Venetoclax Is A Powerful New Kind of Cancer Drug Effective In Chronic Lymphocytic Leukemia

In In The News by Barbara Jacoby

By: Elaine Schattner


If there’s one message I’d take home from the annual meeting of the American Society of Hematology (ASH) in Orlando, concerning blood cancers – like leukemia, lymphoma and multiple myeloma – it’s that there are a lot of new drugs for doctors and patients to know about, consider and possibly try. If I had to pick a favorite, it would be this: AbbVie ABBV -1.85%’s Venetoclax.

Impressive clinical results for this novel medication were presented in at least six oral sessions, about its use in chronic lymphocytic leukemia (CLL). Doctors also discussed preliminary findings for Venetoclax in a handful of other malignancies, and with other drugs in combination. This week, the New England Journal of Medicine reports Venetoclax as a single-agent drug that’s effective in patients with refractory and progressive and hard-to-treat CLL.

Why I like about Venetoclax is that it derives from science, and that it works. Like many other new targeted drugs, it comes as a pill. The problem for patients and doctors, moving forward, will be how to manage its potentially toxic strength – to give it with care – and how best to dose Venetoclax in combination with other agents.

Chronic lymphocytic leukemia differs from other tumors. Nearly fifty years ago, Dr. William Dameshek called it an accumulative disease of lymphocytes. In CLL the malignant cells don’t proliferate much, but they fail to die. What we know now is that CLL cells contain abundant levels of a protein, bcl-2, that keeps them alive.

Venetoclax promotes cell death by interfering with bcl-2. It reduces the bulk of disease in CLL not so much by directly killing the malignant lymphocytes, but by enabling them to die when triggered, or as they otherwise might.

Based on the results of several studies presented, it appears that this experimental drug yields clear, objective responses in the range of 80% among people with symptomatic, relapsed and refractory CLL. A good fraction of the patients included in the ASH studies* had molecular disease features portending a poor prognosis. Some responses to Venetoclax appear to be long-lasting and deep, with no evidence of disease in patients’ bone marrow or blood, persisting after treatment was stopped.

Andrew Schorr has been living with CLL in remission for over 15 years. He founded a non-profit advocacy group, Patient Power. Through his organization, he’s privy to many CLL patients’ experiences, concerns and perspective on new treatment options.

“This is a powerful drug. It’s like we’ve got a tiger by the tail,” Schorr told me. “We, patients, want Venetoclax precisely because it is so powerful. And we want it given safely,” he said.

“We welcome this drug, but we insist on close monitoring.” Schorr and others in the patient community have been hearing about Venetoclax, with tempered enthusiasm. Even after learning of a patient’s death due to the drug’s having such rapid action, causing tumor lysis and the death, patients have continued to request it, he said.

“Ibrutinib, while it knocks CLL down, is not quite as effective,” Schorr said. This is more like a knock-out punch to the tumor.”

“We’re talking about a strong drug that’s oral,” he considered. “Venetoclax is not aspirin. The patient needs to recognize the power of this medicine, to be aware and discuss it with the doctor,” Schorr said. “It’s concerning, that at the community level, if this drug is approved, patients and doctors may not be sufficiently aware of what it can do,” he added.

Schorr contrasted the new drug, Venetoclax, with Rituxan, a monoclonal antibody that’s been approved by the FDA for use in CLL and has been used for longer in other conditions, such as lymphoma. “After Rituxan was approved, when it got into the community, doctors started infusing it like water,” Schorr said. “One could ask, ‘Was it overused?’ But at least the patients who received it were all monitored, because it’s an infusional drug.”

Venetoclax is a pill, and so it may be even more dangerous if patients aren’t aware of its strong effects, Schorr emphasized. “Patients should be monitored in a hospital at least during the first dose,” he stated. “The insurance companies might have to pay for that night in the hospital. But the hope would be, after a period of time, the patient could eventually go off all medicine, and so it would be worth it.”

