A prospective evaluation of the roles of allogeneic marrow transplantation and low-dose monthly maintenance chemotherapy in the treatment of adult acute myelogenous leukemia (AML): a Southwest Oncology Group study.

Between February 1982 and December 1986, the Southwest Oncology Group conducted a prospective study in patients with newly diagnosed acute myeloid leukemia (AML) with two objectives: to evaluate the role of allogeneic marrow transplantation for patients in first remission, and to evaluate the role of low-dose monthly maintenance therapy in those patients not transplanted in first remission. Among 522 evaluable patients, 295 (57%) achieved complete remission (CR), including 70% of patients age 49 or less. Twenty-four patients (15%) age 49 or less in CR were not HLA-typed, mostly because of financial constraints. HLA-identical donors were found for 39% of patients, of whom two-thirds were transplanted in first CR. The 5-year disease-free survival among those transplanted in first CR, those with donors not transplanted in first CR, and those less than age 50 without donors was 41, 42, and 29%, respectively (P = 0.60). A total of 150 eligible patients were randomized to receive late intensification alone or late intensification plus monthly maintenance. In multivariate analyses, treatment with maintenance was associated with prolonged disease-free survival (P = 0.028), but not improved overall survival (P = 0.27). Factors associated with improved overall survival included younger age, lower white blood count (WBC) at diagnosis, having leukemia of M3 morphology, and being of white race. In this study, a diagnosis of M3 AML was particularly favorable, with disease-free and overall survivals of 75 and 56%, respectively, at 7 years.

Therapy-related acute myeloid leukaemia following immunosuppression with azathioprine for polymyositis.

A 52-year-old man developed therapy-related acute myeloid leukemia (AML) following prolonged immunosuppression with azathioprine for polymyositis. Karyotypic analysis showed deletions of the short arm of chromosome 7 and the long arm of chromosome 5. The importance of recognizing this potential complication while treating benign rheumatological and immunological diseases with purine analogues like azathioprine is emphasized. Therapy-related AML is a poor prognostic group that does not respond favourably to standard induction therapy.

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.

Alternated versus syncopated CHOP-PVB: two studies for the treatment of non-Hodgkin's lymphoma by the Southwest Oncology Group.

Based on a preliminary trial that suggested that CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and PVB (cisplatinum, vinblastine, bleomycin), are at least partially non-cross-resistant, the Southwest Oncology Group treated patients with unfavorable histology, non-Hodgkin's lymphoma with CHOP and PVB. In the first study, 76 eligible patients were given three courses of CHOP, with complete or partial responders receiving three courses of PVB followed by three further courses of CHOP. Nonresponders after the initial three cycles of CHOP, received six courses of PVB. In the second study, 154 eligible patients were treated with alternating cycles of the two drug regimens. The overall objective antitumor response (CR + PR) was 77% for the first study and 58% for the second. The complete remission rates were 48% and 38%, respectively. The overall survival for both studies is similar. These results are interpreted in terms of the Goldie-Coldman hypothesis.

Aclacinomycin A in the treatment of multiple myeloma: a Southwest Oncology Group study.

Fifty-two patients with progressive resistant multiple myeloma were entered in this Southwest Oncology Group Phase II study, using weekly intravenous Aclacinomycin A. Of forty-three evaluable patients for response, there was one partial remission of 2 years duration and two sustained clinical improvements with 25% reduction in paraprotein. Major toxicity seen was severe myelosuppression and significant nausea and vomiting requiring dose reduction and delay of the scheduled treatment. Cardiac arrhythmia was seen in one patient. Chronic daily schedule or continuous IV infusion is recommended for future study.

Treatment of acute lymphoblastic leukemia in adults with intensive induction, consolidation, and maintenance chemotherapy.

The Southwest Oncology Group conducted a study of acute lymphoblastic leukemia (ALL) in adults over a 5-year period, testing the utility of the L-10M regimen initially described by the group from Memorial Sloan-Kettering Cancer Center. One hundred sixty-eight eligible patients were treated with this intensive combination chemotherapy regimen. One hundred fifteen (68%) achieved complete remission. With the current median follow-up time of 34.5 months, the median durations of remission, relapse-free survival, and overall survival were 22.9, 20.9, and 17.7 months, respectively. Only 35% of the patients over 50 years of age achieved a complete remission. Age was a significant prognostic factor for complete response, survival, relapse-free survival, and remission duration. In addition, a low initial WBC count was found to have a statistically significant association with longer remission duration. Responders between the ages of 20 and 49 years with WBC counts of less than 15,000 appear to have an exceptionally good prognosis.

Cisplatin, VP-16-213 and MGBG (methylglyoxal bis guanylhydrazone) combination chemotherapy in refractory lymphoma, a phase II study.

