Kenneth B. McCredie

Hematologic Remission and Cytogenetic Improvement Induced by Recombinant Human Interferon AlphaA in Chronic Myelogenous Leukemia

We treated 17 patients who had Philadelphia-chromosome-positive chronic myelogenous leukemia (4 of whom had not received therapy and 13 of whom had been treated with hydroxyurea or busulfan for less than six months) with recombinant human interferon alpha A (Roferon-A). The interferon was given as 5 X 10(6) units per square meter of body-surface area per day intramuscularly during induction therapy. Fourteen patients responded to the treatment, of whom 13 had a hematologic remission and 1 had a partial hematologic remission. The median number of white cells in those patients declined from 60.9 X 10(3) to 3.4 X 10(3) per microliter, and the median number of platelets decreased from 476 X 10(3) to 231 X 10(3) per microliter. Among the five responding patients who had splenomegaly before treatment, the spleen size returned to normal in four and decreased by 75 percent in one, although it remained enlarged. Bone marrow cellularity declined from a median of 92.5 percent to a median of 57.5 percent. In six of the patients with hematologic remission, complete suppression of Philadelphia cells was observed on at least one examination. Of the 14 patients who responded, 11 have received the interferon therapy for 9 to 15 months. One patient relapsed during the treatment, and the treatment has been temporarily interrupted in two patients because of toxicity. These data are preliminary and will need further confirmation, but they suggest that recombinant human interferon alpha A is effective in inducing hematologic remission in most patients with benign-phase chronic myelogenous leukemia and in suppressing the Philadelphia chromosome in some of these patients.

Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia.

Thirty-three patients with chronic lymphocytic leukemia (CLL) with advanced Rai stage (III-IV) or progressive Rai stage (0-II) disease were treated with fludarabine as a single agent. Eleven patients (33%) obtained a complete remission (CR), 13 (39%) a clinical CR with residual nodules as the only evidence of disease (nodular partial remission [PR]), and two patients (6%) achieved a PR for a total response rate of 79%. Response was rapid, usually occurring after three to six courses of treatment. The major morbidity was infection. Febrile episodes occurred in 13% of the courses (pneumonia 6%, minor infection 4%, and transient fever of undocumented cause 3%). Fludarabine appears to be the most cytoreductive single agent so far studied in CLL.

Characteristics of accelerated disease in chronic myelogenous leukemia

Determination of the characteristics of accelerated disease in chronic myelogenous leukemia (CML) helps in individual prognostication, and in the introduction and analysis of investigative approaches based on risk‐benefit ratios. The outcome of 357 patients with Philadelphia chromosome‐positive CML was analysed from the time of development of suspected features of accelerated disease. Median survivals shorter than 18 months were associated with the appearance of any of the following: cytogenetic clonal evolution; extramedullary disease; peripheral blasts ⩾ 15%, peripheral blasts and promyelocytes ⩾ 30%, or peripheral basophils ⩾ 20%; platelet count < 1.0 × 105/μl; marrow blasts ⩾ 15%, marrow blasts and promyelocytes ⩾ 30%, or marrow basophils ⩾ 20%. Relative hazard ratios, or risk of death per unit time, were calculated based on the relative survivals of patients who did or did not develop the particular feature of accelerated disease, after accounting for the time to development of the characteristic. Further analysis identified five features that have additive independent prognostic importance: cytogenetic clonal evolution; peripheral blasts ⩾ 15%; peripheral basophils ⩾ 20%; peripheral blasts and promyelocytes ⩾ 30%; and thrombocytopenia. By providing an objective estimate of prognosis in accelerated disease, the model identifies patients in need of different therapeutic interventions before the development of blastic crisis.

Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic, and prognostic features.

