Since the advent of tyrosine kinase inhibitors, the impact of age on outcome of chronic myeloid leukemia (CML) patients has changed. We therefore analyzed patients from the randomized CML study IV to investigate disease manifestations and outcome in different age groups. One thousand five hundred twenty-four patients with BCR-ABL-positive chronic phase CML were divided into four age groups: (1) 16–29 years, n = 120; (2) 30–44 years, n = 383; (3) 45–59 years, n = 495; and (4) ≥60 years, n = 526. Group 1 (adolescents and young adults (AYAs)) presented with more aggressive disease features (larger spleen size, more frequent symptoms of organomegaly, higher white blood count, higher percentage of peripheral blasts and lower hemoglobin levels) than the other age groups. In addition, a higher rate of patients with BCR-ABL transcript levels >10 % on the international scale (IS) at 3 months was observed. After a median observation time of 67.5 months, no inferior survival and no differences in cytogenetic and molecular remissions or progression rates were observed. We conclude that AYAs show more aggressive features and poor prognostic indicators possibly indicating differences in disease biology. This, however, does not affect outcome.
Background: Multidrug resistance is caused by overexpression of P-glycoprotein (P-gp, encoded by the mdrl gene), a transmembrane energy-dependent efflux pump which acts by expelling a wide variety of cytostatic drugs from the cytosol, thus decreasing intracellular drug accumulation. The multidrug-resistant phenotype has been identified as a major cause of treatment failure in many malignancies. In acute leukemia, overexpression of P-gp has been observed at diagnosis as well as in patients with resistant disease. The aim of the present study was to correlate response to induction therapy with mdrl gene expression in newly diagnosed acute leukemia. Material and Methods: The mdrl gene product P-gp expression was studied in 51 adult patients with newly diagnosed leukemia (9 acute lymphoblastic leukemias, 42 acute nonlymphoblastic leukemias) by means of immunocytochemistry and the alkaline phosphatase/anti-alkaline phosphatase method, using the two monoclonal antibodies C219 and MRK16. In all patients induction therapy was performed according to currently ongoing German multicenter trials. Results: At diagnosis, the mdr phenotype was observed in 47% of the patients. Following induction therapy, 56% of the P-gp-positive patients were induced into remission, compared to 78% of the P-gp-negative patients. The surface marker CD34, known to be associated with a poor prognosis in acute leukemia, was expressed in 58% of the samples. In cases where both markers were positive, the complete remission rate was only 50% as compared to 82% when both markers were negative. 8 of 11 P-gp-positive patients refractory to initial chemotherapy expressed both markers, thus indicating the existence of a possible subgroup with a very poor prognosis. Conclusions: Our data are concurrent with other reports and support increasing evidence that mdrl gene expression contributes to chemoresistance in newly diagnosed acute leukemia as an independent factor.
Chromosomal findings are reported in three patients with acute myelomonocytic leukemia and in one with reticulosarcoma leukemia who had been treated for multiple myeloma with melphalan and X-ray. All four patients had striking chromosomal anomalies. An iatrogenic causation of aneuploidy is suggested. This is supported by chromosomal findings in patients with acute leukemia following polycythemia vera and Hodgkin's disease; practically all of the leukemias have been aneuploid. A comparison is made of such "secondary" acute leukemias with "primary" acute leukemias that are aneuploid in only 40% of the cases. Chromosomal changes are not considered to be the initial event in leukemogenesis.
Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival.Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival.Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression.MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
