Lenalidomide plus Rituximab-CHOP: A Potential New Treatment for Untreated ABC-type DLBCL
Until recently, diffuse large B-cell lymphoma (DLBCL) was seen as one cancer. However, research has shown that DLBCL comprises two subtypes; namely activated B-cell type diffuse large B-cell lymphoma (ABC-type DLBCL) and germinal centre B-cell type DLBCL (GCB-type DLBCL). What has also become clearer is that the standard treatment for DLBCL – rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) – has not been a successful treatment option for those with ABC-type DLBCL.
“Unfortunately, in patients with ABC-type DLBCL when treated with R-CHOP, the outcomes are inferior compared with those seen in patients who have GCB-type DLCBL,” said Dr. Grzegorz Nowakowski, Assistant Professor of Medicine, Mayo Clinic Cancer Center, Minnesota, USA.
Worldwide, the cure rate for DLBCL is between 60% and 65% with R-CHOP. In patients with GCB-type DLBCL, complete response (CR) rates are 70%; in patients with ABC-type DLBCL, the CR is no more than 30% and patients may relapse within two years following treatment.
“The challenge is that we need to improve outcomes in patients with ABC-type DLBCL because R-CHOP is not enough for them,” said Dr. Umberto Vitolo, Director of the Department of Oncology and Hematology, Turin, Italy.
Dr. Nowakowski said that treatments such as dose-adjusted EPOCH (etoposide, prednisolone, oncovin, cyclophosphamide, hydroxydaunorubicin) or R-CHOP followed by transplant or other intensive regimens have also not been efficacious in this patient population.
Globally, the incidence of ABC-type DLBCL is approximately 40% among patients with DLBCL and higher among the elderly.
“In those aged 60 to 65 years, the incidence of ABC-type DLBCL is between 50% and 55%,” said Dr. Vitolo.
Rationale for the ROBUST Clinical Trial
In an effort to find an improved treatment option for those with ABC-type DLBCL, a phase III randomised, double-blind, placebo-controlled, multicentre clinical trial (known as the ROBUST trial) is underway. It is comparing the efficacy and safety of lenalidomide plus R-CHOP (R2-CHOP) versus placebo plus R-CHOP in patients with ABC-type DLBCL who are treatment naïve (not yet been treated).1 The primary end point is progression-free survival.
The rationale for undertaking this study is based on findings from two phase II studies.2,3
“Both phase II studies were a combination of R-CHOP and lenalidomide. The overall results were quite good. When we retrospectively analysed the cell of origin in both studies, the benefit of adding lenalidomide to R-CHOP seemed to be higher in the ABC-type DLBCL subgroup,” said Dr. Vitolo.
Dr. Nowakowski said that there had also been some preclinical studies that showed lenalidomide was active in ABC-type DLBCL.
“I think the findings from the preclinical studies support our clinical data very nicely,” said Dr. Nowakowski.
While the findings from the phase II studies were very promising, the results need to be validated.
“I’m the first one to say all results of phase II studies need to be validated in phase III studies in a randomised fashion because we’ve seen in the past that sometimes results from phase II studies have not been replicated in a phase III study,” said Dr. Nowakowski.
The ROBUST trial started at the beginning of 2015 and preliminary results are expected in three years.
“The goal is to enrol more than 500 patients so we need at least three years to achieve that,” said Dr. Vitolo.
Determining DLBCL Subtype
Two ways exist for determining the DLBCL subtype.
“The gold standard for identifying the DLBCL subtype is gene expression profiling and the other technique is immunohistochemistry (IHC),” said Dr. Nowakowski.
In the past, using gene expression profiling was a fairly involved technique but in the ROBUST trial, it is being done with a technology called NanoString which provides information about the patient’s subtype very quickly.
“In the ROBUST trial, we’ve committed to providing information on the cell of origin within five calendar days. This includes the weekends because we realise that there are patients in need of treatment and we want to provide this information as soon as possible,” said Dr. Nowakowski.
With IHC, the immune markers are studied to try and define the subtype using the Hans’ algorithm4 which divides the DLBCL into GCB or non-GCB.
“The issue with IHC is the poorer reproducibility in the laboratory. As well, if it’s not a laboratory with lots of experience, interpretation can be unreliable. In contrast, NanoString is free of interpretation bias,” said Dr. Nowakowski.
Dr. Nowakowski envisions that NanoString technology will eventually be done everywhere but right now it’s only being used in the clinical trial setting.
“It (NanoString technology) is not done routinely worldwide because there is no evidence yet that doing anything different for patients with ABC-type DLBCL will actually be of benefit. If ROBUST is a positive trial, then there would be a reason to use NanoString more widely,” said Dr. Nowakowski.
Patient Enrolment in ROBUST
Since the trial started in January 2015, more than 50 patients have been enrolled.
