When there is no expert consensus or clear path forward the patients’ preferences can help to guide what to study.
Patients will often choose the approach that has the least perceived risk and that keeps future options open. While patients may willingly choose high dose therapy with stem cell rescue (transplant) in the refractory setting; few will choose this option independently as their first treatment if other approaches are deemed reasonable by some experts, particularly if transplant can be effective as second line therapy.
Where are we now? The patient newly diagnosed with mantle cell lymphoma (MCL) may be offered several types of treatment options as there appears to be no consensus on the optimal first line approach: aggressive versus less aggressive (NCCN). Younger patients may be guided to transplant and there is evidence to support this approach. But even for these patients the recommended approach can be based mainly on the center they happen to go to. Most patients are 60 to 70 years of age at diagnosis (not an ideal age for transplant). Sometimes MCL has an indolent course and can be observed without treatment until the disease progresses or causes symptoms. Ki67 could be a useful biomarker to predict poor result from any standard approach. Standard R-chemo with R maintenance is often prescribed when SCT is excluded by preference or by patient characteristics. Bendamustine-R could be better than CHOP-R, but is not expected to be curative. Maintenance Rituxan appears to improve outcomes following standard Rituxan-chemotherapy. There are many investigational lower-toxic agents showing promising activity in the relapse setting, such as Ibrutinib, Idelalisib, lenalidomide, ABT-199 as single agents, or in combination, such as concurrently with Rituxan. These developments giving hope to patients who have relapsed from initial treatment and is now inspiring the design of new study concepts to incorporate these agents into initial treatment.
How to move the lower-toxic agents forward into first therapy? Is it best to study the agents in combination with standard chemotherapy, or added to Rituxan maintenance, or to test both simultaneously? Or should investigators test combinations of the most promising of these together and leave out chemotherapy? What is the reference point for comparison in controlled trials – the aggressive (transplant) approach or R-chemo with maintenance? Can you select patients appropriately for studies: by prognostic index, by age alone, by specific biomarkers?
Whatever the decision, these important study questions can only be answered reliably through randomized clinical trials that include adequate numbers of patients. For a relatively uncommon lymphoma like MCL, completing enrollment is challenging - particularly for a randomized trial design. The challenge increases when there are competing studies recruiting participants from the same limited pool of eligible patients. (As of this writing there are about 30 trials recruiting patients for untreated MCL ClinicalTrials.gov
To be accepted, the uncertainty about the compared protocols in a randomized trial must be genuine and shared by the referring physicians and the patients. Perception counts. Belief that one of the study arms is more promising will hurt accrual due to the concern for being randomized to the arm of the study that they feel to be less promising - or has the higher risk. The reluctance to be assigned by chance to a study arm increases if both or the preferred protocol can be used off study. Further, clinical trials that assign patients randomly to very different treatment approaches (such as targeted-oral drugs vs. transplant) will make achieving full enrollment even more challenging.
What follows are suggestions that I hope will help to guide these difficult decisions - with an emphasis on giving the participants’ attractive options and choices:
When feasible to get the study drugs, put emphasis on the study of targeted, non-cytotoxic induction agents as initial therapy:
- This approach can help to identify candidates to improve induction and maintenance chemo- or Rituxan-based protocols as well.
The patient perception and expectation being that these approaches will not preclude benefiting optimally from chemotherapy-based protocols on relapse.
... In theory, eliminating chemotherapy as part of first line investigational therapy will improve the response rate and the quality of responses to standard R-chemo or chemo-based salvage therapy in chemo-naive patients at relapse. This potential along with the high median age of MCL patients at diagnosis, and the lack of consensus on first line transplantation for MCL supports the study of non-transplant, non-chemotherapy approaches to MCL as first line therapy.
Select patients for study approaches based on disease and patient risk factors
- based on age, fitness, medical conditions
- based on biomarkers that predict poor outcomes with standard approaches or predict good outcomes with the study drugs
Compare apples to apples - similar approaches in terms of risks and goal of therapy
- Transplant to Transplant
- Lower-toxic approach to Lower-toxic approach (pick the winner)
- Avoid comparing transplant to lower-toxic management approaches, because such studies will be more challenging to complete and may be more difficult to interpret. For example, when two transplant protocols are compared, the participating patients will be appropriate candidates for that approach and the findings can be applied to such patients in regular practice with greater confidence.
When feasible, provide a crossover option in randomized trials to improve the feasibility of enrolling patients
- Crossover is probably not feasible when comparing transplant to low-toxic approaches.
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