Alana Hippensteele, Senior Editor

The FDA has issued an emergency use authorization (EUA) for nirmatrelvir (PF-07321332) tablets and ritonavir tablets (Paxlovid, Pfizer) for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years and older, following positive SARS-CoV-2 viral test results.

Specifically, the EUA is for patients who weigh at least 88 lbs and who are at high risk for progression to severe COVID-19, including hospitalization or death.

The oral antiviral treatment includes nirmatrelvir, a novel main protease (Mpro) inhibitor that was specifically designed to block SARS-CoV-2 Mpro activity. Mpro is an enzyme that the coronavirus must replicate to advance and progress within the body.

“Today’s authorization of Paxlovid represents another tremendous example of how science will help us ultimately defeat this pandemic, which, even 2 years in continues to disrupt and devastate lives across the world,” Albert Bourla, chairman and CEO of Pfizer, said in a statement.

The FDA’s decision to issue an EUA for this oral antiviral treatment was based on clinical data from the phase 2/3 EPIC-HR trial. During this trial, investigators enrolled non-hospitalized patients aged 18 years and older who had positive COVID-19 test results and who were at increased risk of progressing to severe illness. The trial data showed patients experienced an 89% reduction in risk of COVID-19-related hospitalization or death when treated with the oral antiviral within 3 days of symptom onset compared with patients on the placebo.

The investigators noted that, in the treatment group, no patient deaths occurred. However, in the placebo group, 9 deaths had occurred by day 28. Investigators also observed similar results in those treated within 5 days of symptom onset, as these patients experienced an 88% reduction in risk with no deaths occurring.

During the trial, investigators found the treatment-emergent adverse events (AEs) from the oral antiviral were comparable to the placebo (23% vs 24%). Furthermore, most of the AEs were found to be mild in intensity.

Although the clinical trials assessing the oral antiviral did not include patients under aged 18 years, the trial investigators noted an expectation that the authorized adult dosing regimen would be comparable in pediatric patients aged 12 years and older weighing at least 40 kg.

Additionally, further phase 2/3 clinical trials are ongoing in adults at standard risk of progressing to severe illness from COVID-19 (ie, low risk of hospitalization or death) and in patients who have been exposed to the virus through exposure within their households.

With the oral antiviral for COVID-19 receiving this EUA from the FDA, Pfizer noted in the statement that the company is ready to begin delivery of the treatment to the United States immediately. In November 2021, an agreement between Pfizer and the US government had been settled that established a supply of 10 million treatment courses of the oral antiviral treatment to be delivered to the United States, with the completion of the delivery fulfillment expected in 2022.

“This breakthrough therapy, which has been shown to significantly reduce hospitalizations and deaths and can be taken at home, will change the way we treat COVID-19, and hopefully help reduce some of the significant pressures facing our health care and hospital systems,” Bourla said. “Pfizer stands ready to begin delivery in the United States immediately to help get Paxlovid into the hands of appropriate patients as quickly as possible.”

Pfizer receives U.S. FDA emergency use authorization for novel COVID-19 oral antiviral treatment. Pfizer. News release. December 22, 2021. Accessed December 22, 2021. 

https://www.businesswire.com/news/home/20211221005795/en/Pfizer-Receives-U.S.-FDA-Emergency-Use-Authorization-for-Novel-COVID-19-Oral-Antiviral-Treatment

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The emergency use authorization is based on data from the EPIC-HR trial, which showed that the drug significantly reduced the risk of hospitalization or death compared with the placebo.

FDA Issues EUA for COVID-19 Oral Antiviral Treatment From Pfizer for At-Home Use

The drug is available in both oral suspension and tablet dosage forms for use in individuals aged 18 years or younger.

The FDA has approved 2 additional pediatric indications for rivaroxaban (Xarelto, Janssen Pharmaceutical).

The first indication is for the treatment of venous thromboembolism (VTE) and risk reduction for recurrent VTE in patients aged 18 years or younger, following a minimum of 5 days of initial parenteral (injected or intravenous) anticoagulant treatment. The second indication is for thromboprophylaxis in children aged 2 years and older with congenital heart disease, following a Fontan procedure. The latter indication now makes rivaroxaban the only direct oral anticoagulant (DOAC) that is FDA-approved for thromboprophylaxis in pediatric patients following this procedure.

