Clinical correlations of leukemic clonogenic cell chemosensitivity assessed by in vitro continuous exposure to drugs.

This study was performed to assess the value of prolonged, as opposed to short-pulse, in vitro exposure of leukemic cells to chemotherapeutic drugs in leukemic clonogenic assay for prediction of clinical response. In 21 patients with acute nonlymphocytic leukemia treated with intensive combination chemotherapy based on an anthracycline and 1-beta-D-arabinofuranosylcytosine infusion, chemotherapy sensitivity of leukemic clonogenic cells was assessed in comparison with that of normal myeloid clonogenic cells by the in vitro continuous exposure to drugs throughout the entire culture period. Analysis of these in vitro data in terms of prediction of achieving clinical complete remission was carried out in comparison with data on 22 cases in which in vitro sensitivity was assessed by the pulse 1-hr exposure. The in vitro sensitivity index, expressed as a log odds ratio, was positive (greater than 0) in 8 of 11 patients achieving complete remission and negative (less than 0) in 7 of 10 patients failing to achieve complete remission, with an overall correlation of 71%. This is at least as good as the pulse exposure method, which has a correlation of 68%. If sensitivity indexes of marginal magnitudes (--1.0 approximately +1.0) are excluded, the correlation increases to 92% (12 of 13 patients). The correlation appears to improve especially for 1-beta-D-arabinofuranosylcytosine by the continuous exposure method (71%) as compared with the pulse method (57%). This study establishes the feasibility of an in vitro chemotherapy sensitivity testing of leukemic clonogenic cells by continuous in vitro drug exposure and suggests that the continuous exposure method may be better than the pulse method for antimetabolites such as 1-beta-D-arabinofuranosylcytosine. The data also suggest that simulation of the in vivo drug schedule may be important in this in vitro test.

Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone alone or with levamisole or with levamisole plus BCG for malignant lymphoma: a Southwest Oncology Group Study.

Between 1977 and 1983 the Southwest Oncology Group (SWOG) evaluated chemotherapy alone (cyclophosphamide, doxorubicin, vincristine, prednisone; CHOP) or chemoimmunotherapy (CHOP-levamisole or CHOP-levamisole-BCG) in a randomized prospective clinical trial involving 715 eligible patients with all types of malignant lymphoma (ML). Of 281 evaluable patients with favorable histologic types of ML, 171 (61%) achieved complete remission (CR) and there was no difference in CR rate, CR duration, or survival according to the type of initial treatment. Of 388 evaluable patients with unfavorable histologic types of ML, 194 (50%) achieved CR. Levamisole appeared to adversely affect CR rates in nodular mixed and nodular large-cell lymphoma and CR duration in patients with unfavorable histology ML. Chemoimmunotherapy with levamisole or levamisole-BCG offers no advantage in terms of CR rates, CR duration, or survival compared to CHOP chemotherapy alone, and levamisole may have had an adverse impact on outcome in certain subtypes of ML.

Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance.

Between August 1978 and September 1982, 642 patients with newly diagnosed acute myelogenous leukemia (AML) were entered onto a Southwest Oncology Group Study which addressed four questions. (i) What is the comparative utility of rubidazone versus adriamycin in remission induction? (ii) What is the role of prophylactic intrathecal therapy in AML? (iii) Does late intensification affect treatment outcome? (iv) Does maintenance with levamisole affect disease-free survival or overall survival? Among 611 evaluable patients, 329 (54%) achieved complete remission. There was no difference in the remission rate between those patients receiving rubidazone (54%) and those receiving adriamycin (54%) as part of the induction regimen. Prophylactic intrathecal therapy with cytosine arabinoside had no effect on the incidence of central nervous system disease or survival. After nine months of complete remission, patients were randomized between late intensification with POMP (mercaptopurine + vincristine + methotrexate + prednisone) or continued maintenance with OAP (vincristine + cytosine arabinoside + prednisone). T patients randomized to late intensification had better survival and disease-free survival, compared to those randomized to receive no late intensification (p = 0.027 and 0.030, respectively). At twelve months of remission, surviving patients were randomized to receive levamisole or no further treatment. There was no evidence that levamisole affected survival or disease-free survival.

Acute megakaryocytic leukemia. Description of a case initially seen as preleukemia syndrome.

