Selected Summaries

High dose chemotherapy in aggressive non-Hodgkin lymphoma [PDF]

Milpied N, Deconinck E, Gaillard F, Delwail V, Foussard C, Berthou C, Gressin R, Lucas V, Colombat P, Harousseau J-L for the Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang. (University Hospital of Nantes, Nantes; Jean Minjoz Hospital of Besancon, Besancon; Jean Bernard Hospital of Poitiers, Poitiers; University Hospital of Angers, Angers; University Hospital of Brest, Brest; University Hospital of Grenoble, Grenoble; Centre Hospitalier Departmental of Orleans, Orleans; University Hospital of Tours, Tours, France.) Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004;350:1287–95.

SUMMARY
This prospective, randomized study was done to compare high dose chemotherapy (HDCT) and haematopoietic stem cell transplantation (HSCT) with standard chemotherapy (CHOP) in the initial treatment of aggressive non-Hodgkin lymphoma (NHL). Two hundred and seven previously untreated patients were enrolled at 16 centres in France. Patients between 15 and 60 years of age with aggressive NHL (intermediate or high grade as per the working formulation criteria), those in Ann Arbor stage III/IV or stage II with bulky abdominal disease and a low-, low-intermediate and high-intermediate risk according to the age-adjusted International Prognostic Index (IPI) were included in the study. In the standard chemotherapy arm, patients received 8 cycles of CHOP (cyclophosphamide 750 mg/m2; adriamycin 50 mg/m2; vincristine 1.4 mg/m2 and prednisolone 100 mg/m2 for 5 days) every 21 days. Patients who had at least partial response after 4 courses were given 4 more courses of CHOP. At the end of the chemotherapy, involved-field radiotherapy was given to bulky disease sites. In the HDCT arm, the patients were given 2 cycles of CEEP (cyclophosphamide 1200 mg/m2; epirubicin 100 mg/m2; vindesine 3 mg/m2 on day 1 and prednisolone 80 mg/m2 for 5 days) 15 days apart supported with growth factors (granulocyte colony-stimulating factor [G-CSF] 5 mg/kg/day). This was followed by HSCT using the standard BEAM regimen for conditioning. At the end of treatment, radiotherapy was given to bulky disease sites.
   The primary end-points were event-free survival (EFS) and overall survival (OS). The characteristics of patients randomized to the two groups were comparable except for a younger median age in the HDCT arm (45 v. 50 years; p=0.02). One hundred and ninety-seven patients were fit for evaluation at a median follow up of 4 years. Overall, 78% of the patients could complete therapy (CHOP: 72% and HDCT: 85%). The main reason for non-completion was the lack of an early response or disease progression (which was higher in the CHOP arm; 27% v. 13%). The rates of complete remission and unconfirmed complete remission were not significantly different in the two arms (76% v. 57%; p=0.37). An elevated lactate dehydrogenase (LDH) level was the only factor that adversely affected the response rates on univariate analysis. The 5-year EFS was significantly higher in the HDCT than the CHOP arm (55% v. 37%; p=0.037). However, the OS was not significantly different in the two groups (56% v. 71%; p=0.076). The subset analysis showed that HDCT resulted in a better OS (74% v. 44%; p=0.001) and EFS (56% v. 28%; p=0.003) than CHOP in patients with a high-intermediate risk according to the age-adjusted IPI. Elevated LDH was the only factor that negatively affected the OS on multivariate analysis (p<0.026). A significantly higher number of patients had progressive or relapsed disease in the CHOP than the HDCT arm (p<0.005). These patients were treated with various salvage regimens and the 5-year survival did not differ significantly among the two groups (36% in HDCT and 26% in CHOP; p=0.63). There were 3 treatment-related deaths in the HDCT compared with 1 in the CHOP arm.

