B-Cell Lymphomas Coverage from Every Angle

Ibrutinib Plus Bendamustine and Rituximab

Posted: Tuesday, January 24, 2023

SHINE Regimen for Older Patients With Mantle Cell Lymphoma

Mantle cell lymphoma is a rare subtype of non-Hodgkin lymphoma that accounts for approximately 4,000 cases a year, with a median age at diagnosis in the mid to late 60s. The standard approach for newly diagnosed mantle cell lymphoma has been the use of intensive first-line chemoimmunotherapy regimens followed by high-dose therapy and autologous stem cell rescue (associated with a median progression-free survival of more than 8 years). Progress over the past few years has resulted in the development of better treatment options in the second-line setting, as well. In older patients, however, common comorbidities often prevent the use of intensive therapies, and the standard of care has been the use of less intensive regimens (eg, bendamustine plus rituximab)1 followed by maintenance rituximab. There are now six drugs approved in the United States in the relapsed or refractory setting, yielding a high overall response rate and duration of response, even in patients whose disease is resistant to chemoimmunotherapy.

“Given the game-changing paradigm that Bruton’s tyrosine kinase [BTK] inhibitors [ibrutinib was the first approved agent in the class] represent in relapsed or refractory mantle cell lymphoma, it was logical to bring this approach into earlier lines of therapy,” said Andre Henri Goy, MD, Chairman and Chief Physician Officer, and Lymphoma Division Chief, John Theurer Cancer Center at Hackensack University Medical Center, in New Jersey.

Ibrutinib has notable single-agent efficacy in later lines of treatment for mantle cell lymphoma, and the results of the SHINE trial demonstrated the efficacy of ibrutinib in the first-line setting when used in combination with bendamustine plus rituximab.  [Editor’s Note: The SHINE regimen is not currently listed as an option for induction therapy in the NCCN Guidelines for B-cell lymphoma.]

The median age of patients on the SHINE trial was 71 years. Rituximab was also given as maintenance therapy for 2 years in patients with a complete or partial response.

Findings presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine showed a 50% increase in progression-free survival among patients (> 65 years) who received the triplet regimen of ibrutinib plus bendamustine/rituximab versus bendamustine plus rituximab alone.2,3 Patients who were randomly assigned to receive ibrutinib plus bendamustine/rituximab had a median progression-free survival of 80.6 months versus 52.9 months for bendamustine plus rituximab alone. The complete response rate was 65.5% in the ibrutinib-containing arm versus 57.6% in the placebo arm (P = .0567).

Testing for Genetic Abnormalities

According to Dr. Goy, the more than 2-year difference in progression-free survival and the increase in the time to next treatment are “highly significant in this population” (median age, 71 years), “but there was no difference in overall survival at this point. It is also a bit surprising to see no difference in complete response rate, given the high activity of ibrutinib in the relapsed/refractory setting, although measurable residual disease (MRD)-negative status by flow cytometry seemed higher in the ibrutinib plus bendamustine/rituximab arm compared with bendamustine/rituximab alone (62% versus 51%),” Dr. Goy told JNCCN 360.

“For newly diagnosed, older patients who are ineligible for transplant, the combination of bendamustine/rituximab and ibrutinib offers a longer mileage than bendamustine/rituximab alone,” he continued. Nevertheless, “one also needs to consider the added toxicity of ibrutinib, and the fact that high-risk patients showed less benefit with the combination.”

For newly diagnosed, older patients who are ineligible for transplant, the combination of bendamustine/rituximab and ibrutinib offers a longer mileage than bendamustine/rituximab alone.

According to Dr. Goy, genetic testing using next-generation sequencing is now increasingly available and may help identify patients who do poorly with standard approaches, particularly patients with p53 mutations, for example.

“Even with high-dose therapy, regardless of intensity, the median survival for patients with p53 mutations is dramatically shorter at approximately 18 months,” said Dr. Goy. “For those patients with p53 abnormalities, exposure to cytotoxic agents leads to earlier chemoresistance and impaired outcomes.”

On the other hand, Dr. Goy explained, patients with a complex karyotype who are chemotherapy-naive tend to respond well to ibrutinib and rituximab. For those with genetic abnormalities, a clinical trial should be a priority.

“Using novel combinations prior to chemotherapy, such as doublets or, more likely, triplets like rituximab/lenalidomide/ibrutinib, leads to a very high complete response rate upfront and might offer new options for patients with molecular features that place them at high risk,” said Dr. Goy. [Editor’s Note: The NCCN Guidelines do not currently recommend this combination for induction therapy.]

Key Toxicities

Because patients receiving the SHINE regimen tend to be older and more frail, with multiple comorbidities, Camille Ballance, MSN, FNP-BC, a hematology-oncology nurse practitioner with Sarah Cannon Cancer Institute, in Nashville, emphasizes patient education about the potential toxicities associated with chemoimmunotherapy.

