Mantle cell lymphoma is a somewhat rare B-cell hematologic malignancy that comprises approximately 6 percent of non-Hodgkin lymphoma cases. Each year, there are roughly 4,000 new cases in the U.S., while the 5-year survival rates range from 70 percent for those with limited stage disease to 50 percent for those having advanced disease. The average age at diagnosis tends to be in the mid-60s. Typical treatment for those younger patients with few comorbidities often includes systemic chemotherapy that is often followed by autologous stem cell transplantation; however, for older patients with preexisting comorbidities, standard treatment consists of systemic chemotherapy followed by maintenance rituximab.
Recently, therapies have emerged that target B-cell malignancies, such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and venetoclax (formerly known as ABT-199), a BH3-mimetic that is a specific inhibitor of BCL2. Since these two particular therapies act via different pathways, it was postulated that combining these drugs would result in synergism when treating mantle cell lymphoma. To evaluate that combination, the phase II ABT-199 and Ibrutinib in Mantle-Cell Lymphoma (AIM) study (NCT02471391) was initiated.
One of the leading clinicians in the study was Constantine Tam, MBBS, MD, Hematologist and Disease Group Lead at Peter MacCallum Cancer Centre, Melbourne. A report on this study was recently published in the New England Journal of Medicine (2018;378:1211-1223). Regarding the results in this trial, Tam noted, “Dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in mantle cell lymphoma patients who had been predicted to have poor outcomes with current therapy.”
The pathogenesis of B-cell malignancies is thought to arise, in part, due to abnormal activation of BTK-mediated B-cell receptor signaling pathway (Nature 2010;463:88-92). Signals mediated by cell survival pathways such as NFκB, RAS/RAF/MEK/ERK, and PI3K/AKT can be triggered by BTK activation.
Ibrutinib is an irreversible inhibitor of BTK, which plays a pivotal role in mantle cell lymphoma. As a result of clinical trial data, the FDA granted accelerated approval in November 2013 to ibrutinib for the treatment of mantle cell lymphoma patients having had at least one prior therapy. Subsequently, in February 2014, the FDA granted accelerated approval to ibrutinib as a second-line treatment for chronic lymphocytic leukemia (CLL).
Then, in July 2014, ibrutinib was granted breakthrough therapy designation for the treatment of CLL patients having the chromosome 17p deletion. However, ibrutinib monotherapy is not expected to cure mantle cell lymphoma, as genetic mutations that resulted in resistance to that drug had been observed in CLL patients and altered cell signaling pathways are often common mechanisms of resistance to single agents (New Engl J Med 2013;369:571-572).
The BCL2 family proteins, which are often highly expressed in lymphoid malignancies, play a critical role in the regulation of apoptosis. Venetoclax, which is a BH3-only mimetic, selectively inactivates BCL2 and is thus considered a promising agent for treatment of BCL2-dependent malignancies. However, it is thought that acquired mutations may result in resistance to venetoclax in lymphoma cells (Blood 2014;123:4111-4119). Given these observations, it was thought that the combination of venetoclax with other agents may be a viable strategy for circumventing acquired resistance. In April 2016, the FDA granted approval for venetoclax for the treatment of CLL patients having the chromosome 17p deletion as well as at least one prior therapy.
Since the mechanisms of action for these two compounds appeared to be the blockade of presumably non-overlapping pathways, it was hypothesized that the ibrutinib/venetoclax combination might overcome the resistance observed with single agents alone, as complete resistance would most likely arise from mutations affecting both pathways. Strongly synergistic effects were noted for the ibrutinib/venetoclax combination in preclinical assays that utilized cell lines and primary cells from patients having recurrent mantle cell lymphoma. Mechanistically, the synergy for this combination against mantle cell lymphoma cells was thought to result from disruption of the p-BTK and p-AKT mediated survival signals and of BCL2 family proteins (Br J Haematol 2015;168:765-768).
Mantle cell lymphoma patients from two different sites in Melbourne, Australia, were enrolled in this single-group, open-label, phase II study. Among the inclusion criteria were the following: adult (18 years or older); relapsed or refractory mantle cell lymphoma, or previously untreated disease or unsuitable for cytotoxic chemotherapy; an ECOG performance status score of 0 (fully active) to 2 (ambulatory, self-care capable and bed- or chair-confined for less than 50% of waking hours); a neutrophil count of 750/mm3; platelet count of 75,000/mm3.
One potential risk when treating hematologic malignancies such as this one is a potentially fatal condition termed tumor lysis syndrome (TLS). “This condition arises from destruction of tumor cells, which causes the release of toxic chemicals into the bloodstream,” Tam noted. “It's great to have the tumor cells dying; however, when this happens all at once, that can tax the patient's ability to safely remove those toxins.
“To circumvent this potentially dangerous complication, clinicians can limit pace of tumor kill, keep the patient hydrated, administer preventive medications, and frequently monitor the patient's blood chemistries.”
In this study, to reduce the chances of patients developing TLS, treatment was initiated as oral ibrutinib monotherapy (560 mg/day) for the first 4 weeks. Starting in week 5, oral venetoclax was initiated at 50 mg/day. After that, the dosing was ramped up in a stepwise manner (1 week at a time) to 100 mg, 200 mg, and ultimately 400 mg/day. This dosing scheme was implemented based on the recommended regimen for CLL at the time of study planning. The recommended phase II dosage for mantle cell lymphoma was subsequently reported to be 800 mg/day (J Clin Oncol 2017;35:826-833).
As a result, the study protocol was amended to allow those patients who did not experience a complete response (CR) to have dose escalation up to 800 mg/day after week 16. After venetoclax ramp-up had been completed, patients were dosed with daily ibrutinib and venetoclax until disease progression (PD) or unacceptable adverse events (AEs) were noted.
