A Matching-Adjusted Indirect Comparison of Acalabrutinib vs. Zanubrutinib in Relapsed or Refractory CLL

The Bottom Line:

Acalabrutinib and zanubrutinib have similar excellent efficacy in relapsed or refractory chronic lymphocytic leukemia (CLL). However, acalabrutinib had a lower rate of serious hemorrhage, hypertension, and the need for dose reduction due to adverse events compared to zanubrutinib.

Who Performed the Research and Where Was it Presented:

Dr. Adam Kittai of Ohio State University led a group of international researchers who presented the result of the comparison between acalabrutinib and zanubrutinib at the American Society of Clinical Oncology (ASCO) annual meeting in 2023 in Chicago.

Background:

BTK Inhibitors (BTKi) have revolutionized the treatment of CLL. All three approved BTKi have similar impressive efficacy, so treatment choices are often guided by which drug is safer and better tolerated. Direct comparisons between acalabrutinib and zanubrutinib are lacking, so this research was an effort to start answering the questions about safety and tolerability.

Methods and Participants:

Matching-adjusted indirect comparison (MAIC) is a method to compare data from different trials. For this MAIC, individual patient data on acalabrutinib from the ASCEND trial were weighted to match zanubrutinib patient data from the ALPINE trial.

Weighted variable included:

• Sex
• ECOG, a measure of a patient’s ability to care for themself, daily activity, and physical ability (walking, working, etc.) developed by the Eastern Cooperative Oncology Group (ECOG),
• Bulky disease
• Prior chemoimmunotherapy
• del(11q) status
• del(17p) status
• TP53 without del(17p)
• IGHV status
• Region
• Age
• Prior lines of therapy
• Rai stage

Results:

• Progression-free survival (PFS) was similar for both drugs.
• There were similar risks for those on either drug development:
• Any grade ≥ 3 adverse events (AE). Grade 3 adverse events are serious and interfere with a person’s ability to do basic things such as eating or getting dressed without help. Grade 3 events may also require medical intervention. Grade 4 AE results in being hospitalized, and a Grade 5 event is “medical jargon” for the patient dying.
• Atrial fibrillation
• Grade ≥ 3 atrial fibrillation/atrial flutter
• Grade ≥ 3 hemorrhage
• An AE leading to discontinuation
• Those taking acalabrutinib had a lower risk than those taking zanubrutinib of having:
• A serious AE
• Any grade and ≥ 3-grade hypertension
• Any grade hemorrhage
• An AE leading to dose reduction

Conclusions:

Progression-free survival was similar for both drugs, but acalabrutinib led to fewer specific adverse events. However, MAIC is, at best, an imperfect way to compare therapies, and we really won’t know the validity of these results until we make a head-to-head comparison between the two drugs as has already been done by each medication with ibrutinib (both drugs caused CLL patients fewer problems than ibrutinib). There are, however, reasons to doubt that we will ever see a trial comparing acalabrutinib and zanubrutinib.

Links and Resources:

To read all the details of the ASCO abstract, please click on A Matching-Adjusted Indirect Comparison (MAIC) of The Efficacy and Safety of Acalabrutinib Versus Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia.

Stay strong. We are all in this together.

Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.

 

My personal decision to restart my CLL (chronic lymphocytic leukemia) treatment

I have good reasons to believe it is time to re-treat my CLL.

Before deciding on the best therapy choice to treat my CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma), I first needed to determine if it was the right time to start therapy.  

 

In most cases, the decision about when to treat CLL is usually just that: a decision. iwCLL has clear guidelines for when treatment is indicated, which we outline in this article: CLL: When to Watch and Wait and When to Start Treatment. I think these might be more helpful in outlining when therapy is not likely appropriate because none of the iwCLL indications are met. For example, someone might have a lymphocyte count that has reached 100,000 or even 500,000 and not need any therapy if they are feeling well and have no low blood counts. 

