Blood cancers

How to optimise therapy in mantle cell lymphoma

Thursday, 23 Aug 2018


A better understanding of the disease pathogenesis of mantle cell lymphoma and the availability of better therapies means people with mantle cell lymphoma are living longer. Chair of the Lymphoma group at Weill Cornell Medicine in New York Associate Professor Peter Martin gives advice to local haematologists on how to optimise outcomes for their MCL patients.  

MCL patients are living longer

“Mantle Cell Lymphoma (MCL) is challenging to treat and we all recognise that it is currently an incurable disease with standard therapies,” Professor Martin told delegates attending the H3 conference hosted by Janssen Oncology in Sydney.

He said that historically the disease had a short overall survival, however people with MCL were now living longer than they used to. This was apparent when comparing survival outcomes from German clinical trials in the 1970s and 1980s with trials in the late 1990s.

“You can see survival outcomes in the 70s are clearly inferior to survival times at the turn of the millenium1 … but population experience is probably more relevant for what happens in the real world and a population study from the UK presented at ASH in 2016 shows patients are doing better now than they’ve ever done in the past2.

A tale of two MCLs

So why are people doing better and are there things we can do to optimise survival further? Professor Martin asked.

Showing the audience a proposed model of molecular pathogenesis of major subtypes of MCL3 he explained that MCL had classically been recognised as an aggressive but incurable B-cell lymphoma that developed in a linear fashion from naïve B cells. However, understanding of the disease had since moved on and two clinical variants were now recognised that reflected that MCL developed along two different pathways.

“Classical MCL is usually composed of IGHV-unmutated or minimally mutated B cells that usually express SOX11 and typically involves lymph nodes and other extranodal sites. But it’s not all the MCL that exists, in fact some of those classical MCLs can evolve further into blastoid MCL,” he said.

“There’s a second pathway in MCL which sounds familiar to those of us who treat CLL. Some patients with MCL have a variant that is derived from cells that have in fact made their way through the germinal centres to a SOX11 independent pathway. These patients typically present in a way that’s very similar to typical CLL. They tend to have an enlarged spleen, lymphocytosis, less significant lymphadenopathy although they can still have some lymphadenopathy.

“These patients are what we now refer to as leukaemic non-nodal MCL. Additionally, some of these patients can acquire additional mutations.”

The true incidence of uncommon presentations was hard to know but they may not be that uncommon, he said.

Non-nodal MCL, like patients with CLL, was associated with hypermutated IGHV and was SOX11- and studies showed that these patients tended to have a better prognosis4.

However, he said some leukaemic non-nodal MCL harboured mutations in TP535 which was “probably not a good thing”.

“We don’t really know how to treat non-nodal leukaemic MCL patients because in general they are not included in clinical trials. It would be great if we knew how to treat these patients, particularly those with the worst outcomes such as those with TP53 mutations. There is some evidence that novel agents could overcome these poor risk factors in some of these patients.”6

He said that it was unclear what the optimal treatment was for most leukaemic non-nodal MCLs, both indolent and aggressive.

“My bias is to look for these high-risk features wherever possible and consider treating differently, however it remains to be seen what that ‘differently’ means right now,” he told delegates.

What about ‘Super-high risk’ MCL?

In general, blastoid histology, high expression of Ki-67, MIPIc, and TP53 deletions have been clearly associated with unfavourable prognosis Professor Martin told the conference7.

“When we are dealing with Ki-67 scores in the mid-range however I will always look at the slides with the pathologist and decide together and see where the patient fits in”.

“Most of us don’t have the ability to sequence TP53 in all of our patients but there’s encouraging data from the MCL network8 that immunohistochemistry for p53 can be helpful… Once you have 10 percent of cells expressing p53 outcomes tend to get considerably worse.”

“Unfortunately, we don’t have a lot of data about how to treat these super high risk MCL patients, it’s easier and easier to identify them but how to treat them is challenging. And there’s limited data looking at novel agents in this patient population.”

Professor Martin told delegates that generally, intensive treatments do not overcome super high-risk features.

“Although our first impression as oncologists is that when we see higher risk patients we treat them with the most intensive treatments possible but those intensive therapies tend to come with a lot of toxicities and probably won’t offer a lot of benefit,” he said.

“In general, I do not offer the most high-risk MCL patient the highest intensity therapy and my bias is to consider the early use of novel agents or early alloSCT where possible”.

More lines of therapies are improving outcomes in MCL

According to Professor Martin multiple population studies showed that MCL patient outcomes were improving, most likely because of the availability of better front line therapies. He noted that observational studies showed clear improvement in outcomes in patients that were able to have an autologous stem cell transplant (ASCT)9: “obviously there’s bias in that which the authors full recognise, and that’s because only some patients were able to receive transplant,” he said.

“As oncologists, we unfortunately have very little impact on survival in our patients and the primary factors that drive patient survival in mantle cell lymphoma is disease biology, patient population and comorbidities”.

Results from the European MCL Younger trial10that looked at R-CHOP* induction versus alternating R-CHOP with R-DHAP* induction showed that patients in the R-CHOP/R-DHAP group had higher complete response rates with deeper remissions. After a median follow-up of 6·1 years, time to treatment failure was significantly longer in the R-CHOP/R-DHAP group (median 9·1 years [95% CI 6·3–not reached], 5-year rate 65% [95% CI 57–71]).

