Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B.
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Biomedical subjects
Publications and source records attributed to O R McIntyre.
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A patient with chronic myelogenous leukemia (CML) had a Philadelphia chromosome (Ph') [t(9q+;22q-)] in all cells and trisomy C in 13% of cells (later determined to be trisomy 8) at the time of diagnosis. After 21 months of intermittent treatment with busulfan, the acute phase developed with the appearance of an additional abnormality (trisomy ? 19). During a complete remission and reconversion to the chronic phase, trisomies 8 and ? 19 DISAPPEARed, although the Ph' remained. Following a period of marked thrombocytosis, a second relapse occurred with the reappearance of both marker chromosomes.
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Sixty-eight previously untreated patients with IgG myeloma who were entered into five protocols of Cancer and Leukemia Group B (CALGB) were studied in order to determine the possible influence of excretion of kappa versus lambda urinary light chains on responses to treatment and survival. All patients in these protocols were included if the serum and urine protein abnormalities were confirmed by one of the two group reference laboratories. Pretreatment characteristics of the two groups of patients did not differ significantly. Of 44 patients with kappa Bence Jones proteinuria, 19 patients (43%) had good responses to treatment, whereas only 3 of 24 patients (13%) with lambda Bence Jones proteinuria had good responses (p = 0.02). Survival for the patients excreting kappa light chains was significantly better than survival for patients excreting lambda chains (median survival 31 versus 12 mo, p = 0.02).
Ten patients developed allergic reactions to iv melphalan (L-PAM) during therapy for multiple myeloma. The incidence of such reactions was 2.4% among 425 patients receiving iv L-PAM with or without other drugs and 3.9% among 255 patients receiving iv L-PAM alone. Only one such reaction was demonstrated in 294 patients who initially received oral L-PAM. The median day of first reaction to iv L-PAM was Day 222 (range, Days 44-909) and the median total dose prior to a reaction was 185 mg (range, 51-250 mg). Of five patients who subsequently received oral L-PAM, four developed a reaction similar to that experienced with the iv drug.
Two hundred fifty-two previously untreated evaluable patients with multiple myeloma were entered into a study testing a regimen of three intravenous alkylating agents, melphalan, cyclophosphamide, and carmustine (BCNU), given in combination (BCMP) against a regimen employing oral melphalan (MP). Both regimens included a tapering course of prednisone. Objective responses based on the Myeloma Task Force criteria were significantly more frequent in the group receiving BCMP. Survival for the entire group of BCMP-treated patients was not significantly better than that for MP-treated patients (p = 0.62). However, when the survival of the poor-risk (high tumor cell load) group of patients treated with BCMP was compared with the survival of the poor-risk (high tumor cell load) group of patients treated with MP, an improvement in survival attributable to BCMP therapy was seen (p = 0.049 and 0.02, respectively). In the good-risk (low and intermediate tumor cell load) group, BCMP treatment resulted in a trend toward poorer survival, but this did not achieve statistical significance (p = 0.080 and 0.23, respectively). These results indicate that optimal therapy in myeloma may be dependent on the extent of disease at the time of first treatment. Additional studies to explore the effects of treatment intensity and duration are needed in order to design improved myeloma treatment based on the patient's extent of disease.
Eighty-nine patients with multiple myeloma resistant to melphalan were randomized to receive cyclophosphamide plus prednisone (CP) (47 patients) or cyclophosphamide plus BCNU plus prednisone (CBP) (42 patients). No differences were detected in the two groups prior to therapy. Objective responses occurred in three (7%) of the CP patients and in seven (17%) of the CBP patients. About 40% of the patients in each group achieved some response. Toxic reactions consisted mainly of leukopenia and thrombocytopenia. Median survival was not different in the two groups. The median survival time was 31 months among those patients with an objective response and 9.4 months among those without an objective response. The addition of BCNU to CP increased the frequency of objective response, but not significantly. This triple combination (CBP) cannot be recommended.
