Jeremiah Moore, PharmD, BCOP

Mantle cell lymphoma (MCL) is a rare type of B-cell non-Hodgkin lymphoma (NHL) characterized by the 

(11;14) translocation, resulting in cycle D1 overexpression.

The median age of diagnosis ranges between aged 60 and 70 years and is more common in males.

 MCL is generally aggressive, with patients often diagnosed with advanced stage disease, lymphadenopathy, and bone marrow involvement.

Standard upfront treatment for younger and fit patients includes induction chemo-immunotherapy, followed by consolidation with autologous stem cell transplant and rituximab maintenance. Older and less-fit patients receive induction therapy with less aggressive chemo-immunotherapy with or without rituximab maintenance. MCL is an incurable disease, and most patients relapse. In the relapsed setting, treatment options include Bruton’s tyrosine kinase (BTK) inhibitors (acalabrutinib, ibrutinib, zanubrutinib), lenalidomide-rituximab, and chimeric antigen receptor T-cell (CAR-T).3

Two recent clinical trials (ZUMA-2 [NCT04880434] and SHINE [NCT01776840]) highlight the novel treatment options available to patients in the upfront and relapsed settings.

SHINE, a multi-centered, phase 3, randomized trial, evaluated the addition of ibrutinib to bendamustine-rituximab (BR) in the upfront treatment of MCL. Patients aged 65 years or older were randomized in a 1:1 ratio to 6 cycles of BR, with or without ibrutinib 560 mg daily, those achieving a partial response or better continued placebo/ibrutinib plus rituximab maintenance. The primary endpoint was progression-free survival (PFS) as assessed by the study investigators. With a median age of 71 years, 523 patients were randomized, 261 in the ibrutinib group and 262 in the placebo group. PFS was 80.6 months in the ibrutinib group vs 52.9 months in the placebo group (HR 0.75; 95%CI 0.59-.96, p=0.01).

 No new safety concerns were noted with the combination of BR and ibrutinib. The addition of ibrutinib therapy significantly increased the PFS when given in combination with BR.

Because many patients with MCL are older and/or not candidates for upfront treatment options, novel treatment approaches are needed. The results of the SHINE trial showing a PFS difference of >27 months are remarkable.

The ZUMA-2 trial, a multi-centered, open-label, phase 2, single-arm, study evaluated the anti-CD19 CAR-T therapy KTE-X19 in relapsed or refractory MCL patients. Eligible patients needed to be ≥ 18 years of age and received MCL directed therapy, including anthracycline or bendamustine chemotherapy, anti-CD20 monoclonal antibody, and BTK inhibitor therapy. The primary endpoint was the objective response rate (ORR), as assessed by an independent review committee. Seventy-four patients enrolled, with 68 receiving KTE-X19 therapy. The median age was aged 65 years, and 81% had received ≥3 lines of therapy. Sixty patients were included in the primary analysis showing an ORR of 93% and a complete response rate of 67%.

Based on the results of the ZUMA-2 trial the FDA approved brexucabtagene autoleucel (Tecartus) for patients with relapsed or refractory MCL. Brexucabtagene autolecuel carries a black box warning for cytokine release syndrome and neurological toxicities and is available through the Tecartus risk evaluation and mitigation strategy (REMS) program.

BTK inhibitor therapy for relapsed/refractory MCL is standard of care. the SHINE trial highlights the potential benefit of incorporating this class of medication into the upfront setting. Limited treatment options exist for patients who have not been successful using BTK inhibitor therapy. The results of the ZUMA-2 trial show the promise of CAR-T therapy for this patient population.


The results of the SHINE and ZUMA-2 trials highlight the novel treatment approaches that are being used in the upfront and relapsed MCL settings.

1. Armitage JO, Longo DL. Mantle-cell lymphoma. 

2022;386(26):2495-2506. doi:10.1056/NEJMra2202672

2. Silkenstedt E, Linton K, Dreyling M. Mantle cell lymphoma - advances in molecular biology, prognostication and treatment approaches. 

