Optimizing therapy in mantle cell lymphoma
Mantle cell lymphoma (MCL) is an uncommon but aggressive subtype of lymphoid malignancy, generally considered to have a poor prognosis.1 Although the disease responds well to initial treatment, relapse will inevitably occur,1 and with an increase in annual incidence,2 there is a need for novel agents to achieve optimal treatment outcome. Ibrutinib, an oral and potent Bruton’s tyrosine kinase (BTK) inhibitor, was approved by the US Food and Drug Administration (FDA) in 2013 for patients with MCL whom have received at least one prior therapy.3 Professor Georg Hess from the Department of Hematology, Oncology and Pneumology, University Medical School of the Johannes Gutenberg University, Mainz, Germany, was invited to discuss the use of ibrutinib in current practice and how to achieve optimal treatment outcome in MCL at a symposium in Hong Kong, organized by the Hong Kong Society of Haematology.
MCL accounts for approximately 3-6% of non-Hodgkin lymphomas and is more common in men than women.1 Median age of diagnosis is 65 years, with the disease commonly presented at an advanced stage (Ann Arbor stage III and IV).4 There are two types of MCL as recognized by the World Health Organization (WHO): 1) Classical MCL with immunoglobulin heavy-chain variable (IGHV)-unmutated/minimally mutated B cells with SOX11 expression; and 2) Leukemic non-nodal MCL, composed of IGHV-mutated genes without SOX11 expression.5
Patients more frequently present with the classic MCL form, with an aggressive clinical course.5 The leukemic non-nodal form is generally more clinically indolent, though secondary abnormalities can lead to extremely aggressive disease.5
First-line treatments in MCL
Patients presenting with the indolent form may often start with a “watch and wait period” under close observation as tumor burden will be low.2 Results are often brief after good initial results and patients will eventually relapse,4 so treatment after relapse is also of importance.
In patients requiring treatment, though several induction regimens for MCL are available, there is no universally accepted standard of care and the treatment choice is often dependent on patient factors, such as age and comorbidities.1 Generally, patients aged under 65 years who are fit with no or less impactful comorbidities will be put on more intensive treatments, such as chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT).6 A commonly recommended first-line treatment for these patients is rituximab and high dose cytarabine, followed by ASCT.6
Patients ineligible for intensive therapy and ASCT would start with non-intensive chemoimmunotherapy regimens, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or BR (bendamustine and rituximab).4,6 Response rates to these therapies ranged from 60-95%, with a median progression-free survival (PFS) of ≤5 years.4 Prof. Hess informed that “in Germany and in Europe, we accept that R-CHOP and BR are two of the standard [therapies].”
Two studies were presented at the symposium, one by the European MCL Network in which a comparison was made between R-CHOP to R-FC (fludarabine, cyclophosphamide, and rituximab), and another a phase 3 study comparing BR and R-CHOP as first-line treatments. Prof. Hess highlighted from the first study that there was no large difference in time to treatment failure between R-CHOP and R-FC (median of 28 months vs. 26 months respectively, p=0.5), but the R-CHOP arm showed a higher OS compared to R-FC arm (median 67 months vs. 40 months; p=0.005).7 Prof. Hess stated that the significant OS benefit in patients on R-CHOP, despite the similar outcomes in time to treatment failure in both groups, meant that R-FC was so toxic that patients were unable to tolerate the second-line of treatment.7 “If you treat patients in a way where you could not use a suitable second- or third-line option, you have chosen the wrong [first-line treatment]. We have to always keep in mind that our patients in the end should be able to receive another line [of treatment],” Prof. Hess explained.
