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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - Annual Meeting of the American Society of Hematology

Atlanta, Georgia / December 9-12, 2017

Atlanta - The recent approvals of many effective, well-tolerated novel agents for chronic lymphocytic leukemia (CLL) have changed the treatment landscape. Researchers are learning how best to sequence and potentially combine novel agents, including ibrutinib, idelalisib, and venetoclax, both with respect to chemoimmunotherapy and other novel agents. A handful of combination and single-agent CLL therapies show promising results, according to reports at the ASH 2017. A major aim of CLL treatment is to eradicate detectable minimal residual disease (MRD), which is associated with improved outcomes regardless of the therapy used to achieve it. Deep remissions including MRD negativity may be achieved with the added benefit of fixed duration of therapy.  A consistent safety profile is also important to expand therapy to as many patients as possible.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Advances in Combination Therapy
for Relapsed/Refractory CLL

According to investigators here this week, a combination of the BCL-2 inhibitor venetoclax plus the anti-CD20 monoclonal antibody rituximab (VR) is superior to standard chemotherapy with bendamustine plus rituximab (BR) in patients with relapsed/refractory CLL. (ASH Abs#LBA-2, Seymour et al.)

An interim analysis of the open-label, randomized, phase III MURANO trial presented during the late breaking clinical trial sessions, included 389 CLL patients, (194 VR patients and 195 BR patients). In the VR arm, a four- to five-week graduated dose ramp-up of venetoclax from 20 to 400 mg daily was used to mitigate the risk of potential tumor lysis syndrome (TLS). Beginning at week 6, rituximab was then given monthly for six 28-day cycles intravenously 375 mg/m2 first dose, then 500 mg/m2 in combination with venetoclax daily. Patients continued with venetoclax 400 mg for a maximum of two years or until disease progression. In the BR arm, patients were given bendamustine intravenously 70 mg/m2 on days 1 and 2 of each of six 28-day cycles in combination with rituximab using the same rituximab dosing schedule.

After a median follow-up of two years, median progression-free survival (PFS) was significantly prolonged with VR (median PFS not reached) as compared with BR (median PFS of 17 months) (Figure 1).The 24-month PFS rate estimates were 84.9% in the VR group versus 36.3% in the BR group. Higher peripheral blood MRD-negativity rates attained at any time were seen with VR (83.5%) than with BR (23.1%) by ITT analysis. In addition, MRD-negativity was more durable in the VR arm. The safety profiles were consistent with those found with the regimens, with no new signals.

“This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach,” said Dr. John Seymour of Royal Melbourne Hospital, Melbourne, Australia. “It suggests that venetoclax should replace chemotherapy for relapsed/refractory CLL. There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this setting.”

Combination of Novel Oral Agents Shows Promise

Other findings presented during the scientific sessions demonstrated that thee Bruton’s tyrosine kinase inhibitor ibrutinib plus venetoclax leads to high rates of overall response, complete remission (CR), and MRD eradication in patients with relapsed/refractory CLL.

The phase II CLARITY trial enrolled 50 patients, median age 64 years, with relapsed/refractory CLL. After six months of combination therapy with the targeted agents ibrutinib and venetoclax, one-third of patients with previously treated CLL had no detectable disease, with no increase in the occurrence of TLS, reported United Kingdom researchers (ASH Abs#428, Hillmen et al.).

In a U.S. study, researchers at MD Anderson Cancer Center provided ibrutinib and venetoclax to 70 CLL patients, 34 patients with relapsed/refractory disease and 36 patients with high-risk disease who received first-line therapy. Almost half of the relapsed/refractory patients who completed six months of the combination therapy had a response, with a significant decrease in bone marrow infiltrate, including MRD-negativity in several patients with high-risk cytogenetics. (ASH Abs#429, Jain  et al.) In the high-risk cohort, all patients who completed six months of therapy responded and several patients achieved undetectable bone marrow MRD status.

Durable Clinical Outcomes

A combination of the anti-CD20 monoclonal antibody obinutuzumab and venetoclax shows a high level of deep, durable responses with unprecedented MRD-negativity rates compared with chemoimmunotherapy regimens and other novel chemotherapy-free therapies in first-line studies.