2021;195(2):162-173. doi:10.1111/bjh.17419

3. B-cell lymphomas (version 5.2022). National Comprehensive Cancer Network. Accessed July 29, 2022. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf

4. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. 

2022;386(26):2482-2494. doi:10.1056/NEJMoa2201817

5. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR t-cell therapy in relapsed or refractory mantle-cell lymphoma. 

2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

Articles

Two recent clinical trials highlight the novel therapy options available to patients in the upfront and relapsed settings. 

Explore Novel Treatment Modalities for Mantle Cell Lymphoma

The University of Rochester Specialty Pharmacy is an integrated health system specialty pharmacy (HSSP) that serves nearly 20 different clinical areas. 

Integrated HSSPs focus on services outside the traditional dispensing role in collaboration with the interdisciplinary health care team. These services include benefits investigation, financial assistance evaluation, medication education and monitoring related to adherence, adverse reactions, drug interactions, labs, and other disease- or medication-specific monitoring parameters. 

Wilmot Cancer Institute is part of the University of Rochester Medical Center and serves approximately 3 million patients diagnosed with cancer across Central and Western New York. To support the outpatient population treated within Wilmot Cancer Institute and prescribed oral anticancer therapy, the University of Rochester Specialty Pharmacy has 7 board-certified clinical pharmacists dedicated to the oncology specialty area. 

Patients taking oral anticancer therapy are frequently in contact with their assigned clinical pharmacists and medication access specialists, who complete a financial assistance evaluation prior to starting therapy to mitigate out-of-pocket costs. Patients then meet with a clinical pharmacist prior to medication initiation, when a thorough medication  reconciliation is completed to assess for interactions with OTC and prescribed medications. 

If a drug interaction exists with the anticipated anticancer therapeutic agent, the pharmacist communicates with the primary oncologist to make any necessary medication adjustments. In addition, patients are followed regularly by clinical pharmacists during in-office clinic visits and follow-up telephone calls, which are completed in tandem with monthly refill assessments.

A retrospective chart review was conducted at the University of Rochester Specialty Pharmacy to evaluate the clinical impact of concomitant proton pump inhibitor (PPI) therapy in patients treated with acalabrutinib (Calquence). Acalabrutinib is an oral Bruton tyrosine kinase inhibitor that  is FDA approved for treatment-naïve and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and relapsed/refractory mantle cell lymphoma.

Acalabrutinib solubility decreases with increasing pH, therefore the coadministra-tion of acalabrutinib with acid reducing agents decreases plasma concentrations and may decrease efficacy. The acalabrutinib prescribing information recommends avoiding PPIs and separating antacids or H2 receptor antagonists.

In clinical practice, if a patient does not have a successful trial with a PPI, providers may revert to PPI therapy despite the interaction. Although trials have been completed to determine coadministration recommendations based on under-the-curve measures, data are limited to assess the clinical impact of concomitant acalabrutinib and PPI use. This study aimed to evaluate the clinical impact of concomitant PPI therapy in patients treated with acalabrutinib therapy. 

Adults diagnosed with CLL/SLL on acalabrutinib therapy for  at least 3 months and treated at the Wilmot Cancer Institute between October 31, 2017, and September 15, 2020, were identified via electronic medical records (EMRs). 

The primary outcome of this study was defined as response to acalabrutinib (clinical complete remission, complete response, partial response, or partial response with lymphocytosis) at 3 months after the initiation of therapy  +/- 1 month) in CLL in patients with concomitant PPI therapy vs no concomitant PPI therapy.

It was anticipated that not all patients would have restaging bone marrow biopsies or imaging completed at 3 months. Therefore, patients meeting clinical and laboratory complete remission criteria were considered to have achieved a clinical complete remission. Participants were considered to have taken concomitant therapy if they had documented evidence of taking a PPI while on acalabrutinib for a minimum of 1 day. 