 

On the other hand, just because one's platelets have dropped below 100,000, which is an iwCLL indication to treat, that does not mean that one urgently has to start to knock back the CLL with medication, especially if the downward trend is slow with ups and downs. One might choose to wait and follow the trend. Or not. It’s a shared medical decision.

 

What about the opposite decision, namely starting sooner than iwCLL guidelines might suggest? 

 

That is what I am choosing.

 

Let me start by saying this is my personal decision, relevant to my circumstances, and likely not applicable to anyone else.

 

In brief, I was diagnosed with CLL in 2005, an aggressive variant, and within a year, I was in a world of trouble with single-digit platelets from a rare and, in my case, difficult-to-treat autoimmune complication (immune thrombocytopenic purpura or ITP) that resulted in multiple hospitalizations, an urgent splenectomy, and massive internal bleeding. ITP tried hard to kill me several times, came close, and I know how lucky I am to be alive. The ITP and the fear of it raging again drove my decision to get a first remission hematopoietic stem cell transplant (HSCT or bone marrow transplant) that quickly failed. My subsequent jump into two phase 1 clinical trials saved my life; the first was for PCI-32765, later to become the practice-changing therapy, ibrutinib, and then for JCAR-014. This CAR-T construct helps birth list-cel, a promising CAR-T cellular therapy already approved in other blood cancers but still experimental in CLL. Both gave me years of deep and wonderful remissions. My fear of recurrent ITP is my primary driver to treat it early again.

 

After beating the odds with a 5½ year remission with CAR-T, my CLL is demanding my attention again. But not in the usual way.

 

True, I have some symptoms that need attention. 

 

True, there are advantages to starting some therapies earlier when the disease burden is low. With some therapies, this can mean both higher efficacy and lower risk of adverse events when the cancer is being rapidly killed, especially early in the treatment.

 

True, some treatment options, especially those in trials, may have narrow windows of accessibility, and when a slot is available, it may force a quicker move than planned.

 

But the real impetus behind my decision to treat now is that I am not waiting for my blood counts to fall. I know that when my platelets fall, they fall off a cliff. In the past, my lymphocyte counts were only slightly elevated when my platelet count fell dangerously low. My other blood cell counts were all perfectly normal at the time. My ITP doesn't send a notice that it’s on its way.

 

Today my absolute lymphocyte count is only 3.8, barely above normal, and only about ¼ of those are monoclonal chronic lymphocytic leukemia cells. That is a very low number, but I know it’s been doubling every 2-3 months for a long time with no signs of slowing down because I have been following it closely with MRD(measurable residual disease) testing using NGS (next-generation sequencing) specifically Clonoseq since it was barely detectable at 1/1,000,000 cells.

 

I am not waiting. My CLL is coming back. It’s not if I’ll need therapy; it's when. With my CLL’s return, it carries the risk of reawakening my ITP. 

 

I am making a preemptive strike. In Julius Caesar, the play by Shakespeare, Brutus could have been talking about my ITP instead of his plot against Caesar “Think him as a serpent's egg, / Which, hatched, would as his kind, grow mischievous, / And kill him in the shell."  

 

I won't let my ITP hatch. I am treating early.

 

Your decision is likely to be different. Waiting and postponing therapy is often the very best option. Everyone's case is unique. The only universal is that nearly always the timing of when to start treatment for chronic lymphocytic leukemia should be a carefully considered shared medical decision between the patient and the healthcare provider.

 

Stay strong; we are all in this together.

 

Brian Koffman MDCM (retired) MS Ed

ASH 2022: Adverse Events from BTK Inhibitors in Clinical Trials

Bottom Line:

This meta-analysis or combination of 61 trials demonstrated that atrial fibrillation, hypertension, and diarrhea were more common with ibrutinib, and some bleeding and infection events were more common with acalabrutinib and zanubrutinib.

Who Performed the Research and Where Was it Presented:

A consortium of doctors led by Dr. Jacqueline Wang of NYU Langone Health presented the abstract at ASH 2022.