Concerning the 800 mg daily dosage, Tam noted, “One fact that we learned subsequent to the publication of the NEJM article is that there may be a drug interaction between ibrutinib and venetoclax, resulting in increased exposure to venetoclax when ibrutinib is concomitantly administered. As a precautionary safety measure, we have since capped the maximum dose of venetoclax at 400 mg daily for our ibrutinib-venetoclax combination studies.”
Patients were stratified for TLS according to the following criteria: high risk—largest tumor diameter of ≥10 cm or largest tumor diameter of ≥5 cm and circulating lymphocyte count of ≥25,000/mm3; medium risk—largest tumor diameter of ≥5 cm or circulating lymphocyte count of ≥25,000/mm3; low risk—did not meet both criteria. After TLS was noted in two of the first 15 participants, the protocol was modified to have an extra week of venetoclax ramp-up initiating at 20 mg/day.
Disease status was reassessed at weeks 4, 16, 28, 40, and 56 using the following techniques: computed tomography, both with and without 18F-fluorodeoxyglucose-based positron emission tomography (PET); flow cytometry analysis of bone marrow (with minimal residual disease (MRD) being defined as less than one cell in 10,000); allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) determination of MRD in peripheral blood. Patient responses were reviewed centrally by the lead clinician and a PET expert. NCI Common Terminology Criteria for Adverse Events version 4.0 was utilized for grading AEs.
The primary endpoint for this trial was the CR rate at 16 weeks as measured using the techniques shown above except PET. When asked why this pivotal study endpoint did not include the diagnostically useful PET analysis, Tam replied, “This was done in order to allow for the direct comparison with the results obtained for the phase II PCYC-1104-CA study of single-agent ibrutinib in mantle cell lymphoma; that study did not utilize PET for restaging.”
The data cutoff date for the results included in these analyses was Oct. 4, 2017. Data was censored for those patients not having an event as of that date. Time-to-event analyses were performed using Kaplan-Meier methodology.
Between July 2015 and September 2016, 24 patients were enrolled in this trial; of these, one patient was treatment-naïve who could not undergo cytotoxic chemotherapy, while 23 had either relapsed or refractory disease. Those having prior treatment had a median of two prior therapies with a range of 1-6.
The median duration of treatment for patients in this study was 14.4 months, while the range was 0.7-25.0 months. Two patients did not receive venetoclax during the investigation; one because of a fatal infection and the other because of rapid PD while receiving ibrutinib monotherapy. As of the cutoff date, 16 patients remained in the study, including two patients who had experienced PD but continued treatment because of ongoing clinical benefit. The remaining eight patients discontinued therapy either because of PD (six) or death without PD (two).
The rate of CR at 16 weeks without consideration of PET analyses was 42 percent (95% CI: 22%-63%), which compared favorably to the figure of 9 percent that was obtained for ibrutinib monotherapy in the PCYC-1104-CA study. When one considers the use of PET analyses, the overall rate of CR was 71 percent (95% CI: 49%-87%). In total, 62 percent of patients experienced a CR, while 8 percent noted a PR. In further discussing these data, Tam noted, “Two patients who had a partial response at week 16 subsequently had a complete response, and of these, one occurred after the patient had a dose escalation of venetoclax to 800 mg/day.”
The median progression-free survival (PFS) had not been reached after a median follow-up period of 15.9 months. The estimated rates of PFS for 12 months and 18 months were 75 percent (95% CI: 60%-94%) and 57 percent (95% CI: 40%-82%), respectively.
In the total patient population (24), the flow cytometry-assessed absence of MRD in bone marrow was recorded in 16 patients (67%) and in nine patients (38%), in the ASO-PCR blood-based analyses. “A total of six patients underwent ASO-PCR testing of blood and bone marrow, and all had negative results in both compartments,” Tam added.
When asked about the overall trends noted in mantle-cell lymphoma patients, Tam replied, “TP53 mutations appear to be a critical prognostic factor in mantle cell lymphoma, as they are strongly associated with treatment resistance and inferior survival among patients receiving intensive chemotherapy and undergoing first-line autologous stem-cell transplantation.” In this study, 50 percent of the patients had aberrant TP53, and of these, roughly half had CRs, many of which were durable. “However, the number of such patients is small, and the follow-up is less than 2 years.”
Previous studies have noted the association of mutations in the NF-κB pathway as mediators of poor patient responses to ibrutinib or chemotherapy. “In our study, preexisting NF-κB pathway mutations did not appear to affect the response to combination ibrutinib and venetoclax therapy,” Tam stated. “The small number of patients in these genetically defined subgroups means that these conclusions should be considered preliminary, and as a result, larger studies will need to be done in order to determine their validity. In that regard, the potential superiority of the combination therapy to single-agent ibrutinib in mantle cell lymphoma is being formally evaluated in an ongoing phase III study (NCT03112174).”
Another potential regimen that he mentioned was the stopping of treatment in those patients having a CR with clearance of MRD. “This strategy of therapy cessation has been effective in patients with CLL receiving combination venetoclax and rituximab therapy (Lancet Oncol 2017;18:230-240). However, this question remains open, given that two patients with MRD-negative CRs in our series had a relapse.” Concerning this development, Tam stated, “Yes, those relapses were disappointing but no one was under the illusion that we had cured patients; they did allow us to study mechanisms of resistance, which is a work under review.”
Regarding the limitations of this study, he stated “This was a very small study with a single experimental arm that participants from heterogeneous genetic subgroups. The major positive findings from this study were that you can use the ibrutinib/venetoclax combination together, and that a synergistic effect was observed.”
Richard Simoneaux is a contributing writer.