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During the Society of Hematologic Oncology (SOHO) annual meeting, in Houston, US, a session on mantle cell lymphoma (MCL) was held. Doctor (Dr.) Anita Kumar, Memorial Sloan Kettering Cancer Center, New York, US, presented a talk entitled “Who Is a Candidate for Watch and Wait Therapy” in MCL1 and Professor (Prof.) Simon Rule, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth, UK, gave two presentations; the first was on front-line therapy2 and the second on options for salvage therapy for patients with relapsed/refractory (R/R) MCL.3 This article provides a comprehensive summary of these talks regarding the current standard of care (SOC) for patients with MCL.
This presentation by Dr. Kumar aimed to define which subgroup of patients with MCL are candidates for watch and wait therapy, as opposed to upfront treatment. A study by Martin et al.4, showed that observation was an acceptable option for patients with newly diagnosed MCL. In this study, 32% of patients were successfully monitored for over three months, with no adverse impact on overall survival (OS) through deferring therapy. The OS improved in the observation group compared to the treatment group, though the authors attributed this to the preferable disease biology of the patient group.4
Having established this, the question of how to identify the appropriate patients for observation remains. To determine this, it is necessary to look at the clinical and biological features of patients successfully observed. There are two subtypes of MCL:1
Additionally, there are known prognostic factors in MCL associated with OS, though these do not necessarily indicate the need for treatment (Table 1).
Table 1. Prognostic factors in MCL1Type of prognostic factor
Prognostic factor
Clinical
MCL International Prognostic Index (MIPI) score (incorporating; age, lactate dehydrogenase [LDH] level, performance status and white blood cell [WBC] count)
B-cell symptoms
Radiographic
SUVmax
PET features
Pathologic
Blastoid or pleomorphic
Proliferative signature
SOX-11 status
IGHV mutation status
Karyotype
Genomic alterations e.g. TP53, deletion 17, NOTCH 1/2
Dr. Kumar proceeded to present results from a study at Memorial Sloan Kettering Cancer Center, which aimed at describing the clinical and biological characteristics of patients with MCL who were either observed or treated and evaluated their subsequent outcomes. The hypothesis was that patients should be observed, or treated, based on clinical presentation and that negative prognostic features such as TP53mut should not exclude a patient from observation.1
In patients observed for over two years (n =30), there were three clinical categories;
The study showed that observation did not have a negative impact on median OS (observation vs treatment: 11.4 vs 9.4 years).
Dr. Kumar and colleagues concluded:
Therefore, Dr Kumar recommended that clinical criteria should drive the selection of patients fit for observation compared to upfront treatment.
Prof. Rule began his presentation by discussing the current treatment pathway for patients with MCL, explaining that the first evaluation to be made, is whether the patient requires therapy. If the answer is yes, the patient is then assessed for eligibility for autologous stem cell transplant (ASCT). If they are fit for ASCT, the current treatment algorithm recommends induction with rituximab (R) plus a high-dose (HD)-cytarabine-containing regimen, followed by ASCT. If the patient achieves a complete response (CR) or partial response (PR), maintenance should be given.
If the patient is not fit for ASCT, they are assessed for eligibility for cyclophosphamide (C), doxorubicin, vincristine, and prednisone (P; CHOP) therapy. If they are eligible, CHOP- or bendamustine (benda)-based therapy is given, followed by maintenance with R. If they are not, R-benda, R-C + vincristine + P (R-CVP) or R-chlorambucil (R-Cbl) is given, followed by maintenance.
As discussed by Dr. Kumar, patients who do not require therapy are observed until they require treatment. At this point they are assessed for eligibility for ASCT and the treatment pathway above is assessed.
Prof. Rule noted that the only maintenance that has been proven to be efficacious in this patient population, is R.
There are four main therapy choices for patients who are ineligible for transplant, but who are eligible for CHOP therapy:
To summarize, Prof. Rule noted that patients should be treated when clinically indicated, and that in young patients, cytarabine is key to intensive treatments, with rituximab maintenance. For older patients, CHOP- and benda-based treatments are advisable, though he added that novel agents are rapidly moving into the frontline setting and will likely form part of the SOC.
In his second talk, Prof. Rule began by noting the five currently available therapies for the treatment of R/R MCL:
Prof. Rule then discussed other potential therapies developed for MCL, with varying degrees of success (Table 2). He noted that many of these drugs have not been tested in patients who previously received BTK inhibitors, which is a limitation of these investigations.
