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The prognosis for patients with acute myeloid leukemia in first relapse is generally poor. The ability to induce a second complete remission (CR) with the same chemotherapy used in initial induction therapy is limited. Remission inversion rate, defined as achieving a longer second CR than the first CR in response to standard chemotherapy for relapse, is important in assessing studies of novel chemotherapy or immunologic treatment strategies for patients with relapsed disease. One hundred and twenty-four patients entered on two Eastern Cooperative Oncology Group (ECOG) studies for patients with relapsed AML were analyzed to determine the remission inversion rate. Twenty-two of the 124 patients (18%; 95% confidence interval 12-26%) experienced a longer second CR duration than the first CR duration by at least 2 months. Inversion of CR duration is thus not a rare event. The inversion frequency reported here establishes a baseline upon which future studies in relapsed disease need to be defined.

Considering the recent interest in large granular lymphocyte (LGL) proliferation and the frequent association of severe granulopenia ("T-y neutropenia") with T-LGL leukemia leading to intractable and often fatal infections, we wish to describe a case of T-LGL leukemia with absolute agranulocytosis which showed an excellent, rapid, and sustained response to nontoxic doses of cyclosporine after failing steroid and growth-factor therapy. CASE REPORT A 36-year-old woman was admitted to Cedars-Sinai Medical Center in Los Angeles in December 1993 because of agranulocytosis associated with intractable fever and resistant staphylococcus septicemia not responding to polyantimicrobial therapy. Nine months before admission, she developed a severe upper respiratory infection associated with myalgia, arthralgia, weakness, fatigue, and other systemic symptoms. Repeated blood counts were within normal range (white blood cell [WBC] count 6.5 to 7.7 X IO3&) with slight lymphocytosis. The absolute neutrophil count (ANC) was between 2.9 and 3.6 X 103/L. There was no evidence of rheumatoid arthritis or other collagen diseases. Five months before admission, she developed shaking chills, 104°F fever, and pneumonia that required prolonged antibiotic therapy. Anemia and absolute neutropenia (ANC decreasing from 1.9 to 0.8 X 103/L) was observed, and she was treated with ferrous sulfate and prednisone without hematologic response. From this point on, the patient experienced increasingly frequent episodes of respiratory infections, sepsis, acneiform dermatitis, abscesses, and other infectious problems. One month before admission, the patient was again hospitalized at a community hospital with fever, chills, pneumonia associated with chest-wall pain, generalized muscle aches, and joint pain diagnosed as fibromyalgia. Blood counts showed the ANC persistently below 500; the bone marrow showed markedly reduced granulocyte precursors. Treatment with high-dose prednisone, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and antibiotics had no effect. She became delirious and was transferred to Cedars-Sinai Medical Center. On admission, the patient exhibited chills, rigor, 103°F fever, perioral ulcerative herpes (HSV l), ulcerative stomatitis, pharyngitis, and swollen large joints. Examination revealed no lymphadenopathy or splenomegaly. Subsequent cultures yielded no growth while on antibiotic therapy. The total WBC count was 0.6 X 103/L with 98% lymphocytes and 2% eosinophils; neutrophils and monocytes were absent from the blood film, and 70% of the lymphocytes exhibited large granular morphology with pale blue cytoplasms and multiple azurophilic granules. The hemoglobin and hematocrit was 9.0 g and 27.7%; the platelet count was 130,000; the reticulocyte count was 2.6% (Table l). A Coombs test was positive, ANA (antinuclear antibodies) was negative, the lactate dehydrogenase (LDH) was elevated, and serum protein electrophoresis, quantitative Igs, serum B12, and serum folic acid levels were within normal range. Immunofixation el...

Sorrell AD, Lee S, Stolle C, Ellenhorn J, Grix A, Kaelin Jr WG, Weitzel JN. Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma.This report describes clinical characteristics in families with a Type 2A phenotype and functional properties of a novel von Hippel Lindau variant (X214L). Pedigrees were analyzed. Analysis of von Hippel Lindau (VHL) coding exons and flanking intronic sequences in DNA from a proband with pheochromocytoma and islet cell tumor was performed. Western blot assays for VHL protein (pVHL), HIFα, and Jun B were conducted using VHL null renal clear carcinoma cell lines that were engineered to produce wild-type or X214L mutant pVHL. Pedigree analysis indicated that the variant tracked with disease and the same or similar VHL point mutations were identified in several Type 2A families. The predicted 14 amino acid extended pVHL variant, when reintroduced into VHL null cells, was stable and retained the ability to downregulate HIFα in a hydroxylation-dependent manner. In contrast, the variant was defective with respect to downregulation of JunB. pVHL X214L, like other pVHL variants associated with a low risk of clear cell renal carcinoma, largely preserves the ability to downregulate HIF. In contrast, this variant, like other pVHL variants linked to Type 2A disease, fails to suppress JunB. This underscores that JunB may play a role in the pathogenesis of Type 2A VHL disease.