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.

High-dose ifosfamide in combination with etoposide and epirubicin (IVE) in the treatment of relapsed/refractory Hodgkin's disease and non-Hodgkin's lymphoma: a report on toxicity and efficacy.

One hundred and seven patients (61 with diffuse large B-cell non-Hodgkin's lymphomas and 46 with Hodgkin's disease) in relapse or following of primary therapy received ifosfamide 3 g/m2 i.v. daily for 3 days in combination with epirubicin 50 mg/m2 i.v. day 1 and etoposide 200 mg/m2 i.v. days 1-3. Of the 46 patients with Hodgkin's disease (28 male, 18 female, and a median age of 28 years) 85% of patients had a response to treatment, with 17 achieving complete remission and 11 good partial remission. Twenty-eight proceeded to autologous bone marrow or peripheral blood stem cell transplantation. Twenty-three patients remain alive in continuous remission with a follow-up of 12-61 months. The median overall survival time for all patients in this group is 36 months. Haematological toxicity, particularly WHO Grade IV neutropenia, occurred in all patients but improved over the three courses of treatment. There was no major non-haematological toxicity. Further trials of this regimen in this clinical situation are indicated. The patients with non-Hodgkin's lymphomas in this study had diffuse large B-cell lymphomas and had only received first-line treatment. Twenty had primarily refractory disease, 15 had only achieved partial remissions (PR), and 26 had developed relapse following primary treatment. The overall response rate was 43%; it was 60% for those who had achieved initial PR, 58% for those in relapse after an initial CR or very good PR following initial therapy, but only 10% for those with primarily refractory disease. Tolerance to the regimen was similar to that observed in treatment of the patients with Hodgkin's disease and many were able to undergo stem cell collection, following mobilization with this regimen. The 2-year overall survival result was 22% for patients with some response to first-line treatment but 0% for primary refractory patients.

Validation of the Hasford score in a demographic study in chronic granulocytic leukaemia.

Chronic granulocytic leukaemia (CGL) is a rare disease. For most patients the only curative treatment (an allogeneic stem cell transplant) is not available. Survival varies between a few months to many years from diagnosis, and an accurate prediction of the duration of survival could help patients and clinicians make informed decisions about the many treatment options. In 1984, the Sokal score was introduced to stratify patients into risk groups. Recently, a new prognostic scoring system was proposed by Hasford and co-workers for interferon treated patients. We have analysed survival on an unselected population based cohort of patients using both the Hasford and the Sokal scores. In the group overall, neither score was predictive of survival, but in younger patients (< 60 years) treated with interferon, the Hasford score was highly predictive of survival, dividing patients into groups with a five year survival of 77% (45 patients) v 33% (six patients) v 14% (31 patients) (p = 0.01).

High dose ifosfamide in combination with etoposide and epirubicin followed by autologous stem cell transplantation in the treatment of relapsed/refractory Hodgkin's disease: a report on toxicity and efficacy.

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of ïfosfamide at a dose of 9g/m(2) over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M:18F) with a median age of 28 years (range 13-45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Haematological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with difficult Hodgkin's disease and warrants further study.

Management of non-Hodgkin's lymphomas.

The non-Hodgkin's lymphomas (NHL) are a heterogeneous group of disorders characterised by malignant proliferation of lymphoid cells. The cellular origin is relatively well established with subtypes corresponding to the various stages of lymphocyte differentiation. The term encompasses a hotchpotch of conditions with very different morphological appearance, behaviour and clinical outcome. NHL comprise 2.4% of all cancers, with incidence increasing with age. The commonest presentation is with progressive lymphadenopathy, though extranodal manifestations are present in a significant proportion. The clinical behaviour ranges from a benign, indolent course to rapidly progressive disease; prognosis varies from weeks to many years. Treatment is correspondingly diverse, from 'watchful waiting' to high-dose chemotherapy with bone marrow stem cell transplantation. Cure is possible in an increasing number of patients and much interest currently lies in identifying patients with high-risk disease necessitating the use of intensive treatment regimens.

Low incidence of myelodysplastic syndrome following transplantation using autologous non-cryopreserved bone marrow.

Between May 1984 and October 1995 we performed 114 autologous stem cell transplants for lymphoma in our centre; 77/114 (68%) were transplanted after primary therapy. The conditioning regimen varied according to diagnosis; 26 patients were conditioned with melphalan and total body irradiation, 66 received melphalan and etoposide and the remainder (50) were conditioned with melphalan alone. The median follow-up is 62 months. Only two new haematological malignancies have occurred, both in patients with Hodgkin's disease. One patient developed Ph+ chronic myeloid leukaemia 18 months post-transplant. In this case, because of the timing of the haematological disorder, we considered the malignancy to be concurrent with or to have preceded the transplant. A second patient developed acute myeloid leukaemia 20 months post-transplant. She had been treated for Hodgkin's disease for 10 years and was transplanted in third complete remission. Cytogenetic analysis in this case showed trisomy 11. We believe this to have been an unequivocal second malignancy. Our finding of a 1.1% incidence of secondary haematological malignancy (95% CI 0.02-4.96) from a census population adds weight to the hypothesis that haematological problems post-transplant reflects prior chemotherapy rather than toxicity from the transplant procedure itself.

