Watch-and-Wait Approach Can Be Beneficial Strategy in MCL

Simon Rule, MD, PhD

Prognostic indices for mantle cell lymphoma (MCL) are good for classifying patients but do little in the way of guiding treatment, and often the best course of action is to watch and wait, according to Simon Rule, MD.

"I've been watching and waiting in this disease for 15 years, which seems counterintuitive in aggressive MCL, but there's a group of patients who do very well if you leave them alone," he said.

Rule, who is a professor of clinical hematology on the faculty of medicine and dentistry at the University of Plymouth in the United Kingdom discussed treatment strategies, new findings, and new agents in MCL at the 23rd Annual International Congress on Hematologic Malignancies^®.¹

In a recent study of management strategies for 222 patients with newly diagnosed MCL in the UK from 2015 to 2017, 27.1% (n = 60) of patients were on watch and wait at the 1-year follow-up, versus 63.3% on systemic therapy and 7.2% receiving radiotherapy, Rule noted. At the 2-year follow-up, 16 of 85 patients (18.9%) remained on watch and wait, and no deaths were recorded among those. Estimated 2-year survival of the whole population was 80.6%. Authors of the study concluded that watch and wait as a conservative management strategy “can be reasonably adopted in a significant proportion of patients.”²

Further, the indolent nature of MCL means physicians should be more restrained about moving forward with treatment, Rule said. “If you think the patient has stage I disease, first of all you haven’t looked hard enough, because it won’t be…almost one-third of patients will still be on watch and wait in a year’s time.”

Young patients with MCL should be considered candidates for high-dose cytarabine, Rule said. A European phase III study of patients aged 65 or younger with untreated stage II to IV MCL found that for patients receiving high-dose cytarabine as part of their regimen, median time to treatment failure was 9.1 years versus 3.9 years for the non-cytarabine cohort (HR, 0.56; P = .038).³

In addition, just published data on the value of autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy demonstrated that in younger transplant-eligible patients with MCL, AHCT was associated with significantly improved median progression-free survival (PFS): 75 months versus 44 months for those with no AHCT.⁴

Following high dose cytarabine, “you’ve got to consolidate that with some rituximab [Rituxan] maintenance,” Rule said. The LyMa trial followed patients on observation versus rituximab (every 2 months for 3 years) following courses of rituximab, dexamethasone, and cisplatin (R-DHAP) and rituximab, etoposide, aracytine, and melphalan (R-BEAM). At 24 months, OS was 93.3% versus 93.3% in the observation and rituximab groups, respectively. At 48 months, the respective numbers were 81.4% versus 88.7%.

Patients with TP53 mutations tend to do “spectacularly badly,” Rule said. Intensive chemo-immunotherapy was not a benefit to younger patients with MCL and TP53 mutations in the Nordic MCL2 and MCL3 trials. Those with TP53 mutations did strikingly worse than those without: median OS of 1.8 years versus 12.7 years for TP53-unmutated cases (P < .0001). The authors concluded that patients with MCL should be stratified according to TP53 status and those with the mutation should be considered for frontline trials exploring novel agents.⁵

"How are you going to treat those patients? You’re thinking, 'I’ll give them ibrutinib [Imbruvica], because that works pretty well in this situation,'" Rule said. However, in a study published in Haematologica in 2018, Rule and colleagues reported that patients with mutated versus wild-type TP53 who were treated with ibrutinib had a median PFS of just 4 months versus 12 months, respectively, and median OS of 10.3 months versus 33.6 months. The respective overall response rates (ORRs) were 55% versus 70.2%, with no complete responses in the TP53-mutated group.

But a recent study of ibrutinib as a bridge from allogeneic hematopoietic cell transplantation in patients with chronic lymphocytic leukemia (n = 48) and MCL (n = 22) demonstrated value in this employment of the agent. The investigators reported median PFS and OS of 60% and 72%, respectively, in the CLL group and 76% and 86% in the MCL group. “You have to do it while the patient is responding. If you wait until the patient has failed, you’re going to do spectacularly badly,” Rule said.

With respect to treatment at relapse, ibrutinib and acalabrutinib (Calquence) are among the best BTK inhibitors available, although, “if you’re going to use a BTK [inhibitor], you’d better use it early. If you use the drug at first relapse, you get much more benefit than if you use the drug later,” Rule said.

In addition, rituximab is a good partner agent for ibrutinib, bortezomib (Velcade), lenalidomide (Revlimid) and temsirolimus (Torisel), significantly contributing to improved ORR and complete response rate, based on a composite analysis. “When you have a drug that works on lymphoma, the no-brainer next thing is to add rituximab,” he said.

References

1. Rule S. What is the goal for patients with mantle cell lymphoma: long remission or cure? Presented at: 23rd Annual International Congress on Hematologic Malignancies®; February 28-March 1, 2019; Miami Beach, Fla.
2. McCulloch R, Berrow M, Wainman B, Crosbie N, Pettitt, Rule S. Population based observational study demonstrates significant increase in watch-and-wait for newly diagnosed mantle cell lymphoma. Presented at: 2018 American Society of Hematology Annual Meeting; December 2, 2018; San Diego. Abstract 2877.
3. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. 2016;388(10044):565-575. doi: 10.1016/S0140-6736(16)00739-X.
4. Gerson JN, Handorf E, Villa D, et al. Survival outcomes of younger patients with mantle cell lymphoma treated in the rituximab era. January 2019. Published online at JCO.org. doi: 10.1200/JCO.18.00690.
5. Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017. doi: 10.1182/blood-2017-04-779736.

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