The FDA has approved zanubrutinib for the treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.
The FDA has approved zanubrutinib (Brukinsa) for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
The approval was based on findings from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials.
Findings from SEQUOIA showed that at a median follow-up of 25.0 months, the median progression-free survival (PFS) was not reached (95% CI, not estimable [NE]–NE) with zanubrutinib vs 33.7 months (95% CI, 28.1-NE) with bendamustine and rituximab (Rituxan; BR) in patients with treatment-naïve CLL/SLL enrolled in a randomized cohort (HR, 0.42; 95% CI, 0.28-0.63; P ≤ .0001).
In a separate non-randomized cohort of SEQUOIA, zanubrutinib produced an overall response rate (ORR) of 88% (95% CI, 81%-94%) in patients with previously untreated CLL/SLL with 17p deletion (n = 110). The median duration of response (DOR) was not reached after a median follow-up of 25.1 months.
In ALPINE, zanubrutinib led to an ORR of 80% (95% CI, 76%-85%) vs 73% (95% CI, 68%-78%) with ibrutinib (Imbruvica) in patients with relapsed or refractory CLL/SLL (response rate ratio 1.10; 95% CI, 1.01-1.20; P = .0264). The median DOR was not reached in either arm after a median follow-up of 14.1 months.
In the randomized cohort of SEQUOIA, which included patients without 17p deletion, 479 patients were randomly assigned 1:1 to receive zanubrutinib until disease progression or unacceptable toxicity or 6 cycles of BR. PFS assessed by an independent review committee (IRC) served as the primary end point.
In ALPINE, a total of 652 patients with relapsed/refractory CLL/SLL were randomly assigned 1:1 to receive treatment with zanubrutinib or ibrutinib. The median number of prior lines of therapy was 1 (range, 1-8). IRC-assessed ORR and DOR served as the primary efficacy end points.
Regarding safety across trials of zanubrutinib, the most frequent adverse effects occuring in at least 30% of patients who received the second-generation BTK inhibitor were neutrophil count decrease (42%), upper respiratory tract infection (39%), platelet count decrease (34%), hemorrhage (30%), and musculoskeletal pain (30%).
Second primary malignancies, including non-skin carcinomas, occurred in 13% of patients. Atrial fibrillation or flutter were reported in 3.7% of patients, and 0.2% of patients experienced grade 3 or higher ventricular arrhythmias.
Per the FDA label, the recommended dose of zanubrutinib is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.
Reference
FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed January 19, 2023. bit.ly/3D1iUjq
Len
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lankisterguy
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Great to see Len, but it's a bit of an anticlimax, given Brukinsa/zanubrutinib has been able to be prescribed off label in the USA since FDA approval for the treatment of the close cousins to CLL, Mantle Cell Lymphoma, back in 2021. Accordingly, NCCN began recommending zanubrutinib for the treatment of CLL two years ago.
Still, it's excellent news to have two BTKi drugs with considerably lower adverse event profiles than ibrutinib, particularly with respect to cardiovascular toxicity. That's shown well in the off target kinase inhibition comparison illustration you provided a while back. An ideal drug would have one large red circle on the target enzyme (Bruton's kinase in this case) and none elsewhere.
Neil
In off target kinase order acalabrutinib, then zanubrutinib, outperform ibrutinib
In a Targeted Oncology interview this week (27 Jan 2023), Dr Jennifer Brown "discussed the mechanism of action of zanubrutinib and how it differs from other Bruton’s tyrosine kinase inhibitors".
"Zanubrutinib is much more specific for BTK than ibrutinib is. Acalabrutinib is also more specific for BTK. That doesn't distinguish them that much, but 1 thing that does distinguish zanubrutinib from both of them is its pharmacokinetic properties. The drug remains present in the bloodstream throughout the entire dosing interval so that if new BTK is generated by the cells, the drug can still inhibit BTK and it's available to inhibit it again."
"This is not true of ibrutinib and acalabrutinib. After they do their initial inhibition covalently, they don't stay in the bloodstream, so new BTK would not be inhibited until the next dose. That's perhaps the main biological rationale for why zanubrutinib could be more effective than ibrutinib. The other would be that the dosing was optimized to maintain BTK occupancy. Part of that's the PK but part of it's also the dose and schedule."
well I’m not sure I understand everything in this report. But I can say that I had 6 months of FCR and 9 months of BR and I didn’t get into remission with either and had to be treated within 24 months after each of these treatments.
I should also add that I had almost a year of Ibrutnib and I was allergic to it and landed in the hospital. I then had a year of V&O. I finally was in remission but for less than 2 years. I am again in treatment with V@O and it took over 7 months too see any positive results.
I would agree that you and I are atypical, we are both far to the left side of the statistical bell curves for any genetic data (I'm Tri 12 UnMutated, and would guess you are UnMutated and not 13q or 11 q). I was also diagnosed in 2008 but never had FCR or BR, only the newer targeted drugs approved since 2010.
Your history with infections is far more serious than mine, but my remissions are shorter than yours. Neither of us tolerated Ibrutinib, and Venetoclax works OK but nothing spectacular.
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What the report suggests and my experience confirms, is that Ibrutinib has some serious side effects for some of us, but as long as we get some benefit from a BTK inhibitor, Zanubrutinib / Brukinsa or Acalabrutinib / Calquence might be worth a trial.