COMMENT
Non-Hodgkin lymphoma is the most common haematological malignancy. Its incidence is 16.1 per 100 000 (men) and 10.8 per 100 000 (women) in the USA, whereas in India the corresponding figures are 5.1 and 3.1, respectively.1 Diffuse large B-cell, anaplastic large cell and peripheral T-cell lymphomas are some of the important subtypes included under the aggressive NHL category.2 Treatment with CHOP has been the gold standard for the past 25 years for such patients with advanced stage (III–IV) aggressive NHL; the 10-year disease-free survival is 30%.2,3 The IPI (age >=60 years, stage III–IV, poor performance status [European Cooperative Oncology Group >=2], high serum LDH [above normal], and >=2 extranodal sites of involvement) has been developed to predict the prognosis in a given case of diffuse large cell lymphoma. Based on the number of adverse factors, the patients are categorized as low- (0 or 1 risk factor ), low-intermediate (2 factors), high-intermediate (3–4 factors) and high-risk (5 factors). The 5-year disease-free survival is 70% for the low-, 50% for the low-intermediate, 49% for the high-intermediate and 40% for the high-risk groups.4
   A number of therapeutic strategies have been developed to improve the prognosis of patients with advanced, aggressive NHL. These include the development of second- and third-generation regimens incorporating multiple drugs,5,6 increasing the dose of doxorubicin and cyclophosphamide in CHOP,7 use of monoclonal antibody (e.g. rituximab) 8,9 and HDCT followed by autologous stem cell transplantation (ASCT).10 Even though phase II studies have shown a superior outcome with the use of multiple drugs or higher doses of doxorubicin and cyclophosphamide, randomized trials have failed to do so. In a recent randomized study the use of rituximab with CHOP chemotherapy was associated with an improved outcome (response rate, OS and disease-free survival) in elderly patients (60–80 years of age) with diffuse large B-cell NHL.8,9 Results in younger patients are awaited.
   HDCT followed by ASCT is currently considered the standard treatment of relapse in patients with aggressive NHL who are in second remission or have achieved a good partial remission following salvage chemotherapy. However, the role of HDCT in the primary management of aggressive NHL is debatable. Data on 2208 patients (HDCT=1093, control=1115) have been reported in 11 studies.11–22 The number of patients ranged from 27 to 273. The median follow up time was 48 months (range: 36–60 months). In 5 studies, the bone marrow was used as a source of stem cells, in 4 peripheral blood and in 2 a combination of bone marrow and peripheral blood. A comparison of the available data is difficult because of: (i) variation in the therapeutic regimens used, both among standard and high dose therapies; (ii) HDCT being used as a part of frontline therapy after a shortened induction therapy in some studies, while others have used it as consolidation therapy after full course induction therapy and a few studies have used it as upfront treatment; (iii) a difference in the remission status requirements for stem cell transplantation; (iv) a variation in the proportion of histological subtypes; (v) non-comparable characteristics of the patients; and (vi) variation in the source of stem cells.
   The present study is relevant because, unlike previous studies, the authors have compared HDCT with CHOP, which has been the gold standard. In this study, patients in the high-risk subgroup (according to the age-adjusted IPI) were excluded because the results of CHOP have been very poor in this subgroup and randomized phase III trials have confirmed that high dose therapy with stem cell rescue, either as consolidation therapy or initial treatment, increases progression-free survival and OS among high-risk patients who are <60 years of age. Therefore, it was considered unethical to randomize such patients. This study did not show any significant difference in OS at 5 years between the HDCT and CHOP arms. This is possibly due to the fact that patients who progressed or relapsed while on CHOP were further salvaged by chemotherapy. This study showed that elevated levels of LDH adversely affected the survival. The levels of LDH reflect the rate of cell turnover. Therefore, in patients with NHL, higher LDH levels suggest aggressive disease biology responsible for the poor outcome. HDCT may be more beneficial in this subgroup. The subset analysis showed that HDCT was beneficial in improving both EFS and OS in the high-intermediate risk group, which is not the case with those who are at low- or low-intermediate risk. This suggests that this subgroup of patients should not be given HDCT, especially in view of 3 treatment-related deaths in this arm. In the present study, high dose methotrexate and cytosine arabinoside were given as consolidation therapy. This may have contributed to a better outcome in the HDCT arm by reducing the load of residual disease prior to transplantation. The use of a shortened induction followed by consolidation has reduced the drop-out rates (26%) leading to a better outcome.
   In summary, HDCT followed by ASCT in the initial treatment of aggressive lymphoma should not be used for patients with low- and low-intermediate risk. In high-risk patients, there is evidence that it improves the results. It is hoped that the favourable results in the HDCT arm in the present study would be confirmed in future studies with more uniformity in terms of patient characteristics, histology, methodology and treatment regimens. Till then, HDCT should be a part of the clinical trial for the high-intermediate risk group.