Long-term survival advantage of MACOP-B over CHOP in intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group.

BACKGROUND: The initial publication of the results of the Australian and New Zealand Lymphoma Group (ANZLG) randomized controlled trial comparing MACOP-B and CHOP in patients with intermediate-grade non-Hodgkin's lymphoma (NHL) showed equivalent complete response rates, time to treatment failure, and survival. Here we report the long-term follow-up of the 236 patients entered on that study to determine if there were any long-term advantages or disadvantages associated with MACOP-B. PATIENTS AND METHODS: Two hundred thirty-six eligible patients were randomized between October 1986 and June 1991. The median duration of follow-up has been extended from 3.2 years in our previous publication to 6.5 years. RESULTS: As previously reported, the complete response (CR) rate for MACOP-B and CHOP chemotherapy was 51% and 59%, respectively. The estimated failure-free survival rate for MACOP-B and CHOP patients was 42% and 30%, respectively, at 5 years (P = 0.045) and 37% and 25%, respectively, at 8 year (P = 0.057). The estimated overall survival rate at 5 years was 54% for MACOP-B and 41% for CHOP patients (P = 0.035) and at 8 years was 45% and 36%, respectively (P = 0.16). CONCLUSION: With this extended follow-up, we have shown a long-term survival advantage for MACOP-B chemotherapy over standard CHOP in patients with intermediate-grade non-Hodgkin's lymphoma.

Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group.

PURPOSE: To compare complete response rates, time to failure, survival, and toxicity for patients with intermediate-grade non-Hodgkin's lymphoma (NHL) treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) versus those treated with a regimen consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin (MACOP-B), in a multicenter, randomized controlled trial performed by 22 centers of the Australian and New Zealand Lymphoma Group (ANZLG). PATIENTS AND METHODS: Between October 1986 and June 1991, 304 patients were randomized, of whom 236 were eligible for analysis. Eligibility criteria included diffuse small cleaved-cell, diffuse mixed small- and large-cell, follicular large-cell, diffuse large-cell, and large-cell immunoblastic, stages I bulky or II to IV. RESULTS: There was no significant difference in complete response rates (51% for MACOP-B v 59% for CHOP), failure-free survival, or overall survival in the two treatment arms. The rate of death of MACOP-B patients relative to CHOP patients was estimated to be 0.91 (P = .64) when stratified by prognostic group. There were no significant differences between the two regimens in any of the prognostic subgroups. Toxicity was significantly more severe with MACOP-B, particularly cutaneous toxicity, stomatitis, and gastrointestinal ulceration. The average relative dose-intensity (RDI) of MACOP-B was 0.91 and of CHOP was 0.90, indicating good dose delivery in this multicenter group setting. CONCLUSION: CHOP chemotherapy produced results equivalent to those of MACOP-B in patients with intermediate-grade NHL and with significantly fewer toxic complications. Despite relatively poor results in some patient subgroups, CHOP remains the standard chemotherapy for this disease, against which all new regimens should be compared.

Sequential changes in the bone marrow trephine biopsy in B-cell chronic lymphocytic leukaemia.

BACKGROUND: Trephine biopsy of the bone marrow is integral to both diagnosis and prognosis in B-cell lymphocytic leukaemia (B-CLL), but its usefulness would be enhanced by more information on the type, degree and rate of change that occur over time in histologic pattern and lymphocytic infiltration. AIMS: To investigate these changes by serial trephine biopsy in totally untreated patients, in treatment-free intervals in treated patients and during intervals of treatment. METHODS: In 82 patients with predominantly early B-CLL observed for a median of 65 months (13-331), 309 trephine biopsies were carried out, a median of three (two to eight) per patient. The biopsies were classified into nodular, interstitial, mixed and diffuse patterns. Lymphocytic infiltration was subjectively graded into minimal (< 20%), intermediate (20-50%) and majority (> 50%) categories and all changes were compared. RESULTS: Intensity of infiltration increased through this histologic range, as did the relative risk of death. Survival of patients with > 50% involvement was significantly poorer than those with < 50%. Changes in both lymphocyte numbers and pattern occurred slowly in early disease but quickened as the leukaemia advanced. Under treatment, lymphocytes decreased but the histology did not alter significantly. Examining the marrow for disease progression should be part of regular follow-up. It may help identify the minority of patients with early disease which will run a more active course and in whom early therapy may yet be indicated. We recommend biopsy at two-yearly intervals in early disease, more frequently as the leukaemia advances. The minimal, intermediate and majority classification in addition to the histologic pattern is a useful grading.