“Perhaps it could be given in lower doses,” Schorr said. “Everything I’ve been hearing is you’ve got to combine medicines to outsmart the wily CLL cells long-term,” Schorr said. “Maybe the best idea is to give multiple drugs, to cut off the tumor’s ‘escape route,’ to avoid resistance.”

“We’ve been studying ways to block bcl-2 activity in tumor cells for two decades,” said Gary Gordon, PhD, a vice president of oncology and pharmaceutical development at AbbVie. He’s a scientist with the company, formerly Abbott Laboratories ABT -2.27%. The Venetoclax trials follow early-phase studies of other compounds the company had tried previously, to interfere with bcl-2, to promote cancer cell death.

The Bcl-2 protein, abundant in CLL cells, is a key regulator of programmed cell death. The gradual accumulation of cells, rather than proliferation, results in a slow-growing, hard-to-kill cancer. In some patients the CLL cells divide more rapidly, expanding in bone marrow, lymph nodes, the spleen and circulation. That’s when the disease becomes problematic.

Last year, I wrote about some of the new drugs for CLL, including the new anti-CD20, PI3K inhibitors, and ibrutinib. Years ago the standard treatment was observation, until the disease became problematic. There were so few drugs around, like Chlorambucil, so monitoring was an easy choice.

In patients with advanced CLL, the cells may become so numerous that they take over physical space in the bone marrow and diminish capacity for other cells, like healthy white blood cells, red blood cells and clotting cells (platelets) to grow. Patients suffer complications of infection, anemia and bleeding, and death.

If the leukemic cells could be triggered to die, that would reduce the cancerous cells and lessen their untoward effects. And that is AbbVie’s plan. The drug, a small molecule, mimics BH3. Normally, that protein (BH3) holds on to bcl-2 at the outer wall of mitochondria, within cells including malignant CLL lymphocytes. When Venetoclax passes through the outer cell wall and reaches the bcl-2-BH3 pair, it releases BH3 inside of the cells. A cascade of death-signaling events ensues.

Chronic lymphocytic leukemia is a relatively common leukemia in adults, with nearly 15,000 new U.S. cases each year. The risk for developing CLL increases with age. It occurs with disproportionate frequency in men. Although most CLL diagnoses occur after age 70, 30% of patients find they have this malignancy before age 65. As the population expands and ages, the need to manage this form of leukemia will increase.

AbbVie is developing Venetoclax (ABT-199) in collaboration with Genentech (GDC-0199). Together, the companies have the potential to test this drug in combination with a large roster of approved and experimental anti-cancer agents.

Those would include monoclonal antibodies like Genentech’s Rituxan and its newer anti-CD20 antibody, Gazyva, drugs that block lymphocyte signals through the B cell receptor, like Imbruvica (ibrutinib,  Pharmacyclics PCYC +%, an AbbVie subsidiary), and the experimental agent duvelisib, a PI3 kinase (PI3K) inhibitor that interferes with two components (gamma, delta) of that signaling molecule. Duvelisib is another small-molecule drug, owned by Infinity Pharmaceuticals, in co-development with AbbVie.

As of today, the FDA has approved one PI3K inhibitor, Zydelig (idelalisib, Gilead) for treatment of relapsed CLL and other refractory blood tumors, such as follicular lymphoma. That drug promotes cancer cell death by blocking signals through the delta component of PI3K. At this point, the comparative effectiveness of these two PI3K inhibitors, and comparative toxicity, is not clear, especially as they’re being tested in various combinations with other drugs.

Dr. Jeffrey Jones is a medical oncologist and blood specialist who directs clinical CLL research at the Ohio State University (OSU) Cancer Center in Columbus. He presented one of the new Venetoclax papers at the ASH meeting. “Since we have a large clinical CLL program at OSU, we have a lot of patients who are interested in these new drugs” he told me in an interview. His clinical practice centers on patients with CLL and closely-related conditions.