"Historically, there has been limited guidance and options for health care providers on how to help reduce potentially serious, even fatal, blood clots and related events in young children," Andrew Van Bergen, MD, pediatric cardiologist, Advocate Children's Hospital, said in a statement.

"We have had to adjust adult doses of standard anticoagulation therapies, which are both burdensome and uncomfortable for patients, and require frequent monitoring,” he said. “Now that Xarelto is FDA-approved with weight-based dosing options, either as tablets or liquid formulation, a convenient option is available allowing flexibility to tailor the treatment for my patients."

Although physicians are often recommended to adjust adult doses of standard anticoagulation therapies for pediatric patients, available data are limited on the efficacy and safety of these therapies in younger patients. Following this FDA approval, the oral suspension formulation is expected to become available for pediatric patients in the United States in mid-January 2022. Upon its availability, the oral suspension formulation can be administered to pediatric patients through a color-coded dosing device to minimize dosing errors. Only oral tablets are available for pediatric patients in the United States.

"When a child is experiencing health challenges, learning that they are also at risk for a blood clot can feel overwhelming for the patient and also their parents or caregivers," Andrea Baer, MS, BCPA, executive director of Mended Hearts, said in the statement. "Knowing that there is now an FDA-approved oral treatment option to reduce the risk of blood clots that's easy and may be more comfortable than injections to administer may help ease that burden."

Rivaroxaban has 11 FDA-approved indications in the United States. The latest approval is based on data from 2 phase 3 pediatric clinical trials, including the EINSTEIN-Jr study, which was the largest to date assessing rivaroxaban in pediatric patients from birth to aged 18 years with previously diagnosed VTE, and the UNIVERSE study, which was the first clinical trial to assess the use of a DOAC in the prevention of VTE in pediatric patients after undergoing a Fontan procedure.

"Today's FDA approval marks 2 new Xarelto indications for pediatric patients, an often underrecognized but especially important patient population," James List, MD, PhD, global therapeutic area head, cardiovascular, metabolism, and retina at Janssen Research & Development, said in the statement. "The approval of the 10th and 11th indications for Xarelto underscores its capability in reducing the risk of blood clots and cardiovascular events in patients from young to old and with a variety of conditions."

FDA approves two new Indications for Xarelto® (rivaroxaban) to help prevent and treat blood clots in pediatric patients. Janssen Pharmaceutical. News release. December 20, 2021. Accessed December 22, 2021. 

https://www.prnewswire.com/news-releases/fda-approves-two-new-indications-for-xarelto-rivaroxaban-to-help-prevent-and-treat-blood-clots-in-pediatric-patients-301448701.html

FDA Approves 2 New Indications for Rivaroxaban to Prevent, Treat Blood Clots in Children

The FDA has approved apremilast (Otezla, Amgen) for adult patients with plaque psoriasis who are candidates for either phototherapy or systemic therapy.

With approximately 8 million individuals diagnosed with plaque psoriasis in the United States, 5 million of whom have mild to moderate disease, this expanded indication for apremilast makes it the first and only oral treatment approved for adult patients with plaque psoriasis at all severity levels.

"Plaque psoriasis can place a significant burden on the lives of patients, regardless of the severity of skin involvement. A substantial unmet need remains for mild to moderate plaque psoriasis patients for whom topical therapies may not be sufficient, especially for those with difficult-to-treat areas, like the scalp," David M. Reese, MD, executive vice president of research and development at Amgen, said in a statement.

"With this expanded indication for Otezla, patients across all levels of disease severity now have an oral, systemic option that has already been used by more than 650,000 people worldwide and has no lab monitoring requirement,” he said.

The FDA approval is based on the results from the phase 3 ADVANCE trial assessing response in patients with mild to moderate plaque psoriasis. During this trial, 5 times as many adults with mild to moderate plaque psoriasis administered apremilast at 30 mg twice daily were found to achieve the primary endpoint of the Static Physician's Global Assessment (sPGA) response at week 16 compared with those in the placebo group (21.6% versus 4.1%, p<0.0001).