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I hope you are under the care / supervision of one of our CLL expert "rock stars" at a leading research center like MD Anderson, OSU or NY Presbyterian, since we will keep even the best and brightest of them from being bored with navigating our treatment choices.
thanks Lankister. Going into city tomorrow rinse CLL doc . Neck filled with nodes !!! But most numbers still in green zone. Platelets down to 178. Always been in 200's. But neck nodes keep coming and they were the only ones that didn't respond to the Zanubrutinib. They actually got bigger. And no one is even trying to find out why. If numbers are good why worry ? That's what they say. Maybe I do need a bone marrow biopsy. Never had one. First ever CLL doc I had said "just because your numbers are good doesn't mean it's not raging through your bone marrow" 😳😳. Scared the crap out of me and I went somewhere else. But maybe he was right.
Bone marrow biopsies don't tend to be done by CLL specialists unless something really unusual seems to be happening, which can't be determined by blood tests. You can get a reasonable feel for bone marrow capacity by monitoring trends in your red blood cells and haemoglobin, platelets and neutrophils. Platelet counts tend to bounce around a fair bit, so it's hard to say whether your drop to 178 (comfortably into the the healthy range of 150 to 450) is part of a trend is due to bone marrow infiltration or normal variation.
Thanks Neil. My platelets actually went up to 198 a week later on this lab. I was more concerned about the "anisocytosis" which I have never seen before and the red blood cell distribution width. Doctor said that even tho there are more nodes in my neck the rest of my numbers are in the green so no meds yet, which is fine with me lol.
Don't worry about your anisocytosis, it's your neutropenia that's important. You need to take greater care to avoid infections as you are bordering on stage 3 neutropenia (neutrophil count under 1.0).
Anisocytosis just means that your red blood cells are of uneven size. I don't know what's meant by the 1 + (A) entry for that item, but anisytosis is highlighted by your high RDW (Red blood cell Distribution Width) result. That's an expected result when your bone marrow is under stress from CLL infiltration or the effects of drugs or other factors on the regular production of red blood cells. It will take over 3 months after your bone marrow has settled down for your RDW result to stabilise, simply because red blood cells last about 100 days, so it will take up to that long for unevenly sized red blood cells to replaced.
I actually told him I was concerned about neutropenia and he said i was fine ! I also mentioned to him about bone marrow. Once again his response. Everything fine !
My question to him : IS everything REALLY fine??? How many stages are there with neutropenia and what is it caused by?
Your neutropenia is of course also caused by the same disruption to your bone marrow which is causing your anisocytosis. It should resolve much faster, but needs to be monitored to see that it doesn't worsen.
"Him" is my CLL specialist at NY Presbyterian!! He said he'll see me in four months ! What symptoms or signs should I be looking out for since he obviously thinks I'm fine. I actually questioned him about everything you mentioned because I never saw those results before. He felt that since all my other numbers were in the "green" zone that I was fine. How is neutropenia treated? I wouldn't have to go back on CLL meds to treat that, would I?
There are no outward symptoms that you have neutropenia; you wouldn't know without a blood test. A neutrophil count of 1.0 may not be that risky; I averaged that in my 11 years of watch and wait. It depends on how stable it is and your level of exposure to infections, in particular bacterial and fungal infections. You need to quickly treat any cuts and scrapes, then cover them until they heal. You also probably shouldn't have teeth cleaning or dental work done without prophylactic antibiotics taken an hour beforehand. My specialist advised me not to floss, but my neutrophils dropped below 0.5 at times.Neutropenia when you have CLL can be due to one or more of the following; an infiltrated bone marrow, swollen spleen or autoimmune condition. Infections and some drugs are more common causes.
If you are having treatment, the protocol varies with the drugs concerned. Infusions are delayed until neutrophil counts are over at least 1.0. Doses of oral medications may be reduced or neutrophil counts boosted with granulocyte-colony stimulating factor injections into the skin over your abdomen or thigh.
you know it's interesting...I had some viral warts on my hands "cryofreezed" by my usual dermatologist's assistant who I've never seen before. I told her I had leukemia and when she performed the procedure I felt she did overkill on them. Two of them were black for almost a month and I went through boxes of bandaids trying to keep them clean and dry. I mean how do you wash your hands when you have bandages on? I finally took them off to wash my hands and replaced them four or more times a day. The last one is just barely healed. I wonder if my increase in neck lymph nodes is a result of possible infection caused by this process. My regular dermatologist was always very careful when treating me. He got burned out running two offices 7 days a week. Taking some time off. I'm not going to let her do any more to me. I actually remember feeling like my body went into shock after the procedure. I had trouble driving home. Too much "attack" for a body incapable of receiving it.
I think an infection in your hand would most likely cause raised nodes under your arm, not in your neck. Also, you'd likely get a painful hand from cellulitis and possibly a red line running up your arm (phlebitis). Good question for your CLL specialist!
I honestly didn't think about it however I do know about red lines and infection. Right now I'm suffering with a neck filled with "pebbles" so many that I had trouble finding my pulse !!!! I do think my past thyroid cancer history is rearing it's nasty head here and I'm either hypo or hyper thyroid. Endo appt squeezed in in March. Hopefully old endo is soon back in a new office with my new PA! Heard rumors !
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