Another agent is lenalidomide, an immunomodulatory drug often used in multiple myeloma. Lenalidomide has demonstrated modest activity in rFL as a single agent; in combination with rituximab, efﬁcacy is signiﬁcantly improved. The PD-1/PD-1L pathway has also been explored in FL. One example of an agent targeting this pathway is pidilizumab, a mAb against PD-1 that has induced response rates when combined with rituximab, although larger studies are needed to validate its efficacy. Other checkpoint inhibitors are also being studied.
Another “exciting prospect,” noted the authors, is the use of chimeric antigen receptor T-cell (CAR-T) therapy. However, only very small numbers of patients have been treated in the context of a clinical trial, and CAR-T therapy is not yet considered a treatment option.
Stem Cell Transplantation
In the era of novel agents, where does SCT fit in? The authors noted that understanding the optimum sequence and combination of therapies can be challenging, and the choice of whether a patient should undergo transplantation is dependent on an array of patient-related, disease-related, and transplant-related factors. All of these factors should be taken into consideration when a patient experiences relapse.
Once the decision is made to treat with SCT, an additional challenge for clinicians is deciding whether to use ASCT or alloSCT in relapsed disease. There has only been 1 prospective randomized trial that investigated this issue, but it closed early due to insufficient patient accrual. However, it did suggest that there was a benefit with reduced intensity conditioning (RIC) alloSCT compared with ASCT. A retrospective trial that compared the 2 modalities showed that the 5-year rate of progression-free survival was 57% for patients receiving RIC alloSCT and 48% for those receiving ASCT, though overall survival was similar in both cohorts. The authors concluded that the decision to undergo ASCT or alloSCT is dependent on the patient, and both modalities are associated with excellent results. They recommended referral to a specialist transplant unit for assessment and counselling regarding the various options a patient may have.
Koen van Besian, MD, PhD, professor of medicine at Weill Cornell Medical College in New York, explained that high-dose chemotherapy (either ASCT or alloSCT) should be part of the conversation for any patient with recurrent or refractory FL.
“The long-term outcome data of patients with rFL are robust and demonstrate the potential for [a] cure,” he said. “This contrasts with newer agents, which typically [require] prolonged treatment, and for which there is no evidence of a cure rate. “
He continued, “The assessment of toxicity associated with transplant is complex because it involves both short- and long-term toxicity, the latter reflecting, in part, accumulated toxicities of prior therapies, and because it is markedly different between autologous and allogeneic transplantation. The risk for early treatment-related mortality has become quite low and at most institutions is in the range of 2% or less. The data on treatment-related mortality with novel agents by contrast are not nearly as well known and [the risk] may be higher than generally believed.”
For example, recent data indicate a higher than expected risk of mortality with the bendamustine-rituximab combination, and bleeding and infectious complications have been reported with Bruton’s tyrosine kinase inhibitors.
Dr van Besian noted that late toxicities linked to ASCT relate mostly to the risk of developing therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS), which is undoubtedly increased compared with age-matched controls. “But prior treatment, as well as the occurrence of clonal hematologic abnormalities of indeterminate prognosis, also plays a role,” he said. “In other words, some of the patients destined to develop t-AML/MDS already harbor such abnormalities prior to transplant.”
For alloSCT, the rate of fatal complications remains in the range of 15% to 20% in most studies despite marked improvements in supportive care and donor selection. This increased rate may be due to associated immunocompromise.
Another consideration is that ASCT may have a favorable economic effect compared with novel treatments that require lifelong treatment. “This may be particularly important in resource-limited environments,” said Dr van Besian. “Like the authors of this paper, we reserve alloSCT for patients who [did not respond to] ASCT or who are not candidates for ASCT because of inability to collect stem cells or poor quality of stem cells.”
Overall, ASCT should be considered for all patients with who have a high likelihood of a poor outcome, he added. “This includes those who relapse or progress within the first 2 years after first-line therapy and patients with multiple relapses.”
Dr van Besian also cautioned against delaying transplant beyond second relapse. More extensive prior treatment may be associated with increased difficulties in collecting stem cells and heightened risk for t-AML/MDS. And overall, he agreed with the authors of the paper that eligibility for transplant should be discussed with a transplant specialist. “There are very few absolute contraindications to transplantation, and age or comorbidities should not be a deterrent,” he said.
1. Norman JE, Schouten HC, Drefer P, Robinson SP. The role of stem cell transplantation in the management of relapsed follicular lymphoma in the era of targeted therapies [published online November 2, 2018]. Bone Marrow Transplant. doi:10.1038/s41409-018-0372-5