Abstract

Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle cell lymphoma in 2012. Because he was ineligible for intensive treatment (age, previous myocardial infarction [MI]), he received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy for 6 cycles (reaching complete response) and then rituximab maintenance (RM) for 2 years. One year after the end of RM, he relapsed with disseminated disease. He was started on ibrutinib 560 mg/day. Two weeks after the start of ibrutinib, he developed grade 3 diarrhea that required interruption of ibrutinib. Two weeks after the regular dose was restarted (month 3), the patient had repeated bleeding (patient was receiving aspirin for previous MI) and had to stop ibrutinib again. Because the patient was in partial response (PR) with lack of disease-associated symptoms, he was restarted on ibrutinib 280 mg/day with no further adverse events, and he had maintained PR at last follow-up (month 9 on ibrutinib).

Learning Objectives
  • Treatment of MCL varies significantly between elderly and young patients

  • In elderly MCL, the achievement of deep responses should balance the management of co-morbidities and treatment toxicity

  • New targeted agents, like ibrutinib, could potentially change the treatment paradigm for elderly MCL thanks to their high efficacy associated with manageable toxicity

Mantle cell lymphoma (MCL) represents 6% to 8% of non-Hodgkin lymphomas and has an annual incidence of 1 to 2 per 100 000 people in the United States and the European Union.1  MCL typically presents predominantly in males who have late-stage disease and a median age at diagnosis of 65 to 68 years.2,3  More recent real-world studies indicate that the median age of patients with MCL may be older than 70 years.4-6  Therefore, MCL is considered a disease of the elderly, and a significant subset of patients displays reduced performance status at diagnosis. Overall, MCL has a poor prognosis with 4 to 5 years of median survival,7  and elderly patients (age 65 to 70 years or older) have a worse outcome compared with younger patients, mostly because of increased treatment-related toxicity. This is reflected by the fact that age is one of the 4 key prognostic factors of the Mantle Cell Lymphoma International Prognostic Index.8 

Elderly MCL patients are typically excluded from dose-intensified chemotherapeutic approaches and stem cell transplantation. However, in the absence of contraindications, they usually receive rituximab plus a chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]; bendamustine; or other drugs), with possible rituximab maintenance for 2 years after CHOP (the role of rituximab maintenance after bendamustine is still controversial9 ).1,10  Unfortunately, the majority of elderly MCL patients will relapse and then have a very poor prognosis. Managing relapsing or refractory (r/r) MCL is particularly challenging because these individuals often have a reduced performance status and are particularly prone to experience treatment-related adverse events (AEs) as a result of previous chemotherapies and increased age. Furthermore, unexpected complications of AEs may occur because of coexisting geriatric impairments or comorbidities, sometimes with life-threatening consequences.

There is no broadly accepted standard treatment for elderly MCL patients relapsing after first-line therapies; if patients are fit, they can receive further chemotherapy. Nevertheless, in the last few years, multiple new drugs have been evaluated in r/r MCL. The Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica)11  was approved in the United States, the European Union, and other countries for the treatment of MCL patients relapsing after 1 prior therapy.11  In this population, ibrutinib as a single agent led to an overall response rate (ORR) of 67% with 23% complete responses. These results for ibrutinib compare favorably with other new agents such as bortezomib,12  temsirolimus,13,14  and lenalidomide.15  However, responses were not maintained long term in the majority of patients, with a 2-year progression-free survival (PFS) of 31% and a median PFS of 13 months.16,17  In this article, we review the current knowledge about the role of ibrutinib in MCL and discuss its incorporation into the clinical management of elderly patients with MCL, with an understanding of the potential benefits and shortcomings of this agent.

We performed a PubMed search for “ibrutinib” and “lymphoma” with “clinical trial” as a filter, which returned 19 published studies. We excluded 9 studies because they did not include MCL patients, 2 studies because they did not include the use of ibrutinib, and 2 studies because they were not clinical trials, which yielded 6 evaluable trials (Table 1). Across the studies in r/r MCL, single-agent ibrutinib led to an ORR of 67% to 72% and complete responses of 19% to 33%.14,17,18  In a subgroup analysis of the trial comparing ibrutinib with temsirolimus, the PFS advantage of ibrutinib was maintained in the elderly population.14  Because of this promising response and with the goal of increasing long-term disease control, ibrutinib has also been evaluated in combination with rituximab with or without chemotherapy (CHOP, bendamustine) with improvement of ORR and PFS (Table 1).19-21 

Table 1.