Background:

We are aware of how Bruton’s tyrosine kinase inhibitors (BTKi’s) have revolutionized the therapeutic landscape of B-cell malignancies, including chronic lymphocytic leukemia/small lymphocytic leukemia (CLL / SLL), mantle cell lymphoma (MCL), and Waldenstrom’s macroglobulinemia (WM). Ibrutinib was the first FDA-approved BTKi. Unfortunately, its off-target effects have resulted in several adverse events (AEs) of concern, such as atrial fibrillation (an irregular heart rhythm), hypertension, hemorrhage, and diarrhea. Acalabrutinib and zanubrutinib are second-generation, more selective BTKIs developed to minimize off-target effects. While multiple trials have been conducted for these BTKi’s in B-cell malignancies, direct comparison of toxicity profiles between BTKi’s has been limited to just three trials. The purpose of this study was to augment our understanding of these side effects reported with the three approved BTKIs by compiling together many clinical trials.

Methods:

PubMed and major hematology/oncology conference abstracts such as ASH or EHA, or ASCO were searched (last updated query on July 11, 2022) for trials of ibrutinib, acalabrutinib, and zanubrutinib in B-cell malignancies. In addition, adverse events (AEs) of clinical interest or AEs reported by ≥10% of the included trials were analyzed.

Results:

• A total of 61 trials were included involving 6458 patients and 68 treatment arms: ibrutinib (n=30; 44%), ibrutinib plus CD20-mAb (n=14; 21%), acalabrutinib (n=11; 16%), acalabrutinib plus CD20-monoclonal antibodies (mAb) such as rituximab (n=2; 3%), zanubrutinib (n=10; 15%), and zanubrutinib plus CD20-mAb (n=1; 1%).
• More than half of the trials were in CLL / SLL (n=32), the rest in MCL (n=10) or WM (n=9);
• 38 trials were relapsed/refractory setting and 14 in frontline.
• Only three trials involved a randomized comparison between different BTKis (ASPEN, ELEVATE-RR, and ALPINE).
• A total of 65 different AEs were analyzed.
• The most common all-grade AEs across all drugs and trials were infection (62.2%), hemorrhage (41.5%), diarrhea (34.3%), fatigue (22.8%), neutropenia or low neutrophil count (21.6%), and upper respiratory infection (URI) (21.0%).
• The most common grade ≥3 or more serious AEs included neutropenia or low neutrophil count (14.9%) and infection (12.3%).
• All grade/grade ≥3 atrial fibrillation incidences were 6.0%/2.5%, respectively, and for hypertension were 12.5%/7.8%, respectively.
• Comparisons between AEs in trials resulting from ibrutinib and AEs in either acalabrutinib or zanubrutinib were made.
• AEs of any grade that occurred more frequently with ibrutinib included atrial fibrillation (acalabrutinib/zanubrutinib vs. ibrutinib odds ratio or OR 0.30), hypertension (OR 0.47), anemia (OR 0.67), low platelets or thrombocytopenia (OR 0.57), nausea (OR 0.67), vomiting (OR 0.77), and diarrhea (OR 0.49).
• Grade ≥3 or more severe AEs that occurred more frequently with ibrutinib included atrial fibrillation (OR 0.29), hypertension (OR 0.37), diarrhea (OR 0.52), and rash (OR 0.30).
• All grade AEs that occurred more frequently with acalabrutinib/zanubrutinib included contusions (OR 1.50), hematuria (blood in the urine) (OR 1.96), leukopenia (low white blood cell count (OR 2.93), second primary malignancies (OR 1.53), upper respiratory infections such as the common cold (OR 1.29), and headaches (OR 2.03). The risk of headaches when starting acalabrutinib is well known.
• Grade ≥3 AEs that occurred more frequently with acalabrutinib/zanubrutinib included leukopenia (low white blood cell counts) (OR 2.08), upper respiratory infections (OR 1.74), and pneumonia (OR 1.35).

