Jose M. Trujillo

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.

Interferon-Alpha Produces Sustained Cytogenetic Responses in Chronic Myelogenous Leukemia: Philadelphia Chromosome-Positive Patients

OBJECTIVES To evaluate the frequency and the course of complete cytogenetic responses in interferon-alpha (IFN-alpha)-treated patients with chronic myelogenous leukemia. DESIGN Two prospective trials in consecutive patients. SETTING A major tertiary cancer center. PATIENTS Ninety-six consecutive patients with chronic myelogenous leukemia with disease duration of less than 1 year. INTERVENTION Patients received partially pure IFN-alpha intramuscularly, from 3 to 9 million U/d (51 patients) or recombinant IFN-alpha 2a (Roferon, Hoffmann-LaRoche, Inc., Nutley, New Jersey), 5 million U/m2 body surface area daily (45 patients). MEASUREMENTS Hematologic and cytogenetic tests were administered. MAIN RESULTS Seventy of the patients (73%) achieved hematologic remission (95% CI, 63% to 81%), and 18 (19%) had complete suppression of the Philadelphia chromosome on at least one cytogenetic test. A complete cytogenetic response was induced in 7 of 51 or 14% (CI, 6% to 26%) of the patients treated with the partially pure IFN-alpha and in 11 of 45 or 24% (CI, 13% to 40%) of the patients treated with recombinant IFN-alpha 2a. The difference in complete cytogenetic response between the two groups was 10.7% (CI, - 5% to 26%; P greater than 0.2). Eleven patients had durable, ongoing, complete cytogenetic responses from 6 to more than 45 months (median, more than 30 months). CONCLUSION This study was the first to show sustained, complete cytogenetic responses in a subset of patients with chronic myelogenous leukemia treated with single-agent therapy. The nature of this remission, that is, whether it depends on continuous therapy, requires further study.

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.

Stimulation of Myelopoiesis in Patients with Aplastic Anemia by Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

Aplastic anemia is a syndrome in which pancytopenia occurs in the presence of hypocellularity of the bone marrow. To assess the biologic activities of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in aplastic anemia, we gave GM-CSF (60 to 500 micrograms per square meter of body-surface area) to 10 patients with moderate or severe disease, by continuous intravenous infusion daily for two weeks, and repeated the treatment after a two-week rest period. The treatment increased the white-cell count (1.6- to 10-fold) in all patients, primarily because of an increase in the numbers of neutrophils (1.5 to 20-fold), eosinophils (12- to greater than 70-fold), and monocytes (2- to 32-fold). Rates of hydrogen peroxide production in purified granulocyte fractions increased during GM-CSF treatment. Increases in bone marrow cellularity, myeloid precursor cells, and myeloid:erythroid cell ratios accompanied the white-cell response. Despite the in vivo response of the white-cells, the concentration of colony-forming cells remained the same. Measurable concentrations of interleukin-2 (2 to 15 units per milliliter) were found in the serum of 8 patients, and high levels of erythropoietin (81 to 1200 IU per liter) were found in 10 patients. The predominant side effects were constitutional symptoms. These results indicate that recombinant human GM-CSF is effective in stimulating myelopoiesis in patients with severe aplastic anemia and may benefit some patients in whom the disorder is refractory to standard forms of therapy.

Toward a clinically relevant cytogenetic classification of acute myelogenous leukemia

Cytogenetic studies with Giemsa banding were performed on the bone marrow cells of 384 patients with acute myelogenous leukemia treated between 1975 and 1983. An abnormal karyotype was detected in 54% of patients, being present in 100% of metaphases (AA) in 31% and only a proportion of cells (AN) in 22%. Specific translocations or other abnormalities were noted in 22% of patients, the most common of which were t(8;21) (q22;q22) in 7%, t(15;17) (q22;q21) and inv (16) (p13q22) in 5.5%, t(9;22) (q34;q11) in 3% and abnormalities of 11q23 in 1.3%. Loss of the Y chromosome was noted in 21 patients, associated with t(8;21) in 11 patients and the sole abnormality in eight patients (45, X, -Y). Most (66%) of the other abnormalities involved addition of chromosome 8 or loss or deletion of 5 or 7 (+8, -5 or -7, 5q- or 7q- group). The remaining patients had miscellaneous abnormalities (MA). A marked assymetry was noted in the distribution of important clinical prognostic variables such as age, sex, history of an antecedent hematologic disorder and presence of Auer rods within the various cytogenetic categories. The specific translocation/abnormalities were more common in younger patients (p less than 0.01). Analysis of response, remission duration and survival demonstrated that inv 16 and t(8;21) were favorable prognostic categories; diploid, t(15;17) and 45,X,-Y had intermediate prognosis, and all other categories were unfavorable prognostic groups. The response rate and survival for diploid patients (NN) was superior to patients with abnormalities. No difference in response rate, CR duration or survival was noted between the AA and AN groups. A prognostic classification according to cytogenetic category based on clinical associations is proposed which will be tested prospectively in subsequent studies.

Intensive combination chemotherapy (ROAP 10) and splenectomy in the management of chronic myelogenous leukemia.

