Chemotherapy-free Regimens: An Evolving Therapy Option

Over the last few years, a number of therapies have received approval for the treatment of lymphomas that are not traditional chemotherapy. 


One such treatment is“R2”. It stands for Revlimid (lenalidomide) plus Rituxan/MabThera (rituximab). However, it’s not the only one.

“R2 is not the only non-chemotherapy that has been approved and that continues to be studied. Other non-chemotherapy drugs that have been approved for use in some parts of the world are idelalisib, an oral therapy, and radioimmunotherapy,” said Dr. John Leonard, Chief, Lymphoma/Myeloma Service, Division of Hematology and Oncology, Weill Medical College of Cornell University, NewYork-Presbyterian Hospital, New York Weill Cornell Center, New York.

Both idelalisib, an oral therapy, and the radioimmunotherapy agent ibritumomab tiuxetan have been approved by the Food and Drug Administration in the USA for the treatment of recurrent follicular lymphoma (FL). The European Medicines Agency (EMA) recently approved idelalisib for the treatment of recurrent (FL). Ibritumomab tiuxetan has been approved by the EMA.

R2 is currently being studied for the treatment of relapsed or refractory indolent non-Hodgkin lymphoma (NHL) (FL and marginal zone lymphoma [MGL]). R2 has already been approved for the treatment of recurrent or refractory mantle cell lymphoma (MCL) in the USA. Lenalidomide, an oral therapy, is currently not approved for FL in the USA.

Defining a Non-chemotherapy Regimen

“Chemotherapy drugs are cytotoxic agents that kill tumour cells. Lenalidomide is a drug that has a number of different effects. It has immunologic effects, it has effects on the microenvironment of lymphoma cells so it doesn’t directly kill rapidly dividing cells like chemotherapy tends to do in a toxic way,” said Dr. Leonard.

While it may be somewhat of a semantic argument as the perception is that chemotherapy has adverse effects and non-chemotherapy does not, Dr. Leonard noted that there are both toxic and non-toxic chemotherapy regimens as well as toxic and non-toxic non-chemotherapy regimens.

“At the end of the day, it’s really what the patient experience is like rather than how it is labelled. The concept is that lenalidomide is a relatively new drug and the hope is that it will be better tolerated by many patients and be more effective because it works in a different fashion,” he said.


The use of lenalidomide in combination with rituximab indicates a movement forward from chemotherapy but results are needed from the larger clinical trials currently underway to confirm that it is a viable option.

One such study is the AUGMENT trial. This trial is examining the use of R2 in patients with relapsed/refractory indolent NHL (FL and MGL).

“In relapsed patients, single-agent rituximab is a well-tolerated and effective therapy but it only works for a limited time. By adding lenalidomide to rituximab, the hope is that it will be more effective but not more toxic, although it may be more toxic than single-agent rituximab,” said Dr. Leonard.

R2 is also being studied in other patient populations including chronic lymphocytic leukaemia/small lymphocytic leukaemia, MCL, diffuse large B-cell lymphoma and large cell lymphoma. For all studies examining this combination go LC’s website

Toxicities with Lenalidomide

According to Dr. Leonard, the principle toxicities associated with lenalidomide are low blood count, rash, fatigue and occasional issues with blood clotting.

“Even if the toxicities associated with lenalidomide are minor or not relevant to many patients, for some patients they will be issues. So, the question will be: what’s the value of the drug versus tolerating the toxicities?” he said.

While the toxicities seen with lenalidomide are fewer than those seen with CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) and CVP (cyclophosphamide, vincristine, prednisone), regimens such as CHOP and CVP are typically given for four months whereas in the AUGMENT trial, lenalidomide will be given for 21 days every month for 12 cycles, a longer timeframe.

Impact on Patient Lives

R2 will also likely have a positive impact on how patients live their lives.

“The idea of patients being able to control their disease with outpatient therapy that has manageable toxicity for long periods of time would be a good thing,” said Dr. Leonard.

The issue with therapies like lenalidomide, however, is that it is a chronic therapy that may need to be taken for many years.

“When you’re on an oral drug for potentially years at a time, it changes the dynamic. A positive impact is that patients stay in remission longer and a negative one is that there may be side effects with an ongoing chronic therapy rather than an intermittent therapy,” he said.

Cost will also be another factor to take into consideration.

“Lenalidomide is an expensive drug and whether or not society can afford or should afford to pay for this type of regimen is an important question,” said Dr. Leonard.

The AUGMENT trial has only recently got underway but, like most clinical trials, enrolment will likely be challenging.

“Recruitment to all trials is not great. Most patients don’t go on a clinical trial; most doctors don’t do a good job referring or enrolling patients in clinical trials,” he said.

To help with enrolment, Dr. Leonard thinks that patients need to know that the early data are promising and that R2 represents a generally well-tolerated alternative to chemotherapy.

“We’re encouraged by this or we wouldn’t be doing this study,” said Dr. Leonard.

October 27, 2014


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