Treatment Results in Adolescent and Adult Acute Lymphoblastic Leukaemia Using a Uniform Chemotherapy Protocol.

Fifty-four adolescent and adult patients with newly-diagnosed acute lymphoblastic leukaemia (ALL) were treated with combination chemotherapy at three Australian hospitals. The protocol consisted of one month of induction therapy with five cytotoxic agents, followed by consolidation therapy and prophylactic treatment to the central nervous system, then maintenance chemotherapy for 30 months on an outpatient basis. Complete remission was achieved in 47 (87%) patients, with 5 deaths due to treatment-related toxicity. Two patients had drug-resistant disease. Twenty-two patients subsequently relapsed in the bone marrow (18) or in the central nervous system (4). The median survival for all 54 patients is 45.6 months, while the median duration of remission for the 47 complete responders is 39.0 months, with 38.1% projected to be disease-free at 5 years. Age at diagnosis was found to be the only parameter at presentation with a significant predictive effect on outcome. Patients between 10 and 20 years of age had a median survival of 120.6 months, with the median duration of remission not yet reached. In contrast, patients aged 20 years or more had a significantly poorer outcome, with median survival and remission of 25.8 and 20.8 months respectively. These results would support the use of intensive chemotherapy for adolescent patients with ALL. The poor results in adults however justify the use of alternative approaches such as bone marrow transplantation.

Autologous bone marrow transplantation for acute myeloid leukaemia in remission: a preliminary report.

Autologous bone marrow transplantation, using unpurged cryopreserved autologous marrow, was performed on ten adult patients with acute myeloid leukaemia in remission. Seven patients were in first chemotherapy-induced remission of their disease, while three were in later remission. Patients ages ranged from 24 to 52 years, with a median of 38.5 years. Conditioning therapy consisted of oral busulphan 16 mg/kg over four days and intravenous cyclophosphamide 60 mg/kg on two days. Bone marrow cells were thawed and infused two days later. All patients showed signs of marrow engraftment, however this was delayed in comparison with patients receiving allogeneic transplants. All patients developed fever requiring antibiotic therapy and one patient died of overwhelming sepsis. Another patient died of hepatic veno-occlusive disease two months after transplant. Serious, but non-fatal, hepatic complications occurred in two other patients. One patient, transplanted in third remission, relapsed 16 months post-autograft. No other relapses have been seen, with one second remission patient remaining leukaemia-free at 24 months, and six first remission patients in continuing remission 11 to 23 (median 20) months post transplant. These encouraging results require confirmation in a randomised clinical trial comparing autologous marrow transplantation versus standard chemotherapy.

Complications and causes of death in B cell chronic lymphocytic leukaemia: a long term study of 105 patients.

The complications and causes of death of 105 patients with B cell chronic lymphocytic leukaemia followed for a median period of 5.5 years are described. Infection and secondary primary malignant tumours were the most common complications and also caused most deaths. S. pneumoniae, S. aureus, S. haemolyticus, E. coli and the zoster-varicella virus accounted for most infections and the lungs, skin and urinary tract were the sites affected. Even trivial infections were potentially serious. Haemolytic anaemia and vascular complications were also common. Older patients tended to have a shorter survival than the mean for the group whereas younger patients fared better. The mean survival was 6.2 years. Analysis confirmed the prognostic value of Rai staging. Advancing disease increased the liability to major infection. Light bone marrow infiltration five years post diagnosis indicated a good prognosis and preservation of normal immunoglobulin levels seemed beneficial. Immunoglobulin deficiency is the factor that correlates best with the frequency, severity and pattern of infection. Early stage disease provides a distinct benefit and there may be advantages in prompt diagnosis, regular assessment by immunoglobulin levels and bone marrow pattern and treatment on the first evidence of advancing disease. Fresh symptoms should be investigated in their own right because of the likelihood of second tumours.

