. A third-order model with delay fitted to the frequency response predicted the step response very well. Our results suggest that low-order models cannot predict the high-frequency performance of a mass spectrometer.

Response to alpha-interferon in children with Philadelphia chromosome-positive chronic myelocytic leukemia.

The therapeutic efficacy and toxicity of alpha-interferon (alpha-IFN) (Roferon, Hoffmann-La Roche, Inc., Nutley, NJ) were determined in 15 children (age range, 6 to 20 years) with Philadelphia chromosome-positive chronic myelocytic leukemia (Ph+ CML). All patients had received cytoreductive therapy with either hydroxyurea (n = 13) or busulfan (n = 1) or both (n = 1) for 6 weeks to 46 months (median, 7 months) before beginning alpha-IFN therapy at a dose of 5 x 10(6) U/m2/d intramuscularly. This dose was escalated to 10 x 10(6) U/m2/d if leukemia was inadequately controlled. Ten children had a hematologic response, with nine showing a reduction in the percentage of Ph+ marrow cells, including four who had no detectable Ph+ cells in marrow samples collected 48 to 204 weeks after the initiation of therapy. Two of 15 patients remain free of Ph+ cells. Therapy was discontinued before week 104 in ten patients because of the following: (1) early hematologic responses without a decrease in Ph+ cells (three patients); (2) early resistant disease (one patient); (3) blast crisis (one patient); (4) progressive disease (two patients); (5) seizure attributed to high-dose alpha-IFN (one patient); or (6) an inadequate trial of alpha-IFN caused by aseptic necrosis or poor compliance (two patients). The most common side effects were mild and have included fever, malaise, headache, myalgias, and pain at the injection site. Adverse events causing interruption of therapy were seizures, aseptic necrosis, and myelofibrosis. alpha-IFN stabilizes the chronic phase of Ph+ CML in some children, is adequately tolerated when administered at a dose of 2.5 to 5 x 10(6) U/m2/d intramuscularly, and results in a significant decrease in the proportion of Ph+ metaphases in some patients. alpha-IFN in combination with an effective cytoreductive agent or agents appears worthy of further clinical testing in this disease.

A comparison of induction and maintenance therapy for acute nonlymphocytic leukemia in childhood: results of a Pediatric Oncology Group study.

Two hundred fifty-six children with previously untreated acute nonlymphocytic leukemia (ANLL) were evaluated on a Pediatric Oncology Group (POG) phase III randomized trial of both induction and continuation chemotherapies. Induction therapy compared vincristine, cytarabine, and dexamethasone (VADx) with daunorubicin, cytarabine, and thioguanine (DAT). The complete remission (CR) rate using DAT was superior (82% v 61%, P = .02). Postremission therapy consisted of either "standard" two-cycle therapy or a more intensive four-cycle regimen given for 2 years. Overall, there was no difference in outcome for patients randomized to either continuation regimen. The overall complete continuous remission rate (CCR) for the "best" induction/continuation therapy combination at 2 years was .50 (SE = .06), at 3 years was .35 (.04), and at 4 years was .34 (.05). Analysis of selected clinical and laboratory parameters demonstrated differences in induction responses favoring DAT induction but did not impact eventual disease-free survival. There were two subgroups of patients who responded better to four-cycle continuation therapy. These were patients with French-American-British (FAB) M1/M2 (2-year CCR was .20 v .44, P = .01) and patients older than 10 years at diagnosis (.32 v .62, P = .004).

Remission induction and continuation therapy in children with their first relapse of acute lymphoid leukemia. A Pediatric Oncology Group study.

