Pallawi Torka, MD, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the BTK inhibitors available for treatment of patients with relapsed/refractory mantle cell lymphoma (MCL).

Four BTK inhibitors have been approved by the FDA for the treatment of patients with relapsed/refractory MCL, Torka begins. Ibrutinib (Imbruvica), which was a first-generation BTK inhibitor, was the first BTK inhibitor approved in this space, and the second-generation BTK inhibitors acalabrutinib (Calquence) and zanubrutinib (Brukinsa) later followed. In January 2023, 

the FDA approved pirtobrutinib (Jaypirca) for patients with relapsed or refractory MCL

 who have received at least 2 prior lines of therapy, including a BTK inhibitor, based on findings from the phase 1/2 BRUIN trial (NCT03740529).

Since pirtobrutinib is currently approved for use after a prior BTK inhibitor, ibrutinib, acalabrutinib, and zanubrutinib are the first options for patients with relapsed/refractory MCL. Torka notes that in her clinical practice, ibrutinib has drifted away from being a preferred agent, and she are typically opts for either acalabrutinib or zanubrutinib.

In the past, Torka’s preference leaned toward acalabrutinib, unless a patient was on a proton pump inhibitor, which would serve as a contraindication, in which case zanubrutinib would be preferred, Torka says. However, acalabrutinib now has a formulation which is proton pump inhibitor agnostic, making it a viable option for those patients. Selecting between acalabrutinib and zanubrutinib may come down to physician preference and other patient factors, but Torka adds that both are good choices. The preference for acalabrutinib or zanubrutinib over ibrutinib stems from a better safety profile and slightly better efficacy, Torka continues.

Since pirtobrutinib is indicated for patients after disease progression on another BTK inhibitor, it is not a consideration in the same setting as the other 3 BTK inhibitors. For patients who do experience disease progression on a BTK inhibitor, pirtobrutinib represents a viable option, Torka concludes.

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Pallawi Torka, MD, discusses the BTK inhibitors available for treatment of patients with relapsed/refractory mantle cell lymphoma.

Dr. Torka on BTK Inhibitors Available for Patients With R/R MCL

Pallawi Torka, MD, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the clinical implications of the FDA approval of pirtobrutinib (Jaypirca) in patients with relapsed or refractory mantle cell lymphoma (MCL).

the FDA approved pirtobrutinib in adult patients with relapsed/refractory MCL

 who have received at least 2 prior lines of therapy, including a BTK inhibitor. The approval was backed by findings from the phase 1/2 BRUIN trial (NCT03740529), in which treatment with the agent at 200 mg daily led to an overall response rate of 50%, including a 13% complete response rate.

Pirtobrutinib represents an additional BTK inhibitor option for patients with MCL, especially older patients in whom CAR T-cell therapy may not be an option, Torka says. Prior to the FDA approval of pirtobrutinib, once patients with MCL relapsed on first-line therapy, they typically received a BTK inhibitor followed by CAR T-cell therapy after they relapsed on the BTK inhibitor, Torka explains. Brexucabtagene autoleucel (Tecartus; brexu-cel) was approved by the FDA in 2020 for adult patients with relapsed or refractory MCL, based on findings from the phase 2 ZUMA-2 trial (NCT02601313).

Before switching from a BTK inhibitor to CAR T-cell therapy, most patients need bridging therapy, especially those who are receiving treatment at a community cancer center and need to wait to be referred to a site that administers CAR T-cell therapy, Torka notes. Bridging therapy for patients with MCL can include venetoclax (Venclexta) or additional chemotherapy agents such as bendamustine, Torka says. Now, pirtobrutinib can also be considered as a bridging therapy, as it is not toxic to stem cells and does not cause adverse effects to T cells, Torka emphasizes.

Another advantage of pirtobrutinib is its toxicity profile, Torka explains. In the BRUIN trial, 36% of patients received the agent for at least 6 months, and 10% received it for at least 1 year. Additionally, 4.7% of patients required adverse effect (AE)–related dose reductions, and 32% of patients needed AE-related pirtobrutinib interruptions. AEs of grade 3 or higher included fatigue, edema, musculoskeletal pain, arthritis or arthralgia, abdominal pain, dyspnea, pneumonia, upper respiratory tract infections, peripheral neuropathy, and hemorrhage.

In older adults with MCL who often have few therapeutic options, pirtobrutinib provides an extra option that can help patients live longer with minimal AEs, Torka concludes.

Pallawi Torka, MD, discusses the clinical implications of the FDA approval of pirtobrutinib in patients with relapsed or refractory mantle cell lymphoma. 