“It’s exciting to see the patients doing as well as they are,” Jones said. “I have patients who for whatever reasons couldn’t tolerate ibrutinib, and they’re tolerating this.”

For the report Jones presented in an oral session (abstract #715), 54 patients who had relapsed or become refractory to either of two new CLL drugs: Imbruvica (ibrutinib) or Zydelig (idelalisib), enrolled in the open-label, Phase 2 trial. Enrollment was skewed; it includes more patients (41) who progressed after Imbruvica, and only 13 after Zydelig.

The asymmetry in recruitment is a historical artifact, Jones explained. The FDA first approved Imbruvica in November 2013 and specifically for CLL in February of 2014. Approval for Zydelig came later, in July of 2014, he said. “So we have more patients who have developed resistance to the earlier drug, and were eligible for this trial.”

Follow-up is short, with a median time on Venetoclax approaching just five months. But the results are phenomenal, Jones said. “Patients who take Venetoclax, with previously refractory CLL, are entering remissions not just as assessed in their blood, but in some instances by careful molecular assessment in the bone marrow, where this tumor tends to hide.” Some blood specialists refer to this degree of response as a “deep remission.”

What distinguishes Venetoclax, in part, from some other new CLL drugs is that in some cases it can, when given alone, achieve a deep and complete remission. By contrast, with ibrutinib the responses to single agent therapy are less complete until much later in the course of treatment, Jones said.

One reason some CLL patients are starting to ask for Venetoclax, now available only in clinical trials, is the possibility it offers for time-limited therapy, Jones said. “If you’re 55 and have CLL, and you’re thinking am I going to take a drug, like ibrutinib, for the rest of my life, this other treatment may seem worth trying out.” Venetoclax, in combination with other drugs, may lead to remissions sufficiently deep to be durable off of therapy, he suggested.

I asked Jones about his patients’ experience with Venetoclax toxicity. Overall it’s been well-tolerated, he said. “Gastrointestinal problems, like nausea and diarrhea, tend to occur early and can be managed if necessary with medications. The main, potentially treatment-limiting problems are low blood counts, he said. A few patients develop severe infections, like pneumonia.

“Keep in mind, already in CLL patients have compromised immunity,” Jones said. “And these tend to be older patients. So it’s hard to know how much of those complications are from the drug, or from the underlying disease.”

Dr. Nancy Valente is a physician who leads the hematology drug development program at Genentech. “It’s a pleasure to be working with AbbVie in developing this drug,” she told me in an interview.

Venetoclax received breakthrough designation from the FDA earlier this year. “That’s because it has a novel mechanism of action and offers a benefit for patients who have run out of other treatment options,” Valente said.

“We’re seeing activity with Venetoclax in CLL cases that are otherwise really hard to treat,” Valente said. CLL cases with chromosomal deletions of 17p, or mutations in p53, are notoriously difficult; the tumors tend to progress through other treatments. “Venetoclax appears to work in those patients,” Valente noted. “It’s remarkable. The mechanism is independent of p53.”

“It’s an interesting molecule,” Valente said. “Apoptosis, or programmed cell death, is tightly regulated in CLL,” she said. “Bcl-2 is one of the key apoptosis-blocking proteins. In many cancers it’s dysregulated and overexpressed. It stops the malignant cells from dying.” Venetoclax selectively and specifically binding to bcl-2, she said. “Venetoclax interferes with proteins that control the cell death process, and permits the cells to die.”

“We’re seeing durable responses in CLL patients who have stopped taking the drug after achieving undetectable disease levels,” Valente said.  She then referred to work presented at the meeting by Dr. Shuo Ma, who has documented lasting and deep remissions in some previously-resistant cases after discontinuation of treatment.

In that work, presented in an oral session by Dr. Ma on December 7 (abstract #830), the investigators presented follow-up on patients who elected to stop Venetoclax after complete remission had been established. The patients were typical for CLL, older (median age 68), and predominantly male. A third of the patients had either a 17p deletion of a p53 mutation. The overall response rate, among these heavily pretreated and older patients, was 86%.

