David A. Winfield

Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial

High-dose chemotherapy and radiotherapy with autologous bone-marrow transplantation (ABMT) are increasingly used for the treatment of relapsed and resistant Hodgkins disease, although there has been no randomised trial of this treatment. The British National Lymphoma Investigation therefore undertook a randomised comparison of high-dose chemotherapy (BEAM = carmustine, etoposide, cytarabine, and melphalan) plus ABMT with the same drugs at lower doses not requiring bone-marrow rescue (mini-BEAM) in patients with active Hodgkins disease, for whom conventional therapy had failed. 20 patients were assigned treatment with BEAM plus ABMT and 20 mini-BEAM. All have been followed up for at least 12 months (median 34 months). 5 BEAM recipients have died (2 from causes related to ABMT and 3 from disease progression) compared with 9 mini-BEAM recipients (all disease progression). This difference was not significant (p = 0.318). However, both event-free survival and progression-free survival showed significant differences in favour of BEAM plus ABMT (p = 0.025 and p = 0.005, respectively). Recruitment to the trial became increasingly difficult because patients refused randomisation and requested ABMT. It was therefore closed early (40 patients rather than 66 intended). Nevertheless, we found a dose-response effect in these patients with relapsed and resistant Hodgkins disease. High doses facilitated by ABMT can lead to better disease-free survival.

Diagnosis of acute promyelocytic leukaemia by RT-PCR: detection of PML-RARA and RARA-PML fusion transcripts

Summary. Acute promyelocytic leukaemia (APL; AML M3) is identified by a unique t(15;17) translocation which fuses the PML gene to the retinoic acid receptor alpha gene (RARA). Reverse transcription coupled with the polymerase chain reaction (RT‐PCR) has been used to develop a diagnostic test for APL based on the PML‐RARA fusion message. Separate PCR assays were designed to amplify either PML‐RARA (15q+ derived) or RARA‐PML (17q‐ derived) chimaeric transcripts. PML‐RARA transcripts were detected in every case from a series of 18 APL patients with cytogenetically confirmed t(15;17) translocations, whereas RARA‐PML messages were detected in only 67% (12/18) of these patients. This suggests that it is the 15q + derivative which mediates leukaemogenesis. Furthermore the PCR approach (or Southern analysis) may be used to identify in which of the alternative PML introns the breakpoint occurs; 52% of cases (15/29 patients) utilize a 5′ PML intron and 48% the 3′ intron (14/29 cases). Neither the choice of PML intron nor the expression of the 17q‐derivative could be correlated with the microgranular variant of APL (M3V), overall survival rate, age, sex or presence of coagulopathy. Finally, the fusion message is undetectable in five remission samples. This indicates a possible use for RT‐PCR in monitoring remission patients for evidence of relapse.

A comparative analysis of radiological and surgical placement of central venous catheters

PurposeTo compare the differences in practice and outcome of all radiologically and surgically placed central venous catheters retrospectively over a 2-year period simultaneously, at a single institution.MethodsA total of 253 Hickman catheters were inserted in 209 patients; 120 were placed radiologically in 102 patients and 133 were placed surgically in 107 patients. The indication was chemotherapy in 76% of radiological and in 47% of surgical cases; the remainder were for total parenteral nutrition and venous access.ResultsThere were 6 (4.5%) primary surgical failures and a further 17 (13%) surgical cases requiring multiple placement attempts. Pneumothorax occurred once (0.8%) surgically and four times (3.3%) radiologically. There were no radiological primary misplacements but there were five (3.7%) surgical ones. Catheter or central vein thrombosis occurred in four (3.3%) radiological and five (3.7%) surgical cases. The rate of infection per 1000 catheter-days was 1.9 in radiologically placed catheters and 4.0 in surgically placed ones (p<0.001). Average catheter life-span was similar for the two placement methods (100±23 days).ConclusionRadiological placement is consistently more reliable than surgical placement. There are fewer placement complications and fewer catheter infections overall.