One hundred twelve patients who developed acute leukemia or a myelodysplastic syndrome (MDS) after chemotherapy or irradiation for another malignancy were reviewed. The median time from initial therapy to development of secondary leukemia or MDS was 71 months (range, 7 to 331 months). The initial malignancy was hematologic in 43%. An MDS presentation occurred in 57 patients (51%), 55% of whom subsequently transformed to acute leukemia. Chromosomal abnormalities were documented in marrow specimens from 70 of 89 patients with analyzable metaphases (79%; 69% of the total group). Compared with 34 patients with metachronous secondary leukemia without prior chemotherapy or irradiation, those with therapy-related leukemia exhibited a significantly higher frequency of abnormalities of chromosomes 5 and/or 7 (43% v 18%), and lower incidence of diploid karyotypes (18% v 50%). Chromosome 5 and/or 7 abnormalities were also significantly higher in patients previously treated with alkylating agents, procarbazine, and nitrosoureas (72% to 83%), compared with those who had received cyclophosphamide-based regimens (29%), other chemotherapies (14%), or irradiation alone (29%). The median overall survival from diagnosis of the secondary leukemia or MDS was 30 weeks. Survival was significantly shorter for patients with acute leukemia compared with MDS presentation (21 v 45 weeks); in the latter category, it was similar whether evolution to acute leukemia occurred or not. Of 72 patients treated with antileukemia therapy, 29% achieved complete remission (CR). A multivariate analysis of prognostic factors demonstrated the cytogenetic pattern to be the most important characteristic determining remission rate and survival. Other important prognostic features were the morphologic presentation (MDS v acute leukemia) for probability of achieving remission, and patient age and marrow blasts percentage for survival.

Chemotherapy, Immunocompetence, Immunosuppression and Prognosis in Acute Leukemia

Abstract Immunologic competence was evaluated in 25 patients with acute myelogenous leukemia before and after intensive combination chemotherapy for induction of remission. Cell-mediated immunity correlated with the response to chemotherapy; 86 per cent of patients with normal delayed hypersensitivity to a battery of antigens achieved remission as compared to 25 to 50 per cent of anergic patients. In vitro lymphocyte responses to phytohemagglutinin before and after therapy showed 41,000 and 42,000 counts per minute in patients achieving remission and of 15,000 and 9000 counts per minute in patients not achieving remission. Sixty per cent of patients showing delayed hypersensitivity after immunization entered complete remission as compared to only 37 per cent of those without this reactivity. Patients converting from immunoincompetence to immunocompetence during therapy achieved remission, whereas those converting from immunocompetence to immunoincompetence did not. Prior treatment had no effect on immune ...

Cells Capable of Colony Formation in the Peripheral Blood of Man

Colony-forming cells have been found in the peripheral blood of man and have been grown in vitro by use of a soft agar gel technique. It has been possible to collect these cells with a blood-cell separator in numbers similar to those found in the peripheral circulation. Repeat leukapheresis of the same donor does not reduce the number of circulating colony-forming cells.

Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia

PURPOSE Several prognostic models or staging systems have been published that identify different risk groups in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). The aims of this study were (1) to test, in an independent population, the prognostic reproducibility of these staging systems; and (2) to develop a synthesis staging system that could be easily applied in clinical practice. PATIENTS AND METHODS A total of 406 patients with newly diagnosed Ph-positive CML were evaluated by the four published staging systems of Tura, Cervantes, Sokal, and our group. The proposed synthesis staging system was developed based on the most consistent prognostic characteristics, and the presence or absence of accelerated disease features at diagnosis. The staging systems were compared according to survival outcome, as well as by looking for differences of survival outcomes within a specific stage of a defined system, when patients in this stage were subclassified by a second staging system. RESULTS Whereas the staging system of Cervantes et al identified only two prognostic groups (median survivals of 49 versus 40 months; p = 0.01), the remaining three staging systems were able to segregate patients into stage 1, 2, and 3 risk groups with respective median survivals of 56 to 57, 41 to 42, and 28 to 36 months, respectively (p less than 0.001 to p less than 0.002). The new proposed staging system, based on the existence of zero to one (stage 1), two (stage 2), or three or more unfavorable (stage 3) characteristics, or the presence of accelerated disease features (stage 4), categorized patients into four prognostic groups with median survivals of 56, 45, 30, and 30 months, respectively (p less than 0.001), the latter stage (stage 4) being associated with a higher one-year mortality rate (29%). The synthesis staging system was also able to subclassify patients within most of Turas and Sokals stages into significantly different prognostic groups by survival outcome. CONCLUSION The predictive prognostic capacity of three of the four published staging systems was confirmed in this independent or test population. The new proposed staging system was superior to the staging systems of Tura and Sokal in identifying different prognostic subgroups.