CHOP-based chemotherapy is as effective as alternating PEEC/CHOP chemotherapy in a randomised trial in high-grade non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma Group.

The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.

Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK.

As more centres consider autologous bone marrow and peripheral blood stem cell transplantation for patients with high risk Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) in first complete remission (CR1) the long term sequelae of such treatments have to be considered. One of the most important side effects of such intensive treatment is loss of fertility. Sperm banking before treatment commences is available for males but unfortunately cryopreservation of ova/ovarian tissue is not yet possible for females. We have transplanted 30 women, 23 were under 40 years and report ten females who have had successful pregnancies (including two twin pregnancies and one triplet pregnancy), leading to live births following autologous bone marrow transplantation (ABMT) for poor prognosis HD and NHL in first or second complete remission. None of these children have shown evidence of birth defects (median follow up of two years). Of the twenty one pregnancies reported to the European Bone Marrow Transplantation Registry (EBMTR) following ABMT for lymphoma, eight of the seventeen unassisted cases came from our centres. The Newcastle/SNLG autotransplant differs from the approach in many EBMTR centres in that it uses melphalan or melphalan/etoposide alone instead of the more common four drug containing regimens and yet sustained complete remission rates indicate that the non-ablative approach is equally effective as more aggressive regimens on the disease with the huge advantage of preserved fertility in females. This approach to conditioning for ABMT should be considered when treating women in the reproductive age group.

Autologous bone marrow transplantation in poor-risk high-grade non-Hodgkin's lymphoma in first complete remission. Newcastle and Northern Lymphoma Group.

We report the safety and efficacy of autologous bone marrow transplantation (ABMT) in 30 patients with high-grade non-Hodgkin's lymphoma (NHL) in first complete remission (CR1) following remission induction chemotherapy. Two patients relapsed prior to ABMT. All patients were conditioned with high-dose melphalan. In Addition, ten received fractionated total body irradiation, one hemi-body irradiation and four high-dose etoposide. Unmanipulated non-cryopreserved autologous marrow was reinfused within 56 h of harvesting. Engraftment occurred in all patients with a median of 11 days of neutropenia (< 0.5 x 10(9) l-1), a median requirement for platelet transfusion of 3 days and packed red cell transfusion of 2 units, with a median hospital stay of 18 days post transplant. There was no procedure-related mortality and only minor morbidity was observed. Two patients relapsed at 1 and 2 months post transplantation, and one patient died of carcinoma of the lung 33 months after transplantation. The remaining 25 patients remain alive, well and in CR1 with a median follow-up of 44 months. The event-free survival at 3 years for all patients considered for ABMT was 83%. We conclude that ABMT for high-grade NHL in CR1 with non-cryopreserved marrow results in rapid haematological recovery without growth factor support. It is safe and is associated with high survival when used as consolidation of CR in high-risk patients.

Autologous bone marrow transplantation in acute lymphoblastic leukaemia.

There has been a great deal of interest in the use of high dose chemotherapy and/or radiotherapy, with autologous bone marrow/peripheral blood stem cell rescue, in the treatment of haematological malignancies including acute lymphoblastic leukaemia (ALL). In this review we assess the role of autologous bone marrow transplantation (ABMT) in ALL. The heterogeneity of this disease makes the analysis of treatment results in ALL difficult to interpret. There is some evidence that ABMT may be useful in second complete remission (CR) and increasing interest in ABMT as a therapeutic option in first CR in adults. At the moment there is little evidence that such an approach will have an impact in childhood ALL. ABMT is considerably less toxic than allogeneic bone marrow transplantation and the major cause of 'treatment failure' is disease relapse. There has been considerable effort put into purging autologous bone marrow of malignant stem cells but whether purging is effective remains controversial and not proven. Newer studies involving cytokines post-ABMT to stimulate an artificial 'graft versus leukaemia' effect may prove of value.

Rapid onset of chronic granulocytic leukaemia after treatment for Hodgkin's disease.

A 17-year-old white female presented with stage IVB Hodgkin's disease. After chemotherapy and radiotherapy she achieved a complete clinical remission and underwent an autologous bone marrow transplant (ABMT). 22 months later she developed chronic granulocytic leukaemia (CGL). Polymerase chain reaction (PCR) analysis of bone marrow harvested at the time of ABMT did not show any evidence of the bcr-abl sequence that was detectable at the diagnosis of CGL. This case provides further information on the kinetics of the development of CGL and adds to the small pool of data on CGL developing after treatment for Hodgkin's disease.

Autologous transplantation in poor risk Hodgkin's disease using high dose melphalan/etoposide conditioning with non-cryopreserved marrow rescue. The Newcastle and Northern Region Lymphoma Group.

