Chromosome studies in acute leukemias developing in patients with multiple myeloma.

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.

The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: a prospective randomized clinical trial by Cancer and Leukemia Group B.

Cancer and Leukemia Group B undertook a randomized trial of intensification treatment in adults aged 15 to 79 years with acute lymphocytic leukemia (ALL) in complete remission (CR). Daunorubicin (DNR), prednisone, vincristine (VCR), intrathecal (IT) methotrexate (MTX), and asparaginase produced 177 CRs in 277 patients. One hundred fifty-one patients were randomly assigned to receive treatment as follows: 74 received intensive cytarabine and DNR, and 77 received cycles of mercaptopurine (6-MP) and MTX, followed by 6MP, MTX, VCR, and prednisone for 3 years in all. One hundred twelve patients received CNS prophylaxis. Intensification produced major myelosuppression but did not improve remission duration (median, 21 months). Of the 151 patients with CRs who entered the intensification phase, 29% remain in continuous CR (43 to 117 months); in 19 patients, CRs have lasted for longer than 7 years. No relapses occurred after 60 months. Median survival from the time of randomization was 30 months. Those under 30 years of age responded more frequently, with longer CR and survival. While 53% of those aged 15 to 19 years remain in continuous CR, 92% of patients over 59 years have relapsed. The presence of a myeloid antigen on the leukemic cells was adversely prognostic for CR achievement and for survival. Pretreatment WBC and platelet levels independently affected CR duration and survival. Early M1 marrow development presaged longer remissions. CNS relapse occurred in 47 of 256 patients with normal CSF before treatment, in 29 before CNS prophylaxis. CNS disease occurred after CNS prophylaxis in 18 patients: 13 of 61 who had received standard premaintenance and five of 51 who received intensification. No advantage in CR duration or survival resulted from intensive treatment with DNR and cytarabine following induction of CR.

Combination chemotherapy with mastectomy or radiotherapy for stage III breast carcinoma: a Cancer and Leukemia Group B study.

One hundred thirteen evaluable patients with previously untreated stage III breast carcinoma were treated with three monthly cycles of cyclophosphamide (CYC), doxorubicin (DOX), 5-fluorouracil (5-FU), vincristine (VCR), and prednisone (PRED) (CAFVP). Subsequently, 91 (81%) were deemed operable. Patients were then randomized to receive surgery or radiotherapy (RT) to determine which of these modalities afforded better local tumor control. All patients also received 2 additional years of CAFVP in a further attempt to eradicate local disease and systemic micrometastases. Forty-one of the randomized patients have relapsed. Approximately half of the initial relapses in each arm were local. The overall duration of disease control was similar following either modality, with a median of 29.2 months for surgery patients and 24.4 months for RT patients. Similarly, there was no major difference in survival related to randomized treatment with an overall median of 39 months (median follow-up 37 months). Pre- or perimenopausal status and inflammatory disease were associated with shorter disease control and survival. Treatment was generally well tolerated and toxicity was acceptable. This study demonstrates that prolonged control of stage III breast carcinoma can be achieved with combined modality therapy in which cytotoxic chemotherapy precedes and follows treatment directly primarily at the breast tumor, using either surgery or RT. Nevertheless, new regimens must be designed if significant advances that may lead to the cure of this disease are to be achieved.

Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study.

One hundred ninety-five adult patients with refractory or first relapse acute myelogenous leukemia (AML) were randomly assigned to receive high-dose cytarabine (HiDAC), 3 g/m2 as a three-hour intravenous (IV) infusion every 12 hours for four doses, followed by 6,000 IU/m2 asparaginase (ASNase) administered at hour 42, or HiDAC without ASNase. Treatment was repeated on day 8. The median patient age was 52 years. There was an overall superior complete remission (CR) rate for HiDAC/ASNase (40%) v HiDAC (24%), P = .02. Subset analysis according to prior response and age showed the following CR rates: 54% from HiDAC/ASNase treatment of refractory AML in patients less than 60 years, and 31% in patients greater than 60 years; CR from HiDAC in the same refractory groups were 18% (less than 60) and 0% (greater than 60); 37% from HiDAC/ASNase treatment of relapsed AML in patients less than 60 years, and 43% in patients greater than 60 years; CRs from HiDAC in the same relapsed groups were 33% (less than 60) and 21% (greater than 60). Toxicity in the two treatment arms was comparable and consisted primarily of leukopenia, thrombocytopenia, mild hepatic dysfunction, diarrhea, conjunctivitis and serositis, and hyperglycemia. There was only one case of transient cerebellar toxicity and no cutaneous toxicity. Median time to full hematologic recovery was 5 weeks. There was an overall survival benefit for patients treated with HiDAC/ASNase (19.6 weeks) compared with HiDAC (15.9 weeks), P = .046, primarily attributable to effects in refractory patients. Median time to failure for refractory patients who achieved CR was 38.5 weeks with HiDAC/ASNase, and 13.3 weeks for those treated with HiDAC. For relapsed patients in CR from HiDAC/ASNase the median time to failure was 17.7 weeks and 18.3 weeks for HiDAC. The overall 42% CR rate from HiDAC/ASNase v 12% from HiDAC in patients with refractory AML indicates that HiDAC/ASNase is not cross-resistant with standard-dose cytarabine (SDAC) and anthracyclines. We conclude that HiDAC/ASNase has substantial activity in poor-prognosis AML and that this combination warrants further trials in earlier stage disease.

Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B.

PURPOSE: The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II multicenter trial to evaluate the activity of two cisplatin-containing regimens (cisplatin and mitomycin [CM], or cisplatin and doxorubicin [CD]) in patients with malignant pleural or peritoneal mesothelioma (protocol CALGB 8435). PATIENTS AND METHODS: Seventy-nine patients were entered between June 1984 and October 1986. Eligibility included a performance status of 0 to 2 by CALGB criteria, and no prior chemotherapy. Central pathology review was performed. Randomization was stratified according to the cell type (epithelial v mixed or sarcomatous) and the presence of measurable versus assessable disease. Of the 79 patients entered, 70 were included in this analysis (35 on CM and 35 on CD), including 48 with epithelial cell type and 22 with mixed or sarcomatous cell types. Sixty-six patients had pleural mesothelioma and four had peritoneal mesothelioma. There were 34 cases with measurable disease and 36 with assessable disease. RESULTS: The overall response rate was 26% for CM (two complete responses [CRs], three partial responses [PRs], and four regressions) and 14% for CD (four PRs and one regression). Median time to treatment failure was 3.6 months for CM and 4.8 months for CD, and median survival duration from study entry was 7.7 and 8.8 months, respectively, with no significant differences between treatments. Good performance status (0 or 1) was associated with significantly longer survival duration (P = .013). Both regimens were well tolerated and there were no treatment-related deaths due to toxicity. CONCLUSION: Moderate antitumor activity has been observed with both regimens. In this randomized phase II trial, the overall response rates, time to treatment failure, and overall survival appear to be similar for the two regimens tested.

Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081.

In a prospective, randomized trial Cancer and Leukemia Group B (CALGB) evaluated CAF chemotherapy (cyclophosphamide + doxorubicin + 5-fluorouracil [5-FU]) v CAF plus tamoxifen (TCAF) in advanced breast cancer. Patients were stratified by estrogen receptor (ER) status, dominant site of metastatic disease, menopausal status, and prior adjuvant therapy. Regardless of ER status or menopausal status, the addition of tamoxifen conferred no significant advantage in response rate, response duration, time to treatment failure (TTF) or survival over CAF alone. A secondary objective was to compare the response to CAF of ER positive (ER+) and ER negative (ER-) patients to determine if there was a differential response to cytotoxic chemotherapy. Response rates of ER+ and ER- patients to CAF were identical (56%), but the response duration, time to treatment failure, and survival of ER+ patients were significantly longer than ER- patients. This lack of differential response implies that chemotherapy and hormonal therapy may compete for the same pool of ER+ cells. It also suggests that chemotherapy kills breast cancer cells indiscriminately, regardless of ER status.

Morphologic and cytochemical characterization of adult lymphoid leukemias which express myeloid antigen.