A 52-year-old man had aregenerative anemia unresponsive to pyridoxine hydrochloride. Acute leukemia developed, and he died four months after diagnosis. At autopsy he had acute megakaryocytic leukemia with involvement of bone marrow, liver, spleen, adrenals, kidneys, and thyroid. Chromosomal analysis revealed absence of both diploid and Ph1 chromosomes. A mode of 45 chromosomes and aneuploidy were present. This is similar to the only other case with chromosomal studies. Of the 15 acceptable documented cases, eight were men and seven were women. Their age varied from 28 to 76 (mean, 55) years. Only two were less than 40 years of age. Most had pancytopenia, and all were dead within six months of diagnosis.

Mitoxantrone in refractory nonHodgkin's lymphoma. A Southwest Oncology Group study.

A phase II study of mitoxantrone in nonHodgkin's lymphoma was conducted by the Southwest Oncology Group between July 1981 and May 1982. The study involved 37 patients with histologically proven nonHodgkin's lymphoma, who were not eligible for higher priority protocols but had clearly measurable disease. Patients received mitoxantrone, 12 mg/m2 at intervals of 3 weeks, with a 10% increase in dose in the absence of myelosuppression and a 17% reduction for a WBC of less than 2 X 10(9) cells/L or a platelet count of less than 50 X 10(9)/L. The median number of previous regimens was three. Doxorubicin, in a median dose of 242 mg/m2 (range 12 to 650 mg/m2) had been previously given to 34 of the 37 patients. The Pathology Panel for Lymphoma Clinical Studies reviewed 31 (84%) of the lymphomas. Four of the ten follicular, small cleaved cell lymphomas responded compared with one of nine diffuse, large cell lymphomas. The median duration of response was 231 days. A median of two doses of mitoxantrone (range 1 to 18) was given. The median WBC nadir was 5.1 X 10(9)/L (range 04. to 9.4 X 10(9)/L), and the median lowest WBC for all doses was 2.4 X 10(9)/L (range 0.4 to 16 X 10(9)/L). Among 17 patients with a first WBC nadir of less than 3 X 10(9)/L, there were three partial responses compared with four responses (one complete, three partial) from nine patients with a WBC over 3 X 10(9)/L. There were seven responses (one complete, six partial) among 23 patients who had received up to three previous regimens, whereas only two of 14 patients receiving more than three previous regimens responded (one complete, one partial response). The response rate was independent of the previous dose of doxorubicin with five responses out of 23 patients who received a total dose of less than 300 mg/m2 and four responses out of 14 patients who received greater than 300 mg/m2. These data are compatible with the hypothesis that mitoxantrone alone is active against previously treated low-grade lymphomas and that the response rate is independent of the total dose of prior doxorubicin received and the degree of myelosuppression. Mitoxantrone may not be cross resistant with doxorubicin.

Transient acquired factor X deficiency: report of the use of activated clotting concentrate to control a life-threatening hemorrhage.

Acquired deficiency of factor X is an uncommon occurrence. It has usually developed in association with amyloidosis [8] and, in that setting, it has been irreversible. Transient deficiency appears to be associated with an acute respiratory infection in the majority of cases. Bleeding in these patients can be life-threatening and has been difficult to control. Konyne produces a brief correction of the prothrombin time and an elevation in the factor X level, but has not been effective in stopping bleeding. We report the first successful correction of prothrombin time and clinical resolution of bleeding attending the use of Autoplex T. If bleeding persists after appropriate specific factor replacement and the clinical condition warrants, the use of Autoplex T (activated prothrombin complex) deserves prompt consideration.

A Southwest Oncology Group: chemotherapy versus chemotherapy plus radiotherapy in treatment of stage III Hodgkin's disease.

The Southwest Oncology Group (SWOG) performed a randomized study (SWOG 7518, CAR 2) of chemotherapy using ten courses of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) plus low-dose bleomycin (LDB), versus three courses of combined therapy, MOPP + LDB plus radiotherapy (XRT) from October, 1974, to April 1980, in pathologic stage III Hodgkin's disease. The present report includes data on 136 registered patients, of whom 112 are fully or partially evaluable. At this preliminary analysis, complete remission rates are 82% for chemotherapy alone and 82% for combined treatment. There are no statistically significant differences in survival or relapse-free survival between the two treatment programs, and no specific trends for stage IIIA versus IIIB. The estimated 3-year survival rate for all patients was 82%. Toxicities are comparable when considering the highest grades. There was one case of acute myeloblastic leukemia on combined treatment. Preliminary evidence suggests that patients with nodular sclerosis histologic type are more likely to relapse on chemotherapy alone than on combined treatment.