Between January 1979 and April 1983, 113 children undergoing their first relapse of acute lymphoid leukemia (ALL) at any site were registered in Pediatric Oncology Group study 7834; 98 were eligible and evaluable. In addition to radiotherapy administered to sites of local relapse, induction consisted of vincristine, doxorubicin, and prednisone (VAP) chemotherapy. Continuation therapy consisted of triple-drug intrathecal therapy and regimens of 6-thioguanine and cytarabine alternating with vincristine, prednisone, cyclophosphamide, and cytarabine. Randomization in continuation was between VAP pulses or no pulse, regardless of the site of relapse. This report provides long-term follow-up of these patients. Thirty-two of 39 children with bone marrow involvement achieved a complete response (CR). Only one of these is alive in an unmaintained remission, a child who did not have an initial CR. Thirty-four of 36 evaluable children with central nervous system involvement as the site of relapse achieved CR. Of these ten are alive; eight are in continuing CR. Nineteen of 20 boys with testicular relapse achieved CR. Of these, 14 are still alive and not receiving therapy, although only one half received treatment in compliance with the protocol described. These results illustrate the possibility of cure of patients who have relapsed with ALL when it is (1) confined to a meningeal or gonadal site and (2) treated vigorously with radiotherapy and a new regimen of systemic chemotherapy. The results reconfirm the need to prevent an initial relapse at any site.

Season-of-birth and acute leukemia of infancy.

Because of its short and clearly delineated latency period, acute leukemia of infancy is particularly suited to etiologic analysis. From 1950 to mid-1985, 31 infants with acute leukemia (less than 1 year of age) were registered at the University of Texas, M.D. Anderson Cancer Center at Houston. The medical records of these infants were reviewed for demographic and birth information. Of the 31 infants, 14 (45%) were Hispanic. The sex ratio was 3:1 male/female) for white infants and 5:9 for Hispanic infants. Of the white infants, half had acute lymphocytic leukemia, compared with all but one of the Hispanic infants. There was a significant excess of winter births among the infants diagnosed with acute leukemia (P less than 0.05). The significant association between season-of-birth and the occurrence of leukemia cases is suggestive of periodicity of an environmental etiologic agent, perhaps acting in concert with endogenous rhythmicities in susceptibility to that agent. This finding is deserving of further study.

Long-term results in the treatment of acute nonlymphocytic leukemia: a Pediatric Oncology Group Study.

Complete remission (CR), 5-year remission duration (RD), and overall 5-year survival rates are 74%, 28% and 25%, respectively, for previously untreated children with acute nonlymphocytic leukemia diagnosed between 1977 and 1981, following induction therapy with vincristine, doxorubicin and prednisone (VAP), consolidation therapy with 6-thioguanine, cytosine arabinoside (TA) and cyclophosphamide/vincristine/cytosine arabinoside/prednisone (COAP), and maintenance therapy of alternating TA and COAP with or without VAP pulses. Approximately 20% are free of their disease for more than 5 years. High white blood cell counts (WBC) at diagnosis and M3 and M6 morphology were associated with lower CR rates, while M5 morphology was associated with higher CR rates. Patients with M1 morphology had shorter remission duration as compared to those with M4 or M5 morphology. Low WBC and age between 2 and 10 years at diagnosis were associated with longer remission durations and survival. Patients with M4 morphology also survived longer. The observed CR rates are comparable to other studies initiated at the same time as this study but survival is less than those reported more recently. Low WBC at diagnosis and M4/M5 morphology may identify relatively favorable prognostic groups.

A lineage switch in acute monocytic leukemia. A case report.

A case of congenital monocytic leukemia that underwent a lineage switch to acute lymphocytic leukemia (ALL) is described. The original leukemia had typical monocytic features, as evidenced by morphology (FAB M5), cytochemistry (nonspecific esterase) and immunophenotype (My4 positive). Cytogenetic study showed a pseudodiploid clone t(9;11)(p22;q21) that could be interpreted as a variant of the t(9;11)(p22;q23) reported in patients with the M5 type of leukemia. After successful remission induction with single-agent chemotherapy (VM-26) and subsequent sustained remission for 12 months with alternating VM-26 and VP-16-213, lineage switch to ALL (FAB L1) occurred. The presence of both lymphoid and myeloid markers on leukemic cells at lineage switch suggested the biphenotypic character of the patient's ALL. Our observation indicates that a lineage switch can occur from monocytic leukemia to ALL, although most of the cases previously reported have been in the reverse direction. This case emphasizes again the need to carry out careful and comprehensive marker studies to gain insight into the possible prognostic significance and the application of appropriate therapy.