Immune tolerance therapy utilizing factor VIII/von Willebrand factor concentrate in haemophilia A patients with high titre factor VIII inhibitors.

Factor VIII (FVIII) inhibitors remain a serious complication of treatment for patients with haemophilia A. Immune tolerance induction (ITI) can eliminate inhibitors in the majority of patients, but there are major concerns related with this therapy. Investigators have raised the possibility that the use of FVIII/von Willebrand factor (FVIII/VWF) concentrates may improve the success rate of ITI and may shorten the duration of therapy necessary to attain tolerance. This retrospective study describes 25 patients at five institutions in the USA, who were treated with FVIII/VWF concentrate as part of their ITI. These were all patients who were considered poor prognosis because of clinical and laboratory characteristics, which made ITI less likely to be successful or because of a poor response to initial ITI with a monoclonal/recombinant FVIII concentrate. Overall success (complete tolerization) was 32% with another 40% attaining partial tolerization, but not complete tolerization. Of those patients attaining only partial tolerization, two patients ultimately discontinued ITI and had return of their high titre inhibitors. Eight percent of patients failed to attain either partial or complete tolerization and discontinued ITI. Another 24% are continuing with ITI but have titres of >10 BU. This study adds further retrospective data to the information regarding the use of FVIII/VWF concentrate in ITI.

Therapy of refractory or recurrent childhood acute myeloid leukemia using amsacrine and etoposide with or without azacitidine: a Pediatric Oncology Group randomized phase II study.

PURPOSE: A randomized study compared the combination of amsacrine (100 mg/m2/d on days 1 to 5) and etoposide (200 mg/m2/d on days 1 to 3) with the same two agents plus azacitidine (250 mg/m2/d on days 4 to 50) for the therapy of induction-resistant or relapse childhood acute myeloid leukemia (AML). PATIENTS AND METHODS: One hundred sixty-seven assessable children with AML who either had failed to respond to primary induction therapy (group 1, n = 41) or had relapsed (group 2, n = 126) were randomized. RESULTS: Overall, there were 56 complete responses (34%; SE 4%). Among primary refractory patients (group 1), the complete response rate was higher with the three-drug regimen (18% vs 53%, P = .03). In the relapsed patients (group 2), there was no difference in complete response rates related to treatment (31% vs 35%, P = .3). There were 17 early deaths. The major toxicities for both regimens were myelosuppression and infection. CONCLUSION: The overall complete response rate of 34% in this patient population is indicative of effective antileukemic activity. For patients with relapsed leukemia, the addition of azacitidine to etoposide and amsacrine did not improve response. The suggested advantage of the three-drug regimen for induction failures warrants further investigation.

High-dose cytarabine for intensification of early therapy of childhood acute myeloid leukemia: a Pediatric Oncology Group study.

In June 1984, the Pediatric Oncology Group (POG) initiated a pilot study (8498) using high-dose cytarabine (HdA; 3 g/m2) for intensification of early therapy in childhood acute myelogenous leukemia (AML) (group I). Remission induction therapy consisted of two courses of daunorubicin, cytarabine (Ara-C), and thioguanine (DAT). Postremission therapy consisted of four sequential courses, each consisting of (1) four doses of HdA (HdA4) followed by asparaginase (L-Asp), (2) etoposide (VP) plus azacytidine (Az), (3) prednisone, vincristine, methotrexate, and mercaptopurine (POMP), and (4) Ara-C daily for 5 days by continuous infusion. Six doses of intrathecal Ara-C were given for CNS prophylaxis. In December 1986, the protocol was amended (group II) to substitute six doses of HdA (HdA6) for the second DAT (two + five) induction course; postinduction, a single course of HdA6 was given instead of four HdA/L-Asp courses, and the remainder of the therapy was unchanged. One hundred forty group I patients and 145 group II patients were assessable. The two groups were similar with regard to clinical prognostic groups. No significant differences were noted in the two groups with regard to remission induction (85% [SE = 2%] in each group), induction deaths (6.5% v 7.0%), or deaths in remission (one in each group). Cerebellar toxicity was reported in three patients in group II (with HdA6) but none in group I (HdA4). At present, patients who received HdA6 (group II) had higher event-free survival than patients in group I (EFS at 3 years, 34% [SE = 11%] v 29% [SE = 4%]), and disease-free survival (DFS at 3 years, 42% [SE = 14%] v 34% [SE = 4%]), but the differences were not statistically significant. In both groups, children less than 2 years and those with WBCs less than 100,000/microL had significantly better outcome (EFS of 55% [SE = 10%] and 36% [SE = 5%] at 3 years, respectively) than children greater than or equal to 2 years and those with WBCs greater than or equal to 100,000/microL (EFS of 27% [SE = 5%] and 20% [SE = 9%] at 3 years, respectively.