Table 2. Therapies investigated for the treatment of R/R MCL15-20Drug/ combination
Drug type
Study
Conclusion
Idelalisib15
Phosphoinositide 3-kinase (PI3K) inhibitor
Phase I
ORR: 40% (16/40)
CR: 5% (2/40)
Median duration of response (DoR): 2.7 months
Median PFS: 3.7 months
One-year PFS: 22%
Prof. Rule stated this is not a clinically superior therapy
Umbralisib (TGR-1202) + ibrutinib16
PI3K inhibitor
Phase I/Ib
ORR: 67%
PR: 6/9
Median time on study: 10.9 months
Prof. Rule questioned whether the addition of umbralisib enhanced the activity of ibrutinib significantly
Palbociclib + ibrutinib17
Cyclin-dependent kinase (CDK) inhibitor
Phase I
ORR: 67%
CR: 37%
Two-year PFS: 59.4%
Dose-limiting toxicity: grade 3 rash
Phase II study ongoing
Entospletinib (GS-9973)18
Spleen tyrosine kinase inhibitor
Phase II
PFS at 16 weeks: 63.9%
ORR: 17.9%
Limited single agent activity
R + lenalidomide19
mAb + IMiD
Phase I/II
Grade 3-4 hematological toxicity: neutropenia (66%), lymphopenia (36%), leucopenia (30%) and thrombocytopenia (23%)
ORR: 57%
CR: 36%
Median DoR: 18.9 months
Median PFS: 11.1 months
Median OS: 24.3 months
Bortezomib + lenalidomide20
PI + IMiD
Phase II
CR: 15%
PR: 25%
One-year PFS: 40%
One-year EFS: 25%
One-year OS: 68%
Combination not pursued further
Therefore, Prof. Rule stated that BTK inhibitors are the best options for patients with R/R MCL based on the ORR and CR rates shown in Table 3.
Table 3. Response rates to BTK inhibitors21-24 * For total cohort; including patients with treatment naïve disease (n= 8) and R/R disease (n= 37)
N
ORR (%)
CR (%)
Median DoR (months)
Median PFS (months)
Median prior lines of therapy
Ibrutinib21
111
68
21
17.5
13.9
3
Acalabrutinib22
124
81
40
Not reached
Not reached
2
Tirabrutnib23
16
92
46
Not reported
Not reported
3
Zanubrutinib24
37
87
30
14.7
15.4*
1*
A recent study by Kumar et al.25 showed median OS and PFS decreases after each subsequent line of therapy (Table 4), and early treatment failure after first line therapy is associated with poorer OS.25 Prof. Rule therefore noted that using the most effective options upfront and at first relapse is crucial.3
Table 4. Decreasing responses to each line of therapy in patients with MCL25Line of therapy
OS
PFS
First
9.7 years
4 years
Second
41.1 months
14 months
Third
25.2 months
6.5 months
Fourth
14.4 months
5 months
Prof. Rule noted that there are many other novel therapies under investigation, including epigenetic modulators such as cladribine, mTOR inhibitors like temsirolimus and chimeric antigen receptor (CAR) T cell therapies. Prof. Rule added that data on CAR T in MCL is due to be presented in upcoming congresses, and it could have a role in treatment following the use of BTK inhibitors.3
There are also many ongoing trials in the R/R MCL setting, for example; ibrutinib in combination with various agents such as bortezomib, selinexor, ixazomib, lenalidomide + R, and venetoclax, with an aim of further increasing efficacy. Additionally, other combinations are being investigated such as venetoclax with BR, ixazomib + R and benda + obinutuzumab.3
For R/R patients with TP53mut status, outcomes with ibrutinib are less favorable compared to patients with TP53wt (Table 5).26
Table 5. Responses to ibrutinib by TP53 mutation status26
Median PFS (months)
Median OS (months)
ORR (%)
TP53wt
12
33.6
70.2
TP53mut
4
10.3
55
The PHILEMON study, investigating the use of ibrutinib with lenalidomide and R, has shown a 64% complete remission rate in patients with TP53mut. These promising results indicate this regimen may be able to overcome the negative prognostic feature of TP53mut:3
Prof. Rule lastly discussed the use of venetoclax for R/R MCL:
Prof. Rule concluded that combination therapy with a BTK inhibitor is the future of therapy for R/R MCL, and that MRD-status may help guide treatment decisions in future, potentially dictating when to stop treatment, and helping to identify the most appropriate treatment options.
References
Your opinion matters
What is your preferred therapy class when planning treatment for a patient with R/R DLBCL after 2 or more lines of systemic therapy ?