Recombinant immunotoxins and other therapies for relapsed/refractory hairy cell leukemia.

Standard treatment for hairy cell leukemia (HCL) is markedly effective, but the constant decrease in disease-free survival, together with the presence of minimal residual disease (MRD), suggests that few if any are cured. HCL cells in MRD are always strongly CD20 + and CD22 + , and also CD25 + unless the patient has the poor-prognosis variant HCLv. To target relapsed/refractory HCL, immunotherapy has been developed using anti-CD25 and anti-CD22 recombinant immunotoxins, or the anti-CD20 monoclonal antibody (mAb) rituximab alone or combined with purine analogs. The recombinant immunotoxins contain an Fv fragment of a mAb fused to a truncated form of Pseudomonas exotoxin called PE38. BL22 targeting CD22, in phase I and II testing of relapsed/refractory HCL, achieved 47-61% complete remissions (CRs), several of them ongoing after 9-10 years. A completely reversible form of hemolytic uremic syndrome (HUS) was observed in 12% of patients, several of whom could later achieve a partial remission (PR) or CR with LMB-2 targeting CD25. A higher-affinity version of BL22, termed HA22, CAT-8015, or moxetumomab pasudotox, developed to more effectively treat other hematologic malignancies, also achieves CRs in HCL, and with only non-dose-limiting HUS. In separate randomized trials, rituximab is undergoing phase II testing with cladribine for early HCL and with bendamustine or pentostatin for multiply relapsed HCL.

Aeromedical decision making in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder is a problematic diagnosis in the context of aeromedical certification. Certain characteristics of the disorder such as impaired attention potentially affect the safe conduct of flying. Pharmacological treatment with stimulants also has issues surrounding short half-lives and effects on the recognition of fatigue. This article gives a broad overview of the issues involved and provides certification guidelines as adopted in the Australian Civil Aviation Safety Authority which may be helpful if adopted by other certification bodies.

Insulin-dependent diabetes and aeromedical certification - the Australian perspective.

Whether pilots with insulin-dependent diabetes should be allowed to fly has long been a controversial issue. Hypoglycaemia remains a significant threat to flight safety, and a barrier for pilots with insulin-dependent diabetes to overcome. Some countries allow recreational pilots to fly while treated with insulin under strict conditions. Recent changes in aeromedical certification in Australia will give pilots with diabetes more freedom to exercise the privileges of their licence, while adopting mechanisms to ensure the safety of air navigation.

Approach to the patient after relapse of hairy cell leukemia.

The current hairy cell leukemia (HCL) treatment is excellent, but evidence of cure with purine analogs cladribine and pentostatin, is lacking. Significant long-term immune suppression, particularly to CD4+ T-cells, and declining complete remission rates with each course, make the identification of new therapies an important goal. The anti-CD20 monoclonal antibody (Mab) rituximab displays significant activity, and, while causing prolonged normal B-cell depletion, spares T-cells. Recombinant immunotoxins, containing an Fv fragment of a Mab fused to truncated Pseudomonas exotoxin, have shown efficacy in HCL resistant to both purine analogs and rituximab. LMB-2 targets CD25 and can induce remission providing the HCL cells are CD25+. All HCL cells display CD22. Recombinant anti-CD22 immunotoxin BL22, targeting CD22, has shown significant efficacy in phase I and II testing, and avoids prolonged suppression of both normal B- and T-cells. An improved high-affinity version of BL22, termed HA22, is currently undergoing phase I testing.

Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia.

PURPOSE: To conduct a phase II trial in chemoresistant hairy cell leukemia (HCL) with BL22, a recombinant anti-CD22 immunotoxin which showed phase I activity in HCL. PATIENTS AND METHODS: Eligible patients had relapsed/refractory HCL and needed treatment based on blood counts. Patients were stratified into three groups: response to cladribine less than 1 year, those with a response lasting 1 to 4 years, or no response and uncontrolled infection. Patients received BL22 40 microg/kg every other day for three doses on cycle 1. Those achieving hematologic remission (HR), defined as neutrophils > or = 1,500/mm(3), hemoglobin > or = 11 g/dL, and platelets > or = 100,000/mm(3), were observed. Patients without HR were re-treated at 30 microg/kg every other day for three doses every 4 weeks beginning at least 8 weeks after cycle 1. RESULTS: Thirty-six patients were enrolled including 26, nine, and one in groups 1 to 3. The response after one cycle (CR, 25%; PR, 25%) improved when 56% were re-treated (CR, 47%; PR, 25%). CR rate was similar in groups 1 and 2 (P = .7). Twenty-two with baseline spleen height lower than 200 mm had higher CR (64% v 21%; P = .019) and OR rates (95% v 36%; P = .0002) compared to 14 with spleens either absent or higher than 200 mm. The only serious toxicity was reversible grade 3 hemolytic uremic syndrome, not requiring plasmapheresis, in two patients (6%). High neutralizing antibodies were observed in four patients (11%) and prevented re-treatment. CONCLUSION: BL22 activity in HCL is confirmed. Best responses to BL22 after cladribine failure are achieved before the patients develop massive splenomegaly or undergo splenectomy.

Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies.

PURPOSE: To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 microg/Kg every other day x 3 doses. RESULTS: BL22 was active in HCL, with 19 complete remissions (CRs; 61%) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at > or = 40 microg/Kg every other day x 3, and 41% at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 microg/Kg IV. QOD x 3. The most common toxicities at 30 to 50 microg/Kg every other day x 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema. CONCLUSION: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response.

Cytotoxic activities of recombinant immunotoxins composed of pseudomonas toxin or diphtheria toxin toward lymphocytes from patients with adult T-cell leukemia

We have previously shown that the recombinant single-chain immunotoxin anti-Tac (Fv)-PE40, composed of the variabe domains of the anti-Tac monoclonal antibody in a single-chain form joined to a derivative of pseudomonas exotoxin (PE), is cytotoxic toward malignant cells form adult T-cell leukemia (ATL) patients. Using this assay, we have now compared the activity of anti-Tac(Fv)-PE40 with that of an improved version, anti-Tac (Fv)-PE40KDEL which contains an altered carboxyl terminus, and also with two chimeric toxins made with diphtheria toxin (DT). One of these is a fusion of amino acids 1-388 of DT with anti-Tac(Fv) and is termed DT388-anti-Tac(Fv). The other, DT388-IL2, contains interleukin 2 (IL2) at the carboxyl terminus of the same DT derivative. We incubated these toxin with malignant ATL peripheral blood mononuclear cells (PBMCs) for 1-3 days and then measured [3H]leucine incorporation. We found that anti-Tac(Fv)-PE40KDEL was the most cytotoxic agent and was followed in decreasing order of activity by anti-Tac(Fv)-PE40, DT388-anti-Tac(Fv), and finally DT388-IL2. Trypan blue staining showed that inhibition of protein synthesis correlated with cell death. Time course studies show that the recombinant toxins containing anti-Tac(Fv)-PE40DEL was 30 minutes. Normal PBMCs were resistant to all four toxins. Recombinant immunotoxins made with anti-Tac merit further study as potential reagents in the treatment of ATL.(AU)