Abstract
Background:
For patients with indolent lymphoma, the optimal timing, sequence and choice of therapeutic regimens remain matters of debate. The Nordic Lymphoma Group performed two randomized trials (the phase II M39035 accrual 1998-1999 and the phase III ML16865 accrual 2002-2008) including a total of 439 (126+313) patients with symptomatic indolent CD20+ lymphoma (Kimby et al. 2008, 2015) with rituximab monotherapy or rituximab in combination with interferon(IFN)-α2a as initial treatment. In the first trial responding patients (CR, PR or MR) after 4 weekly infusions of single rituximab were randomized to 4 additional infusions + IFN-α2a MIU/day subcutaneously week 1, followed by 4.5 MIU/day weeks 2-5. In the second trial randomization was performed already at inclusion. Most were previously untreated but patients with late relapse after a previous response to chlorambucil, local radiation or both were also eligible. The trial rationales were to delay chemotherapy and associated acute and long-term side effects by initial immunotherapy and investigate whether priming with IFN-α2a in addition to rituximab improves progression-free survival. Yet, some concerns have been raised regarding the risk of undertreatment without chemotherapy and possibly a higher incidence of transformation to high-grade lymphoma and premature death.
Aim/ Purpose:
To evaluate the long-term effect and safety of mere biologic therapy, consisting of rituximab 375 mg/m2, 2 x 4 weeks with or without IFN-α2a, by assessing overall survival (OS), late toxicities and need of additional treatment in patients with indolent CD20+ lymphoma.
Methods:
Eligible were all Danish, Norwegian and Swedish patients from the previous trials with the exclusion of patients with mantle cell lymphoma (MCL), with immunocytoma, with chronic lymphocytic lymphoma phenotype and those whose biopsy reviews rendered diagnoses of any high-grade lymphoma, leaving in total 395 patients (84% with follicular lymphoma) eligible for follow-up. Those who still alive were asked for participation including permission of extensive medical file reviews. Diseased patients were included under the presumption of consent as they all had approved the former clinical trials. 31 patients who had data available only from the original trials were censored at their individual follow-up time point of 3-5 years. The study was approved of by the Regional Ethical Committees in each country. Treating physicians at the participating centers collected data on patients' therapies after the end of trial, any evidence of transformation to high-grade disease, infectious complications and second cancers.
Results:
After a median follow-up time of 9,4 (0,1 -18,1) years from randomization, 286 patients were still alive (fig. 1) more women than men (p < 0,05). Median follow-up for living patients was 10,5 years. Cause of death was for 62 patients progression of disease or therapy complications whereas 30 had died of non-lymphoma related causes. After protocol induction therapy, 107 patients (27%) had not required any additional treatment. Median time to new therapy was 2,1 (0,01-17,5) years. At a median follow-up of 8,7 (0,1-17,8) years from randomization 82 patients with indolent disease had transformed to diffuse large B cell lymphoma (DLBCL), a rate of 2,3% per year. Two patients transformed to Hodgkins lymphoma and one to MCL after 1, 6,5 years and 2 years (fig. 2). At least one second malignancy was diagnosed in 39 patients, whereof 7 were acute myeloid leukemia/myelodysplastic syndrome, one was a T cell lymphoproliferative disease and one was chronic myeloid leukemia (table 2). Infections were most likely somewhat under reported (not shown).
Conclusion:
Most low-grade lymphoma patients included in the M39035 or ML16865 trial are alive at a median follow-up of more than 10 years, providing an opportunity to achieve long-term data on relapse, transformation, late toxicity and survival. We found that the overall survival and rate of transformation after initial treatment with biological agents was comparable to trials with immunochemotherapy. A subgroup of patients show longstanding remission, suggesting initial therapy with only biological agents may well be considered. Close ahead is an extension of this follow-up project with comparative analyses including a matched group of indolent lymphoma patients treated with standard immunochemotherapy as first-line therapy.
Holte: Nordic Nanovector: Consultancy; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Oslo University Hospital: Employment. Kimby: Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.
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