“We spent about a year setting up the study. We had to determine what method to use to identify the patient’s cell of origin, there were additional inclusion and exclusion criteria to be considered and not all sites have been activated yet. All factors that take time,” said Dr. Vitolo.
In the USA, the biopsy requirements have been modified which Dr. Nowakowski thinks will help with accrual.
“A lot of patients will just have a core needle biopsy. When we started ROBUST those patients were not eligible because we didn’t have enough tissue to assess the cell of origin. We worked really hard and were able to develop a method that allowed us to use the core biopsy,” said Dr. Nowakowski.
Making this change opens up the study to patients who may not have been willing to undergo an additional biopsy.
Participating in ROBUST
In the past, all patients with DLBCL have been treated with R-CHOP. Now, however, through an improved understanding about DLBCL and the knowledge that it has two subtypes, those with ABC-type DLBCL have a possibility of receiving a treatment that may help them if they participate in the ROBUST clinical trial.
“I believe ROBUST is of value because patients have a 50% chance of receiving lenalidomide which has been shown to be effective when used in combination with R-CHOP,” said Dr. Vitolo.
To determine the efficacy and safety of R2-CHOP compared with R-CHOP, it is necessary to undertake a randomised, double-blind, placebo-controlled trial. Patients in both treatment arms will be monitored very carefully and, depending on their outcomes, treated accordingly.
Dr. Vitolo pointed out that DLBCL is a curable disease.
“Overall, 60% of patients are curable. It’s the other 40% that need help. I think it would be useful to them to have the opportunity of trying this new treatment regimen,” he said.
Toxicities with R2-CHOP
While results from the ROBUST will not be known for a few years, toxicities seen in the phase II studies done in the lead up to the ROBUST trial showed that the toxicities seen with R2-CHOP were similar to those seen with R-CHOP although the incidence of neutropenia and thrombocytopenia was higher.
The rate of infection was not any higher than that seen with traditional chemotherapy and there was no unexpected neurotoxicity.
“Lenalidomide could be neurotoxic but the rate of neurotoxicity was really low, about 2% to 3%, the same as what we see when we use R-CHOP,” said Dr. Vitolo.
Blood clotting could also be of potential concern with the use of lenalidomide.
“Patients on the study are encouraged to take prophylaxis against thrombosis with aspirin or other methods,” said Dr. Nowakowski. Patients are urged to speak with their doctor about their particular situation.
Helping Patients Know Their Subtype
Both Drs. Nowakowski and Vitolo indicated that knowing the subtype is critical. In the case of DLBCL, they both suggested that patients be referred to a clinical trial site where their subtype would be determined.
“The problem in clinical practice is that you don’t usually test for the DLBCL subtype because, until now, the treatment has been the same for both subtypes,” said Dr. Vitolo.
Dr. Nowakowski surmised that if patients started asking about what subtype of DLBCL they had, more centres would test for it.
“I think over time, we’ll see more and more centres implementing gene expression profiling and profiling the cell of origin as the standard of practice,” said Dr. Nowakowski.
At the Mayo clinic, he said it’s the clinic’s standard of practice to perform cell of origin determination by IHC using the Hans’ algorithm.
“As a result, our patients know if they have GCG or non-GCB,” he said.
Dr. Vitolo said that a simple diagnosis of non-Hodgkin lymphoma can’t be relied upon because there are so many different treatments for the different subtypes of lymphoma.
“If you look just at DLBCL, there is not only ABC and GCB. In elderly patients, there is growing evidence that some of the subtypes express certain proteins that may not react as well to R-CHOP,” said Dr. Vitolo.
Dr. Nowakowski said that diagnosis can be challenging as the pathology of lymphoma is very difficult and requires an experienced pathologist.
“What I would do if I was a patient, I would probably want to make sure I was going to a centre which sees a reasonable number of patients with lymphoma and which has a pathologist experienced in lymphoma or where samples are sent to a centre that specialises in diagnosing lymphoma,” said Dr. Nowakowski.
While it is encouraging that a new treatment option for those with ABC-type DLBCL is under investigation, more research is needed in ABC-type DLBCL. It is also key that patients who are diagnosed with DLBCL not only know that they have DLBCL but also whether they have ABC-type or GCB-type. If patients have ABC-type DLBCL, they should be encouraged to ask about participating in a clinical trial.
- Efficacy and safety study of lenalidomide plus R-CHOP chemotherapy versus placebo plus R-CHOP chemotherapy in untreated ABC type diffuse large B-cell lymphoma (ROBUST). https://clinicaltrials.gov/ct2/show/NCT02285062. Accessed October 30, 2015.
- Vitolo U, et al. Lancet Oncol 2014;15:730-7.
- Nowakowski GS, et al. J Clin Oncol 2015;33:251-7.
- Hans P et al. Blood 2004;103:275-82.
Author: Leonie Bedford, Medical Writer, Lymphoma Coalition
November 30, 2015