To investigate the role of intensive chemotherapy in chronic myelogenous leukemia (CML), we treated 37 patients who had Philadelphia-positive benign-phase disease with rubidazone 300 mg/m2/d 1 (or daunorubicin 30 mg/m2/d X 4), cytosine arabinoside 80 mg/m2/d X 10, vincristine 2 mg/d 1, and prednisone 100 mg/d X 5 (ROAP 10), every four weeks for a median of three cycles. This treatment was followed by splenectomy and by subsequent maintenance therapy with 1 to 5 g hydroxyurea daily in intermittent courses. After a median follow-up of 42 months (range, 24 to 54 months), 20 patients (54%) remain in benign phase. The projected median survival is 52 months, and the three-year survival rate is 67%. Six patients (16%) developed blastic crisis, and eight died in the benign phase. A significant cytogenetic response, defined as a fall in the percentage of Philadelphia-positive cells to less than or equal to 30%, occurred in 18 (53%) of 34 patients who had serial cytogenetic studies. Six patients (18%) had reductions to 35% to 90%, whereas ten remained 100% positive. Cytogenetic response lasted for a median of six months from the time of maximal response (range, 1 to 18 months). Blastic crisis or accelerated disease developed in seven (44%) of the 16 patients who manifested minimal or no cytogenetic response, compared to only two of the 18 patients (11%) who achieved a significant cytogenetic response. Toxicity, which resulted in one death, was due to myelosuppression and consisted of febrile episodes during neutropenia (24% of courses), documented infections (8% of courses), and bleeding (8% of courses). ROAP 10 intensive therapy produces moderate survival improvement for CML patients compared to a matched historical control group of patients treated at our institution, but it has considerable myelosuppressive toxicity. The Philadelphia chromosome response is an important treatment-related prognostic factor.

Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation

BACKGROUND Patients whose leukemia relapses after allogeneic bone marrow transplantation have a poor prognosis; few respond to further chemotherapy, and almost none survive over the long term. We present preliminary observations on the use of filgrastim (granulocyte colony-stimulating factor) for relapse after transplantation. METHODS Seven female patients with leukemia (one with chronic myelogenous leukemia, five with acute myelogenous leukemia, and one with a myelodysplastic syndrome that transformed into acute myelogenous leukemia) whose disease relapsed within 360 days after allogeneic bone marrow transplantation received filgrastim (5 micrograms per kilogram of body weight per day by subcutaneous injection) to reinduce remission by stimulating residual donor marrow cells. Cytogenetic analysis of bone marrow, fluorescence in situ hybridization, and determination of restriction-fragment--length polymorphisms were used to assess response and chimerism. RESULTS Three of the seven patients had a complete hematologic and cytogenetic remission, with reestablishment of hematopoiesis of donor origin. Mild chronic graft-versus-host disease developed in one patient, and acute graft-versus-host disease in none. One patient had a relapse 12 months after treatment, and two others remained in remission after 10 and 11 months. In two of the patients with a response, fluorescence in situ hybridization demonstrated stimulation of donor cells without differentiation of the leukemic clone. CONCLUSIONS Filgrastim may be effective in selected cases of leukemic relapse after allogeneic bone marrow transplantation.

Acute Leukemia in Multiple Myeloma

Of 476 patients with multiple myeloma treated during a 9-year period, 11 developed acute myelogenous leukemia or sideroblastic anemia. In all, the myeloma was in remission from chemotherapy with melphalan-prednisone combinations that had been continued for a median duration of 3 years. The incidence of acute leukemia or sideroblastic anemia was about 100 times higher than found in normal individuals of the same age. In all patients studied, major cytogenetic abnormalities were present, with hypodiploidy and evidence of chromosomal damage being noted most frequently. The frequency and nature of the chromosome changes were attributed to effects resulting from the prolonged drug therapy. These findings supported the long-term follow-up of selected patients with myeloma without any chemotherapy when marked degrees of remission followed the initial treatment courses.

Clinical implications of aneuploid cyto genetic profiles in adult acute leukemia

In a series of 170 adult patients with acute leukemia, sequential cytogenetic studies were conducted during a period which included either the initial and, at times, the terminal phase of the disease, or the relapse and remission phases. On the basis of morphological similarities in the karyotype changes, the patients carrying aneuploid clones were categorized into several profiles of aneuploidy. Analysis of the survival times determined from the time of diagnosis suggested that some of these abnormal cytogenetic profiles may have definite clinical implications.

Rearrangement in the Breakpoint Cluster Region and the Clinical Course in Philadelphia-Negative Chronic Myelogenous Leukemia

We have followed one patient with Philadelphia (Ph)-negative chronic myelogenous leukemia and identified an additional four patients from the literature who showed the rearrangement in the breakpoint cluster region (bcr) on chromosome 22 characteristic of Ph-positive chronic myelogenous leukemia. The clinical course of these five patients was similar to that of Ph-positive patients, with easily controlled leukocyte counts, a prolonged benign phase, and prolonged survival. Furthermore, we have shown, for the first time, that bcr rearrangement in Ph-negative chronic myelogenous leukemia can result in expression of the aberrant 210-kilodalton bcr-abl fusion protein, which has been strongly implicated in Ph-positive leukemogenesis. Research data pertaining to possible cytogenetic mechanisms leading to production of p210bcr-abl in the absence of the Ph chromosome are reviewed. Molecular analysis provides an important tool for classifying and predicting prognosis of some patients with Ph-negative chronic myelogenous leukemia.