Cancer and Leukemia Group B demonstrated that adults with acute lymphoid leukemia (ALL) possessing blast cells with myeloid antigens (My+ALL), as identified by monoclonal antibodies against CD13 and CD33, have a worse prognosis than those lacking myeloid antigens (My-ALL). Consequently, we further studied this group of adults with ALL to determine if these immunological groups could be distinguished by morphological and cytochemical criteria. Bone marrow films were classified according to French-American-British Co-operative Group Criteria, assessed for myelodysplasia, and examined for blasts with azurophilic granules. More cases of My+ALL had L2 morphology than did My-ALL (68% vs. 49%, p = 0.04), and more cases of My+ALL were positive for acid alpha-naphthyl acetate esterase (61% vs. 31%, p = 0.03). The presence of myelodysplastic changes was not significantly different in My+ALL (13%) as compared to My-ALL (5%), but more cases of My+ALL had unusual blasts (monocytoid features and cytoplasmic buds) than did My-ALL (19% vs. 0%, p less than 0.01). In addition, more cases of My+ALL had greater than 5% of the blasts with azurophilic granules (42% vs. 13%, p = 0.01). In the My+ALL group the presence of azurophilic granules was associated with a longer median survival (13.5 months vs. 1.5 months, p less than 0.01). We conclude that My+ALL can be suspected when cases possess L2 morphology, unusual blasts, positive staining for acid alpha-naphthyl acetate esterase, and greater than 5% azurophilic granules. In addition, the poor risk group (My+ALL) can be further subdivided into better and poorer risk subgroups based on the presence of azurophilic granules.

Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes.

The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic disorders derived from an abnormality affecting a multipotent hematopoietic stem cell. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of the pyrimidine nucleoside cytosine, as a continuous intravenous infusion, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 evaluable patients: five (12%) in complete remission (CR, complete normalization of bone marrow and peripheral blood counts); 11 (25%) in partial remission (PR, > or = 50% restoration of the deficit from normal of all three peripheral blood cell lines, elimination of transfusion requirements, and a decrease in percentage bone marrow blasts by > or = 50% from prestudy values); five (12%) improved (> or = 50% restoration in the deficit from normal of one or more peripheral blood cell lines and/or a > or = 50% decrease in transfusion requirements). A trilineage improvement (CR and PR) occurred in 37% of the patients. The median survival for all patients was 13.3 months and the median duration of remission for those with CR and PR was 14.7 months. Mild to moderate nausea and/or vomiting was the most common side effect (63%). Myelosuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33% of the patients. Prior to treatment, bone marrow erythroid progenitor cells were assayed in vitro. Colonies derived from erythroid burst-forming units (BFU-e) were undetectable in one patient and reduced in two. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two patients with detectable colony growth prior to treatment, colony number decreased by day 8 of the first cycle, followed by a subsequent increase. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony number correlated with the spontaneous rise in hemoglobin levels and red cell transfusion independence.(ABSTRACT TRUNCATED AT 400 WORDS)

The reproducibility of acute lymphoblastic leukemia phenotype determinations: evaluation of monoclonal antibody and conventional hematopoietic markers.

Peripheral blood and/or bone marrow lymphoblasts from 25 patients with acute lymphoblastic leukemia (ALL) were tested with a panel of monoclonal antibodies (MoAbs) and conventional hematopoietic markers by three different laboratories. The results were analysed to evaluate the reproducibility of ALL phenotype determinations. Specimens were transported between laboratories by 24-h courier service and were classified on the basis of indirect immunofluorescence MoAb reactivities as follows: B-lineage ALL (BA-1+T-MCS-2-); T-lineage ALL (T+BA-1-MCS-2-); myeloid antigen ALL (MCS-2+BA-1-CALLA-T-) and unclassified ALL (BA-1-MCS-2-CALLA-T-). Conventional marker studies for surface immunoglobulin (sIg), cytoplasmic immunoglobulin (cIg), sheep erythrocyte rosette formation (E) and nuclear terminal deoxynucleotidyl transferase (TdT) were also performed. In the cases with sufficient marker data to permit classification, 90% (18/20) were identically classified by different laboratories and this concordance was statistically significant (p less than 0.05). The agreement between laboratories for individual MoAb and conventional marker analyses was statistically significant (p less than 0.05) for all markers with the exception of BA-2, cIg and TdT determinations. Six of 7 discordant BA-2 cases represented BA-2+ evaluations which had subsequent BA-2- results following specimen transportation. These findings suggest instability of the BA-2 antigen to transport conditions. A similar pattern of positive to negative evaluations following transportation was observed in 5/5 discordant results involving other MoAbs. Disagreement between laboratories for cIg and TdT determinations implies that the detection of cytoplasmic or nuclear antigens may be more prone to subjective interpretation than cell surface antigen marker analyses. Our findings suggest that immunofluorescence marker studies employing MoAbs to cell surface antigens are in general highly reproducible. Our results also indicate that specimen storage conditions and the cellular location of target antigens are important variables which may affect the reproducibility of ALL phenotype determinations.

Management of acute leukemia in adults.

