G. John Swansbury

Prognostic features of splenic lymphoma with villous lymphocytes: A report on 129 patients

Summary. Splenic lymphoma with villous lymphocytes (SLVL) is a low‐grade B‐cell lymphoma defined in the World Health Organization classification as the leukaemic form of splenic marginal zone lymphoma. Presenting features and response to therapy have been described, but information on prognostic factors is scanty. Clinical, laboratory and follow‐up data were collected on 129 patients with SLVL to determine features predicting disease behaviour and survival. Diagnosis was made on clinical, morphological and immunophenotypic features and, where available, bone marrow and spleen histology. Median age was 69u2003years (range 39–90u2003years) and male:female ratio, 0·9. The majority had splenomegaly, but lymphadenopathy and hepatomegaly were rare. Median Hb was 11·8u2003g/dl, white blood cell count was 16u2003×u2003109/l and platelet count was 145u2003×u2003109/l; 27% of patients had monoclonal protein in serum and/or urine. While 27% of patients remained untreated, 10% transformed to high‐grade lymphoma. Median follow‐up was 61u2003months and median survival was 13u2003years, with 72% of patients alive at 5u2003years. Cox regression analysis showed that increasing age, anaemia, thrombocytopenia and lymphocytosis >u200a16u2003×u2003109/l were independent adverse predictors of overall survival. However, only anaemia and lymphocytosis >u200a16u2003×u2003109/l remained highly significant independent prognostic factors when only deaths due to lymphoma were analysed. Splenectomized patients fared better than those receiving chemotherapy only (Pu2003=u20030·001 for SLVL deaths). We conclude that SLVL is mainly a disease of the elderly with a relatively benign course but, when treatment is required, splenectomy is beneficial.

Additional chromosome abnormalities confer worse prognosis in acute promyelocytic leukaemia

Acute promyelocytic leukaemia (APL) has been associated with a favourable prognosis in many studies of acute myeloid leukaemia. A series of 54 patients treated at the Royal Marsden Hospital between 1979 and 1996, with APL and the t(15;17) chromosome translocation at pres‐entation, was examined for the effect of additional chromosome abnormalities in their presentation karyotype on survival.

Inversion of chromosome 16 with the Philadelphia chromosome in acute myelomonocytic leukemia with eosinophilia: Report of two cases☆

Two cases are described with the rare combination of inv(16)(p13q22), strongly associated with acute myelomonocytic leukemia with eosinophilia, M4Eo, and the Philadelphia translocation, t(9;22)(q34;q11), hallmark of chronic myeloid leukemia (CML) and rarely found, (less than 1%), in acute nonlymphocytic leukemia. The patients were: case 1, a 9-year-old girl presenting with a white blood cell count (WBC) 42 x 10(9)/L with 32% blasts and bone marrow with blasts and eosinophil precursors consistent with M4Eo, and case 2, a 25-year-old man with WBC 34.7 x 10(9)/L with 13% blasts and bone marrow with features of M4Eo and basophilia. Both patients achieved remission but died following bone marrow transplantation in first remission (case 1) or in relapse (case 2). Cytogenetic findings were: case 1, at diagnosis, 46,XX,inv(16)(p13q22)(21)/46,XX,t(9;22) (q34;q11),inv(16)(8)/46,XX(10), and case 2, at diagnosis, 46,XY,t(9;22) (q34;q11),inv(16)(p13q22) (16) and in remission, 46,XY,t(9;22)(q34;q11) (1)/46,XY (24). Investigation of the breakpoint on 22 in case 1 with Southern blotting and the polymerase chain reaction demonstrated the presence of a p190 mRNA and a breakpoint typical of acute leukemia. Thus a diagnosis of M4Eo was supported by clinical and cytogenetic sequelae in each case; the Ph in case 1 was apparently secondary to inv(16), in case 2 the Ph probably preceded inv(16) in the etiology of the leukemia.

der(16)t(1;16)(q21;q13) as a secondary change in Alveolar Rhabdomyosarcoma: A case report and review of the literature

Alveolar rhabdomyosarcoma is an aggressive childhood tumor that exhibits muscle cell differentiation. Cytogenetically, it is characterized by t(2;13)(q35;q14); no consistent secondary abnormalities have been reported. Cytogenetic analysis of bone marrow in a case of alveolar rhabdomyosarcoma revealed t(2;13)(q35;q14) and der(16)t(1;16)(q21;q13). The present case and a review of the literature suggest that up to 11% of these tumors possess der(16)t(1;16)(q21;q13). This is similar to the incidence observed in the Ewing family of tumors, where unbalanced der(16)t(1;16) translocations, resulting in partial trisomy of 1q, are regarded as a consistent secondary cytogenetic change.