Descriptive statistics were used to report baseline demographics and the number of patients with clinical complete remission, complete response, partial response, partial response with lymphocytosis, and stable disease. Response rates were summarized as a percentage of the number of patients per clinical response group over the total number of patients taking acalabrutinib therapy. Fisher’s exact test was used to compare responses between patients ever taking concomitant acalabrutinib and PPI therapy throughout the study period vs those never taking concomitant therapy. 

A total of 65 participants met inclusion criteria. The median duration of follow up was 12 months (range 3.2-26.9 months). Baseline demographics and disease characteristics were similar to those living with CLL in the general population (Online Table 1).

Prior to starting acalabrutinib, 23 of 65 (35.4%) patients were taking a PPI. At the start of acalabrutinib, 4 patients remained on a PPI and 19 (83%) were taken off PPI therapy (18 patients switched to alternative acid suppression therapy and 1 successfully discontinued all acid suppression therapy). When the response rate was assessed at 3 months, 7 patients were taking concomitant PPI therapy (as 3 patients resumed). 

Fifty-five patients were included in the response assessment at 3 months. Of  7 patients taking a PPI, 57% had a complete clinical remission and 43% had a partial response with or without lymphocytosis. Of the 48 patients not taking a PPI, 25% had a complete clinical remission and 69% had a partial response with or without lymphocytosis (Online Table 2).

 There was no evidence of a significant association of PPI status, with best response at 3 months post acalabrutinib initiation (P = .59). 

The results of this study did not support a statistically significant difference in the clinical impact of concomitant acalabrutinib and PPI therapy based on response rates between groups (Online Table 21-3; P = .59). However, the results did highlight the critical role the clinical pharma-cists have in identifying drug interactions prior to initiating a medication. Acid suppression therapy is available for patients to purchase OTC. Therefore, it does not always appear on a patient’s documented medication list within the EMR. 

Clinical pharmacists at the University of Rochester Specialty Pharmacy involved in the management of acalabrutinib complete a thorough counseling session with medication reconciliation prior to the initiation of acalabrutinib. In total, 19 of 23 (83%) patients who were taking a PPI prior to the start of acalabrutinib were switched to alternative antacid therapy to avoid this significant drug interaction. 

This high substitution rate can be attributed to a highly integrated clinical pharmacist having a discussion with the patient prior to the initiation of acalabrutinib. The clinical pharmacists at the University of Rochester Specialty Pharmacy use a thorough documentation process via an integrated flow sheet within the EMR. 

It was confirmed via this documentation that discussions with providers regarding the interaction did occur for the remaining 4 of 23 patients.  These patients were not ultimately considered to be candidates for a switch in therapy because of either failing with a previous switch attempt or having a separate diagnosis that requires PPI therapy. 

There were several limitations to this study. First, there was a small sample size exposed to concomitant therapy, as just 7 patients had been on both acalabrutinib and a PPI at least once when the primary outcome was measured at 3 months post acalabrutinib initiation. A larger sample size with more concomitant use of acalabrutinib and a PPI would allow for further evaluation of the clinical impact of this interaction. 

Additionally, this study was completed over a time period affected by the COVID-19 pandemic, when telemedicine  visits frequently replaced in-person office visits. Therefore, patients with telemedicine visits at 3 months lacked objective laboratory and physical assessments to verify clinical response.

Finally, a large number of patients were taking additional therapies other than acalabrutinib to target their disease state, which could have affected response rates. Additionally, all had differing disease features, which put some at a higher risk than others for disease progression. Although these confounders may have affected response rates, the heterogeneity in the patient population  included in this study is representative of the real-world population seen in clinical practice. 

The high rate of acid suppression therapy substitution noted in this study highlights 1 benefit of the integrated HSSP model. These observations suggest specialty pharmacists’ continuous assessment, ongoing monitoring, and counseling services lead to mitigation of drug interactions and optimization of drug therapy in this patient population. 