Improved treatment results for lymphoblastic lymphoma in adolescents and adults using a doxorubicin-based (APO) protocol.

A multi-drug chemotherapy (APO) protocol incorporating doxorubicin was used to treat 12 patients (median age 19 years) with lymphoblastic lymphoma. The APO protocol consisted of intensive induction and consolidation phases, prophylactic CNS treatment, and 24 months of maintenance therapy. Eleven patients had an anterior mediastinal mass, while T cell markers were found on the lymphoma cells in eight of the nine cases tested. Two patients had initial CNS involvement, with one also having bone marrow replacement. Complete remission was obtained in all patients, with no deaths due to treatment toxicity. There have been four relapses, one in the patient with initial CNS and leukemic disease, two in abdominal sites, and in the mediastinum in one patient. With a median follow-up time of 30 months from diagnosis, 67% of patients remain alive in first remission. These results indicate that the APO protocol provides a highly effective approach to the management of this high grade lymphoma in adolescents and adults.

An acquired Bernard-Soulier-like platelet defect associated with juvenile myelodysplastic syndrome.

Bernard-Soulier syndrome is an inherited bleeding abnormality characterized by thrombocytopenia with large platelets and deficiency of the platelet membrane glycoprotein (GP) Ib-IX complex. We have identified a young female with an acquired Bernard-Soulier-like platelet defect and a coexisting primary myelodysplastic disorder. Abnormal bruising had developed at age 5. A normal platelet count with some giant platelets was noted at age 7. At age 9 she developed a large haematoma following surgery. Laboratory investigation revealed thrombocytopenia and large platelets. Platelet membrane glycoprotein analysis showed a marked deficiency of the components of the GP Ib-IX complex (approximately equal to 25% of normal). Flow cytometry revealed two populations of platelets: a predominant population of large platelets lacking the GP Ib-IX complex and a minor population of normal-sized platelets with normal GP Ib-IX expression. The patient developed progressive anaemia, more severe thrombocytopenia and neutropenia, and circulating blast cells were seen. A bone marrow showed gross hypercellularity with marked dysplasia of all three lineages and increased blasts. Marrow cytogenetic studies showed the presence of monosomy 7 in all metaphases, with an additional trisomy 21 in 10%. Peripheral blood cells were normal 46XX. The above data are consistent with an acquired myelodysplastic syndrome associated with a Bernard-Soulier-like platelet defect.

Oral histoplasmosis treated with miconazole.

A case of localised histoplasmosis of the gingivae, with no osseous involvement is described in a 50-year-old man. The diagnosis was based on histology, growth on culture and a positive histoplasmin latex test. Therapy was commenced with intravenous amphotericin but was changed to intravenous miconazole because of serious immediate side effects and the development of marked renal impairment and moderate suppression of erythropoiesis. Rebiopsy of the gingival margin showed therapy to be effective. No source of the infection could be traced.

Fungal retinitis: a case of Torulopsis glabrata infection treated with miconazole.

Presumptive embolic chorioretinal Torulopsis glabrata infection is described in a patient who had received prolonged intravenous antibiotic therapy. The ocular findings are compared and contrasted with embolic lesions due to Candida albicans. The patient was treated for 6 weeks with intravenous miconazole. During this time there was shrinkage of the ocular lesions, some improvement in vision and abolition of fungaemia. Improvement in tests of immune function during treatment suggests that an early immunological deficit was secondary to the infection. Intravenous miconazole is a relatively nontoxic alternative to amphotericin and deserves further evaluation in the treatment of ocular mycosis.