Clinical trials evaluating ibrutinib as a single-agent or in combination for MCL

Reference NCT ID Disease status Study type Treatment No. of patients Age (y) Efficacy Adverse event 
Median Range 
18 NCT00849654 r/r Multicenter, open-label, phase 1 Ibrutinib (dose escalation) 65* 41-84 ORR 77%
CR 3/9
PFS NA
OS NA 
Diarrhea 55.5%*
Fatigue 22.2%*
Nausea/vomiting 42.9%*
Cough 32%*
Bleeding NA
Infection NA
Atrial fibrillation NA 
16, 17 NCT01236391 r/r Multicenter, open-label, phase 2 Ibrutinib 560 mg 111 68 40-84 ORR 67%
CR 23%
2-y PFS 31%
2-y OS 47% 
Diarrhea 54%
Fatigue 50%
Nausea 33%
Dyspnea 32%
Bleeding 50%
Infection 78%
Atrial fibrillation 11% 
14 NCT01646021 r/r Multicenter, randomized open-label; phase 3 Ibrutinib vs temsirolimus 139† 67† (≥65 y, 62%)  ORR 72%†
CR 19%†
2-y PFS 41%†
1-y OS 68%† 
Diarrhea29%†
Fatigue 22%†
Nausea 14%†
Cough 22%†
Major bleeding 10%†
Infection NA 
20 NCT01880567 r/r Single-center, open-label, phase 2 Ibrutinib plus rituximab 50 67 45-86 ORR 88%
CR 44%
1-y PFS 75%
1-y OS 85.5% 
Diarrhea 82%
Fatigue 98%
Nausea 54%
Dyspnea 52%
Bleeding NA
Infection NA
Atrial fibrillation 14% 
19 NCT01479842 First-line and r/r Single center, open-label, phase 1/1B Rituximab-bendamustine plus ibrutinib (dose escalation) 17 62* 23-84 ORR 94%
CR 76%
2-y PFS 50.3%*
2-y OS 56.5%* 
Diarrhea NA
Grade 3-4 fatigue 2%*
Grade 3-4 nausea 4%*
Dyspnea NA
Bleeding NA
Grade 3-4 infection 6%*
Rash 25%
Atrial fibrillation NA 
21 NCT01569750 First-line Multicenter, open-label, phase 1B R-CHOP plus ibrutinib (dose escalation) 60.5* 41-84 ORR 94%*
CR 72%*
PFS NA
OS NA 
Diarrhea 39%*
Fatigue 45%*
Nausea 70%*
Dyspnea 27%*
Bleeding NA
Upper respiratory tract illness 15%*
Pneumonia 12%*
Febrile neutropenia 18%*
Urinary tract infection 9%*
Atrial fibrillation NA 
 
Reference NCT ID Disease status Study type Treatment No. of patients Age (y) Efficacy Adverse event 
Median Range 
18 NCT00849654 r/r Multicenter, open-label, phase 1 Ibrutinib (dose escalation) 65* 41-84 ORR 77%
CR 3/9
PFS NA
OS NA 
Diarrhea 55.5%*
Fatigue 22.2%*
Nausea/vomiting 42.9%*
Cough 32%*
Bleeding NA
Infection NA
Atrial fibrillation NA 
16, 17 NCT01236391 r/r Multicenter, open-label, phase 2 Ibrutinib 560 mg 111 68 40-84 ORR 67%
CR 23%
2-y PFS 31%
2-y OS 47% 
Diarrhea 54%
Fatigue 50%
Nausea 33%
Dyspnea 32%
Bleeding 50%
Infection 78%
Atrial fibrillation 11% 
14 NCT01646021 r/r Multicenter, randomized open-label; phase 3 Ibrutinib vs temsirolimus 139† 67† (≥65 y, 62%)  ORR 72%†
CR 19%†
2-y PFS 41%†
1-y OS 68%† 
Diarrhea29%†
Fatigue 22%†
Nausea 14%†
Cough 22%†
Major bleeding 10%†
Infection NA 
20 NCT01880567 r/r Single-center, open-label, phase 2 Ibrutinib plus rituximab 50 67 45-86 ORR 88%
CR 44%
1-y PFS 75%
1-y OS 85.5% 
Diarrhea 82%
Fatigue 98%
Nausea 54%
Dyspnea 52%
Bleeding NA
Infection NA
Atrial fibrillation 14% 
19 NCT01479842 First-line and r/r Single center, open-label, phase 1/1B Rituximab-bendamustine plus ibrutinib (dose escalation) 17 62* 23-84 ORR 94%
CR 76%
2-y PFS 50.3%*
2-y OS 56.5%* 
Diarrhea NA
Grade 3-4 fatigue 2%*
Grade 3-4 nausea 4%*
Dyspnea NA
Bleeding NA
Grade 3-4 infection 6%*
Rash 25%
Atrial fibrillation NA 
21 NCT01569750 First-line Multicenter, open-label, phase 1B R-CHOP plus ibrutinib (dose escalation) 60.5* 41-84 ORR 94%*
CR 72%*
PFS NA
OS NA 
Diarrhea 39%*
Fatigue 45%*
Nausea 70%*
Dyspnea 27%*
Bleeding NA
Upper respiratory tract illness 15%*
Pneumonia 12%*
Febrile neutropenia 18%*
Urinary tract infection 9%*
Atrial fibrillation NA 
 