Streptozotocin (NSC-85998) in children with acute lymphocytic leukemia. A Southwest Oncology Group study.

Streptozotocin (NSC-85998), a nitrosourea antibiotic, was given to 18 children with acute lymphocytic leukemia in relapse in a dose of 500 mg/m2/day intravenously every day for five days. There were no responses in 14 fully evaluable patients. The principal toxicity consisted of gastrointestinal disturbances. Based on our findings and those of others in adults, steptozotocin appears to play no role in the management of acute lymphocytic leukemia.

Cranial hemophilic pseudotumor. Case report.

Hemophilic pseudotumor is a rare complication of hemophilia occurring in 1% to 2% of individuals with a severe factor VIII or IX deficiency. This pseudotumor has been defined as a progressive cystic swelling involving muscle that is produced by recurrent hemorrhage and may be accompanied by roentgenographic evidence of bone involvement. The case is presented of a 12-month-old child with mild factor VIII deficiency (10% of normal factor VIII activity), who developed a pseudotumor of the skull.

Reversible treatment-related leukoencephalopathy.

We present two children with acute lymphocytic leukemia who developed leukoencephalopathy following administration of a combination of intravenous ara = C and methotrexate during the consolidation phase of chemotherapy. Cranial magnetic resonance imaging showed widespread, abnormally high signal intensity in the deep white matter in both patients, though one patient had normal cranial computed tomographic scan. Treatment was modified, symptoms resolved in 1 to 2 weeks, and the white-matter changes resolved over 6 to 12 months. Intravenous cytarabine and methotrexate appear to act synergistically to enhance the potential for central nervous system toxicity. Awareness of this potentially serious complication of chemotherapy can facilitate timely recognition of leukoencephalopathy with the use of magnetic resonance imaging.

Anemia of chronic renal failure.

Anemia is one of the most characteristic and visable manifestations of chronic renal failure. Investigators in the past decade have provided a better understanding of this anemia. The etiology of the anemia of chronic renal failure has three facets: first is reduced erythropoietin production by damaged kidneys; second is the presence of inhibitors to red blood cell (RBC) production in uremic serum; and third is red blood cell hemolysis. Unfortunately, transfusion therapy with its expense and risk of transmissable viral disease remains the mainstay of management for symptomatic anemia. Other modalities include dialysis, androgens, histidine supplementation, and erythropoietin replacement.

Comprehensive care for patients with hemophilia: an expanded role in reducing risk for human immunodeficiency virus.

Hemophilia is an inherited coagulation disease that affects approximately 1 in 5,000 to 10,000 males worldwide. Chronic joint disease and other long-term complications of recurrent bleeding persist in patients with hemophilia despite improved and more available clotting protein concentrates. The best care can be provided to patients who are followed regularly in specialized treatment centers. Services of every "comprehensive" hemophilia treatment center (HTC) have expanded since previous treatment with clotting factor concentrates infected many hemophilics with the human immunodeficiency virus (HIV). Each HTC offers therapeutic, educational, and counseling expertise in care for the complications of HIV. A nationwide network of specialists now provides care for patients with hemophilia and related congenital abnormalities. In Region VI (Texas, Oklahoma, and Arkansas), the treatment centers and their affiliates provide medical, psychosocial, orthopedic/physical therapy, dental, and case management services. Extramural funded research programs provide care and laboratory testing at no cost to individual subjects.

The use of a single von Willebrand factor-containing, plasma-derived FVIII product in hemophilia A immune tolerance induction: the US experience.