Polycythemia vera (PV) represents an apparent monoclonal stem cell proliferation with a frequent transition to full neoplastic behavior. Up to 26% of untreated PV patients can be expected to have some chromosome abnormalities in the marrow at the time of diagnosis, and 10--15% have an abnormal cell line or clone. Both structural and numerical aberrations occur. Aneuploidy is the most common type of chromosome abnormality, however, with hyperdiploid clones occurring more frequently than hypodiploid clones. Chromosomes 1, 8, 9 and 20 are involved in a non-random pattern, and aberrations of all the F group, or at least the No. 20 chromosome seem to be associated to some extent with diseases involving erythroid hyperplasia. Leukemia develops in a certain percentage of patients regardless of the type of treatment they have received, but the relationship, if any, between the chromosome abnormalities and the development of leukemia is still uncertain. The abnormal clones that occur in PV appear to be quite stable and there is no indication at this time that they correlate with a prognosis of leukemic transformation.
Cytogenetic studies of patients with multiple myeloma and plasma cell leukemia have shown that chromosome abnormalities occur in the bone marrow and/or the PHA-stimulated blood of at least half the patients. The abnormalities include numerical and structural aberrations and are highly variable. Hypodiploid modes occur fairly frequently. Addition of material to the long arm of the No. 14 chromosome (14q+ marker) occurs in about 17% of the small series of patients that have been studied with banding so far.
A randomized therapeutic trial of three induction regimens for patients with lymphosarcoma and reticulum-cell sarcoma was conducted by the Cancer and Leukemia Group B (CALGB) (formerly Acute Leukemia Group B.) Addition of streptonigrin, but not cyclophosphamide, to the combination of vincristine and prednisone improved the complete remission rate achieved after a 42-day induction program. The duration of the subsequent remission and survival was not influenced by the induction combination assigned. Remission maintenance with cyclophosphamide was superior to maintenance with methotrexate. The results of this study are compared with others in which advantages for three or four drug treatment regimens have been reported.
Antibody to keyhole limpet hemocyanin (KLH) has been detected in normal unimmunized subjects by means of a sensitive micropassive hemagglutination technique. Prior sensitization was not detected by either skin testing or lymphocyte transformation. After immunization with KLH there was no correlation between the level of this antibody and subsequently acquired skin test reactivity and lymphocyte transformation.
Two young women had painful ecchymoses of their extremities. In one, this purpuric syndrome followed a chronic course and resulted in severe joint disability. In the other woman, the problem was transient and relatively benign. Emotional factors in their disease were of major importance. No abnormalities of hemostasis or immune function were found. These cases demonstrate the many problems encountered in the diagnosis and management of such patients.
Erythropoietin stimulates the erythropoietin responsive cell to undergo DNA synthesis and subsequent mitosis. To define further the physiology of this effect, a liquid suspension microculture utilizing mouse fetal liver cells was developed. Tritiated thymidine incorporation into erythroid precursors was found to parallel radiolabeled iron incorporation with peak DNA synthesis occurring after 24 hours of culture. Both tritiated thymidine and iron incorporation were dependent on erythropoietin concentration. The responsiveness to erythropoietin decreased when erythropoietin was withheld and this diminishment in reactivity paralleled a morphological differentiation of the cells. This observation, together with the finding that erythropoietin activity could be removed by absorption with large numbers of cells, suggests the proliferation induced by erythropoietin depends on a specific stage in the differentiation of the red blood cell and may be mediated through a specific cellular receptor.
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To investigate the systemic, clinical and laboratory effects of iv polyriboinosinic-polyribocytidylic acid (poly I-poly C), 32 doses of poly I-poly C were administered to 22 patients. Doses between 1 and 10 mg/kg induced the formation of serum interferon (IF) and fever. Whereas a direct relationship was seen between the poly I-poly C dose and fever, serum IF levels were not significantly changed by increasing the dose of poly I-poly C over a log range from 1 to 10 mg/kg. Transient abnormalities were noted in liver function tests in 4 of 13 patients who received greater than 6.0 mg/kg. Other laboratory changes were confined to an increase in the absolute granulocyte count that paralleled fever development and abnormalities in coagulation parameters of 1 patient. In vitro lymphocyte DNA synthesis in response to mitogens was transiently impaired at times corresponding to serum IF appearance. These studies have established dose levels of poly I-poly C that can be safely administered to man with minimal toxicity and result in IF induction.
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