Summary. 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.

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.

The cranial magnetic resonance (MR) images of 25 children with acute lymphocytic leukemia (ALL) who were undergoing chemotherapy were retrospectively studied to determine the frequency of white matter changes and to analyze the significance of these observed changes in predicting subsequent neuropsychologic deficiencies. MR images showed transient white matter abnormalities in 17 of the 25 patients during consolidation therapy. Twelve of 20 children showed neuropsychologic deficits. There was no correlation between white matter changes and neuropsychologic deficits. In the subgroup of children under age 5 years at the time of diagnosis, 10 of 11 showed neuropsychologic deficits, and eight of 11 had white matter changes. Children under age 5 who undergo chemotherapy for ALL are at high risk to develop neuropsychologic deficiencies. Age at diagnosis is a reliable predictor of subsequent neuropsychologic deficits.

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.

PWHs who received clotting factor concentrates before 1990 may be at risk for infection with hepatitis B or hepatitis C and should be tested.