Given the large switch rate (83%) at baseline from a PPI to a different antacid therapy that was observed within this study, there were minimal data for patients who were concomitantly  administering acalabrutinib and PPI therapy. Throughout the entire duration of follow-up, 84% of patients were able to remain off PPI therapy. Further investigation with a clinical trial that has a larger patient population taking concomitant acalabrutinib and PPI therapy is required to determine the impact of this interaction on clinical practice.

1. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/jco.19.03355

2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667. doi:10.1016/S0140-6736(17)33108-2

3. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395 (10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

4. Calquence. Prescribing information. AstraZeneca; 2017. Accessed August 8, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf

5. A study of acalabrutinib vs investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in R/R CLL. ClinicalTrials.gov. Updated June 23, 2022. Accessed August 8, 2022. https://clinicaltrials.gov/ct2/show/NCT02970318

6. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398


This study highlights one benefit of the integrated health system specialty pharmacy model for patients who are prescribed acalabrutinib.

HSSP Leads to High Rate of Acid Suppression Therapy Substitution

Chronic Myeloid Leukemia (CML) is a rare myeloproliferative disorder that accounts for approximately 15% of all leukemia cases, with approximately 9000 people projected to receive a diagnosis of the disease in the United States in 2022.1-4 CML is characterized by the translocation between the 

 gene on chromosome 22, forming the constitutively activated 

 fusion gene, which is also known as the Philadelphia chromosome.

Patients with CML are often asymptomatic at diagnosis, or they may present with constitutional symptoms, such as splenomegaly, along with anemia and elevated white blood cells and platelets.

 CML can be further classified into chronic phase (CP-CML), accelerated phase (AP-CML), or blast phase, but the large majority present with CP-CML.

Currently, 6 FDA-approved oral tyrosine kinase inhibitors (TKIs) are available for the treatment of CML. With the introduction of BCR-ABL1 small molecule TKIs, patients with a CML diagnosis can expect a near-normal life expectancy. This scenario means an increased prevalence of CML will likely be a result in the United States, due to the increased number of survivors of the disease present in the country.

As initial therapy for CP-CML, National Comprehensive Cancer Network guidelines recommend either the first-generation TKI imatinib (Gleevec; Novartis) or one of the second-generation agents: bosutinib (Bosulif; Pfizer), dasatinib (Sprycel; Bristol Myers Squibb), or nilotinib (Tasigna; Novartis).

 Additionally, the third-generation TKI ponatinib (Iclusig; Takeda) and the recently approved allosteric ABL1 inhibitor asciminib (Scemblix; Novartis) are options in later lines of therapy.

Imatinib, dasatinib, nilotinib, bosutinib, and ponatinib all target the adenosine triphosphate binding pocket of 

, which leads to inhibition of BCR-ABL1 signaling.

 These agents differ in their BCR-ABL1 potency, toxicity profile, and dosing schedules. Despite a multitude of treatment options, patients may not tolerate treatment or may develop treatment resistance, such as in the case of the T315I mutation, which would necessitate the need for novel therapy options.

Asciminib has a unique mechanism of action: As a STAMP (specifically targeting the ABL myristoyl pocket) inhibitor of BCR-ABL1, it allows for activity in patients with CML who have developed resistance or intolerance to prior therapies.

Based on the results of the CABL001X2101 and ASCEMBL trials (NCT02081378 and NCT03106779), the FDA approved asciminib in October 2021 for patients with CP-CML who were previously treated with 2 or more TKIs, and for adult patients with CP-CML with the T315I mutation. The approval was granted under the accelerated approval process, with continued approval dependent upon longer follow-up.

The CABL001X2101 clinical trial was a phase 1, multicenter, open-label, dose-escalation study that included 141 patients with CP-CML and 9 patients with AP-CML. Participants previously had an inadequate response or unacceptable adverse effects (AEs) from 2 or more BCR-ABL1 TKIs and were treated with asciminib either once or twice daily over a range of doses. Forty-five patients with CP-CML and the T315I mutation received asciminib at 200 mg twice daily. Nineteen of the 45, or 42%, achieved a major molecular response (MMR), defined as 

at less than or equal to 0.1%, at 24 weeks, and 22, or 49%, achieved it at 96 weeks. In a heavily treated population, including those with the T315I mutation, a maximum tolerated dose was not reached and treatment was well tolerated by those with disease activity.