Preliminary clinical data showed this combination was associated with an acceptable safety profile and promising efficacy in relapsed/refractory or previously untreated CLL. (ASH Abs#430, Flinn  et al.). In this new analysis, a group of 32 patients, median age 63 years, were given first-line therapy with obinutuzumab cycle 1: 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15; cycles 2–6: 1000 mg day 1, based on a 28-day cycle plus venetoclax 400 mg daily. Venetoclax was gradually ramped up to the final dose. This was followed by an additional six cycles of venetoclax monotherapy for up to one year of treatment, depending on CLL disease status.

All 32 patients responded to the treatment, and 72% achieved CR or CR with incomplete blood count recovery and 75% had bone marrow MRD-negativity. Undetectable peripheral blood MRD rates were maintained after end of treatment. The 18-month estimated PFS was 90.5%. The therapy was well-tolerated, with no clinical TLS.

“High rates of CR, MRD-negativity, and preliminary PFS results predict durable clinical outcomes for patients treated with this one-year fixed duration, chemotherapy-free regimen in first-line CLL,” reported Dr. Ian Flinn of Sarah Cannon Research Institute, Nashville, TN. “Obinutuzumab appears to be a better anti-CD20 antibody than rituximab, with higher efficacy. Combinations with venetoclax are safe, well-tolerated, and moving earlier in the course of treatment into the front-line setting.”

Single-agent Therapies

A pooled analysis from three ongoing studies shows venetoclax monotherapy induces deep, durable responses in relapsed/refractory CLL patients, including those with del(17p).

A total of 352 patients, median age 66 years, about two-thirds of them with del(17p), received venetoclax starting with weekly dose ramp-up to 400 mg daily over 4–5 weeks and continued the drug until disease progression or discontinuation.

CR, PFS, and overall survival (OS) were most favorable for patients with less disease bulk and fewer prior therapies ASH Abs#4329, Wierda et al.). Potential poor prognostic indicators of del(17p) CLL and prior exposure to B-cell receptor inhibitors appeared to predict similar outcomes for patients, depending on their disease bulk or line of therapy (Table 1).

“These data suggest that patients may derive greater benefit from venetoclax if used earlier in the treatment sequence and, for patients with active disease, prior to the development of bulky lymphadenopathy (more than 5 cm),” reported Dr. William Wierda of the University of Texas MD Anderson Cancer Center in Houston, Texas.

Data from a recent retrospective cohort analysis of patients treated with venetoclax in the real world setting showed that ibrutinib had activity after venetoclax failure. (ASH Abs# 4315, Mato et al.) Among the 16 patients who discontinued venetoclax and were subsequently treated with ibrutinib, ORR was 69%. Some 63% of patients had prior kinase inhibitor exposure. These researchers reported that prior ibrutinib exposure and poor risk genetics were associated with inferior PFS, particularly for those with del(17p) or prior kinase inhibitor exposure. Ibrutinib is active following venetoclax discontinuation. Optimal sequencing of newer CLL therapies such as these, requires further study following venetoclax discontinuation.

Another study presented by Dr. Flinn, (ASH Abs#493, Flinn et al.) showed that the PI3K inhibitor duvelisib as monotherapy holds potential as a new, convenient treatment option for previously treated CLL and small lymphocytic lymphoma (SLL) patients. A phase III randomized study evaluated duvelisib oral monotherapy 25 mg twice daily continuously versus ofatumumab monotherapy 300 mg intravenous infusion on day 1 and 2000 mg intravenous infusion weekly (x7) then monthly (x4) in 319 patients with relapsed/refractory CLL/SLL.

These investigators found that duvelisib monotherapy achieved significant improvement in PFS (13.3 months) over ofatumumab (9.9 months). Similar benefit was seen in patients with del(17p). According to investigators, duvelisib significantly reduced lymph node burden more than 50% in most patients (85%) as compared to ofatumumab (16%). With a median exposure of 50 weeks, the adverse event profile of duvelisib was manageable and consistent to what had been previously observed.