From the second study presented, the results showed that the patients on BR had a median PFS of 69.5 months, which was significantly longer than a median PFS of 31.2 months in patients on R-CHOP (HR=0.58; 95% CI: 0.44-0.74; p<0.0001), but there were no difference in OS, with median OS not reached in either treatment group.8 There was an updated analysis of the VR-CAP regimen (bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone) versus R-CHOP in newly diagnosed MCL patients post-symposium, which showed a substantial OS benefit for VR-CAP (90.7 months vs. 55.7 months; HR=0.66; 95% CI: 0.51-0.85; p=0.001).9 This makes VR-CAP a reasonable alternate treatment.9
Maintenance therapy to improve response duration
Maintenance therapy is a common option to improve response duration due to the short-lived remission from standard MCL treatments.6 Rituximab as maintenance has a good safety profile and shown to improve PFS in other incurable lymphomas.6,10 The ESMO Clinical Practice Guidelines for MCL also recommended rituximab as maintenance in both young and elderly patients after chemoimmunotherapy and ASCT (in those eligible).2
From the above mentioned study by the European MCL Network, patients in both the R-FC and R-CHOP groups who responded underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression.7 Maintenance with rituximab resulted in a large improvement in the duration of response (DOR) compared to those on interferon, and improved OS amongst patients from the R-CHOP arm.1
Importantly, in patients with intensive induction and consolidation, benefit of maintenance rituximab could be demonstrated in the LYSA trial, where 3 years of maintenance was compared to observation following high dose therapy.10 The rate of OS was 89% in the rituximab group verses 80% in the observation group (HR=0.50; 95% CI: 0.26-0.99; p=0.04).10
When the disease progresses: Relapsed or refractory MCL (R/R MCL)
Despite the availability of guidelines for the management of patients with R/R MCL, there is no established standard therapy for these patients.1,11 Professor Hess stated that as “MCL is a genetically unstable disease, first-line and subsequent lines treat biologically different diseases.” Important factors to consider when choosing relapse treatment include the patient’s age and performance status, approaches used in the earlier treatment lines and disease dynamics, including the quality of remission induced and the duration of remission.7
However, patients with R/R MCL generally have poor responses to additional treatment, with the overall response rates (ORR) ranging from 22-72% and increasingly shorter remission periods with consecutive lines of treatment.11,12 Depending on the treatment used, median OS was only 1-2 years and median PFS ranged between 3.9 months and 14.6 months.12
Currently approved therapeutic options for R/R MCL include cellular therapies, such as allogeneic stem cell transplant (alloSCT) and ASCT (since the use of ASCT in this setting was inferior when compared to the use in first-line, it is not preferred),13 chemotherapy (such as bendamustine, CHOP, gemcitabine-based therapies) and novel agents (such as BTK inhibitors and lenalidomide).7
With chemotherapy combinations, patients have roughly 1.5 years of PFS, but we must “keep in mind that the patient characteristics of these trials, most of the data were generated in the first relapse.” The trials for novel agents were mostly on patients whom have received two to four prior lines of therapy, and as Prof. Hess had explained, “quality of remission rapidly goes down and a lot of patients will not tolerate intensive treatments anymore,” so the data between these trials should not be directly compared.
The ESMO Clinical Practice Guidelines for MCL suggested that “selection of treatment is dependent on the efficacy of prior regimens.”2 Early relapses are those incidences that occur within less than 12-24 months and ESMO recommends a non-cross-resistant scheme should be preferred, such as bendamustine or high dose cytarabine-containing regimens, such as R-BAC (rituximab, bendamustine, and cytarabine) after CHOP or vice versa.2 For younger patients, alloSCT may also be an option as it has shown to achieve long-term remissions in patients following early relapse and in those with refractory disease.2 Prof. Hess stated that 30% of patients will respond to alloSCT, some even if they were unresponsive to chemotherapy before.