The impact of karyotype on remission rates in adult patients with de novo acute myeloid leukemia receiving high-dose cytarabine-based induction chemotherapy.

One hundred and twenty-eight patients aged 15 years or over (median 34) with de novo acute myeloid leukemia (AML) received 2- or 3-drug induction chemotherapy comprising 5 days of daily high-dose cytarabine (2 g/m2 q12h) and etoposide (100 mg/m2), without (n=62, 1985-90, protocol BF11) or with (n=66, 1990-97, protocol BF12) daily 5 mg/m2 anthracycline (61 idarubicin, 5 mitoxantrone). Twelve patients with t(15;17) were not included. Evaluable karyotypes were obtained in 110 (86%): 30 (27%) favorable, 60 (55%) intermediate, and 20 (18%) adverse. Three patients dying during chemotherapy were inevaluable. Eighty-four (67%) patients remitted with one cycle, and the overall complete remission (CR) rate was 72%. CR rates were comparable for patients with and without evaluable karyotypes. CR rates with BF11 (64% after one cycle; 72% overall) and BF12 (70% after one cycle; 72% overall) were comparable (P=.4 and 1.0 respectively). CR rates after one cycle (86%, 61% and 55%; P=.03) as well as overall CR rates (90%, 69% and 55%; P=.02) were significantly different for patients with favorable, intermediate and adverse karyotypes respectively. In Cox analysis, the karyotype was the only factor found to influence CR independently. We conclude that the karyotype of the leukemic clone is the most important determinant of response to high-dose cytarabine-based induction chemotherapy in AML. The addition of idarubicin to high-dose cytarabine and etoposide does not appear to improve CR rates. A different treatment strategy may be needed to improve CR rates for patients with non-favorable karyotypes.

Cytogenetics of acute promyelocytic leukaemia: Incidence of t(15;17) at the Royal Marsden Hospital, London

This is the first report from a laboratory in the U.K. of the incidence of t(15;17) in acute promyelocytic leukaemia. One of the cases has a variant translocation, t(15;17)(q22;q25). A t(15;17) translocation was present in all cases considered to be adequately studied.

An eight-way variant t(15;17) in acute promyelocytic leukemia elucidated using fluorescence in situ hybridization.

A complex eight-way translocation was identified, with the aid of fluorescence in situ hybridization (FISH), in a patient diagnosed as having acute promyelocytic leukemia (APL). The balanced translocation was defined as 46,XY,t(1;6;7;6;17;15;12;3) (p22;q27;p15;q13;q21;q22;q13;p13), which includes a der(15) chromosome consistent with the der(15) chromosome of the t(15;17)(q22;q21) typically found in APL. The patient was treated with all-trans retinoic acid (ATRA) and had a clinical course typical of the disease, which is currently in remission after an autologous bone marrow transplant. The other structural rearrangements appeared to have little effect on the biology of the neoplasia.

Outcome of high-dose cytarabine-based induction therapy followed by hematopoietic stem cell transplantation in acute myeloid leukemia: influence of karyotype

One-hundred-twenty consecutive adult patients aged 15–69 years (median 40) with acute myeloid leukemia (AML) excluding t(15;17) received induction therapy comprising idarubicin, high-dose cytarabine and etoposide. Planned post-induction treatment included two courses of moderate-intensity consolidation therapy followed by stem cell transplantation. 11 patients (9%) died during induction therapy. The complete remission (CR) rate with a single cycle of induction therapy was 71%. The overall CR rate, after salvage chemotherapy but excluding allogeneic transplantation for primary refractory disease, was 82%. CR rates with one cycle of therapy for patients with good, intermediate and poor karyotype were 96, 72 and 41%, respectively (P < 0.0001). The impact of karyotype on the overall CR rate was also significant (96 vs. 88 vs. 59%; P = 0.001). Overall, 84 of 98 patients (86%) attaining CR underwent autologous (n = 59), allogeneic (n = 23) or syngeneic (n = 2) hematopoietic stem cell transplantation in first CR. The 5-year overall survival (OS) of 43% (95% CI: 34–52%) was significantly influenced by the karyotype: good 73%, intermediate 41%, and poor 18% (P = 0.0001). These data suggest that the sequence of therapy employed is active in AML, but additional steps are needed to improve the outcome of patients with intermediate- and high-risk cytogenetic abnormalities.

Cytogenetic Techniques for Human Leukemias

It is appropriate that a chapter on cytogenetic techniques for studying leukemic tissue appears in a series on molecular methods since these subjects are closely related, both in history and in application. It is through molecular methods that the significance of specific recurring chromosome abnormalities begins to be understood, but it is these specific recurring chromosome abnormalities that suggest the areas of interest for molecular studies.