CR, complete response; NA, not available; NCT ID, National Clinical Trial identifier; OS, overall survival; R-CHOP, rituximab plus CHOP.

*

No specific data available for the MCL group.

Ibrutinib only.

Although ibrutinib shows encouraging results, it has been associated with AEs that can be particularly important for elderly patients. The incidence of any bleeding in patients treated with ibrutinib as a single agent was 50%, with 6% of patients having grade ≥ 3. Of note, a recent pooled analysis22  showed no significant differences in major bleeding rates among ibrutinib and comparator treatments (response rate [RR], 1.72; 95% confidence interval [CI], 0.95 to 3.11; P = .07). Therefore, patients who need anticoagulants or antiplatelet drugs should be carefully evaluated for their risk of bleeding, especially patients in the elderly population in whom falls can increase the risk of serious bleeding (grade B recommendation). It is generally accepted that warfarin should be avoided (grade B). A similar conclusion should be extended to the new factor Xa inhibitors in the absence of specific clinical data. Furthermore, when surgery is planned, one should consider the risks and benefits of withholding ibrutinib for 3 to 7 days before and after surgery or until bleeding complications are resolved (grade B). Patients at greater risk for grade ≤ 2 bleeding can potentially be identified by platelet function and other coagulation analyses as reported in a recent study.23 

Atrial fibrillation (AF) was a common finding (6% to 9%) in clinical trials in patients with either MCL or CLL who were treated with single-agent ibrutinib.17  AF is common in the elderly, and this condition should be carefully monitored in those being treated with ibrutinib by clinical examination and patient education on how to recognize symptoms. Two pooled analyses22,24  confirmed the association of ibrutinib with increased risk of AF development. One study24  showed a fourfold risk of developing AF in ibrutinib when measured against other comparator treatment. Most patients developed AF in the first 4 months of treatment. AF occurrence led to dose interruption in ∼30% of these patients and treatment discontinuation in 14.3%. The second study22  confirmed an increased RR of 3.8 for developing AF while being treated with ibrutinib compared with comparator treatments. Hypertension and previous frequent exposure to anthracyclines can further complicate the cardiac risk in elderly patients with r/r MCL.

Infections, especially of the respiratory and urinary tracts, are common in elderly patients with MCL because of the disease and because of the immunosuppression related to treatments. In the elderly population, the ability to control severe infections is reduced. In patients treated with single-agent ibrutinib, the occurrence of any infection was 78%; however, most infections were self-limiting and were treated in the outpatient setting.17  A randomized trial of ofatumumab vs ibrutinib in chronic lymphocytic leukemia (CLL) did not show increased risk of infections in patients treated with ibrutinib.22  In a head-to-head comparison of temsirolimus and ibrutinib, ibrutinib had fewer infections that led to treatment discontinuation.14  Moreover, when ibrutinib was given with chemotherapy, the infection rate was not dramatically increased compared with that in previous studies.19,21 

Hematologic toxicity was experienced by <20% of MCL patients who received single-agent ibrutinib but was higher, as expected, when ibrutinib was combined with other agents, especially chemotherapy.19,21  Toxicities, even low-grade toxicities, may have serious consequences in the elderly. Such is the case for nausea and vomiting, diarrhea, and decreased appetite, which may lead to hospitalization for dehydration and hypotension. Fatigue, dyspnea, and musculoskeletal pain are common findings with ibrutinib treatment, and even when these effects are mild, they can have an impact on patients by increasing the risk of falls or dependencies. In most clinical trials, the rate of discontinuation because of AEs has been 6% to 11%. However, this risk has been shown to be age dependent, with higher rates among those older than age 70 years and still higher rates among patients older than age 80 years.23 