Apremilast also was found to show statistically significant improvements in key symptom assessment areas, such as the Scalp Physician's Global Assessment (ScPGA) response (44% versus 16.6%) and the Whole Body Itch Numeric Rating Scale (NRS) response (43.2% versus 18.6%), at week 16 compared with the placebo. As early as week 2, the investigators observed these improvements in the ScPGA, sPGA response, and Whole Body Itch NRS responses, with these improvements maintained through week 32.

During the trial, investigators observed adverse events (AEs) in patients that were consistent with the known safety profile of apremilast. Specifically, the most common treatment-emergent AEs (≥5%) were diarrhea, headache, nasopharyngitis, and nausea.

"Given that psoriasis is a systemic inflammatory disease, some patients may need more than surface level relief," ADVANCE investigator Linda Stein Gold, MD, director of Dermatology Clinical Research at Henry Ford Health System, said in the in the statement. "For the first time, dermatologists can offer patients struggling with plaque psoriasis of any degree an effective oral treatment with an established safety profile."

Following this expanded indication, apremilast has been approved for 3 indications in the United States that include adult patients with active psoriatic arthritis, adult patients with oral ulcers associated with Behçet disease, and adult patients with plaque psoriasis who are candidates for phototherapy or systemic therapy.

Although treatment advancements have been made in recent years, patients with plaque psoriasis continue to have a significant unmet need, particularly among those with mild to moderate plaque psoriasis or among those who experience persistent symptoms even after administering a topical treatment.

"Plaque psoriasis often affects patients more severely than can be measured by Body Surface Area alone, particularly for those with manifestations in difficult-to-treat areas, like the scalp. The location of plaques may make the area sensitive to topical treatments or challenging to apply them,” Stacie Bell, PhD, chief scientific and medical officer at the National Psoriasis Foundation, said in the statement. "It's welcome news to finally have an oral systemic option with a well-established safety profile available for all adult plaque psoriasis patients."

FDA approves Otexla® (apremilast) for the treatment of adult patients with plaque psoriasis, regardless of severity level. Amgen. News release. December 20, 2021. Accessed December 22, 2021.

https://www.prnewswire.com/news-releases/fda-approves-otezla-apremilast-for-the-treatment-of-adult-patients-with-plaque-psoriasis-regardless-of-severity-level-301448542.html

The drug is the first and only oral therapy approved for the treatment of adult patients who are candidates for either phototherapy or systemic therapy.


FDA Approves Apremilast for Plaque Psoriasis, Regardless of Severity Level 

The FDA has approved the first and only long-acting injectable pre-exposure prophylaxis (PrEP) option (Apretude, ViiV Healthcare) to reduce the risk of acquiring HIV-1 in adolescents and adults.

Following clinical trial results assessing the cabotegravir long-acting injectable in men who have sex with men, as well as women and transgender women who have sex with men, the FDA has approved the injectable PrEP for use in patients weighing at least 35 kg following a negative HIV-1 test result.

The injection can be administered as few as 6 times per year at an initial dose of a single 600-mg (3-ml) injection. This initial injection dose should be given 1 month apart for 2 consecutive months. Following the second initiation dose, clinical research demonstrated that the recommended continuation injection dose is a single 600-mg (3-ml) injection given every 2 months. To assess a patient’s tolerability of the injection, cabotegravir oral tablets (Vocabria; ViiV Healthcare) can be given for approximately 1 month before the initial injection dose.

“People who are vulnerable to acquiring HIV, especially those in Black and Latinx communities who are disproportionately impacted in the U.S., may want options beyond daily oral pills,” Deborah Waterhouse, CEO, ViiV Healthcare, said in a statement. “Apretude was studied in 1 of the most diverse and comprehensive HIV prevention trial programs to date, which also included some of the largest numbers of transgender women and Black men who have sex with men ever enrolled in an HIV prevention trial.”

The approval from the FDA was based on data from both the HPTN 083 and HPTN 084 international phase 2b/3 clinical trials, which evaluated the efficacy and safety of cabotegravir long-acting for PrEP in HIV-negative cisgender women, transgender men, and men who have sex with men, as these populations have an increased likelihood of contracting HIV.

During the clinical trials, investigators assessed the cabotegravir long-acting injectable in 7700 participants at sites in 13 countries. Both trials were active-controlled, double-blind, multicenter, randomized trials, but the blinded, randomized portions of the trials were stopped early by an independent data safety monitoring board following results showing the superior efficacy and safety of cabotegravir long-acting injectable to daily oral emtricitabine/tenofovir disoproxil fumarate (TDF/FTC) tablets in the prevention of HIV acquisition.