This study aimed to assess the safety and efficacy of using high dose melphalan and etoposide followed by autologous, non-cryopreserved marrow rescue in advanced Hodgkin's disease (HD). Seventeen patients with poor risk Hodgkin's disease from a single centre underwent autologous bone marrow transplant (ABMT) using high dose melphalan and etopside conditioning. Two patients had primary progressive resistant disease (PD), two were in fourth relapse, six in second or third complete remission (CR), one patient had good partial response (GPR) (> 75% reduction in initial bulk) to primary therapy and six were in first complete remission. The patients transplanted in first CR all has a Scotland and Newcastle Lymphoma Group (SNLG) Prognostic Index (Proctor et al., 1991) which indicated they were in a poor risk prognostic group. Melphalan and etoposide both have a short half life enabling ABMT to be accomplished using unmanipulated marrow stored at 4 degrees C. The marrow was returned to the patient within 56 h of harvest. Complete haematological reconstitution occurred in 16/17 patients, the rate of engraftment reflecting the amount of previous chemotherapy. One patient died of progressive Hodgkin's disease before full engraftment could occur. In patients autografted in first remission, the median number of days with neutropenia (< 0.5 x 10(9) l-1 neutrophils) was 19 (range 9-33) and, in those in subsequent remission, 27 days (range 18-36). The median number of days to 50 x 10(9) l-1 platelets in the same groups were 29 (21-80) and 50 (41-74) respectively. The number of days in hospital post transplant in both groups was similar; median 22 (15-27) and 23 (17-37) respectively. There were no procedural deaths and none of the patients transplanted in first, second or third CR have relapsed (median follow up 21 months). The two patients transplanted with progressive disease showed only temporary responses. The two patients transplanted in fourth relapse went into CR; one is still alive and in CR 15 months post transplant, but the other relapsed 18 months post transplant. This form of intensification therapy with marrow rescue has been shown to be effective and of low toxicity and now forms part of a randomised controlled trial in poor risk Hodgkin's patients as identified by the SNLG index (Proctor et al., 1992).

Interleukin-2 induction of lymphokine-activated killer activity in the peripheral blood of an acute lymphoblastic leukaemia patient--case study.

In this case study an acute lymphoblastic leukaemia (ALL) patient relapsing after autotransplant had remission reinduced with chemotherapy and consolidated after initial response by a course of therapy with recombinant interleukin-2 (rIL-2) given subcutaneously. Immunological parameters measured during therapy demonstrated an increase in the numbers of T cells and in lymphokine-activated killer (LAK) cell activity against autologous leukaemic blasts and LAK-sensitive cell lines. The therapy was well tolerated and administered on an out-patient basis. The patient has remained in haematological remission for over twelve months. Sustained remissions have not been observed previously in relapsed transplant patients using chemotherapy alone. The data suggests that rIL-2 deserves further evaluation in ALL patients who are immunologically intact with residual disease after primary or secondary chemotherapy.

An effective oral combination in advanced relapsed Hodgkin's disease prednisolone, etoposide, chlorambucil and CCNU.

Many patients with advanced Hodgkin's disease continue to need palliative therapy, but where there is no curative intent, patients and doctors may prefer oral treatment only. This paper describes the preliminary experience of such a schedule. A total of 15 patients with advanced relapsed Hodgkin's disease were treated with an oral regimen, PECC (prednisolone at 40 mg daily for 7 days, etoposide at 200 mg/m2 on days 1-3, chlorambucil at 20 mg/m2 on days 1-4 and CCNU at 100 mg/m2 on day 1 only), repeated every 4-6 weeks. 12 patients had been extensively pretreated. 11 patients had extranodal disease and 8 had B symptoms when treatment was started. Eight patients achieved a complete remission, with a median duration of 7+ months, and five achieved a partial remission; the overall response rate was 86%. Haematological toxicity was the major side effect. There were no treatment-related deaths. All patients tolerated treatment well and the oral route has particular advantages for those unwilling or unable to accept intravenous treatment.

Lomustine, vindesine and bleomycin (LVB) used in the treatment of relapsed advanced Hodgkin's disease. A prospective study on behalf of the East of Scotland and Newcastle Lymphoma Group (ESNLG).

Sixty-three patients with relapsed advanced Hodgkin's disease were treated with lomustine (CCNU), vindesine and bleomycin (LVB). Age range was 17-72 years, with 38 males and 25 females. Thirty patients achieved complete remission (CR) with a median duration of 24+ months (range 3-55). Nineteen continue in unmaintained CR. CR rates were highest for those patients who relapsed greater than 6 months after first line treatment and for those at second or subsequent relapse. CR rates were higher in those with nodal only relapse. Twenty-seven patients were non-responders and six were partial responders. These 33 patients were subsequently changed to alternative chemotherapeutic regimes and 26 failed to respond to any therapy and have since died. Only one patient is in unmaintained complete remission. The regimen was well tolerated by patients, and easy to administer. It produced no serious episodes of toxicity. We conclude that LVB is of value in the management of relapsed advanced Hodgkin's disease especially in chronic relapsing patients, and where relapse occurs greater than 6 months after the first line treatment. We are presently unsure whether it offers any advantage over reintroduction of first line treatment in the latter group.