Acute promyelocytic leukemia: M.D. Anderson hospital experience☆

Sixty patients with acute promyelocytic leukemia were treated between 1973 and 1984. The overall median survival was 16 months with a five-year survival rate of 31 percent. The complete remission rate was 53 percent and was similar whether they received amsacrine- or anthracycline-based regimens (60 percent versus 51 percent). The median remission duration was 29 months. At five years, 43 percent of patients with responses to treatment had continuous remission and 57 percent were alive. Salvage therapy produced remissions in 53 percent of patients during first relapse, with two long-term survivors after further consolidation with bone marrow transplantation. Early fatal hemorrhage associated with disseminated intravascular coagulopathy during induction therapy occurred in 16 patients (26 percent). Multivariate analysis of the pretreatment patient characteristics significantly associated with an increased risk of fatal hemorrhage identified four that have primary prognostic importance: thrombocytopenia, elevated absolute blast and promyelocyte counts, old age, and anemia. Patients having up to two unfavorable features had a low risk of fatal hemorrhage compared with those who had more than two (5 percent versus 58 percent; p less than 0.0001). Overall, patients who received heparin had a lower incidence of fatal hemorrhage than those who did not (19 percent versus 32 percent). Heparin therapy was not beneficial to those at low risk but was associated with a trend towards decreased hemorrhagic deaths among high-risk patients (45 percent versus 67 percent). Cytogenetic studies demonstrated the characteristic 15;17 translocation in 73 percent of patients with analyzable metaphases, whereas 12 percent had other karyotypic abnormalities. Remission induction was often associated with a gradual atypical morphologic evolution into remission without intermediate hypoplasia with the interim marrows showing a high proportion of blasts. It is concluded that acute promyelocytic leukemia is a unique disease with a high potential for cure. Knowledge of its prognosis using present frontline and salvage therapy, of the factors related to fatal hemorrhage, and of the unusual patient marrow profiles during remission induction may improve the therapeutic approach.

Response to salvage therapy and survival after relapse in acute myelogenous leukemia.

The response to and survival following first salvage therapy regimens for 243 patients with acute myelogenous leukemia (AML) treated between 1974 and 1985 were evaluated. Eighty (33%) patients obtained a complete remission (CR), 24% died prior to achieving a response, and 43% were resistant on their first salvage regimen. The median survival was 18 weeks. Five percent overall and 16% of the CR patients are predicted to survive for more than 5 years. The factor most strongly associated with response and survival was the duration of the initial remission with 49 of 82 (60%) patients whose initial CR duration was at least 1 year in duration obtaining a second CR v 31 of 161 (19%) for patients with a shorter remission (P less than .01). Age, liver function, serum lactic dehydrogenase (LDH), karyotype, and the proportion of blasts plus promyelocytes present at the time of starting salvage therapy were strongly associated with probability of response and survival. Multivariate analysis was used to develop logistic regression and proportional hazard models to predict probability of response and survival, respectively. The major regimens used were conventional-dose cytarabine (ara-C) (combined with anthracyclines or amsacrine), high-dose ara-C, rubidazone, amsacrine (AMSA), other anthracyclines, and autologous or allogeneic transplant programs. After allowing for the prognostic factors in the models, specific treatment regimens were not strongly associated with prognosis.

Factors related to length of complete remission in adult acute leukemia

Two hundred and two adult patients with acute leukemia were analyzed to determine pretreatment and treatment factors that could predict for duration of bone marrow remission. Several factors had a significant effect on remission duration, including morphologic diagnosis (AML > ALL > AUL), initial blast cell count, age, serum LDH, fibrinogen level, labeling index, and in vitro agar colony growth. Patients who attained a remission quickly or in whom leukemic cells in blood and bone marrow were rapidly cleared had long remissions. After applying regression model fitting methods, the six major factors, in order of significance, were the initial serum LDH level, pretreatment fibrinogen level, the number of courses of treatment to obtain a remission, morphologic diagnosis, the halving rate of leukemic cells in the blood, and the age of the patient. The model derived from this study was applied to the 202 patients and suggested that patients likely to have short or long bone marrow remission can be identified.