In the HPTN 083 trial, investigators observed that participants who were administered cabotegravir long-acting injectable showed a 69% lower incidence of HIV compared with those taking FTC/TDF tablets. In HPTN 084, investigators saw a 90% lower incidence rate of HIV acquisition compared with patients administered the FTC/TDF tablets.

During the trials, the most common adverse events (AEs) observed by investigators among patients on the cabotegravir long-acting injectable were abdominal pain, back pain, decreased appetite, diarrhea, dizziness, fatigue, flatulence, headaches, injection site reactions, myalgia, nausea, pyrexia, rash, sleep disorders, somnolence, upper-respiratory-trace infection, and vomiting. In 6% of participants in the HPTN 083 trial and 1% of participants in the HPTN 084 trial, AEs led to discontinuation of the injectable treatment.

In the HPTN 083 trial, investigators looked to assess the efficacy and safety of the injectable in a diverse population that represents the patients most likely to receive the treatment. In the trial sites conducted in the United States, participants included men and transgender women who have sex with men of the Black and Latinx communities. These populations were important to include in the clinical trial, as they are historically disproportionately affected by the HIV epidemic. These populations continue to experience the greatest percentage of new HIV diagnoses.

In the HPTN 084 trial, participants included in the study were cisgender women from sub-Saharan Africa. These participants were important to include, as women from this region bear a disproportionate burden of the HIV epidemic. Additionally, this population may be twice as at risk of acquiring HIV as their male counterparts.

“We have the tools to end the HIV epidemic through the implementation of effective antiretroviral treatment and HIV prevention. PrEP has played a vital role in protecting people from acquiring HIV,” Richard Elion, MD, director of research at Washington Health Institute, said in the statement.

“With the availability of cabotegravir long-acting for PrEP as an injection every 2 months to prevent HIV, people now have an important new option besides daily medication,” he said. “This long-acting medication offers more options for prevention, and now providers and patients will be empowered by choices and the ability to choose the approach that is optimal for each individual.”

ViiV Healthcare announces US FDA approval of Apretude (cabotegravir extended-release injectable suspension), the first and only long-acting injectable option for HIV prevention. ViiV Healthcare. News release. December 20, 2021. Accessed December 22, 2021. 

https://www.businesswire.com/news/home/20211220005863/en

The agency’s approval follows trial results demonstrating the superior efficacy of the cabotegravir long-acting injectable to a daily oral PrEP option in reducing the risk of infection.

FDA Approves Apretude, the First, Only Long-acting Injectable Option for HIV Prevention 

Analyses of data from first-line treatment with daratumumab (Darzalex; Janssen Pharmaceutical Companies)-based regimens demonstrated deep and durable responses in patients with newly diagnosed (ND) multiple myeloma (MM), according to a presentation at the American Society of Hematology (ASH) 2021 Annual Meeting. Additionally, investigators observed a potential survival benefit for daratumumab in combination with lenalidomide and dexamethasone (Rd).

Previously, in the primary analysis of the phase 2 GRIFFIN trial (NCT02874742) assessing daratumumab plus lenalidomide, bortezomib, and dexamethasone (D-RVd) in patients with autologous stem cell transplant (ASCT)-eligible NDMM (with a median follow-up of 13.5 months), D-RVd was found to improve the rate of stringent complete response (sCR) by the end of post-ASCT consolidation versus RVd (42.4% vs 32.0%, 1-sided P=0.068).

Following this primary analysis, a longer follow-up at a median of 27.4 months was conducted. This longer follow up data demonstrated patients experienced deepened responses that were improved from D-RVd versus RVd (sCR rate: 63.6% vs 47.4%, 2-sided P=0.0253), according to the investigators. Additionally, this improvement from D-RVd versus RVd was seen in the minimal residual disease (MRD)-negativity (10–5) rate (62.5% vs 27.2%, P<0.0001) as well.