In an effort to improve the treatment of patients with refractory or recurrent lymphoma, we developed a protocol using cis-platinum combined with two other agents of known efficacy in these disorders but with differing side effects: VP-16 and MGBG. Twenty-six eligible patients were treated with this regimen. There were 15 men and 11 women with a median age of 54 years (22-73), and performance status of 1 (0-3). Their diagnoses were Hodgkin's disease 5 and non-Hodgkin's lymphoma [NHL] 21 which included 11 with diffuse histocytic lymphoma [DHL]. The median number of chemotherapy regimens was 2 (1-5); 12 also received radiotherapy. Twenty patients are evaluable for response: 15 NHL and 5 Hodgkin's disease. Three patients, all of whom had DHL entered complete remission (20%) with a median time to treatment failure of 7 1/2 months. Six NHL (40%) and one Hodgkin's disease (20%) patients entered a partial remission. There were three early deaths: one due to progressive disease, one to acute respiratory failure, and one with disease status undocumented. Toxicity included leukopenia, thrombocytopenia, anorexia, nausea, vomiting, stomatitis, alopecia, renal failure, profound peripheral neuropathy, and hypersensitivity vasculitis. Treatment was stopped because of the latter two. These agents are non-crossresistant with doxorubicin-containing regimens. The drugs are possibly synergistic and modestly active with moderate to severe toxicity.

Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study.

Four hundred forty previously untreated patients with active multiple myeloma were entered into a randomized trial (Southwest Oncology Group [SWOG] study 7927/28) comparing vincristine, melphalan, Cytoxan (Mead Johnson & Company, Evansville, Ind), and prednisone (VMCP) alternating with vincristine, BCNU, Adriamycin (Adria Laboratories, Columbus, Ohio) and prednisone (VBAP) with or without levamisole with vincristine, Cytoxan, and prednisone (VCP) with or without levamisole for induction therapy. The treatment groups were well balanced for all of the known major prognostic factors. Patients receiving VMCP-VBAP responded (greater than or equal to 75% regression) more frequently to induction therapy, both without (54%) and with (44%) levamisole v VCP without (28%) or with (28%) levamisole (P less than .001). In addition, patients receiving VMCP-VBAP (+/- levamisole) had a survival duration determined to be significantly increased by all forms of analysis: 48 and 33 months for VMCP-VBAP without and with levamisole v 29 and 26 months for VCP without and with levamisole (P = .011 overall). Levamisole did not improve response rates or survival duration (P greater than or equal to .1), nor did it prolong remission in the maintenance phase (P = .85). Analysis of SWOG study 7704/05 (updated April 1985) confirmed improved survival for combination therapy v MP, but no benefit for levamisole. The overall findings support the use of VMCP-VBAP as an excellent treatment option for remission induction in patients with active myeloma of all stages and prognostic categories.

Phase II evaluation of aclarubicin in refractory adult acute leukemia: a Southwest Oncology Group Study.

Aclarubicin, a new anthracycline antibiotic, was used to treat 24 adult patients with refractory adult leukemia, using a total dose of 300 mg/m2 (75 mg/m2/day X 4). There were 20 patients with acute myelogenous and four with acute lymphoblastic leukemia. Approximately two-thirds of the patients had a Karnofsky score of less than or equal to 2, and two-thirds had received two or more previous induction programs. Interim bone marrow evaluation was obtained in 18 of 30 remission induction courses and revealed marked hypocellularity in 14, inadequate specimens in three, and persistent disease in one. Seven patients received more than one course. Two patients refused further therapy. In patients with myelogenous leukemia, there were two complete remissions lasting 10 and 16 months and one partial remission lasting 4 1/2 months. There were no responders in patients with lymphoblastic leukemia. Toxicity included profound leukopenia and thrombocytopenia, moderate nausea and vomiting, diarrhea, and mucositis. There were no cardiac symptoms associated with the drug infusion, but there were three late events possibly associated with anthracycline cardiotoxicity. Used in this dosage schedule, aclarubicin is an active, but toxic, agent in the acute myelogenous leukemias.

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.

Barrett's esophagus complicating scleroderma.

Two patients with scleroderma whose esophageal involvement was associated with long-standing reflux esophagitis were found to also have Barrett's esophagus. Since Barrett's esophagus is a premalignant condition, these patients with scleroderma should be considered at high risk for the development of adenocarcinoma of the esophagus.

Surgical restaging of Hodgkin's disease.

Twenty-six patients with Hodgkin's disease were restaged both clinically and surgically within 2 months of completing their planned chemotherapy. Six patients (23%) had surgically proven persisting disease. Patients were divided into three groups: group I--eight patients had normal findings at clinical restaging and all were free of disease at surgery; group 2--13 patients had abnormal findings at clinical restaging, but only two (15%) were surgically documented to have persistent disease; and group 3--five patients had incomplete clinical restaging but, because of initial bulky disease, underwent surgical restaging, which showed that four patients had residual disease. The spleen was the site of persisting disease in all six patients with residual disease; four also had para-aortic nodal involvement. All 20 patients in pathologically documented complete remission remain relapse-free, with a mean followup of 26 months. This is significantly better (P less than 0.001) than the 21% relapse rate for 224 comparable patients in complete remission established by clinical but not surgical restaging. It appears that surgical restaging provides useful prognostic and therapeutic information in selected patients with Hodgkin's disease.