Dr. Torka on the Role of Pirtobrutinib in R/R MCL

first day of fellowship, a terrified fellow, and a strict attending.

The inpatient leukemia rotation is considered to be a true test of resilience, requiring both mental and physical prowess. The patients are extremely sick, clinical situations can go south in a heartbeat, hours are long, and emotions run high. On top of that, this was my first rotation in fellowship. New colleagues, an unknown electronic medical record system, and science fiction—esque chemotherapy regimens led to a perfect cocktail that would have made the best of heads spin.

Am I making excuses? My attending, Dr Meir Wetzler, had no time for excuses or tardiness. Rather than ramping up gradually and letting this neophyte find her wits, he just looked at me with a matter-of-factness that conveyed “The job needs to be done—just do it!”

Initially I resented this outlook and considered his expectations unreal, until I realized that even after decades of practice, he held himself to the same high standards. He stayed at work as late as I did, and when I would come in the next morning, evidence of his industry would be flooding my mailbox I literally had no clue when he slept or ate.

Soon, after realizing what a nitwit I was, like a good fellow, I sought solace in Harrison’s Principles of Internal Medicine, that good old friend from residency days who could teach me a bit about hematology. I didn’t know what other textbook to turn to. I opened to the chapter on chronic myeloid leukemia (CML). Lo and behold, my attending was the author! Instantly, my respect for him soared exponentially. This distinguished person, rock star of his world, worked night and day unassumingly, with no airs whatsoever. I want to be like that someday! And that was the moment when in my mind our relationship changed from attending—fellow to mentor–mentee; my leukemia attending physician became my ideal, someone I aspired to emulate from there on.

Of course, it was not all smooth sailing. Dr Wetzler’s teaching style was old-school. We would gather around a table and he would draw quickly and ask pointed questions, most of which, despite my years of training, had me stumped. Embarrassment is a great motivator to read more. To this date, amid all that I have learned and forgotten, I still remember what he taught during those sessions—the lock-and-key analogy of various tyrosine kinase inhibitors in CML, their bizarre adverse effects how the Philadelphia chromosome is differentl mutated in CML and acute lymphoblastic leukemia, and the list goes on.

I cannot say that humility was his strongest suit, but he was quick to admit his limits. When challenged with questions outside his expertise, he would have no qualms admitting, “I am sorry. I am not up-to-date with the literature on this topic.” Of course, he wouldn’t just leave it at that. If he thought the question was significant enough, he would study the evidence until he found the answer or call in an expert. As he said often, being thorough is very important in oncology.

It was not all work and no play with this dynamo. I was shocked to learn that this sprightly man was also a triathlete. Of course, sedentary me decided to draw the line at emulating him right there. Every year, this dignified professor enthusiastically participated in oddball charity events like the Gelatin Splash, which involved wearing a funky costume and jumping into 2000 gallons of red gelatin! Some of his avatars for the splash included the Mad Hatter, Kinky Boots, Gru from Despicable Me, Genie from Aladdin, and, of course, Superman. He would throw himself wholeheartedly into any undertaking if it resulted in the betterment of his patients. His enthusiasm was so infectious that the whole division got involved with his shenanigans and the costume contest became a summer staple.

A common refrain on everyone’s lips was “How does he find the time?” And that’s where his leadership skills kicked in. Dr Wetzler was a true team player. He loved his team, and his team loved him right back. He was a taskmaster and demanded the best from everyone every single day, but behind that tough exterior was a heart of gold—he would be the first person to answer a call for help.

After I finished my leukemia rotation, I saw less and less of him. At times when our paths crossed, even though our interactions were brief, he always left me with a snippet of knowledge. Over time, lymphoma became my calling, I found new mentors and moved on, and thoughts of my first mentor slowly faded. Two years later, tragedy struck. Dr Wetzler met with a fatal accident while skiing and was gone, just like that, leaving behind a gaping wound in the hearts of all whom he had touched. This article is supposed to be about what I felt and how I coped. The truth is that for the first few days, I didn’t feel a thing. I suppose I was sad about the loss and what it meant to my institute, his family and patients, and the leukemia community in general, but I was just numb emotionally. My mind, on the contrary, was spinning.

He worked so hard his whole life, and now in a flash, he was gone. All the unfinished projects, everything left behind. What’s the point of all this research and hard work anyway? Life is so unpredictable. What if I have an accident tomorrow?

If he had known what would happen, would he still have lived his life the same way?