After patients received maintenance therapy for 24 months, investigators found that adding daratumumab to RVd induction and consolidation in conjunction with ASCT, followed by daratumumab plus lenalidomide (D-R) maintenance, provided a continuation of deep and durable responses in patients with transplant-eligible NDMM, including sCR and MRD-negativity (10–5 and 10–6) rates. Additionally, no new safety concerns were observed with this longer follow-up period, supporting the use of D-RVd induction and consolidation and D-R maintenance in patients with transplant-eligible NDMM.

“Despite treatment advances, multiple myeloma remains a complex, currently incurable blood cancer. The latest clinical trial data and real-world evidence presented for daratumumab at ASH shines a light on the potential of daratumumab-based combinations and sequencing approaches in the first-line, to tackle this complexity and improve patient outcomes,” said Edmond Chan MBChB MD (Res), EMEA therapeutic area lead hematology at Janssen-Cilag Limited, in a press release.

In additional updated results from the GRIFFIN study at a median follow up of 38.6 months, investigators noted that the D-RVd regimen for patients with transplant-eligible NDMM showed improved outcomes with the addition of daratumumab to VRd when followed by D-R maintenance therapy.

The key findings from the updated results showed sCR favored D-VRd compared to VRd alone (66% versus 47.4%; p=0.0096), with MRD-negativity rates at a maximum of 10-5 remaining higher in patients treated with D-VRd versus VRd alone (64.4% versus 30.1%; 

0.0001). Additionally, the progression-free survival (PFS) rate at 36 months favored daratumumab-VRd versus VRd alone (88.9% versus 81.2%).

Although the study was not powered by PFS, the investigators did observe that by the median follow-up point of 38.6 months, median PFS had not been reached in either arm. However, the updated trial results with longer-term follow up did not provide any new safety concerns from the earlier trial data.

“These updated findings from the GRIFFIN study are promising when adding daratumumab to VRd in the treatment of newly diagnosed, transplant-eligible multiple myeloma,” said GRIFFIN study investigator Jacob Laubach, MD, MPP, clinical director of the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, in a press release.

At ASH 2021, additional analyses of daratumumab-based regimens in the treatment of patients with transplant-ineligible NDMM were presented from the phase 3 MAIA study. With research showing that 50% of patients with transplant-ineligible NDMM will not receive a second line of therapy, investigators looked to provide potential clinical sequencing scenarios for this population that uses both attrition rates and real-world evidence from the Flatiron Health electronic health record-derived de-identified database.

Using these clinical sequencing scenarios, investigators assessed the use of daratumumab in combination with Rd against bortezomib administered in combination with Rd. Based on the results of this modelled analysis, the data indicated a potential survival benefit for patients who received daratumumab in first-line treatment versus later in their treatment process. The investigators also noted further research remains necessary to generate clinical data that can confirm these results.

In a second ASH 2021 presentation assessing first-line daratumumab-Rd, investigators analyzed real-world evidence to gain additional insight into clinical sequencing scenarios for NDMM. The scenarios used by the investigators were based on results from a retrospective, observational cohort study evaluating patients from the Flatiron database.

Based on their analysis of the real-world data, investigators found that the real-world patient population demonstrated similar results to that of the modelled analysis used in the MAIA study. Furthermore, an early trend of PFS was observed to be similar to that of the MAIA study as well.

In another presentation at ASH 2021, investigators detailed the results of a post-hoc analysis of the phase 3 MAIA study that focused specifically on patients with renal impairment. Based on the results, investigators observed that approximately 20% to 50% of patients with MM have a baseline renal impairment, which can impact both treatment choice and efficacy. However, the exploratory analyses presented at ASH 2021 were able to demonstrate PFS and overall survival benefits in patients with MM who were treated with daratumumab-Rd compared to Rd alone, whether or not lenalidomide was administered as the starting dose.

“The clinical data presented at ASH support daratumumab as a foundational therapy for patients with newly diagnosed multiple myeloma in transplant-ineligible populations,” said Imran Khan, MD, PhD, US vice president, medical affairs, hematology at Janssen Scientific Affairs, in a prepared statement. “Real-world evidence about efficacy, safety, and adherence is becoming increasingly important for clinicians in optimizing treatment approaches for patients with multiple myeloma. We will continue to advance research that can provide important insights about daratumumab as part of a standard of care regimen in the frontline setting.”

