ASH 2021: Dr. Jeff Sharman on Zanubrutinib for BTK Inhibitor-Intolerant Patients with Chronic Lymphocytic Leukemia (CLL)

At the American Society of Hematology (ASH) 2021 Annual Conference and Exhibition, I interviewed Dr. Jeff Sharman, a hematologist/oncologist at Willamette Valley Cancer Institute in Eugene, OR. We discussed zanubrutinib and its use in patients who could not tolerate previous BTK inhibitors.

Chemotherapy was until recently the only treatment available to CLL/SLL patients until the BTK inhibitor ibrutinib revolutionized the treatment of CLL/SLL.

Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib are very effective for treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).But, they are meant to be taken continuously, and some patients can have trouble tolerating their side effects. Therefore, second-generation BTK inhibitors such as acalabrutinib and zanubrutinib have been designed with the goal of reducing side effects.

Takeaways:

• BTK inhibitors are wonderfully effective, but the problem is that they do have side effects.
• Even small to moderate side effects can be discouraging for patients when you have to take a drug indefinitely.
• Some side effects patients may experience with ibrutinib include joint pain, muscle cramps, bruising, high blood pressure, and an irregular heartbeat (atrial fibrillation).
• Second-generation BTK inhibitors such as acalabrutinib and zanubrutinib were designed to be more specific and minimize side effects.
• In head-to-head studies, patients taking acalabrutinib or zanubrutinib have lower rates of high blood pressure and atrial fibrillation than those taking ibrutinib. 
• For this phase 2 study, 64 patients who could not tolerate ibrutinib or acalabrutinib due to side effects were switched to zanubrutinib.
• When patients switched to zanubrutinib, the symptom which previously caused them to stop taking their last BTK inhibitor did not recur in 73% of patients. If a symptom did recur, it tended to recur at a lower intensity.
• When patients switched to zanubrutinib, they experienced fewer side effects or were better able to tolerate those side effects.
• Additionally, patients demonstrated they maintained (41%) and improved (53%) responses with zanubrutinib treatment.

Conclusions:

Zanubrutinib is not yet approved for CLL, but can be used "off-label" to treat CLL/SLL.

Second-generation BTK inhibitors appear to be just as effective as ibrutinib but with fewer side effects making them possibly more tolerable for long term use.

Please enjoy my video interview with Dr. Sharman from the ASH meeting, held in December 2021 in Atlanta, GA, and virtually.

You can read the actual abstract here: Phase 2 Study of Zanubrutinib in BTK =Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Take care of yourself first.

Thanks to Ann Liu for the notes on my ASH interview.

ASH 2020: Dr. Anthony Mato on LOXO-305 A Next Generation Highly Selective Non-Covalent BTK inhibitor.

In an oral presentation during ASH 2020, Dr. Anthony Mato discussed LOXO-305, a new generation BTKi (Bruton Tyrosine Kinase Inhibitor) that blocks a key step in the B cell receptor (BCR) pathway. In doing so, it blocks pro-survival and “homing” messages to the CLL cells, forcing the cancer cells to leave their protective niches in the lymph nodes and bone marrow, and float out into the blood stream, eventually dying.

Ibrutinib was the first approved BTKi and it revolutionized the treatment of CLL because of its ability to provide a durable response in most patients, including those with high-risk features such as del 17p or TP53.

However, especially in the relapsed and refractory setting, some CLL cells may eventually be able to escape inhibition from ibrutinib and other similar BTKis such as acalabrutinib and zanabrutinib (not approved for CLL at the time of this writing). The most common way this happens is by a mutation in the drug’s binding site at C481 preventing those 1st generation BTKis from irreversibly binding to and blocking BTK, rendering those drugs largely ineffective.

LOXO-305 binds “reversibly” and does not seem to be affected by changes in the C481 binding site. It remains able to turn off BTK when the irreversible binders are no longer effective.

Dr. Mato discusses the CLL data from the BRUIN trial, which is the first in-human trial of LOXO-305 for CLL and NHL (Non-Hodgkin Lymphomas)

• 170 CLL patients were studied.
  • 80% had received ibrutinib or acalabrutinib.
• 200 mg is the daily dose.
• Fatigue, diarrhea, and bruising were the only side effects above 10%.
• < 1% had atrial fibrillation.
• Response rate for all 63%. If one looked at just the patients who were assessed at > 6 months or greater giving the medicine some time to work, the response rate went up to 86%.
• 94% of those who responded are still on drug.
• Patients responded well even they failed multiple other drugs and were running out of options.
• First study of one BTK inhibitor after failing another BKI inhibitor.