G-CSF after peripheral blood stem cell transplantation in lymphoma patients significantly accelerated neutrophil recovery and shortened time in hospital: results of a randomized BNLI trial.

We have undertaken a prospective randomized study in 90 patients with relapsed or resistant lymphomas to assess the value of G‐CSF (lenograstim) in the acceleration of myeloid recovery after peripheral blood stem cell transplantation (PBSCT). A common regimen of cyclophosphamide 1.5 g/m2 on day 1 and lenograstim 263 μg s.c. on days 2–10 with two aphereses on days 10 and 11 was used for stem cell mobilization. 77% of patients achieved an adequate PBSC collection in two harvests (>2 × 108 MNC/kg or >2 × 106 CD34+ cells/kg). 65 patients went on to receive high‐dose BEAM chemotherapy and engraftment data was available for 62. 34 patients had been randomized to receive lenograstim 263 μg/d s.c. and 28 to no growth factor. The median time to ANC > 0.5 × 109/l was 9 d in the lenograstim arm versus 12.5 d in the no‐lenograstim arm (P = 0.0001). This was associated with a median duration of time in hospital post PBSCT of 13 d in the lenograstim arm versus 15.5 d in the no‐lenograstim arm (P = 0.0002). Median days to platelet independence, platelet transfusions, incidence of infection and red cell transfusion were the same in both arms. These data indicate that lenograstim significantly accelerated myeloid recovery after PBSCT and shortened the duration of hospital stay.

High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin's disease is unlikely to be associated with a major increased risk of secondary MDS/AML.

SummaryHodgkin’s disease is curable in the majority of patients, although a proportion of patients are resistant to or relapse after initial therapy. High-dose therapy with autologous stem cell support has become the standard salvage therapy for patients failing chemotherapy, but there have been reports of a high incidence of myelodysplasia/acute myeloid leukaemia (MDS/AML) following such treatment. Patients who receive such therapy form a selected group, however, who have already been subjected to other leukaemogenic factors, such as treatment with alkylating agents. In order to ascertain the true risk of MDS/AML, comparison must be made with other patients subjected to the same risks but not undergoing transplantation. We report a retrospective comparative study of 4576 patients with Hodgkin’s disease from the BNLI and UCLH Hodgkin’s databases, which includes 595 patients who have received a transplant. Statistical analysis including Cox’s proportional hazards multivariate regression model with time-dependent covariates was employed. This analysis reveals that the risk of developing MDS/AML was dominated by three factors, namely quantity of prior therapy (relative risk [RR] 2.01, 95% confidence intervals [CI] 1.49–2.71, for each treatment block, P < 0.0001) and whether the patient had been exposed to MOPP (RR 3.61, 95% CI 1.64–7.95, P = 0.0009) or lomustine chemotherapy (RR 4.53, 95% CI 1.96–10.44, P = 0.001). Following adjustment for these factors in the multivariate model the relative risk associated with transplantation was 1.83 (95% CI 0.66–5.11, P = 0.25). This study provides no evidence of a significantly increased risk of MDS/AML associated with BEAM therapy and autologous transplantation in Hodgkin’s disease. Concern over MDS/AML should not mitigate against the timely use of this treatment modality.

Angiotropic lymphoma: report of a case with histiocytic features.

Angiotropic lymphoma, also known as intravascular lymphomatosis, is characterised by widespread intravascular proliferation of malignant lymphoid cells, usually without evidence of focal disease. A case of a 52 year old man referred for investigation of a two year history of pyrexia of unknown origin, skin rash and multiple organ failure is described. Angiotropic lymphoma was seen in gastric, colonic and skin biopsy specimens, and review of an earlier skin biopsy specimen showed similar morphological features. In contrast to previous cases which showed B or T cell differentiation, immunohistochemical examination was positive for histiocyte markers. Molecular studies showed no evidence of immunoglobulin heavy chain gene or T cell receptor gene rearrangement. The patient responded to combination chemotherapy, comprising cyclophosphamide, doxorubicin, etoposide, and prednisolone. This case highlights the fact that advanced lymphoma may be present without evidence of focal disease and that the diagnosis may be missed easily both clinically and histologically.