New Clinical and Real-World Data Support Use of DARZALEX®▼ (daratumumab) in Patients with Newly Diagnosed Multiple Myeloma. Beerse, Belgium: Janssen Pharmaceutical Companies; December 11, 2021. 

https://www.businesswire.com/news/home/20211211005041/en

Data support daratumumab as part of a standard of care regimen in the frontline setting for patients with newly diagnosed multiple myeloma.

Clinical, Real-World Data Support Use of Daratumumab in Newly Diagnosed Multiple Myeloma

The landscape of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) has changed significantly over the past several years, explained Jennifer Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, during a session at the Society of Hematologic Oncology 2021 conference.

For example, patients relapsing after minimal therapy are now considered to be essentially like frontline, which is a significant shift in practice, Brown explained. Most of the data demonstrating this shift in practice pertain to patients relapsing after chemoimmunotherapy with targeted agents. In this way, patients relapsing have been previously treated with targeted agents, and there is not yet enough data available on how to approach this when it occurs.

Brown noted that she generally divides patients with R/R CLL into the following categories: patients exposed to Bruton's tyrosine kinase (BTK) inhibitors (BTKi), patients relapsing after venetoclax, and patients relapsing after BTKi and B-cell lymphoma-2 (BCL-2) inhibitors.

“In terms of patients exposed to BTKi, in data from Ohio State, the most common reason for discontinuation was adverse events (AEs), and then over the long term, progression was the other main reason for discontinuation,” Brown said during the session.

In the study from Ohio State, investigators assessed toxicities and outcomes from ibrutinib-treated patients. The results showed that the most common AEs that led to discontinuation of therapy in patients with frontline CLL were arthralgia (42%), atrial fibrillation (25%), and rash (17%). For patients with R/R CLL, the most common AEs were atrial fibrillation (12%), infection (11%), pneumonitis (10%), bleeding (9%), and diarrhea (7%).

“Unfortunately, this does result in a reduced progression free survival compared to what we’ve seen in patients who stay on therapy in randomized trials,” Brown said during the session. “Those who come off for AEs have a better prognosis than those who progress and can still respond to other kinase inhibitors, such as phosphoinositide 3-kinases (PI3Ks) kinase inhibitors. However, in these real-world data, the best outcomes were with venetoclax.”

In addition to PI3Ks kinase inhibitors, data have demonstrated that patients who stop ibrutinib or another BTK inhibitor for an intolerance can respond with a relatively low rate of recurrence to acalabrutinib and zanubritinib, which demonstrates these are viable options for patients who stop BTKi due to the occurrence of AEs.

Additionally, patients who have stopped BTKi are at an increased risk of progression, Brown explained. Progression among these patients is most commonly due to mutations in BTK, with a subset of patients also having a mutation in phospholipase C gamma 2 (PLCG2).

“We now have data that similar mechanisms of resistance with mutations of C481 in BTK apply to acalabrutinib, in data from Ohio State, and also zanubritinib, in data from Australia. Our only prospective data specifically in this population are from a trial of venetoclax, in which the overall response rate (ORR) was 65%, which is really quite good,” Brown said during the session.

However, Brown noted that the complete response rate of 9% and the undetectable minimal residual disease (uMRD) of 42% are both lower than expected in patients who have not progressed after BTKi. Specifically, progressing after BTKi is associated with a lower response rate to venetoclax in combined analyses of outcomes.

To manage this lower response rate to venetoclax, some groups have responded by adding PI3Ks to venetoclax. In a study assessing umbralisib, ublituximab, and venetoclax, half the patients were R/R prior to BTKi, and the ORR to umbralisib and ublituximab in the first 3 cycles was 64% in patients with R/R CLL, Brown explained.

“This is rather encouraging,” Brown said during the session. “And then, of course, venetoclax was added, with very high rates of uMRD. Our study of duvelisib and venetoclax had similar results. So, there are opportunities for combinations in this space that can potentially enhance the efficacy of venetoclax.”

Brown J. Managing CLL Patients Relapsed or Refractory to Targeted Therapy. Presented at: Society of Hematologic Oncology 2021 Virtual Meeting. September 8, 2021. Accessed September 28, 2021.

Patients with relapsed or refractory chronic lymphocytic leukemia are generally divided by those exposed to Bruton's tyrosine kinase inhibitors (BTKi), patients relapsing after venetoclax, and patients relapsing after BTKi and B-cell lymphoma-2 inhibitors.