The ASCEMBL clinical trial was a multicenter, randomly assigned, phase 3 clinical trial in which 233 patients with CP-CML who experienced either intolerance or treatment failure after 2 or more TKIs were randomized in a 2:1 ratio to either asciminib 40 mg twice daily or bosutinib 500 mg daily. After a median follow-up of 14.9 months, 25.5% of patients in the asciminib group achieved an MMR vs 13.2% in the bosutinib group at 24 weeks.

In addition, at 24 weeks, 49% in the asciminib group had a 

 less than or equal to 1% vs 23.7% in the bosutinib group. Grade 3 or higher AEs occurred in 50% of the asciminib group vs 60% of the bosutinib group. Finally, 5.8% of the asciminib group discontinued treatment because of toxicity vs 21.1% of patients in the bosutinib group.

The recommended asciminib dosing in CP-CML is 80 mg by mouth once daily or 40 mg by mouth twice daily. In patients with CP-CML with the T315I mutation, the recommended dose is 200 mg by mouth twice daily. Commonly reported AEs among patients include upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea. Common lab abnormalities include low blood counts and elevated cholesterol, pancreatic enzymes, creatinine kinase, and liver enzymes.

Asciminib is an exciting new treatment option with a favorable AE profile in the third-line setting for patients with CP-CML, including those harboring the T315I mutation.

, is a hematology/oncology clinical pharmacy specialist at the University of Rochester Medical Center in New York.

1. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring. 

. 2020;95(6):691-709. doi:10.1002/ajh.25792

2. Osman AEG, Deininger MW. Chronic myeloid leukemia: modern therapies, current challenges and future directions. 

. 2021;49:100825. doi:10.1016/j. blre.2021.100825

3. Cancer stat facts: leukemia — chronic myeloid leukemia (CML). National Cancer Institute / Surveillance, Epidemiology, and End Results Program. Accessed February 3, 2022. https://seer.cancer.gov/statfacts/html/cmyl.html

4. NCCN. Clinical Practice Guidelines in Oncology. Chronic myeloid leukemia, version 3.2022. Accessed February 3, 2022. https://www.nccn.org/professionals/physician_gls/ pdf/cml.pdf

5. Réa D, Mauro MJ, Boquimpani C, et al. A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. 

. 2021;138(21):2031-2041. doi:10.1182/blood.2020009984

6. Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. 

. 2019;381(24):2315-2326. doi:10.1056/ NEJMoa1902328

7. Scemblix. Prescribing information. Novartis; 2021. Accessed February 3, 2022. https://tinyurl.com/5epcyv83

Asciminib offers a new option for patients harboring the T315I mutation.

An Overview of the Expanding Treatment Landscape of Chronic Myeloid Leukemia

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy. Approximately 195,000 people in the United States are living with CLL, and an estimated 21,250 new cases and 4320 deaths are predicted for 2021.

“Small lymphocytic lymphoma (SLL)” is used to describe patients with CLL with limited circulating CLL cells.

 The median age of diagnosis is 72 years, and it’s more common in men.

CLL has a heterogeneous presentation and clinical course.

 Treatment options have evolved from chemoimmunotherapy to the use of targeted small molecules that inhibit Bruton tyrosine kinase (BTK), PI3K, and BCL2.

 National Comprehensive Cancer Network guidelines recommend acalabrutinib (Calquence) plus or minus obinutuzumab (Gazyva), ibrutinib (Imbruvica), or venetoclax (Venclexta) plus obinutuzumab as preferred treatment regimens in the first-line setting and acalabrutinib, ibrutinib, or venetoclax plus rituximab (Rituxan) in the second-line or subsequent therapy setting.