Conclusions:

Blocking the BTK pathway works amazing well for CLL patients, so when patients relapse on a first generation BTK inhibitor, there is good sense in trying another drug that uses a different mechanism to block the B cell receptors through BTK inhibition. Early data from the BRUIN trial suggest that LOXO-305 seems is a promising new option with regard to efficacy and tolerability and deserves further study to assess it in larger numbers of patients.

Here is a link to the actual trial on Clinicaltrials.gov that Dr. Mato describes in our ASH interview: A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL.

Please enjoy our interview:

Here is the ASH abstract: LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results from the Phase 1/2 BRUIN Study.

Stay strong.  We are all in this together.

Brian

Brian Koffman MDCM (retired) MS Ed

ASH 2020: Dr. Arnon Nagler on Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation After Targeted Therapy for Chronic Lymphocytic Leukemia (CLL)

At the virtual ASH 2020 Annual Conference and Exposition, Dr. John Pagel of Swedish Hospital and one of CLL Society’s directors interviewed Dr. Arnon Nagler of Sheba Medical Center in Israel concerning using “in-house” CAR-T cells made locally at his medical center for Richter’s Transformation patients.

 

Richter’s Transformation (RT) is usually an aggressive transformation of chronic lymphocytic leukemia into a fast-moving lymphoma, usually clonally related, DLBCL (diffuse large B-cell lymphoma). RT is associated with a very poor response to most therapies and has a discouraging prognosis.

 

It remains one of the most pressing unmet needs in CLL patients.

 

That is why when the Israeli group showed that six of nine Richter’s patients responded to CAR-T therapy, their research was recognized for its importance and given a slot as one of the six oral CLL clinical presentations at ASH 2020.

 

Take Aways:

·      These were mostly heavily pretreated patients, all having progressed on ibrutinib and/or venetoclax

·      Del 17p/TP53 was found in 83% (five out of six) of those tested

·      Despite these poor markers and their aggressive disease, six of nine patients had complete remissions

·      Only two of these six progressed within a year, including one who went on to have a bone marrow transplant

·      One significant advantage of an “in-house” CAR-T is that the waiting time to manufacture the CAR-T is only ten days, so “bridging therapy” to keep the fast-moving Richter’s under control while waiting for the cells is less likely to be needed

·      No new problems or adverse events were noted in this Richter’s population. Just the usual three that are seen in most CAR-T treatments:

1.     Cytokine release syndrome (CRS): An acute systemic inflammatory syndrome characterized by fever, flu-like symptoms, and has the potential for low blood pressure and multiple organ dysfunction. It is usually of short duration, is now well understood, and can be safely managed in nearly all cases.

2.     Neurotoxicity: Might include headache, confusion, delirium, language disturbance, coma, seizures, and rarely acute brain swelling. It is usually mild and is almost always fully reversible.

3.     Low blood counts: May include anemia, low neutrophils, low platelets, and low lymphocytes. It can be persistent, but counts do recover over time.

 

Conclusions:

 

These results give us clear proof that CAR-T cellular therapy can work in Richter’s Transformation, and that is much-needed good news. The numbers are small, so larger studies will be needed, and I am sure will be done to confirm the promising findings.

 

But there remain many unanswered questions.

 

Can CAR-T be curative for some? For at least some patients, there is reason to be hopeful this might be the case.

 

Should it be used as a bridge to an allogeneic stem cell (bone marrow) transplant for RT patients to “consolidate” their response? We know the transplants (while high-risk and not perfect) still offer the best, most durable responses in Richter’s to those who are well enough to undergo the procedure.

 

Here is Dr. Pagel’s interview with Professor Nagler from ASH 2020: https://youtu.be/yFOWNR0x-u0

 

A transcript of the interview is being provided, as some of the interview is difficult to understand. We ask you to rely on the abstract linked below for study details, as we are not certain of the accuracy of every word in the transcript.

 

Here is the ASH abstract: Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia

 

EHA 2021: Dr. Anthony Mato on pirtobrutinib (LOXO-305) for Richter’s transformation in chronic lymphocytic leukemia (CLL)

Richter’s transformation (a.k.a. Richter’s syndrome) is a rare complication of chronic lymphocytic leukemia (CLL) where the cancer cells transform into a much more aggressive lymphoma. It occurs in 2-10% of CLL patients, and it is associated with very rapid disease progression, limited therapeutic options, and poor survival. Outcomes have generally been poor because the lymphoma does not respond well to traditional treatments. While chemotherapy is often used to treat Richter’s transformation, it is not very effective. 