The interesting thing to me however is that patients treated with R-CHOP who had an autologous stem cell transplant (ASCT) and had an average time to treatment failure of roughly 4 years, had an overall survival that was comparable to the more intensively treated group.

“Historically, we were taught that the average survival of MCL patients was quite short, 3-5 years or so. And, the average survival of a patient with relapsed MCL was even worse. Here we see a group of patients living with relapsed MCL for 4-5 years” Professor Martin explained to the limbic.

“The only way that is possible is that these patients had access to effective second, third, and subsequent lines of therapy that were not likely available to historical populations.

“It is likely that our ability to manage relapsed MCL has improved over time, mostly due to the availability of new agents, and that is helping patients to live longer,” he said.

Subsequent therapy in relapsed or refractory MCL

Talking specifically about the best subsequent therapies for relapsed MCL Professor Martin said he did not know the answer, but there was some data that gave an idea of how patients might do with different kinds of therapies.

He referred to pooled data from three clinical trials11 of patients with relapsed or refractory mantle cell lymphoma treated with ibrutinib presented at the 2017 American Society of Hematology meeting.

“It is interesting to me that the analysis showed that patients with one prior therapy treated with ibrutinib in the second line setting had a median PFS of nearly 3 years (33.6 months) with a pretty impressive overall survival”.

“In essence this suggests that some patients with relapsed MCL can have quite a durable remission,” Professor Martin noted.

“When we look at the types of patients most likely to be benefit you can see that unfortunately patients with poor performance status… patients with bulky disease or blastoid histology did not do as well” he said.

“In general patients with fewer prior therapies lower risk disease do quite well on single agent ibrutinib,” he added.

Prognosis post-ibrutinib failure

Ibrutinib doesn’t work forever in anyone and so we need to start thinking about what happens after ibrutinib, Professor Martin said. Several groups have looked at retrospective outcomes in patients that have experienced treatment failure while receiving ibrutinib and uniformly outcomes have been pretty poor12, particularly in super high-risk patients.

“Essentially what these studies show is that patients with the worst disease tend to have poor outcomes when they fail a very effective therapy”.

What remains unknown is how patients who are receiving ibrutinib in the second-line setting for longer periods of time how those patients are going to do post ibrutinib, Professor Martin said.

“The questions is, once a patient fails ibrutinib how should they be treated next? – observational studies haven’t been able to identify a particular therapy that works really well.  Performing prospective clinical trials in this population was also challenging, he said.

“Interestingly there were some patients who did very well but there’s no obvious agent that has shown remarkable activity.

“My bias is to say that it’s worth a shot to try and something and in general my bias is to try another novel agent or bendamustine. My bias is to stay away from highly intensive treatment regimens in the ibrutinib failure setting because my guess is that those patients will experience a high toxicity without a high rate of benefit.”

Recognising the heterogeneity of MCL and looking for high-risk

Summing up Professor Martin said that increasingly we are recognising uncommon presentations and the heterogeneity that exists within MCL.

He urged clinicians to avoid the over treatment of non-nodal patients and to look for the high-risk patients, in particular those with TP53 disruptions.

“It is also important to be aware that super-high risk MCL may not benefit from intensive front-line strategies, although I don’t have an answer for you on how best to treat these patients,” he said.

He advised clinicians to consider the early use of novel agents and novel combinations among all patients but particularly those with TP53 mutations.

References:

  1. Herrmann et al. J Clin Oncol 2009; Feb 1; 27 (4): 511-518.
  2. Patmore et al. Blood 2016; 128: 1112
  3. Swerdlow et al. Blood 2016; 127: 2375-2390
  4. Orchard et al. Blood 2003; 101: 4975; Quieros et al. Cancer Cell 2016; 30: 806-821
  5. Bea et al. PNAS 2013: 110: 18250-18255; Navarro et al. Cancer Res 2012; 72: 5307-5316; Clot et al. Blood 2018;132:413-422
  6. Martin et al. Blood 2016; 128: 150; Jerkeman et al. Blood 2016; 128: 148
  7. Hoster et al. J Clin Oncol 2016; 63: 8387; Eskelund et al. Blood 2016; 128: 1095; Eskelund et al. Blood 2017; 130: 1903-1910
  8. Aukema et al. Blood 2018; 131: 417-420
  9. Abrahamsson et al. Blood 2014; 124: 1288-1295; Gerson et al. Blood 2017; 130: 341
  10. Hermine at al. Lancet 2016; 388: 565-575
  11. Rule et al. Blood 2017; 130: 151
  12. Martin et al. Blood 2016; 127: 1559; Cheah et al. Ann Oncol 2015; 26: 1175; Epperla et al. Haematological Oncol 2017; 16: 1099

Abbreviations:

*CHOP – cyclophosphamide, doxorubicin, vincristine, prednisolone

*R-CHOP – Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone

*D-HAP – Dexamethasone, high-dose cytarabine, Platinol (cisplatin)

*R-DHAP – Ritixumab, dexamethasone, high-dose cytarabine, Platinol (cisplatin)

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