BTK inhibitor therapy (acalabrutinib and ibrutinib) provides high response rates and durable remissions but requires continuous therapy.

 These drugs are generally tolerable, but toxicities developing with continuous therapy include bleeding, cardiac arrhythmias, diarrhea, hypertension, and infection.

 Adherence, cost, drug interactions, and resistance can also pose issues.

Venetoclax inhibits the antiapoptotic molecule BCL2, which is highly expressed in CLL cells. Because venetoclax is highly effective, it can cause tumor lysis syndrome. Venetoclax can also cause neutropenia and thrombocytopenia. Recently, 2 clinical trials investigated fixed-duration therapy with venetoclax and a CD20 monoclonal antibody.

The phase 3 MURANO trial randomized 389 patients with relapsed or refractory (R/R) CLL/SLL after at least 1 prior treatment to either bendamustine-rituximab (BR) for 6 months or venetoclax-rituximab for 2 years. The median age of patients was 65 years. After a median follow-up of 23.8 months, the primary end point of progression-free survival (PFS) was not reached in the venetoclax-rituximab arm and was 17 months in the BR arm.

 Grade 3/4 neutropenia and tumor lysis syndrome occurred in 57.7% and 3.1% of patients treated with venetoclax-rituximab, respectively. A longer follow-up showed continued durability of a fixed-duration regimen with a 4-year PFS of 4.6% in the BR arm and 57.3% in the venetoclax-rituximab arm.

The phase 3 CLL14 trial randomized 432 treatment-naive patients with CLL/SLL for 1 year to either chlorambucil (Leukeran)-obinutuzumab or venetoclax-obinutuzumab. The median age was 72 years. After a median follow-up of 28.1 months, the results favored venetoclax-obinutuzumab (HR, 0.35; P < .001 for PFS).

 Grade 3/4 neutropenia occurred in 52.8% of patients, with no cases of tumor lysis syndrome. At a median of 39.6 months, PFS continued to favor venetoclax-obinutuzumab (HR, 0.31; P < .0001).

The findings of the MURANO trial in R/R and the CLL14 trial in patients who are treatment naive for CLL/SLL showed that fixed-duration venetoclax with a CD20 monoclonal antibody is superior to chemoimmunotherapy (BR or chlorambucil-obinutuzumab) and offers a viable treatment option for patients that allows for treatment-free intervals.

The treatment landscape in CLL/SLL is quickly evolving and offers patients multiple options, including but not limited to continuous therapy with BTK inhibitors and fixed-duration therapy with venetoclax-based regimens. Fixed-duration, venetoclax-based combination therapy may be an option for patients who are resistant or do not tolerate BTK inhibitors or prefer fixed-duration therapy. In addition, fixed-duration venetoclax may limit treatment-related adverse effects, cost, and therapy resistance.

is a hematology/oncology clinical pharmacy specialist at the University of Rochester Medical Center in New York.

1. Chronic lymphocytic leukemia. National Comprehensive Cancer Network. 2021. Accessed August 19, 2021. https://www.nccn.org/patients/guidelines/content/PDF/cll-patient.pdf

2. Cancer stat facts: leukemia — chronic lymphocytic leukemia (CLL). National Cancer Institute. Accessed August 17, 2021. https://seer.cancer.gov/statfacts/html/clyl.html

3. Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosi s, risk stratifi cation and treatment. Am J Hematol. 2019;94(11):1266-1287. doi:10.1002/ajh.2559

4. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398

5. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460-473. doi:10.1056/NEJMra1908213

6. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi:10.1056/NEJMoa1400376

7. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388

8. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

9. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

10. Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020(1):336-345. doi:10.1182/hematology.2020000118

11. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976

12. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi:10.1200/JCO.20.00948

13. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281

14. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5

Patients now have multiple options, including continuous therapy with BTK inhibitors and fixed-duration therapy with venetoclax-based regimens.