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Combo Treatment Offers New Hope in Tough-to-Treat CLL

Combo Treatment Offers New Hope in Tough-to-Treat CLL

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Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • The combination treatment of ibrutinib (Imbruvica) with venetoclax (Venclexta) was well tolerated in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).
  • After 6 months of the combo therapy, 84% had no morphological evidence of CLL in the marrow biopsy, and 76% had less than 1% CLL cells in the marrow.

ATLANTA — The combination treatment of ibrutinib (Imbruvica) with venetoclax (Venclexta) was well tolerated in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), researchers reported here.

In preliminary results from the CLARITY trial, 38 of 54 patients treated with the combination (IBR+VEN) responded to the therapy after 6 months, and 15 of those patients achieved a complete response, according to Peter Hillmen, MBChB, PhD, of the University of Leeds in England, and colleagues.

In addition, only two of 41 patients experienced biochemical tumor lysis syndrome (TLS) to date, they said in a presentation at the American Society of Hematology (ASH) meeting.

“Ibrutinib is an oral BTK-inhibitor affecting antigen-induced proliferation and cell adhesion/migration whilst venetoclax is a potent, highly selective, orally bioavailable Bcl-2 inhibitor affecting CLL cell survival,” the authors wrote. “Ibrutinib treatment leads to a rapid nodal response with re-distribution of CLL into the peripheral blood, whereas venetoclax leads to depletion of CLL cells to levels where they cannot be detected in some patients. Ibrutinib leads to reduction of anti-apoptotic molecules such as MCL1, hence theoretically potentiating the effect of venetoclax.”

The CLARITY trial is a feasibility study to investigate the safety and efficacy of the combination treatment in patients with relapsed/refractory CLL.

The trial enrolled 50 CLL patients who required therapy, and who had either relapsed within 3 years of chemoimmunotherapy (h fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab), or had 17p deletion and had failed at least one line of therapy.

After 8 weeks of ibrutinib monotherapy (420mg/day), venetoclax was added first at a dose of 10mg/day, with weekly escalations to 20mg, 50mg, 100mg, and 200mg. The final dose was 400mg/day. No TLS was seen for the first three patients starting at 10mg/day of venetoclax, so all subsequent patients began venetoclax at 20mg/day.

Hillmen told MedPage Today that the plan is to treat the patients with a complete response for another 6 months, and then take them off medication for CLL to determine if the remission is durable. “

We are just getting to the point now where we will be taking patients off medication,” he said. “We cannot detect residual disease that may be lingering, so we want to extend therapy another 6 months so we can decrease even this undetectable disease several logs lower to the point that the disease may not ever come back.”

There were 37 men and 17 women in the study with a median age of 62. About 92% of the patients were in ECOG performance status of 0 or 1.

The trial’s primary endpoint is minimal residual disease (MRD) eradication, defined as <1 CLL cell in 104 assessed by 8-color flow in the marrow after 12 months of combination therapy. A key secondary endpoints is safety, with laboratory and clinical TLS defined as critical safety events, the authors explained.

All of the patients were given prophylactic uric acid-reducing agents beginning at least 72 hours prior to starting venetoclax, the authors noted. Over the first 3 months of combined therapy, the level of CLL in the peripheral blood was monitored weekly during venetoclax escalation and then every month after that.

The authors reported that the median number of prior therapies was two, including FCR or BR in 94%. Among 45 patients, 20% had 17p deleted, 27% had 11q deleted, and 77% had unmutated VH genes.

Of the two biochemical TLS events reported, one was an increase in creatinine and phosphate, and the other was an isolated phosphate increase, which did not meet the definition of TLS, according to the authors. Dosing of venetoclax was interrupted until the biochemical abnormalities resolved and these patients subsequently escalated to 400mg/day of venetoclax with no further TLS.

As for safety, there were five grade 3 or 4 infections, and 19 episodes of grade 3 or 4 neutropenia. All serious adverse events resolved with appropriate management and all patients remained on therapy following resolution. There were no fatal adverse events.

After 6 months of the combo therapy, 84% (21/25) had no morphological evidence of CLL in the marrow biopsy, and 76% had less than 1% CLL cells in the marrow. Also, 28% achieved an MRD negative remission (<10-4).

“Patients will continue IBR+VEN for the same duration of time as it took them to achieve MRD negativity (i.e. patients who are MRD negative after 6 months IBR+VEN will stop both drugs after 12 months of IBR+VEN). Therefore all patients will continue on IBR+VEN until at least the 14 month assessment (after 12 months of IBR+VEN),” the authors wrote.

“These early results suggest a potent synergy between ibrutinib and venetoclax,” they concluded.

ASH press conference moderator Laurie Sehn, MD, of the British Columbia Cancer Agency in Vancouver, called the results “truly exciting…we are moving towards an era where we can use these targeted therapies to replace some of the toxic agents used to treat hematological disorders.”

“When I trained, CLL was a boring disease to work with because it was a chronic condition, and there were limited treatment options,” she noted. “Now what we have seen with CLL has just been a explosion of an understanding of the disease that has resulted in drugs that have transformed our ability to treat patients. Data like this study are exactly where we want to see the field going. The ability to combine drugs rationally to make them work even better is exciting.”

She called the high response rate “highly impressive…It gives the promise that some of these patients may be cured. This is a first step in moving toward that direction.”

Hillmen disclosed relevant relationships with Gilead, Janssen, GSK, Celgene, AbbVie Company, Novartis, Roche, and Alexion Pharmaceuticals. Co-authors disclosed multiple relevant relationships with industry.

Sehn disclosed relevant relationships with Janssen, Amgen, Seattle Genetics, Abbvie, Celgene, and Roche/Genentech.

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner


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