Ma focused on eleven patients who stopped Venetoclax. Of the nine who had no evidence for residual disease at the time of discontinuing the drug, all remain in complete remission, she said. This sort of durable complete remission is unprecedented in patients with refractory CLL after treatment.

Of note – and concerning, however, one of the patients on this trial, approximately 2 years ago, died from tumor lysis syndrome. This condition is a serious metabolic disorder that can arise when cancerous cells die very quickly, releasing ions and other molecules into the bloodstream. Another patient suffered a similar experience (and death) in a subsequent study. To prevent this condition from developing or becoming problematic, some patients are treated with intravenous fluids (hydration), and monitored when receiving treatment. After those two deaths were reported, the Venetoclax protocol was adjusted and this condition has not been seen again, Ma said.

Ma referred to a paper published this week in the New England Journal of Medicine, a phase 1 trial of over a hundred patients who received Venetoclax for refractory CLL and a related condition, SLL (small lymphocytic leukemia). In that study, three patients in the first (dose-escalation) cohort of 56 patients, developed tumor lysis syndrome, and one died from that cause. Other patients developed laboratory evidence for this complication but, as described, did not suffer clinical signs of toxicity.

In the subsequent “dose-expansion” phase of the study, 60 patients received Venetoclax at 400 milligrams, after a “ramp-up” protocol with gradual dose escalation for each patient. Here, the drug was tried with more checks: patients were admitted to the hospital, hydrated and closely monitored when receiving the first doses. In that segment of the phase I study, as reported, none of the patients experienced tumor lysis syndrome.

Overall, Venetoclax was well-tolerated, and – as a single agent – yielded a response rate of 70% in heavily pre-treated patients who received it, according to the NEJM paper. Many of the patients who responded, in full, had high-risk features in already refractory disease: chromosome 17p deletions and other markers for resistance to other drugs.

At the meeting, in a late-breaking abstract presented by Dr. Stephan Stilgenbauer, investigators reviewed results of an international study of Venetoclax, given as a single agent, patients with “ultra-high risk” disease marked by a chromosomal deletion of 17p. In this study, the overall response rate to Venetoclax was nearly 80%. Half of the patients responded in less than a month. Of note, the median time to achieving a complete remission, in those who did achieve so much disease regression, was just over 8 months. This finding suggests that it may take a while for this drug’s potential to be seen.

Further complicating the picture (in a good way) is another paper just published in the NEJM, and discussed at the meeting, on a new drug called Acalabrutinib (Acerta Pharma). This agent works along the same signaling pathway as Imbruvica, and appears to be effective in CLL patients who became resistant to that drug.

What’s clear is that there are many possible drugs with which Venetoclax, and possibly other, newer drugs in the same class – designed to permit cell death, which might be blocked by any of several molecules related to bcl-2 in CLL, and in some other cancer types – might be tried in combination.

Dr. Valente, of Genentech, referred again to the preliminary papers on combining Venetoclax with other drugs. “We are seeing safe and excellent results when we combine it with Gazyva,” she noted. (Gazyva, or obinutuzumab, is Roche ’s new anti-CD20 antibody; it has been FDA-approved for use in CLL).

“We’re looking at the science, to see what the best combinations will be,” Valente said. “We’re also exploring the use of this drug in other diseases.”

Indeed, at the meeting investigators presented findings for Venetoclax in early-phase trials of lymphoma, multiple myeloma and some forms of acute leukemia. But most of the data in hand come from studies of the drug in CLL.

“It’s all very promising,” Valente concluded. “We’ve always thought about how we might treat CLL with a goal of cure in mind,” she said. “We aim to establish a successful, safe and finite course of treatment for this disease,” she said. “It would be wonderful for a patient to be in remission, to return to normal life. That would be great.”