To anticipate potential adverse consequences of toxicities, a geriatric evaluation of the patient before and during treatment may be helpful (grade B). But this assessment is time-consuming for daily practice and should be implemented only after screening with validated tools such as G8 (a geriatric 8-question screening tool) or the Flemish Version of Triage Risk Screening Tool (fTRST) (grade A).24-26  Evaluating functional status at baseline and during treatment with the help of the Activities in Daily Living (ADL)27  and Instrumental Activities in Daily Living (IADL)28  tools and determining the risk of falls through simple tests such as the “timed up and go”29  may help physicians anticipate the adverse consequences of fatigue, dyspnea, musculoskeletal pain, and risk of bleeding. Furthermore, cognitive impairment or depression may alter patients’ capacity to deal with AEs and delay physician intervention, which may increase potential consequences of severe infection. Assessment of these domains with short tools such as the Mini Mental Status Examination (MMSE)30  and the Geriatric Depression Scale (GDS)31  may be useful. These tools can also be used to evaluate the ability of the patient to be compliant with treatment (ie, taking the ibrutinib capsules every day in the correct way).

Relapse during ibrutinib treatment tends to be aggressive and portends poor overall survival (OS) in patients with either MCL32,33  or CLL.23  As already discussed, ibrutinib as a single agent in r/r MCL generates a median PFS of only 13 months. Therefore, novel combinations are needed to improve disease control. Of the 35 studies currently listed in Clinicaltrials.gov that are investigating ibrutinib for MCL, 21 are open (as of June 25, 2016). Most of the open studies are now evaluating ibrutinib in combination with other agents such as monoclonal antibodies (eg, rituximab, obinutuzumab), bispecific monoclonal antibodies (eg, JNJ-64052781), and small molecules (eg, lenalidomide, bortezomib, venetoclax, carfilzomib, palbociclib, copanlisib, buparlisib, selinexor), or in association with chemotherapy (CHOP; bendamustine; or hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone [hyperCVAD]). A randomized trial (NCT01776840) is currently comparing rituximab-bendamustine with or without ibrutinib in patients age 65 years or older with previously untreated disease. A recently published multicenter open-label phase I/II trial evaluated the combination of lenalidomide-bendamustine-rituximab in untreated mantle cell lymphoma >65 years.34  The CR rate was 64% with 36% of patients being MRD-negative; at a median follow-up time of 31 months, median PFS was 42 months and 3-year OS was 73%. Grade 3-5 infections occurred in 21 patients (42%) and 3 patients had opportunistic infections. Of note, second primary malignancies were observed in 8 patients (16%), likely for the use of lenalidomide, raising concerns about the safety of this combined approach. The goal of these studies is to build upon the promising ORR of ibrutinib as a single agent to prolong PFS. Combination therapies with non–cross-reactive toxicities are warranted, especially in elderly patients with MCL, because the goals of care include improving the quality of life and autonomy in addition to increasing survival. Finally, in an era of economic hardship and with an explosion in the availability of expensive new drugs, the cost-effectiveness of using ibrutinib in older patients should be carefully considered. In our opinion, ibrutinib, if used in patients who are unable to tolerate chemotherapy, can prevent multiple hospital admissions and complications of chemotherapy, overall reducing costs and ensuring better quality of life (grade D).

Like a tightrope walker, the hematologist who treats elderly MCL patients should aim to balance the achievement of a deep clinical response with the management of AEs. Thanks to the convenient route of administration and the relatively manageable AE profile, ibrutinib is a reasonable option for treating elderly patients with MCL who cannot receive chemotherapy, while cautiously monitoring the risk of bleeding, AF, and other potential toxicities. Furthermore, its combination with additional drugs (if considered safe) may enhance rates and depth of response.

Acknowledgment

This work was supported by grants from the Society for Immunotherapy of Cancer (EMD-Serono Cancer Immunotherapy Clinical Fellowship to M.R.), the American Association for Cancer Research (Bristol-Myers Squibb Oncology Fellowship in Clinical Cancer Research to M.R.), the Gabrielle's Angel Foundation (special grant to M.R.), the Societa' Italiana Ematologia Sperimentale–Associazione Italiana Leucemie, Linfomi e Mielomi (research fellowship to M.R.). P.S. is supported by the Sites de Recherche Integree sur le Cancer, Bordeaux Recherche Integree Oncologie (grant INCa-DGOS-Inserm 6046).

Correspondence

Marco Ruella, Smilow Center for Translational Research, 8-196 C, 3400 Civic Center Blvd, Philadelphia, PA 19104; e-mail: marco.ruella@uphs.upenn.edu.

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Author notes

Conflict-of-interest disclosures: The authors declare no competing financial interests.

Off-label drug use: None disclosed.