Indications for and morbidity associated with operative staging in patients with lymphoma.

Operative staging of patients with lymphoma has made an important contribution to the more accurate planning of treatment of this disease. Concomitant improvements in therapy have led to an increase in 5 year survival, particularly in patients with Hodgkin's disease. Nevertheless, considering risk versus benefit, several groups of patients might be spared increased morbidity from postoperative infection by restricting the operation to patients with stage I non-Hodgkin's lymphoma and to patients with Hodgkin's disease, stages I to III, without B symptoms. Groups having a greater risk of infection include all patients with non-Hodgkin's lymphoma and patients with Hodgkin's disease and B symptoms in whom operation is indicated. These exclusions from operative staging may not apply if accurate definition of the extent of disease is essential to evaluation of a new therapeutic program being assessed by a prospective randomized clinical trial.

Combined Collis gastroplasty--fundoplication operations for scleroderma reflux esophagitis.

Thirty-seven patients with scleroderma and reflux esophagitis, including 16 (43%) with peptic esophageal strictures, have been treated with a combination of the Collis gastroplasty and either a Belsey (240 degree) or Nissen (360 degree) fundoplication. Follow-up data have been obtained through personal interviews, esophageal manometry, and acid reflux testing. There have been no postoperative deaths or wound-healing complications. Five (31%) of the 16 patients with strictures still require intermittent dilatations. In the Collis-Belsey group (17 patients), after an average follow-up of 42 months, reflux symptoms have been eliminated in 11, are mild in three, and moderate or severe in three. Distal esophageal high-pressure zone (HPZ) tone and length have increased from an average of 4.6 mm Hg and 1.6 cm preoperatively to 8.6 mm Hg and 2.3 cm postoperatively. Acid reflux testing with the intraesophageal pH electrode, however, has demonstrated moderate-to-severe reflux in seven patients (41%). In the Collis-Nissen group (20 patients), after an average follow-up of 22 months, reflux symptoms have been eliminated in 17, are mild in two, and severe in one. Average HPZ tone and length have increased from 2.5 mm Hg and 1.2 cm preoperatively to 12 mm Hg and 4.2 cm postoperatively. The acid reflux test has revealed moderate or severe reflux in five patients (25%). Gratifying subjective and objective reflux control can be achieved in scleroderma patients with minimal operative morbidity.

Adult acute nonlymphocytic leukemias.

For the first two decades, leukemic chemotherapy had little impact on survival. In the past 10 years, however, remission induction therapy has generated complete remissions which last approximately one year in about half to three fourths of those treated, with a seventh in some series alive at 5 years.

'Secondary' operative staging of patients with lymphoma.

Secondary operative staging (diagnostic celiotomy after initial lymphoma staging and treatment) is of value in selected patients with Hodgkin's disease if, after appropriate clinical staging, there remains a reasonable doubt concerning the presence of residual or recurrent lymphoma. In our experience, although signs indicating possible recurrence were present in 35 patients, only 20 of these were found to have Hodgkin's disease within the abdomen at operation. These findings allowed us to restrict our intensive therapy to those with documented disease and to withhold potentially harmful treatment from the remaining subjects who on follow-up have shown no evidence to date of subsequent recurrence within the abdomen. The utilization of secondary operative staging in ten patients with non-Hodgkin's lymphoma has been less productive and is not recommended on the basis of our limited current experience.

Sialic acid content of erythrocytes in normal individuals and patients with certain hematologic disorders.

The sialic acid content of erythrocytes from healthy individuals of different blood types and of patients with known hematological disorders has been determined. The sialic acid was completely released enzymatically with sialidase and quantitated by the thiobarbituric acid method. The sialic acid content of erythrocytes was constant irrespective of ABO blood type, or anticoagulant used; viz, 0.85-0.92 mumoles/ml of packed erythrocytes or 46-53 X 10(6) sialyl residues per cell. Deviations from these normal values were obtained with erythrocytes from patients with a variety of hematological disorders. Patients with the following disorders have significantly (P less than 0.01) lower sialic acid values compared to erythrocytes from healthy individuals (given in the order of decreasing sialic acid content): sickle cell anemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelomonocytic leukemia, non-Hodgkin lymphocytic lymphoma, chronic granulocytic leukemia, acute myelocytic leukemia, leukemia, and Hodgkin disease.

Occurrence in human bone marrows of an antigen released from continuous cell cultures derived from human leukemia.

Fluorescent antibodies prepared against extracellular particles from a continuous culture of cells derived from a monocytic leukemia stained JIII cells but not cells infected with Rauscher leukemia virus or simian sarcoma virus. These antibodies reacted with 38% of bone marrow preparations from patients with lymphoma, 26% of preparations from patients with nonmalignant blood disorders and 6% of preparations from patients with leukemia. Bone marrow films from patients with lymphoma over the age of 50 stained less frequently than those from patients under 50. These particles released from JIII cells are not antigenically related to two of the commonly studied oncornaviruses, but may be indicative of the etiology or disease process of lymphoma in young patients.