Conclusions:

This is the largest meta-analysis of AEs reported with covalent BTKIs. The results help us better understand the side effects of BTKIs in CLL and other related B-cell lymphomas and cancers. Atrial fibrillation, hypertension, and diarrhea were more common with ibrutinib, similar to what was seen in the head-to-head randomized trials. Additionally, bleeding and infection were more common with acalabrutinib/zanubrutinib. This needs further study to determine whether it is a valid finding.

Links and Resources:

Watch my review of this abstract:

ASH 2022: Dr. Brian Koffman on Adverse Events From BTKi’s in Clinical Trials for B-Cell Malignancies

The actual trial abstract is: Comparison of Treatment-Emergent Adverse Events of Covalent BTK Inhibitors in Clinical Trials in B-Cell Malignancies: A Systematic Review and Meta-Analysis.

Stay strong. We are all in this together.

Brian

Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.

 

Dr. Stephan Stilgenbauer on the Evolution of CLL to Richter’s Syndrome from ASH 2022

Medically reviewed and interview by Dr. Brian Koffman.

The Bottom Line:

This new research identifies some of the genetic changes that drive the evolution of CLL to Richter’s syndrome. Researchers hope this information can be used to develop better treatments for Richter’s syndrome.

Who Performed the Research and Where Was it Presented:

Dr. Stephen Stilgenbauer from Ulm University and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2022.

Background:

Richter’s syndrome (a.k.a. Richter’s transformation) is a rare complication of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), where the cancer cells transform into a much more aggressive lymphoma. It currently has no approved therapies and is associated with an extremely poor prognosis. One way of identifying potential therapeutic targets is to study the biology and mechanisms contributing to the development of Richter’s syndrome. The hope is that it would help scientists to identify better approaches for treating Richter’s syndrome.

Dr. Brian Koffman interviewed Dr. Stephan Stilgenbauer, Professor of Medicine and Medical Director of the Comprehensive Cancer Center at Ulm University in Germany. They discussed new research looking at the genetic changes that drive the evolution of CLL into Richter’s syndrome. Much of this is very technical information that will help inform new therapies.

Methods and Participants:

Researchers analyzed all the DNA in matched Richter’s syndrome and CLL samples from 52 patients. They also analyzed DNA on a validation cohort of 43 independent Richter’s syndrome cases. They used this information to trace the evolution of CLL to Richter’s syndrome.

Results:

• Researchers identified several genes that they think are drivers of Richter’s syndrome (including IRF2BP2, SRSF1, B2M, DNMT3A, CCND3) and other alterations in patients’ genomes.
• Some alterations in key signaling pathways are pre-existing in CLL, such as changes in DNA damage response, NOTCH signaling, and MAPK signaling.
• However, changes in other signaling pathways appear to newly occur with the transformation to Richter’s syndrome, such as changes in inflammatory signaling, cell cycle regulation, immune evasion, and MYC signaling.
• Increasing massive chromosomal rearrangement (chromothripsis) was identified as one of the hallmarks of Richter’s syndrome.
• Richter’s syndrome is genetically distinct from diffuse large B cell lymphoma (DLBCL).
• Though none of the pathways identified in this research have drugs available in the clinic yet, researchers are hopeful that this new information will help to drive the development of new solutions for Richter’s syndrome.

Conclusions:

This new research identifies some of the genetic changes that drive the evolution of CLL to Richter’s syndrome. Researchers hope this information can be used to develop better treatments for Richter’s syndrome.

Links and Resources:

Watch the interview on the abstract here:

ASH 2022: Dr. Stephan Stilgenbauer on the Evolution of CLL to Richter Syndrome

Here is the actual ASH abstract: Evolutionary History of Transformation from Chronic Lymphocytic Leukemia to Richter Syndrome

Ann Liu PhD

 

 

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