There are a number of things to keep in mind when reading the PR.
First that 29 of 53 patients were 17p del and 30 were relapsed or refractory.
These were not the easiest patients to treat.Second remember this was ibrutinib flying solo. No help from bendamustine or an antibody.
Third this is still early data. We don't know the durability of these fantastic results.
Finally , we learn that the drug is active in all lymphocyte compartments, the blood, the lymph nodes, the spleen, and the marrow.
Please take a look of this data in light of Dr. Wiestner's recent plea that we carefully reassess whether we need to continue with business as usual by insisting more is better and pushing for the "ideal chemo cocktail."
Rather I believe that these new targeted therapies demand that we fully reassess how we treat CLL and we don't just add these molecules to the existing mixes, effective as they are, but rather we see what they can do on their own, and make slow and logical decisions about what combinations (if any) to consider.
I like the idea of totally avoiding old school chemo if possible, but only time will tell if that is the wisest approach.
Even mixing two pathway blockers, while mechanistically appealing, is totally unknown territory.
One reason I fear that one reason that chemo or biologicals such as rituximab might get added to these trials (especially true for the very potent and active idelalisib or CAL 101 that where the high counts might linger a bit longer) is that the benign spike seen in the absolute lymphocyte count as the B lymphocyte clone cells exit their protective enclaves in the nodes and marrow and enter the blood stream where they can be counted, may last a long time and makes the early data look weak. Those raised numbers suggest the drug is not working to the uninitiated and it takes works to explain the back story. We all know that is not the case and they are in fact potent therapies, but adding chemo or a mAb solves that short term concern and speeds up the data collection. My questions are: Does it really improve outcome? Does it add unnecessary risk?
Truth is we don't know the answers. That is why we need the trials, but the reported 94% event free survival at 1 year as solo therapy is hard to improve on.
Here is the press release from AACR:
Embargoed for Release: Media Contact:1 p.m. ET, April 8, 2013 Jeremy Moore (215) 446-7109 Jeremy.Moore@aacr.org In Washington, D.C.
April 6-10, 2013:
(202) 249-4005
Ibrutinib Safe, Effective Against Untreated, Relapsed and Unresponsive Chronic Lymphocytic Leukemia
· Ibrutinib disrupts the CLL-driving B-cell receptor signaling pathway.· Phase II trial showed the drug was well tolerated and effective against CLL regardless of del 17p status.· The drug was effective against disease in blood, lymph nodes, spleen and bone marrow.
WASHINGTON, D.C. — The novel drug ibrutinib was well tolerated and highly effective in patients with untreated, relapsed and unresponsive chronic lymphocytic leukemia (CLL), according to phase II data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.
“The degree of tumor reduction achieved by once-daily oral therapy was impressive,” said Adrian Wiestner, M.D., Ph.D., investigator and head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) in Bethesda, Md. “We have seen patients with more than 90 percent reduction of lymph node disease within just two months.”
Many elderly patients with CLL are unable to tolerate current aggressive standard therapies, and those with a deletion in the short arm of chromosome 17, referred to as “del 17p,” have particularly poor outcomes with chemotherapy. These two CLL patient populations that are enrolled in the NIH phase II study have the greatest need for novel treatment therapies, according to Wiestner.
Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL. This study confirms the single-agent antileukemia activity seen in prior phase I/II studies and extends this experience, particularly in del 17p CLL, according to Wiestner.
He and his colleagues enrolled 53 patients with CLL into two cohorts — 29 patients with del 17p and 24 patients without del 17p who were aged 65 years or older. They assigned all patients to 420 mg of ibrutinib daily and evaluated response to the drug at six months and every six months thereafter, until disease progression.
Most adverse events were mild or moderate and included diarrhea, fatigue and rash, severe events occurred in less than 13 percent of the patients.
At six months, 95 percent of patients showed at least a 50 percent reduction in lymph node disease, and all showed reduction in spleen enlargement, with a median reduction of 55 percent. In 26 patients for whom a bone marrow biopsy was done, tumor infiltration decreased by 82 percent. Absolute lymphocyte count decreased by a median of 62 percent. Using standard CLL response criteria, 52 percent of patients had a partial response. At 12 months, the estimated event-free survival rate was 94 percent.
Using blood and tissue samples of lymph nodes collected from 15 patients before and during ibrutinib treatment, Wiestner and his colleagues showed effective inhibition of B-cell receptor signaling and tumor proliferation, which was reduced by more than 80 percent, as measured by Ki67 staining.
“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status,” Wiestner said. “Responses appear to be durable, and the drug is effective against the disease in lymph nodes, spleen and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach will greatly improve the lives of patients with this disease.”
This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute at the NIH.# # #
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About the American Association for Cancer ResearchFounded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit www.AACR.org. On a personal note, I am just back from a wonderful, meaningful high school reunion held in Vancouver, BC though we all went to an all boys school in Toronto (UTS) three thousand miles away. I am hoping to do one of my personal reflective posts soon, but because of the important breaking news and backlog of interviews, I have been weak on telling my CLL and life story that is happily boringly stable these days. Later this week I will be lecturing in Orlando, Florida. No rest.