Background Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. Methods A total of 532 patients with late–chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. Results Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment be...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa011573

Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia

Marco Marra and colleagues identify somatic mutations in EZH2 in diffuse large B-cell lymphomas and follicular lymphomas. EZH2 is a histone methyltransferase that participates in trimethylation of H3 Lys27 (H3K27) as part of the PRC2 complex. The mutations alter a single tyrosine residue in the SET domain of EZH2 and reduce the ability of PRC2 to trimethylate H3K27 in vitro.

/pdf/somatic-mutations-altering-ezh2-tyr641-in-follicular-and-29xffwch4q.pdf

Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin

Differentiation and Proliferation of Hematopoietic Stem Cells

We treated 93 patients who had acute nonlymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate postgrafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival.

Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia

Background About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. Methods We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. Results Of the 693 patients who had a complete remission, 596 we...

https://www.nejm.org/doi/pdf/10.1056/NEJM199410063311402

Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B

Granuloerythropoietic colonies in human bone marrow, peripheral blood, and cord blood

Identification of megakaryocytes, macrophages, and eosinophils in colonies of human bone marrow containing neurtophilic granulocytes and erythroblasts

https://tspace.library.utoronto.ca/bitstream/1807/26402/1/interacting%20cell%20populations%20affecting%20granulopoletic%20colony%20formation%20by%20normal%20and%20leukemic%20human%20marrow%20cells.pdf

Interacting cell populations affecting granulopoietic colony formation by normal and leukemic human marrow cells.

Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia

The growth of large, compact megakaryocyte colonies in cultures of human bone marrow is promoted by fresh human plasma and medium conditioned by phyto-hemagglutinin stimulated leukocytes (PHA-LCM). These colonies are typically composed of large cells with translucent cytoplasma, surrounded by a highly refractile border. In addition, they may also contain smaller cells of similar morphology. Independent of their size, all cells react positively with antibodies directed against human factor VIII antigen. The frequency of megakaryocyte colonies may vary for different individuals from 1-35 colonies per 10(5) mononuclear bone marrow cells. The observed linear relationships between the number of cultured cells and the frequency of colonies suggests a single cell origin. The described culture conditions also support the development of a larger megakaryocyte component within multilineage mixed colonies, so that it will now be feasible to investigate the mechanisms involved in directing pluripotent cells towards megakaryocytopoiesis.

Hans A. Messner

Papers

Granuloerythropoietic colonies in human bone marrow, peripheral blood, and cord blood

Identification of megakaryocytes, macrophages, and eosinophils in colonies of human bone marrow containing neurtophilic granulocytes and erythroblasts

Interacting cell populations affecting granulopoietic colony formation by normal and leukemic human marrow cells.

Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia

The growth of large megakaryocyte colonies from human bone marrow.