Early Responders Could Halt Advanced CLL Combo Therapy

Liam Davenport

December 08, 2020

Patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who achieve an early and sustained response to combination therapy with ibrutinib (Imbruvica, Pharmacyclics/Janssen) and venetoclax (Venclyxto , AbbVie) may be able to stop treatment altogether, suggests extended follow-up data from a leading UK trial.

The research, which was supported by the charity Blood Cancer UK, was presented at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition on December 5.

TAP CLARITY

The TAP CLARITY trial involved 54 relapsed or refractory CLL patients who were given ibrutinib plus venetoclax for a minimum of 14 months, with options to stop treatment if their measurable residual disease (MRD) became undetectable at various points along the protocol.

Previously published results indicated that, at 12 months, MRD negativity was achieved in the peripheral blood in 53% of patients and in bone marrow in 36%, while 51% achieved a complete remission.

Dr Talha Munir

Presenting results to 38 months, Dr Talha Munir, St James University Hospital, Leeds, showed that complete remission had been achieved in 68% of patients, and that MRD negativity rates were approximately 44% across the peripheral blood and bone marrow.

Crucially, 27 patients in the trial stopped venetoclax and 25 stopped ibrutinib for more than a year, with the vast majority maintaining their MRD negative status even after a median of 18 months without treatment.

Dr Munir said results show: "The response to ibrutinib plus venetoclax is sustained, despite planned discontinuation of therapy, in MRD-negative patients," adding that there are "no new safety signals" and two patients who contracted COVID-19 during the study "made a good recovery".

Of note, the initial rate of disease depletion during the first 2 months of treatment was "highly predictive of longer-term response", he said, while those patients "who do not show rapid disease clearance and have persistent MRD after 12 months...usually have stable or slowly decreasing levels akin to those seen in ibrutinib monotherapy".

Deeper Reduction Factors

Dr Chaitra Ujjani

In the post-presentation discussion, Chaitra Ujjani, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA, asked what factors are associated with a deeper reduction in MRD. Dr Munir said that there is "no single feature which dictates whether the patients will achieve MRD negativity", noting that initial MRD depletion within 2 months "appeared to be quite an interesting characteristic that we're finding on its own dictates whether the patients are going to achieve deep remission".

Dr Ujjani next asked whether he would re-initiate therapy in a patient who has relapsed, and with what agent, and Dr Munir confirmed that this is a question that is being examined in the study.

Patients who relapse are currently allowed to restart ibrutinib as part of the trial, "and we are going to monitor their MRD levels over time".

He pointed out that MRD-positive patients who were obliged to stop venetoclax due to adjustment of the trial protocol and then restart the drug were no more likely to achieve MRD negativity than those who did not restart, "so it appears that ibrutinib monotherapy in patients who haven't achieved MRD negativity, most probably, on its own, is sufficient".

Study Details

TAP CLARITY aimed to eradicate detectable disease with the combination treatment in relapsed or refractory CLL patients so that therapy could be stopped early.

Patients were given ibrutinib 420 mg/day alone for 2 months and then venetoclax was escalated for 5 weeks up to 400 mg/day. Combination therapy was then continued out to 14 months.

If patients achieved undetectable disease, defined as MRD of <0.01% in both the peripheral blood and the bone marrow, at month 8, treatment was stopped at month 14. If MRD <0.01% was achieved at 14 months, treatment was stopped at month 26.

Those having MRD <0.01% at month 26 stopped treatment straight away. If patients were disease positive at this stage, defined as MRD ≥0.01%, treatment was initially continued with ibrutinib monotherapy. However, this was adjusted part-way through the trial to allow patients to continue on combination therapy if they were still MRD positive at 26 months.

The study included 54 patients, of whom 69% were male. The average age was 64 years. Dr Munir noted that four patients had to stop ibrutinib therapy before venetoclax could be added due to toxicity, but 50 continued into the combination therapy phase.

At 12 months, 58% of patients were MRD negative in the peripheral blood and 40% had undetectable disease in the bone marrow.

Complete responses, in line with the 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, were seen in 40% of patients at month 8, 50% at month 14, 64% at month 26 and 68% at month 38, at which point the overall response rate was 90%.

At month 38, MRD negative rates were 50% in the peripheral blood and 40% in the bone marrow, and were approximately 44% overall, although Dr Munir noted that there is "quite of lot of missing data, and that is primarily due to the COVID pandemic".

He also highlighted the relationship between the initial rate of decline of detectable disease, expressed as the log depletion in MRD levels, and overall treatment response.

Specifically, among patients who achieved less than two log depletions in MRD levels during the first 2 months of venetoclax therapy, which was seen in 25 patients, only 20% were able to stop therapy due to sustained MRD <0.01%.

This compared with 68% who were able to stop therapy among those with more than two log depletions in MRD levels within 2 months of starting venetoclax therapy.

Moreover, 76% of those with more than two log depletions in MRD levels had an MRD <0.01% in the bone marrow at month 26, compared with just 24% in patients with less than two log depletions.

'Very Good Marker'

"So it looks to be a very good marker, that initial depletion can tell us how our patients will do," Dr Munir said. "This also correlates with the iwCLL criteria", with fewer complete and partial responses in patients with less than two log depletions.

By the time of the data lock on 6 November, 27 patients in the trial had stopped venetoclax for more than one year, and 25 had also stopped ibrutinib therapy.

Of those, 17 patients have sustained their MRD negative status, and have been off therapy for 18 months, while five have MRD <1%, and one has MRD >10%. One patient experienced disease progression.

While the median progression-free and overall survival points have not been reached, it is estimated that progression-free survival at 36 months is 95.9%, while the overall survival is 97.7%.

Overall, 13 patients had any grade reductions in neutrophil counts, but this translated into febrile neutropenia in only two, and one patient experienced tumour lysis syndrome. The adverse effects, which were in line with expectations, were considered mild and/or manageable.

"Of note, there are two COVID-19 cases which were reported," Dr Munir said.

"Both patients have done very well and have been discharged home."

Supported by Blood Cancer UK under the Trials Acceleration Programme, and by the National Institute for Health Research (NIHR) Leeds Clinical Research Facility and NIHR Oxford Biomedical Research Centre. An unrestricted educational grant to support the trial and adjunctive science was provided by Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie.

Munir discloses Honoraria: Alexion; Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland Other: F. Hoffmann-La Roche; Consultancy: F. Hoffmann-La Roche.

Ujjani discloses Honoraria: Genentech; Verastem Oncology; Abbvie; AstraZeneca; Atara; Research Funding: Abbvie; Gilead/Kite; AstraZeneca; Consultancy: Genentech; MorphoSys; Verastem Oncology; Abbvie; Gilead/Kite; Epizyme; AstraZeneca; Atara

62nd ASH Annual Meeting and Exposition: Abstract 124. Presented 5 December.

Blood 2020; 136 (Supplement 1): 17–18. doi: 10.1182/blood-2020-136960

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