 

At the annual meeting of the European Hematology Association (EHA) 2021,I interviewed Dr. Anthony Mato, Director of the CLL Program at Memorial Sloan Kettering Cancer Center. They discussed preliminary results from a clinical trial of pirtobrutinib (formerly LOXO-305) in a subset of patients with Richter’s transformation.

 

Takeaways:

·      This is a phase 1/2 clinical trial of pirtobrutinib, which is a highly-selective, reversible (non-covalent) Bruton’s tyrosine kinase (BTK) inhibitor we have previously discussed here.

·      The trial is currently ongoing, and this portion of the trial is enrolling patients with previously treated Richter’s syndrome.

·      Thus far, 17 patients with Richter’s transformation have been enrolled in the trial. 

·      These patients have already been heavily treated. The median number of prior therapies for CLL was 6, and the median number of prior therapies specifically for Richter’s transformation was 2.

·      Thus far, 15 patients have had a response assessment, and 67% (2 out of 3) responded to treatment.

·      Though it is still early on, some patients have continued to respond after 6+ months of follow-up.

·      Pirtobrutinib is probably not a cure for Richter’s transformation, but it may help stabilize the disease, improve quality of life, and potentially serve as a bridge to other therapies such as CAR-T therapy or stem cell transplant.

·      Thus far, pirtobrutinib has been well-tolerated with very few serious adverse events.

 

Conclusions:

There is a large unmet need for effective treatments for Richter’s transformation. Even though these results are only in a small number of patients with a short follow-up period, pirtobrutinib seems like a promising candidate thus far. This is encouraging news for patients who have few options, and we hope that we continue to see positive results with longer term follow up in more patients. If you are interested in participating, the trial is still ongoing at multiple sites in the United States and worldwide. More information can be found here.

 

Please enjoy this brief interview with Dr. Mato from the virtual EHA meeting which was held June 2021.

 

<Video link> https://youtu.be/OOV7myAT4aA 

 

You can read the actual abstract here: Pirtobrutinib (LOXO-305), a next generation, highly-selective, non-covalent BTK inhibitor in previously treated Richter transformation: results from the phase 1/2 BRUIN study

ASH 2020: Dr. Peter Hillmen on the CLARITY Trial of Ibrutinib Plus Venetoclax for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

 

 

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and BCL2 inhibitor venetoclax have been very successful as individual therapies for treating chronic lymphocytic leukemia (CLL), but on their own they rarely lead to the eradication of measurable (a.k.a. minimal) residual disease (MRD). Researchers have been very interested in whether they can combine these therapies to improve outcomes for patients and achieve better remissions. They also want to determine how long would patients need to take the combination for to achieve deep remissions.

 

At the annual meeting of the American Society of Hematology (ASH) 2020, Dr. John Pagel of the CLL Society Board of Directors interviewed Dr. Peter Hillmen, Professor of Experimental Hematology at the University of Leeds in the United Kingdom. They discussed updates to the phase II CLARITY trial which has been evaluating the efficacy of combination ibrutinib + venetoclax in patients with relapsed/refractory CLL.

 

Takeaways:

·      The CLARITY trial is a phase II study testing the combination of ibrutinib + venetoclax in patients with relapsed/refractory CLL. The primary endpoint the researchers were evaluating was undetectable measurable residual disease (uMRD) after one year, and those results have been published here.

·      Almost all patients (89%) responded to treatment.

·      Responses continued to improve after the first year of combination treatment with 24/50 (48%) patients achieving uMRD in the bone marrow at month 26 compared to 20/50 (40%) at month 14.

·      After 3 years, responses to ibrutinib + venetoclax were sustained even though many patients had discontinued treatment due to achieving uMRD.

·      Patients who had not yet achieved uMRD by year 2 were allowed to extend combination treatment duration for and additional year.

·      While there was some benefit in year 3, most of the benefit occurs earlier on. This suggests that patients who respond probably only need a limited duration of therapy, and more is not necessarily better.

·      The response to treatment in the first 2-3 months seems to predict who will achieve uMRD. Thus, clinicians might want to alter the treatment plan if a patient doesn’t respond to ibrutinib + venetoclax early on.