“Chemotherapy kills good cells and bad cells,” said Ms. Ballance. However, she noted, side effects associated with the bendamustine/rituximab combination tend to be all or nothing. “People either seem to do well, with very few side effects, or they struggle.”

Ms. Ballance prepares patients for potential nausea, vomiting, and diarrhea and cautions that fatigue may be a constant—especially when patients are receiving the chemotherapy portion of the regimen. Ms. Ballance also underscored the importance of close monitoring of patients who are receiving the monoclonal antibody rituximab for the first time.

“Bendamustine does not take long to administer and is given on days 1 and 2 [of a 28-day cycle], but rituximab is given intravenously the first day over a long period to try to reduce adverse reactions,” she explained to JNCCN 360. “Infusion reactions are common if patients have never received rituximab before or if it’s been more than 6 months, but typically, after the first dose, reactions are rare.”

Premedications, such as diphenhydramine, acetaminophen, and dexamethasone, are given with bendamustine plus rituximab along with antinausea medications, such as palonosetron or aprepitant. Because nausea is common, said Ms. Ballance, providers must be sure patients are receiving proper nutrition and staying hydrated. Occasionally, patients need to be brought to the clinic to receive intravenous fluids and/or additional antinausea medication, but dose reductions of bendamustine/rituximab for gastrointestinal issues are rare.

“Unless the symptoms are extreme, we tend not to dose reduce, because we’re trying to put patients into remission,” Ms. Ballance emphasized.

“It’s important to make sure that patients have good nausea medications at home and that they know they can come to the clinic for fluids,” she added. “The team is here to support them.”

It’s important to make sure that patients have good nausea medications at home and that they know they can come to the clinic for fluids.

Ms. Ballance also emphasized the importance of monitoring for infections and bleeding. “Patients with blood cancer are immunocompromised already,” she explained. “Then, on top of that, we give chemotherapy, which brings down their immune system and their platelets even more. It’s important for both patients and their family members to be aware of the risks of infection.”

With ibrutinib, arthralgia is an issue that can lead to noncompliance, and providers should monitor for atrial fibrillation and hypertension. Rashes are also common with the BTK inhibitor and may occasionally require providers to hold medications. Ibrutinib can exacerbate diarrhea, as well, said Ms. Ballance, who recommended loperamide to start. Patients with serious heart disease or uncontrolled arrhythmia should consult with a cardiologist or cardio-oncologist before starting on ibrutinib, she added.

Pharmacy Plays an Important Role

Treating patients with mantle cell lymphoma requires a multidisciplinary effort, said Ms. Ballance, but the pharmacy plays a particularly important role in ensuring compliance while helping to reduce financial toxicity.

The pharmacy plays a particularly important role in ensuring compliance [with the SHINE regimen] while helping to reduce financial toxicity.

“Our pharmacy follows up every month to make sure patients are receiving their drugs, and if they haven’t filled their prescription, the pharmacy will let us know,” she explained. “We also have an entire department of people who work on getting copay assistance for oral therapies, because some of these drugs can cost more than $1,000 per month out of pocket.”

“The pharmacy also keeps us informed regarding potential drug interactions,” Ms. Ballance said. “And, of course, the nurses help to keep everything in motion, handling infusions, watching for reactions and potential side effects, and communicating with physicians and advanced practice providers about additional patient care when it’s needed.”

Clinical Pearl: Start With Four Pills

According to Ms. Ballance, dosing for ibrutinib is typically 560 mg orally once daily. However, the drug also comes in 140-mg tablets. When initiating therapy, Ms. Ballance noted it can be helpful to start with four tablets per day (4 x 140 mg) instead of one (560-mg) tablet, given the potential for side effects.

“If patients start to have a rash or severe arthralgias, you can hold the ibrutinib part of the regimen and then titrate them back to the full dose as tolerated,” suggested Ms. Balance. She noted that fatigue also tends to improve with a break from the drug and/or dose reduction, but that it is rare to adjust medication for that reason specifically.

“Once the side effects have been managed, patients can then switch to one tablet, so they don’t have to swallow four tablets per day,” she added.


Andre Henri Goy, MD, reported financial relationships with Kite/Gilead Sciences, Janssen, Celgene, Acerta, AstraZeneca, and Cota.

Camille Ballance, MSN, FNP-BC, reported no conflicts of interest.


  1. Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 5.2022—July 12, 2022. Accessed January 7, 2023. To view the most recent version of these guidelines, visit nccn.org.
  2. Wang M, Jurczak W, Jerkeman M, et al. Primary results from the double-blind, placebo-controlled, phase III SHINE study of ibrutinib in combination with bendamustine-rituximab (BR) and R maintenance as a first-line treatment for older patients with mantle cell lymphoma. 2022 ASCO Annual Meeting. Abstract LBA7502.
  3. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med 2022; 386:2482–2494.

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