Despite the recent development of novel targeted therapies to treat CLL, the disease remains incurable and many patients will eventually relapse even with optimal treatment. Additional therapies targeting novel pathways are needed. With several classes of non-chemotherapy agents active in CLL, researchers are now investigating both rational drug combinations and monotherapies in hopes of inducing deep responses and durable, long-term survival. Historic reports with chemoimmunotherapy demonstrate that less disease bulk, fewer lines of therapy, and sensitivity to chemotherapy correlate with depth and durability of remission.

The availability of novel agents is an important advance for patients and a challenge for clinicians to learn how best to sequence them. Sequencing should be guided both by the individual patient’s prognostic markers, such as FISH and immunoglobulin heavy chain variable region-mutation status, as well as comorbidities. The big challenge remains to establish the best therapy for all patients with CLL In this era of multiple new targeted therapies and better outcomes, the goal is to improve survival and remission duration for patients with relapsed CLL.

The major clinical implication of new drug development and novel combinations, is the demonstration of effective therapies for relapsed/refractory or previously untreated disease to improve survival and quality of life. Novel oral agents appear to be tolerable, effective, and yield better disease control, affording patients an excellent opportunity to get access to better treatment.

Questions & Answers

Questions and answers with Dr. Carolyn Owen, University of Calgary, Division of Hematology & Hematological Malignancies, Calgary, Alberta, Canada. MURANO clinical trial investigator.

Q: What are the real-world implications of the MURANO trial for Canadian practicing oncologists?

A: MURANO is a study of relapsed/refractory CLL patients treated with venetoclax plus rituximab versus bendamustine plus rituximab, a conventional chemoimmunotherapy regimen available today in most parts of Canada. In this era of new targeted therapies, everybody is motivated to treat patients without chemotherapy. Venetoclax is the newest of the targeted therapies. It is currently available in Canada only through a compassionate access program and private insurance, primarily for highly refractory CLL patients. This study allowed any patient with relapsed CLL including those who had only received 1 prior line of therapy to receive venetoclax and rituximab in combination.

The results of the MURANO study are impressive, including an excellent efficacy outcome, long duration of remission, and tolerability of this time-limited therapy. This is the first of the new targeted therapies used with a finite period of therapy.

Q: What is the importance of fixed treatment duration?

A: Fixed treatment duration is valuable because it gives patients an end point of therapy and is a more cost-effective method of treatment. It’s difficult to forecast for patients treated with ibrutinib, which continues until progression, how much therapy will cost. Currently, we estimate how many CLL patients will be on therapy and how much it will cost. With a time-definite therapy, we know exactly how much it will cost, which is likely to be less and with less toxicity.

Q: Why is the depth of response with MRD-negativity important?

A: MRD-negativity has been linked to overall survival, as well as duration of remission. We see more MRD-negativity in the venetoclax arm in MURANO. The study already shows an overall survival difference favouring the venetoclax arm. The even more impressive difference in MRD-negativity suggests that with time, we may see an even larger overall survival advantage in the venetoclax arm.

Q:  What does the consistent safety profile indicate?

A: With venetoclax, there were only two main toxicities – tumor lysis syndrome, which can be mitigated with dosing maneuvers and dosing ramp-up, and neutropenias. In combination with rituximab, there was a potential concern of more adverse events, but a positive finding of the study was no new adverse events. Neutropenia is still notable, but no worse with the combination. Infectious complications, such as febrile neutropenia, are still quite rare, and no more common in the venetoclax arm.

Q: What is the next step in the research?

A: Most people will argue that bendamustine plus rituximab is not the standard comparator today. Drugs like ibrutinib and idelalisib were not available routinely in Canada when the study started. By the time of this study’s end, the standard of care for relapsed CLL had moved to targeted (kinase inhibitor) therapy. The question is: will venetoclax-rituximab replace ibrutinib for second-line or third-line therapy for patients who have not been exposed to a B-cell receptor inhibitor?

The next step is to compare targeted therapies against each other and to watch patients longer. MRD-negativity is very new to relapsed CLL. If we can demonstrate with time that a proportion of patients are not relapsing, that would be a motivator to move toward the venetoclax-rituximab combination.

To see video complement of this report, please view Canadian Perspectives.


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