BACKGROUND: Inhibitors are a serious complication for patients with severe hemophilia A. Immune tolerance induction (ITI) is the primary method for eradicating these inhibitors. The role of type of concentrate and in particular the use of von Willebrand factor-containing, plasma-derived factor VIII (VWF/pd-FVIII) concentrate in primary or rescue ITI remains unclear. OBJECTIVES: To report retrospective collection of data on the use of a single VWF/pd-FVIII concentrate in primary and rescue ITI. METHODS: Retrospective chart review of hemophilia A inhibitor patients at 11 US institutions who received VWF/pd-FVIII concentrate in primary or rescue ITI. RESULTS: Primary ITI was carried out in eight inhibitor patients with a 75% complete and partial success. Secondary ITI was carried out in 25 inhibitor patients, with 52% attaining complete or partial success. CONCLUSIONS: This report represents the largest group of primarily pediatric, high-titer inhibitor patients treated with a single VWF/pd-FVIII concentrate. It adds retrospective data to the use of VWF-containing plasma-derived factor VIII concentrate in primary and rescue ITI, particularly in those patients with characteristics of poor response to ITI.

End group characterization in DNA of thymocytes after low doses of ionizing radiation.

Investigations into the configuration of the radiation induced strand breaks in the low dose range are presented. DNA sections containing the radiation induced strand breaks were separated from the undamaged sections in order to increase the concentration of lesions. The configuration of 3'terminals in damaged DNA from gamma-irradiated thymocytes was analysed studying the priming ability for the DNA polymerase I. The experiments show that soon after irradiation with a dose of 10 krad DNA strand breaks carry 3'OH end groups as well as damaged 3'terminals not susceptible to Dna polymerase I. The fraction of damaged terminals increases with dose. We conclude that also after low doses an exonucleolytic action is required in cells for removing damaged 3'terminals before repair DNA synthesis can take place.

Noninvasive evaluation of hemophilic pseudotumor of the pelvis.

Hemophilic pseudotumors are a rare complication of chronic bleeding disorders. Invasive diagnostic procedures such as angiography, needle biopsy, or laparotomy carry a high risk in this group. Computerized tomography (CT) and ultrasound are safe alternative methods of evaluation. We report the computerized tomography and ultrasound characteristics of one such pelvic lesions.

Combination chemotherapy study for remission maintenance in ALL: an evaluation of vincristine, cyclophosphamide and vincristine, cyclophosphamide, and BCNU: a Southwest Oncology Group Phase II Study.

Vincristine (VCR), cyclophosphamide (CP), and BCNU have antineoplastic activity in acute lymphocytic leukemia. In animal tumor systems, and in a clinical controlled study, vincristine and cyclophosphamide have been demonstrated to be more effective when given sequentially. In animal models, cyclophosphamide and BCNU have a synergistic effect if given simultaneously. In order to evaluate this potentially synergistic schedule in man, children with ALL in their second or greater remission were randomized to receive either a standard vincristine cyclophosphamide regimen (VCR 2 mg/m2 on day 1 and CP 450 mg/m2 on days 2 and 3) or this same regimen with the addition of 50 mg of BCNU given with the CP given on days 2 and 3. The standard two-drug regimen was given every 3 weeks and the potentially synergistic combination was given on a 4-week schedule. The median duration of remission (MDR) for the 18 children receiving the two-drug combination was 13.5 weeks, and for the 20 children receiving the potentially synergistic three-drug regimen combination, 15 weeks. With 95% confidence, the population MDR for the two-drug combination is from 63% to 125% of the population with the three-drug regimen. The toxicities of both regimens was tolerable. No statistically significant synergistic benefit was demonstrated in these patients with the addition of BCNU to cyclophosphamide.

Negative pion irradiation of mammalian cells. III. A comparative analysis of DNA strand breakage, repair and cell survival after exposure to pi-mesons and X-rays.

The yields of immediate and residual breaks in DNA of X- and peak pion irradiated Chinese hamster cells were measured by hydroxylapatite chromatography in order to investigate the r.b.e. of immediate break production and the relation between residual breaks and survival in the same low dose range of up to 10 Gy. A linear dose response for immediate break induction was observed with an r.b.e. of 0.37 for peak pions, whereas the formation of residual breaks showed a linear-quadratic dose dependence for both types of radiation. The dose-effect curves of residual break can directly be correlated with the corresponding survival curves for both radiation types used indicating that residual breaks are lethal events (most probably unrepaired double strand breaks) formed in this low dose range by single- and multi-hit interactions. Despite their lower efficiency in formation of immediate breaks peak pions produce more residual breaks per dose than X-rays.