 

Conclusions:

These results show that combination therapy with ibrutinib + venetoclax can produce deep remissions with eradication of MRD in many but not all patients with difficult to treat relapsed/refractory CLL. Thus far, these responses seem to be sustained even with planned treatment discontinuation once uMRD is achieved, and researchers continue to follow these patients.

 

The logical extension of this research is to see if ibrutinib + venetoclax can be used as a first line treatment. We know that the best responses are with first line treatment, and some phase II trials of ibrutinib + venetoclax as a first line treatment for CLL have shown promising results. However, phase II trials usually do not have a comparator group so the results can’t be directly compared to other treatments. To address this gap in knowledge, a large clinical trial is currently underway to test ibrutinib + venetoclax as a first line therapy vs. ibrutinib alone or FCR chemoimmunotherapy.

 

Please enjoy this brief interview with Dr. Hillmen from the virtual ASH meeting which was held December 2020.

 

<Video link> https://youtu.be/05oooiOKGDw 

 

You can read the actual abstract here: Continued Long Term Responses to Ibrutinib + Venetoclax Treatment for Relapsed/Refractory CLL in the Blood Cancer UK TAP Clarity Trial

Dr. John Byrd’s Exciting Move to the University of Cincinnati: The significance for me and other CLL (chronic lymphocytic leukemia) patients

I have known Dr. John Byrd since we met at ASH in 2011 and he has been my chronic lymphocytic leukemia (CLL) doctor most of that time.

It would not be a stretch to say that his care in a Phase I/II trial of PCI-32765 (ibrutinib) at Ohio State University in Columbus saved my life.

It would also not be fair if it weren’t mentioned that I have been blessed with excellent care from several other doctors. These have included superstar Dr. Tom Kipps, Drs. Sanjay Sharma (hematology), David Rhodes (family medicine), many local healthcare providers, and a recent addition to my team, CLL expert Dr. Alexey Danilov. There have been many others across the US and from around the world who have generously nudged me or shared breaking news pertinent to my circumstances, even when I was not their patient or had only seen them once many years ago. These consultations have been led by Dr. Furman and have included Drs. Kanti Rai, John Pagel, Adrian Weistner, Michael Hallek, Stephen Forman, and Neil Kay.

While I have been lucky to know so many world-class CLL doctors, for the last 10 years, Dr. Byrd has been my go-to clinician and the final arbitrator of many split decisions in my treatment journey. 

We have become good friends over the past decade, which has been eventful and revolutionary for chronic lymphocytic leukemia patients. Today we had a long talk about a very personal matter that affects me and could have a direct impact on hundreds of CLL patients. 

Dr. Byrd recently accepted the position of Chairman of the Department of Internal Medicine at the University of Cincinnati and will be starting there on July 1, 2021. The University of Cincinnati press release can be found here. Dr. Byrd has been at Ohio State University (OSU) for the past 20 years building a strong team focused on research, clinical trials, and care of patients with CLL and other blood cancers.

The OSU CLL team has contributed to improving outcomes for all of us in moving forward with therapies such as ibrutinib, acalabrutinib, and novel drug combinations. Dr. Byrd also has been a mentor to many CLL physicians, best exemplified by the excellent research and clinical care being led by his younger colleagues who will continue carrying out the great work at OSU.

In discussing the reason for the change with Dr. Byrd, it became clear that he is going to the University of Cincinnati with a renewed sense of personal excitement to grow personally as a leader and build an impactful program there that will benefit the lives of many dealing with cancer. 

Dr. Byrd told me how appreciative he was of the years spent at OSU and all the support he received. At the same time, he shared that he realized his personal need for reinvigoration and to make an even bigger impact in the cancer community that he is hoping the University of Cincinnati will provide. 

The University of Cincinnati is next door to the Cincinnati Children’s Hospital and Research Institute, which has the nation’s top pediatric cancer program. The close proximity and relationship will create the perfect opportunity to build bridge programs in multiple areas. This will impact the ability to accelerate new discoveries that will translate to adult cancer patients, which can then be redirected seamlessly back to children’s cancer. The Cincinnati area is the largest US city that does not have a cancer center that has been designated by the National Cancer Institute (NCI). 

Working with the team at the Barrett Cancer Center in Cincinnati, Dr. Byrd will continue his work in early drug development and translational laboratory research for CLL and other types of cancer. He will also continue expanding precision medicine in blood cancer and be continually reinforcing the charge for empathetic patient-focused care.