The ESMO guidelines also recommended that newer targeted approaches should also be considered after early relapses or in refractory cases.2 At present, ibrutinib and lenalidomide are approved in both the EU and by the US FDA for the treatment of R/R MCL. Temsirolimus and bortezomib are also approved in the EU and by the FDA respectively for the same indication.11
Novel agent ibrutinib showed ‘promising results’ in patients with R/R MCL
In general, poor responses are observed with R/R MCL treatment, yet the novel agent ibrutinib has shown ‘promising results’ in patients with R/R MCL.12 Ibrutinib was associated with a longer PFS ranging from 13.6-14.6 months (compared to 9.2, 3.9-8.7, and 4.8-6.2 months in bortezomib, lenalidomide, and temsirolimus respectively) and an ORR of 54-72%.12 It is the first-in-class Bruton’s tyrosine kinase (BTK) inhibitor to be approved for the treatment of B cell lymphoma, and ibrutinib was first approved for use in Hong Kong in 2015.14-16
RAY Trial: Ibrutinib superior to temsirolimus
Prof. Hess presented the data of the RAY trial which compared the safety and efficacy between ibrutinib and temsirolimus in patients with R/R MCL. Two hundred and eighty patients were randomized in a 1:1 ratio to receive ibrutinib or temsirolimus, and it was found that ibrutinib was superior to temsirolimus in several areas.17
Prof. Hess explained that the data also shows the importance of when ibrutinib should be introduced. Although ORR was similar in patients on ibrutinib regardless of the number of prior lines of therapy they received, a higher percentage of patients achieved complete remission (CR) when treated earlier, as shown in Figure 1.
Prof. Hess also said that there was no difference in PFS as to when temsirolimus was introduced in terms of prior therapy, but the PFS was remarkably longer in those receiving ibrutinib earlier (i.e. one prior line of therapy) than later. The RAY trial showed that PFS was doubled in those who received one prior line of therapy compared to those who had received more than one line of therapy, at 25.4 vs. 12.1 months.18 However, as seen in Figure 2, ibrutinib still showed superiority to temsirolimus even if patients received it at a later stage of the disease.18
The pooled MCL analysis (Figure 3) from three ibrutinib studies were presented and similarly showed that patients who had one prior line of therapy had the longest PFS and OS, where the median was not reached.19 The percentage of patients who were estimated to have a two-year PFS and OS in those on ibrutinib with only one prior line of therapy were 57% and 68% respectively.19
Several trials are currently ongoing to study the use of ibrutinib in the first-line setting, as well as maintenance. “The SHINE trial studies whether ibrutinib should be added to chemotherapy whereas the ENRICH trial asks whether ibrutinib can replace chemotherapy,” Prof. Hess described.
Safety considerations with ibrutinib
Prof. Hess presented that in general, grade 3 or 4 adverse events with ibrutinib were less common in patients with 1 prior line of therapy. Common (occurring in ≥5% of the intention to treat [ITT] patients) adverse events included neutropenia, thrombocytopenia, pneumonia, and anemia, although new onsets of these events decreased after the first year of treatment.7 Other adverse events such as diarrhea and rashes could be symptomatically treated.7 Bleeding events were moderate, but Prof. Hess suggested that clinicians should confer with hematologists on which drugs the patients could stop if they are on a combination of antiplatelets. Hypertension and atrial fibrillation may also occur, and Prof. Hess recommended a cardiograph and pre-treatment work up, and if tolerated, patients could continue ibrutinib. Prof. Hess also mentioned the importance of keeping patients informed on the possible adverse events, such as immediately returning to hospital upon fever or any symptoms that could be related to infections such as pneumonia.
Prof. Hess concluded that first-line therapy has been optimized in the recent years, such as with the addition of rituximab as maintenance. Novel agents, especially ibrutinib, have “changed the fate” in R/R MCL, but Prof. Hess stressed the importance of individualization when it comes to the selection of treatment – that individual patient characteristics, such as quality of remission and duration of response, are important and must be taken into consideration.
Bruton’s tyrosine kinase inhibitors delay disease progression and extend survival in patients with relapsed/refractory mantle cell lymphoma
Mantle cell lymphoma (MCL) is a B cell malignancy that is typically clinically aggressive with a poor prognosis.1 When MCL patients progress into relapsed/refractory MCL (RRMCL), the median overall survival (OS) is usually reduced to around 1 year. Currently, three Bruton’s tyrosine kinase inhibitor