A population-based study of intensive multi-agent chemotherapy with or without autotransplant for the highest risk Hodgkin's disease patients identified by the Scotland and Newcastle Lymphoma Group (SNLG) prognostic index. A Scotland and Newcastle Lymphoma Group study (SNLG HD III).

The aim of the study was to identify all patients with poor risk Hodgkin's disease (HD) using a numerical prognostic index in a defined population and to recruit them into a trial of intensive chemotherapy prednisolone, vinblastine, doxorubicin, chlorambucil, etoposide, bleomycin, vincristine, procarbazine (PVACE-BOP)x3+autotransplant (Arm A) versus PVACE-BOPx5 (Arm B) in first remission. In 10 years, the Scotland and Newcastle Lymphoma Group (SNLG) registered 930 patients with HD of whom 178 (19%) were identified as 'poor risk' by the SNLG index and were aged 16-59 years. 126/178 (71%) entered the study. Of the 120 confirmed poor risk HD cases, all completed PVACE-BOPx3 with a 93% Complete Response/unconfirmed Complete Response (CR/CRu) rate. Only 65/107 in CR accepted the randomisation. With a median follow-up of 6 years, both arms of the trial have a similar time to treatment failure (TTF) (Arm A 79%+/-11 versus 85%+/-7 Arm B, P=0.35). Advanced stage 'good risk' patients not included in the trial receiving standard therapy with CLVPP or ABVD had a 75% 5-year survival. The study demonstrates that PVACE-BOP therapy in the poorest risk group (58% had an IPI>/=3) produces excellent CR rates (93%) and overall survival with minimal toxicity, and that the substitution of autotransplant in first CR does not improve outcome. The use of the objective SNLG index accurately helped in the selection of the poorest risk group in this population study. The placing of a randomised control trial within the context of a population-based study of HD enhances the validity of the outcome.

Interleukin 4 production by peripheral blood lymphocytes in patients with classical Hodgkin lymphoma.

Although the production of interleukin (IL) 2 and interferon (IFN) gamma by peripheral blood lymphocytes in patients with Hodgkin lymphoma (HL) is well documented, the synthesis of IL4 has not been investigated before. The present study examines the production of IL4 by 2-day phytohaemaglutinin (PHA)-stimulated peripheral blood (PB) cells in HL and correlates the cytokine levels with the proportion of the different T-cell sub-populations. We observed a significant increase in the mean level of production of IL4 in patients with HL when compared with normal controls. The increased amount of IL4 in patients with HL correlated significantly with the proportion of the CD3(+)CD8(+) cells but not with CD3(+)CD4(+). The intensity of cytoplasmic IL4 (expressed as relative median fluorescence (RMF)) was significantly higher in the CD3(+)CD8(+) cells of the patients with HL compared with the CD3(+)CD4(+) sub-population, or with the normal CD3(+)CD8(+) cells and correlated with the levels of IL4 release in culture supernatants. In conclusion, there is increased production of IL4 by PHA-activated PB lymphocytes in HL. The CD3(+)CD8(+) T-cell population appears to be responsible for this increased synthesis.

Oestrogen receptor alpha gene polymorphism associates with occurrence of graft-versus-host disease and reduced survival in HLA-matched sib-allo BMT.

Oestrogen receptors mediate the cellular response to oestrogens and related compounds and promote a wide range of effects on haemopoiesis. Polymorphisms of the oestrogen receptor genes have previously been associated with variation in bone mineral density, likelihood of fractures, risk of developing Alzheimer's disease, endometrial cancer and response to hormone replacement therapy. We examined the polymorphisms in both ERalpha and ERbeta genes in 108 patients receiving a bone marrow transplant from an HLA-matched sibling donor, and compared ER genotype with outcomes of occurrence of graft-versus-host disease (GVHD) and survival using logistic regression analysis. Polymorphism of ERalpha (presence of the PX haplotype (PvuII-XbaI RFLP) of intron 1), but not ERbeta, in the patient genotype associates with occurrence of acute GVHD and with lower overall survival, following correction for known clinical and genotypic risk features. Analysis of ER genotype prior to transplant might therefore inform on a patient's likelihood of developing post-transplant complications. Variation in transplant performance because of ER genotype suggests an underlying role for oestrogens in the pathophysiology of transplant-related complications, and suggests that oestrogen-related therapy may offer a new modality of post-transplant support.

Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation.

We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10(-1064) and IFN-gamma genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12.93, P < 0.0001). Analysis of VDR genotype in prospective BMT recipients could indicate patients at risk of severe aGVHD. Analysis of VDR genotype in prospective BMT donors may identify individuals who have greater transplant-related mortality, and also allow appropriately restricted use of increased immunosuppressive prophylaxis.

Acute lymphoblastic leukaemia of the L3 subtype in adults in the Northern health region of England 1983-99.

AIM: Acute lymphoblastic leukaemia (ALL) with an L3 morphological FAB type is regarded by some as being synonymous with B cell ALL or ALL with a Burkitt-type chromosomal translocation-t(8;14), t(2;8), t(8;22). This paper describes a series from a population based study of 24 patients with L3 ALL presenting over 17 years. METHODS: Clinical data were collected prospectively from all adult patients presenting with acute leukaemia in the Northern region since 1982. Data from all patients diagnosed with FAB type L3 ALL were analysed. RESULTS: Overall, L3 ALL accounts for 8.6% of all adult ALL and it is more common in the elderly than has hitherto been recognised. In addition to classic Burkitt-type translocations (11 of 24 cases), the t(14;18) translocation, which is characteristically found in lower grade lymphomas such as follicular lymphoma, is frequently present (five of 24 cases). CONCLUSION: The presence of L3 ALL is often associated with non-Burkitt-type translocations and the presence of a t(14;18) translocation may indicate that in some cases a clinically non-apparent lymphoproliferative disorder, such as a low grade follicular lymphoma, has transformed to a more aggressive form and, thus, presents as a de novo acute leukaemia.

Lymphoma presenting as a parotid tumour: a population-based study of diagnosis, treatment and outcome on behalf of the Scotland and Newcastle Lymphoma Group.

AIMS: Lymphoma presenting as a parotid tumour is rare. Previous published studies have been small and have not characterised fully the nature of lymphoma presenting this way. We studied the clinical features, diagnosis, prognosis and treatment in a patient group identified from the Scotland and Newcastle Lymphoma Registry, which is a prospectively collected population-based register of consecutive cases of lymphoma since 1979. MATERIALS AND METHODS: The study includes all patients with a biopsy-proven lymphoma in the parotid gland as the first presentation of their disease. RESULTS: Of 136 cases identified, 128 had non-Hodgkin's lymphoma (representing 1.5% of the 8499 non-Hodgkin's lymphomas in the registry) and eight had Hodgkin's disease (0.3% of the 2716 cases registered). Female to male ratio was 1.3:1, and median age was 69 years (range 19-94 years). Fifty-six per cent of patients had stage I, 16% had stage II, 11 % had stage III and 17% had stage IV disease. Diagnostic method was recorded in 81 cases; 47 of these were by parotidectomy. Overall median survival was 90 months, with a 5-year survival of 54%, but there was substantial variation according to age, grade, stage and International Prognostic Index (IPI). Diagnosis was often made by unnecessary major facial surgery, which could be avoided in many cases. CONCLUSION: Treatment should be directed by standard practice for lymphoma according to stage and histological classification.

Outcome of a risk-related therapeutic strategy used prospectively in a population-based study of Hodgkin's lymphoma in adolescents.