Adriamycin combined with 10-day Ara-C, vincristine, and prednisone (10-day ADOAP) in the treatment of adult acute leukemia patients under fifty years of age. A Southwest Oncology Group Study.

In a twelve-month period, 56 consecutive patients with acute leukemia, aged 15-50, were treated by administration of a 10-day continuous infusion of Ara-C in combination with adriamycin, oncovin and prednisone (10 day ADOAP). Of 50 evaluable patients, there were 39 complete remissions (78%) with a median remission duration of 71 weeks. After adjustment for age and other known prognostic factors, the complete remission rate is still 10% higher than that found using a similar regimen without adriamycin.

Rubidazone in combination with Ara-C, vincristine and prednisone (ROAP) in the treatment of adult acute leukemia. A Southwest Oncology Group Study.

In an 18-month period, 340 consecutive adult patients with acute leukemia were treated using a 7-day continuous infusion of Ara-C in combination with rubidazone, vincristine and prednisone (ROAP). Of 334 (96%) evaluable cases, 77% were 50 years of age or older. The complete remission (CR) rate was 51% with a standard error of 3%. After adjustment for known prognostic factors this overall CR rate is 10% higher than the predicted CR rate when compared to the last completed SWOG study which used adriamycin in combination with a similar regimen of Ara-C, vincristine, and prednisone. The CR rate in patients over 50 years of age was particularly noteworthy. Using rubidazone, the CR rate was 46.1% (116/256) compared to 37.4% (91/243) for the adriamycin study in this poorly responding age group. The median survival time achieved was 27 weeks. However, in the age groups 40-49 years and 50-59 years the median survival was 70 and 44 weeks, respectively.

Effect of blood transfusion in patients with gynecologic malignancy.

OBJECTIVES: To determine the effect of blood transfusion on long-term outcome (disease-free interval, recurrence of disease after treatment, and survival) in women with invasive gynecologic malignancy. METHODS: In this retrospective study, 125 patients with gynecologic malignancy were assessed over a 36-month period. The variable of whether patients received blood transfusion during therapy was used to divide the sample into two groups. RESULTS: There were no differences in the age, ethnicity, and site-stage of tumor of the two groups. Treatments (surgery, radiotherapy, chemotherapy, or multimodal) were similar between the two groups, as were initial hematocrits. The disease-free interval was significantly better in women who did not receive homologous blood (P < 0.001). Life table analysis illustrated that more patients were alive and free of disease if they did not receive blood (P < 0.001). Likewise, persistence-recurrence of cancer was more common in the transfusion group (P < 0.001). Finally, overall survival time was adversely affected by transfusion (P = 0.045). CONCLUSIONS: The use of blood products in patients with invasive gynecologic cancer is associated with enhanced recurrence or persistence of malignancy, a decrease in the disease-free interval, and reduction in the probability of survival without evidence of disease.

Race, age, and pernicious anemia.

We have described a 22-year-old black man with pernicious anemia, classically considered a disease of middle-aged and elderly Northern Europeans. It is considered rare in non-caucasians and children. The majority of very young patients have been considered to have the congenital form of pernicious and anemia, characterized by absence of intrinsic factor with normal gastric mucosa and acid production. We have seen no patients with this type of the disease. Furthermore, all five patients under 25 years of age and eight of nine under 35 were black. We found no racial difference in the incidence of pernicious anemia, but we believe it may occur at a younger age in black patients.

Septicemia during antibiotic therapy in neutropenic patients.

Two patients with acute leukemia developed septicemia while receiving antibiotic therapy. In both cases, the microorganism grown from the blood was sensitive to the drugs the patients were receiving. Areas of colonization by the same organisms were found at autopsy in the necrotic spleen and in the necrotic colonic mucosa. Septicemia developing during antibiotic therapy can indicate colonization of necrotic organs and appropriate diagnostic and therapeutic measures may be necessary.