Therapeutic choices made by patients with end-stage cancer.

The Oklahoma Children's Memorial Hospital Oncology Service has developed a new approach for its patients with end-stage cancer. The emphasis is on the patients' acknowledgement of the progression of the disease and the imminence of death, and informed choice between the use of research drugs and no further chemotherapy. Forty-three patients between 6 and 20 years of age participated in a conference of this type. The results demonstrated that they understood that their health was declining. They decided about further therapy autonomously or together with their family. The majority of children who chose supportive care without chemotherapy and lived for a period of time, participated in activities at home as far as their state of health permitted. Severe depression and severe behavioral problems occurred rarely. There was evidence that this open approach enabled patients and family members to communicate openly with each other.

Adjuvant chemotherapy for medulloblastoma and ependymoma using iv vincristine, intrathecal methotrexate, and intrathecal hydrocortisone: a Southwest Oncology Group Study.

In a prospective, randomized, cooperative group trial, the value of iv vincristine and intrathecal methotrexate and hydrocortisone as adjuvant therapy to radiotherapy in children with medulloblastoma and ependymoma was evaluated. The data showed no improvement in the survival of such children when adjuvant therapy was given.

Serial sonograms to detect pancreatitis in children receiving L-asparaginase.

The clinical, laboratory, and ultrasonographic findings in children receiving L-asparaginase therapy were retrospectively reviewed and correlated to determine the diagnostic reliability and clinical usefulness of serial pancreatic sonograms in detecting L-asparaginase-induced pancreatitis. A total of 217 sonograms were obtained in 92 patients. Six of the 92 (6.5%) had L-asparaginase-induced pancreatitis. The diagnosis of pancreatitis was based solely on clinical symptoms in three patients, on clinical and laboratory findings in two, and on sonographic and laboratory findings in one. No confirmed cases of pancreatitis were detected solely by ultrasonography before clinical or laboratory evidence was obtained. Sonograms were useful only in confirming clinical and/or laboratory evidence of pancreatitis, but were of no value in making the early or preclinical diagnosis of drug-induced pancreatitis. We have discontinued the practice of obtaining routine serial pancreatic sonograms in children receiving L-asparaginase at our institution.

Toxicity trials of amsacrine (AMSA) and etoposide +/- azacitidine (AZ) in childhood acute non-lymphocytic leukemia (ANLL): a pilot study.

Recurrent or induction therapy-resistant ANLL carries a grave prognosis. The combination of AMSA at 100 mg/M2 daily for 5 days and etoposide at 200 mg/M2 daily for the first 3 days of therapy was given to 40 patients with refractory ANLL. An additional 17 patients received those two agents plus azacitidine at a dosage of 250 mg/M2 on days 4 and 5. All three drugs were given as one-hour infusions. All patients had normal electrolyte determinations daily and were on cardiac monitors during the period of drug administration. No arrhythmias were detected in 522 doses of AMSA. Toxicities observed were primarily related to myelosuppression. Forty-nine of the 57 patients required hospitalization for suspected or proven infection. Nausea/vomiting and mucositis were the next most commonly occurring toxicities. Responses were seen in 22 patients.

Neuroblastoma: therapy for infants with good prognosis.

Therapy was designed to achieve a high cure rate and to prevent serious therapeutic side effects for 11 infants younger than one year old with neuroblastoma who had a favorable prognosis (Evans Stages I, II, III, and IV-S). It consisted of surgery alone if the tumor was totally removed (one infant) and of surgery and low doses of cytoxan and vincristine for a period of 1 year if the tumor was incompletely removed (seven infants). In addition, radiation therapy was applied to unresected dumbbell tumors (three infants). All infants are alive without evidence of disease with the exception of one who died in an accident. The follow-up time varies from 2-8 years. The drug combination prevented recurrences in two infants whose tumor was reduced by surgery to less than 10% of the original size. In five infants, chemotherapy reduced the size of large residual tumor masses. Two of these masses were subsequently removed. The tumors of the three other infants recurred while on chemotherapy and were successfully eradicated by surgery or radiation therapy. Two infants were not treated according to this therapeutic plan. Although they had small residual masses after surgery, no chemotherapy was given. They are alive without recurrence of the disease 2 years or more after diagnosis. In summary, cure was achieved in these infants without intensive chemotherapy.