The treatment of acute leukemia in adults, while not yet as successful as that in children with regard to either remission rate or prolongation of life, can now regularly result in at least 50% responses in acute myelocytic leukemia and 70-80% in acute lymphocytic leukemia. Intensive specific chemotherapy and supportive therapy throughout the resultant period of myelo and immuno-suppression are necessary to achieve these remission rates. Further investigations aimed at both prolonging the remissions so obtained and at improving the response rate further are essential.

Concurrent monoclonal IGM and IGA proteins in lymphocytic lymphoma.

A case of lymphocytic lymphoma with monoclonal elevations of both IgA and IgM is described. The cytogenetic and immunoglobulin findings in this case suggest that the cells producing the abnormal elevated proteins were different cells that appeared to be derived from a common percursor cell.

Ph1-positive megakaryoblastic leukemia.

A case of megakaryoblastic leukemia is presented. Megakaryoblastosis and erythrocytic hyperplasia of the bone marrow, thrombocythemia, and hepatosplenomegaly were the essential features; 100% of the marrow-derived metaphases were found to be Ph1-positive. Cytologic and chromosomal findings are compatible with the assumption that all three marrow systems were involved in the leukemic process.

Collagen degradation and synthesis in experimental corneal grafts.

Thirty-two weanling New Zealand white rabbits were labelled repeatedly with [2,3-3-H]-proline for 4 weeks. Four weeks after the end of labelling, 32 rabbits underwent bilateral 6 mm trephinations for donor purposes. One control cornea of each pair was frozen at -70 degrees C. The contralateral corneas were used for autografts, allografts, and xenografts. Grafts were observed from 7-200 days, then retrephined out for determination of loss in total radioactivity in hydroxyproline (specific for collagen), increase in newly synthesized collagen, and net change in collagen mass, by comparing with the matched, ungrafted control corneas. For all three transplant groups there was a small, but significant, decrease early in total radioactivity (loss of original collagen) and a significant increase in new collagen. These data also indicated that the loss of original collagen was replaced by an equivalent or greater increase in new collagen in all transplant groups. Significant relationships between graft clarity and collagen turnover were noted in both the auto- and allograft groups. The degradation of old collagen was significantly greater in the cloudy vs. the clear grafts; however, there was no significant difference in the increase in new collagen between these groups. A progressive loss of original collagen over time was noted in the cloudy autografts, but not the allografts. A trend toward a progressive increase in new collagen was noted over time in both the cloudy auto- and allografts. No relation for these variables to time, however, was noted in the clear grafts.

Adult acute lymphoblastic leukemia phenotypes defined by monoclonal antibodies.

Pretreatment peripheral blood and/or bone marrow blasts from 90 adults with acute lymphoblastic leukemia (ALL) were analyzed as part of a prospective treatment protocol study. Specimens were tested by immunofluorescence cytofluorometry for reactivity with the following monoclonal antibodies (MoAbs): BA-1 (B cell antigen); T101, OKT11 (pan-T cell antigens [T]); 3A1 (T cell antigen); MCS-2 (myeloid antigen); J5 common ALL antigen (CALLA); BA4 (Ia antigen [Ia]); BA-2 (lymphohematopoietic antigen). Four major phenotypic groups were identified: B lineage ALL (BA-1+T-) (64%), T lineage ALL (T+BA-1-MCS-2-) (13%), unclassified ALL (BA-1-MCS-2-CALLA-T-) (9%) and myeloid antigen ALL (MCS-2+CALLA-T-) (7%). An additional group of patients, miscellaneous ALL (7%), was comprised of cases with unusual marker profiles. In B lineage ALL, all cases tested were Ia+MCS-2-, and the vast majority were CALLA+ (84%). In T lineage ALL, 42% expressed CALLA or Ia positivity. In unclassified ALL, the predominant phenotype was Ia+BA-2+. In myeloid antigen ALL, two of four tested were 3A1+ and all cases evaluated were BA-1-. Patients with myeloid antigen ALL were older (median age, 66 years) than patients in the other groups. The T lineage ALL group had higher leukocyte counts (median WBCs, 183,000/microL) and an increased incidence of anterior mediastinal mass at presentation. All patients received identical induction therapy. In CALLA+B lineage ALL, 30 of 46 (65%) achieved a complete remission. While the number of patients evaluated was small, 9 of 9 CALLA-B-lineage ALL and only two of six myeloid antigen ALL cases responded with a complete remission. The data suggest that these MoAbs are useful in the characterization of adult ALL.