Mitoxantrone for refractory and relapsed acute leukemia.

Seventy‐seven patients with relapsed or refractory acute leukemia and three with acute blastic chronic myeloid leukemia (CML) were treated in an open Phase II study using mitoxantrone 12 mg/m2 intravenously daily × 5 days. Complete remission (CR) was achieved in 32 of 80 (40%), including 23/45 (52%) with relapsed acute nonlymmphocytic leukemia (ANLL), four of 12 (33%) with relapsed acute lymphocytic leukemia ALL, four of 17 (24%) with ANLL refractory to daunorubicin + cytosine arabinoside, and one of three (33%) with refractory ALL. None of the patients with acute blastic CML achieved CR. Median survival time for all patients was 121 days. Median duration of complete response was 303 days with ten of 32 patients in continuing CR for periods varying from 44+ to 1210+ days. Apart from moderately prolonged hematologic suppression toxicity was mild and subjective side effects were tolerable. Mitoxantrone is an active agent in the treatment of acute leukemia and demonstrates incomplete cross resistance with duanorubicin. Mitoxantrone should be considered for first‐line therapy in ANLL.

Epidural granulocytic sarcoma in acute myeloid leukemia with 8;21 translocation

Three patients with M2 acute myeloid leukemia (AML) in whom cord compression developed due to epidural granulocytic sarcoma are reported and compared with six similar patients described previously. These three cases had 8;21 translocation, t (8;21), in the marrow karyotype and also in the karyotype of granulocytic sarcoma tissue obtained from two of the cases. Treatment with chemotherapy and radiotherapy can be effective, but an emergency laminectomy should be performed if there is rapid neurologic progression.

Fatal cold anti-i autoimmune haemolytic anaemia complicating hairy cell leukaemia

Hairy cell leukaemia (HCL) is a rare lymphoproliferative disorder associated with pancytopenia, splenomegaly and the presence of typical hairy B lymphocytes in the bone marrow and/or peripheral blood. The most significant complication relates to opportunistic infections that arise as a consequence of neutropenia and monocytopenia. HCL is occasionally associated with systemic autoimmune disorders including polyarteritis nodosa and rheumatoid disease. Secondary autoimmune haemolytic anaemia (AIHA) appears to be rare. We report on two cases of HCL complicated by fatal cold anti‐i AIHA. Fulminant haemolysis causing death is rare in cold AIHA and only a few individual cases have been reported, none having anti‐i specificity.

Investigation of BCL-2 Gene Rearrangements in a United Kingdom Series of Low and High Grade Non-Hodgkin's Lymphomas

Rearrangements of the BCL-2 gene are thought to be the most frequent genetic changes that occur in non-Hodgkins lymphomas (NHL), and are particularly associated with follicular low grade disease. Wide variations in the frequency of these rearrangements have, however, been reported in studies of NHL series from different parts of the world. We were therefore interested to determine the frequency of BCL-2 gene rearrangements in the different grades of NHL from a U.K. series. We have done this by using a combination of Southern blot hybridization and polymerase chain reaction (PCR) analysis. The frequencies of rearrangements in our series were 9/20 (45%) in low grade follicular NHL, 1/8 (12.5%) in low grade lymphocytic and 5/19 (26%) in high grade NHL. However, estimation of the high grade value was complicated by the fact that a number of the high grade samples in our series were from patients who had transformed from low grade follicular disease. If the patients were ranked on the basis of whether they had a history of low grade follicular disease then the frequency of BCL-2 rearrangement remained the same 13/29 (45%), but was only 1/10 (10%) in high grade NHL with no history of follicular disease. The former figure was intermediate between those reported for the USA and Japan series, but the latter high grade figure was the lowest reported from any series. The significance of BCL-2 rearrangements in the evolution of both low and high grade NHL is discussed.