The aim was to assess outcome in a population-based cohort of adolescents with Hodgkin's lymphoma (HL) diagnosed in the UK's northern region over a 10-year period. Among a population of 3.09 million, 55 of 676 patients (8%) diagnosed with HL were aged 13-19. Seven had nodular lymphocyte-predominant HL, 48 classical HL (cHL). Of the latter, 36 were >or=16 years. Application of the Scottish and Newcastle Lymphoma Group (SNLG) prognostic index meant 21 patients were considered high risk (index >or=0.5). They received PVACEBOP multi-agent chemotherapy as primary therapy. Standard risk patients (SNLG index <0.5) were treated with standard ChlVPP or ABVD chemotherapy+/-radiotherapy. Scottish and Newcastle Lymphoma Group indexing is not valid for patients under 16. Twelve patients therefore received UKCCSG protocols (n=8), ABVD plus radiotherapy (n=2), or PVACEBOP (n=2). Forty-six patients with cHL (96%) achieved complete remission. Seven patients relapsed but all entered complete remission after salvage therapy. Five patients died: three of HL, one in an accident and one of disseminated varicella complicating cystic fibrosis. Five- and 10-year overall survival was 93 and 86%, respectively; disease-specific survival was 95 and 92%. The data suggest that older adolescents with high-risk HL require intensive protocols as primary therapy to secure optimal outcome.

The addition of oral idarubicin to a chlorambucil/dexamethasone combination has a significant impact on time to treatment failure but none on overall survival in patients with low grade non-Hodgkin's lymphoma: Results of the Scotland and Newcastle Lymphoma Group randomized NHL VIII trial.

Two hundred untreated patients with low grade NHL (KIEL), including 155 follicular NHL, were randomized to six courses of treatment with chlorambucil 20 mg m-2 for 3 days and dexamethasone 4 mg bd for 5 days (CD) vs the same regimen plus oral idarubicin 10 mg m-2 for 3 days (CID). Responding patients could be randomized to no further treatment or maintenance treatment for up to 36 months with alpha interferon. Complete remissions/CRu were more frequent in the CID arm (35% vs 24%) but the overall response rate was similar; 87/91 (96%) vs 86/92 (93%). Overall survival (OS) did not differ between the two arms. Time to treatment failure (TTTF) was prolonged in the CID arm, p = 0.03; median time 28 vs 19 months. TTTF for the B-cell follicular group alone was for CID (77 patients) 33 months vs 18 months for CD (78 patients). Interferon conferred no apparent benefit. The Follicular Lymphoma International Prognostic Index (FLIPI) is confirmed as a good predictor of risk groups including a group of 23% with shorter survival. The addition of the oral anthracycline, idarubicin, led to a significant improvement in TTTF with low toxicity. The use of radiotherapy in this sub-group may have contributed to this result. CID is a potential for combination with antibody therapy particularly in older patient groups.

Strategic approach to the management of Hodgkin's disease incorporating salvage therapy with high-dose ifosfamide, etoposide and epirubicin: a Northern Region Lymphoma Group study (UK).

The Northern Region Lymphoma Group is a population-based group covering 3.1 million people in Northern England. From 1991 total data collection for all Hodgkin's disease patients for this population has been in place and it has been possible to demonstrate that the overall survival for Hodgkin's disease for younger patients within this population has moved from 80% pre- 1988 to 87% post- 1988. This improvement has been brought about by the introduction of clinical trials for advanced stage disease and effective salvage regimens. This report describes the outcome of 51 patients treated with the ifosfamide, etoposide and epirubicin (IVE)schedule and includes 28 males and 23 females with a median age of 34 years. Overall 43 of 51 patients responded to treatment (84%) with 31 achieving a complete response, four a good partial response and eight a partial response. Thirty-one proceeded to autologous stem-cell transplantation. In total, with a median follow-up of 24 months (range 6-51), 26 patients remain alive and in continuous remission. Haematological toxicity,in particular neutropenia WHO grade 4, was observed in all cases but improved over the three courses of treatment. Non-haematological toxicity was not a major problem, with no significant cardiac, hepatic, renal or neurotoxicity. We conclude that the high-dose ifosfamide-containing regimens should be prospectively evaluated in the various types of non-responsive and relapsing Hodgkin's disease.