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R. Bruna et al.
Introduction
The current first-line treatment strategy for sympto- matic and advanced follicular lymphoma (FL) is chemo- immunotherapy, with rituximab in combination with var- ious chemotherapy regimens.1-2 For a long time now, the upfront use of intensified chemotherapy with autograft has been proposed as an effective treatment option for patients presenting with high-risk disease.3-8 We previous- ly conducted a prospective randomized trial of these regi- mens in Italy, including patients <60 years of age who were affected by high-risk FL. The results showed no sur- vival advantage from high-dose sequential chemotherapy with rituximab and autograft (R-HDS) compared to con- ventional cyclophosphamide, doxorubicin, vincristine, and prednisone supplemented with rituximab (CHOP-R).9 Despite the limited median follow up of four years, this observation has discouraged the upfront use of intensive chemo-immunotherapy with autograft in FL, including in patients with high-risk disease presentation.
Follicular lymphoma patients now have prolonged life expectancy, with a median survival of ten years. This sur- vival rate is possible because of the availability of ritux- imab along with improvements in the supportive care instruments.10-13 The increase in patient survival warrants a long-term update of clinical trials to evaluate the real ben- efit of any treatment. For this purpose, our previous results of the randomized R-HDS versus CHOP-R have been updated by extending the period of analysis to 2017 with a median follow up of 13 years. The prolonged observation of this prospective cohort of patients offers the opportunity to define the following in advanced-stage, high-risk FL patients: (i) the long-term survival following conventional versus intensified chemotherapy with auto- graft, both delivered with rituximab; (ii) the main causes of death; (iii) the main factors affecting long-term out- come; and (iv) the rate of patients with prolonged survival in the absence of disease recurrence.
Methods
Patients’ characteristics
Between March 2000 and May 2005, a total of 136 patients were enrolled in the multicenter randomized study, launched in Italy among centers affiliated with Gruppo Italiano Trapianto Midollo Osseo (GITMO) and/or to the Italian Lymphoma Intergroup (IIL).9 The institutional review boards of all the partici- pating centers approved the study. The study was designed for the first-line treatment of patients aged 16-60 years with a histologi- cally proven diagnosis of FL.14 Patients were eligible if they had Ann Arbor stage III or IV and a high-risk prognostic presentation, according to the prognostic risk scores in use at the time the pro- tocol was designed, i.e. the age-adjusted International Prognostic Index (IPI) score >2 and the IIL score >3 for FL.15,16 The CONSORT Diagram in the Online Supplementary Appendix gives details about treatment outcome of the 136 enrolled patients. Table 1 describes the main features of the 134 evaluable patients and the main clin- ical features of patients who are presently alive versus those who have died since protocol entry.
Study design, treatment schedule and end points
The aim of the study was to assess the superiority of an inten- sive chemo-immunotherapy strategy including autologous hematopoietic stem cell transplantation (auto-HSCT) compared to
conventional chemo-immunotherapy. A centralized computer generated a simple randomization sequence and patients were randomly assigned either to the intensified or conventional arm.
Both conventional CHOP-R and intensified R-HDS treatments have already been described.9,17-20 Details of the treatment sched- ules along with study end points and molecular analysis per- formed are reported in the Online Supplementary Appendix.9,19,21
Long-term follow up and statistical analysis
The update was made by taking information from 28 out of 29 participating centers regarding the clinical status of each patient entered in the prospective trial: (i) status alive or dead or lost to fol- low up, with the date of death or last follow up alive; (ii) cause of death, i.e. lymphoma progression, secondary neoplasm, non-neo- plastic late fatal complications, or other causes; (iii) occurrence of secondary hematopoietic or non-hematopoietic neoplasm; or (iv) disease status at last follow up alive, i.e. continuous first, second or more complete remission (CR).
In the present update, alive patients were censored at the date of last contact (February 2nd, 2017), providing a median event-free survival (EFS) and overall survival (OS) follow-up time of 13.01 years [range: 0.5-16.6, interquartile range (IQR); 11.8-14.7]. All analyses were carried out on an intention-to-treat basis.
Survival curves were estimated by the Kaplan-Meier method according to the revised response criteria published in 2007, and compared using the log-rank test.22-24 EFS, OS, progression-free sur- vival (PFS), and disease-free survival (DFS) were analyzed by the Cox proportional hazards model, comparing the two treatment arms (R-CHOP vs. R-HDS) by the Wald test and calculating 95% Confidence Intervals (CI).25
The CI of secondary myeloid dysplastic syndrome (sMDS) / acute myeloid leukemia (AML) and solid malignancies in the whole cohort and stratified by the treatment arm were estimated at 5, 10, and 13 years from diagnosis and were assessed by the Gray test.26 All reported P-values were two-sided, at the conven- tional 5% significance level. Data were analyzed as of January 2018 using R 3.4.3.27
Results
Overall survival and causes of death
As of February 2017, 88 (66%) patients were alive at their last follow up. Overall, median survival had not yet been reached at the 13-year median follow up, with a 13- year OS estimate of 66.4% for the whole patient cohort. Similar OS values were observed in the two treatment arms, with 13-year OS estimates of 68.5% and 64.5% for patients in the CHOP-R and R-HDS arms, respectively (Figure 1).
At the latest follow up, 46 patients had died. The main causes of deaths were disease progression for 22 patients (16.4% of the whole series, 47.8% of all deaths), second- ary malignancies (3 solid tumor, 9 sMDS/AML) for 12 patients (8.9% of the whole series, 26.1% of all deaths), 12 patients died of various causes, including six fatal car- diovascular events, three documented infections, one graft failure following autograft, one anaphylactic shock following intravenous immunoglobulin (Ig i.v.) infusion, and one late sudden death. Among patients in the CHOP- R arm, 13 of 20 (65%) died from disease-related causes, whereas lymphoma progression was the cause of death for 9 of 26 (35%) patients in the R-HDS arm. Main causes of death per each treatment arm are summarized in Figure 2.
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haematologica | 2019; 104(11)