I was experiencing deep intellectual turmoil. People around me were choking up at the mention of his name, and here I was standing dry-eyed—sympathizing, despairing, but not from the heart, only from my head. I had expected to be shattered by such a tragic loss. So my stoicism worried me.

How am I supposed to react? Aren’t I supposed to feel something? He was, after all, my attending.

Have I become numbed after caring for patients and seeing tragedy on a daily basis? Have I banished emotion to such deep recesses of my mind that I have lost the ability to experience loss?

How much are you supposed to feel at the passing of a professional colleague? At what point does a colleague become your family?

As weeks passed, Dr Wetzler’s patients were introduced to a new doctor, his clinical trials and administrative and teaching responsibilities were reassigned, and life moved on, but thoughts of him and my lackluster reaction to his passing gnawed at me. The fact that there wasn’t a gut reaction or a spontaneous emotion and that I had to deliberately think what to think left me unsettled.

You see, I had no precedent; I had never been in this situation before, and I didn’t know how to react. People all around me were talking about it, but no one was talking to me about it. They had all experienced my attending in their own way and were busy coping with their own grief. Perhaps no one thought that a fellow should be especially affected by it Should I talk to someone? Should I just carry on as if nothing happened?

My productivity wasn’t affected and I was able to cope otherwise, so I left it at that. Slowly, my mental turmoil settled into a lugubrious gnawing.

It wasn’t until one of the junior fellows called me, crying copiously, one evening that I realized I wasn’t alone in the suffering. I ended up consoling her fo an hour, but when we hung up, she was still in tears. It dawned on me that I shouldn’t have left it at that. I should have talked to my colleagues, for some might have been more distraught than I was, and we might have found solace from one another.

That also got me thinking—mechanisms surely exist for fellows/trainees to vent/talk when an event as momentous as the loss of a mentor occurs. Why don’t we avail ourselves of these mechanisms more often? What stops us from seeking help? I think it is because they rely on the trainee to actively seek them out. I daresay that some in our profession think it is a sign of weakness if one expresses strong emotions overtly. As a result, many providers tend to ignore their personal anguish as long as it doesn’t affect their abilit to do the job.

I bid a final adieu to my teacher on a rainy Sunday afternoon. I went to his funeral partly out of duty and partly out of curiosity about Jewish customs. A simple yet beautiful ceremony with hymns was followed by a motorcade to the cemetery, where friends and family gathered to honor this amazing man. It was there, when I saw his coffin, that the sadness and the nality finally seeped into my heart and the dam broke. Tears started rolling. I was embarrassed but relieved—relieved that I was emotionally whole, a person still capable of feeling and capable of grieving.

As we filled his grave with earth, the skies opened and left us soaked in rain, in memories, in the sense of emptiness and loss. But that’s when true healing began and I finally understood what it meant to have closure. My attending taught me in death as much as he did in life.

Once, Dr Wetzler organized a treetop expedition that involved traversing a rope course over a canopy of trees. It was by far the most physically challenging thing I had ever done. I was struggling on the green rookie courses, while he was acing the most dangerous “black widow” course. I looked down to my surprise to see him taking pictures of me, which, being the epitome of promptness that he was, he sent over right after we finished. His beautiful reply, when I thanked him later, is something that will always remain with me:

Fast-forward 1 year. That terrified first-year fellow has just completed a 30-mile bike ride—getting out of her comfort zone in honor of her amazing mentor. She feels audacious enough to tackle the 54-mile route next year. A lot of lessons are to be learned from his life; I just hope I can remember them all.

As I approach the end of my seemingly unending years of training, I know that I am well prepared, for I carry the legacy of excellence, compassion, curiosity, and love of life instilled in me by my attending. I have truly been trained as a Wetzler’s Warrior!

A leader in field of hematology oncology, Meir Wetzler, MD, died at the age of 60 in February 2015 from injuries suffered in a skiing accident. He was an inspirational figure at Roswell Park Comprehensive Cancer Center in Buffalo, New York, where he was chief of the Leukemia Section. A native of Israel, Dr Wetzler earned his medical degree from Hebrew University’s Hadassah Medical School in Jerusalem and performed his residency in internal medicine at Kaplan Hospital in Rehovot. He joined the Leukemia Division at Roswell Park in 1994.

“You are most welcome. Sometimes one has to get out of his or her comfort zone and try something new. I’m happy that you tried it. As with many things in life, this also is more ‘mind over body’ than anything else.”

Articles

Pallawi Torka, MD, reflects on the lessons learned from an attending physician who inspired his fellows in both life and death.

Pallawi Torka, MD

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