Dr. Byrd will continue seeing patients with CLL and other blood cancers as a consultant to other physicians, as a CLL and blood cancer expert collaborating with local doctors on yearly visits (as he has done with many patients over the years), and by providing direct care to CLL patients in Cincinnati. 

While there have been rumors that Dr. Byrd will stop seeing patients, in my discussion with him he assured me that this remains the most exciting and favorite part of his job. He is already working on the paperwork for clinical privileges there and hopes to be active in the clinic by August of this year. He is also excited to have some ability to see Veterans Administration patients since the University of Cincinnati has an associated VA Hospital, unlike OSU. From the time of his military service, Dr. Byrd has had a strong commitment to supporting soldiers and veterans alike. He will continue working with new clinical trials that will be available for his patients to match the expectations he established at OSU.  

He told me that his greatest regret of transitioning to the University of Cincinnati is leaving many patients in Columbus with whom he has established long-term patient relationships. While Dr. Byrd is very comfortable with the abilities of the CLL team at OSU following up on his active patient panel (Drs. Jennifer Woyack, Kerry Rogers, Adam Kittai, and Seema Bhat), he is openly welcoming those who decide to follow him to Cincinnati. Dr. Byrd intends to continue collaborating with the CLL team at OSU as well as other individuals (Drs. Jennifer Brown, Deepa Samath, Farrukh Awan, and Deborah Stephens) with whom he has worked over the past two decades on different projects.  

During my discussion with Dr. Byrd, I sensed his excitement about this upcoming transition, the chance to build a new cancer center and to do something special that has the potential to be even more impactful for cancer patients in general, and particularly CLL patients in the future.  

On a personal note, while Dr. Byrd may be taking on new responsibilities across all internal medicine, after our conversation I felt reassured that he will still be directly caring for and researching the best cutting-edge therapies in CLL for myself and all of us for many years to come.

Stay strong.  We are all in this together.

 

Brian Koffman MDCM (retired) MS Ed

Co-Founder, Executive VP and Chief Medical Officer
CLL Society 

The passing of a CLL pioneer and hero: Joe Greenblatt

Sad news.

 

My long time CLL buddy and a founding member of the CLL Society Patient Advisory Board, Joe Greenblatt sailed away on January 23, 2021 after a long struggle with COVID-19. Joe had beaten a coma-inducing West Nile Virus encephalitis years ago, learnt to walk again, but his 3rd time on a ventilator proved too much when his lungs and kidneys ultimately failed him.

 

I met Joe more than a dozen years ago when he had the great notion to meet up with fellow CLLers at our homes and share our war stories and insider tips. He realized the uniqueness of CLL and felt that we needed our own support and education group with others who lived with our unique blood cancer. It would be different than other cancer groups. It was to be patient led (no nurses, no social workers) and it would be exclusively for CLL families. 

 

Three of us first met in his living room. And as the say, the rest is history, with CLL Society’s 38 CLL specific support and education groups engaging nearly 2,000 members across the continent today.  

 

In recent years, Joe had drifted away from CLL Society though he continued to serve on the patient advisory board. His CLL was quiescent and he wanted to spend time with his family and his boat. He was a busy guy. But he was proud of his legacy.

 

I will be forever in his debt. And if you enjoy the benefits of one of the CLL Society support groups, you might be too.

 

His passing is also a cautionary note in these dangerous times. I beg readers to not let down their guard. There is an unpredictable killer in our midst hunting for its next victims. Foil it with a mask and soap and social distancing. Get vaccinated. 

 

I mourn his loss. He was a trusted friend who told it like it was, a skilled and competitive sailor, and a pragmatic visionary. 

 

I hope the winds are filling his sails wherever he is now.

 

Over the years, CLL Society has grown beyond support groups with live online education, support, research and advocacy services to serve the many unmet needs of the CLL community. But the recognition of those unmet needs all began with a handful of us meeting in each other's living rooms. I am still reminded of it every time I see the faces and hear the questions and concerns of my fellow patients and caregivers whom I am now meeting monthly thorough the magic of ZOOM.

 

If you haven’t already joined one of our now virtual monthly support and education groups, find out what you have been missing. Simply click on CLL-Specific Patient Support Groups to learn more. Do it for Joe and for yourself.

 

Stay strong, stay safe, we are all in this together.

 

Brian