Hematology: How Far We’ve Come, Where We Go Next
At the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition, blood cancer researchers from around the world gathered virtually to discuss the progress that has been made in the field of hematology. Over the past decade, that progress has been tremendous. We’ve seen not only breakthrough approaches to care, but also significant improvement upon existing novel treatments and exploring combinations within those medicines.1 These advances have transformed expectations of what a blood cancer diagnosis now means for patients. While we’ve come a long way, I believe the most exciting scientific discovery is yet to come, and that future advances will truly transform patient care.
Moving beyond traditional chemotherapy
Looking ahead, we’ll continue to see the conversation in blood cancer move beyond traditional chemotherapy to personalized and targeted therapies, both as monotherapy and in combination.2-5 Take, for instance, chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults.6 Although traditional chemotherapy and chemoimmunotherapy have previously been the mainstay of therapy for CLL, the advent of targeted therapy has improved clinical outcomes and is changing clinical practice.2,4,7,8
Novel agents with new mechanisms of action have enabled effective and differentiated targeting of cancer cells, compared to traditional chemotherapies.3,9-19 Such advancements have, in turn, opened the possibility of prolonging progression-free survival for patients.4,8
Our work with CALQUENCE® (acalabrutinib), a next-generation, selective inhibitor of Bruton tyrosine kinase (BTK) is a good example of this.20-22 We now have long-term follow-up data from our CALQUENCE development program – through the ELEVATE-TN and ASCEND Phase III studies – with CALQUENCE versus chemoimmunotherapy agents in both the untreated and relapsed or refractory CLL settings.23,24 At ASH 2021, we presented long-term follow-up data from the ASCEND Phase III trial, which looked at CALQUENCE at a median three years of follow-up in relapsed or refractory CLL when evaluated versus rituximab combined with the investigator’s choice of idelalisib or bendamustine, two chemoimmunotherapy combinations.23 These data, combined with the long-term follow-up data (median follow-up of ~4 years) from the ELEVATE-TN Phase III trial presented at ASCO 2021, suggest CALQUENCE can be an effective frontline and relapsed or refractory treatment in CLL with an established, consistent safety and tolerability profile.23
While the clinical benefits of targeted therapies are well-established, traditional chemotherapy is still often used for most cancer treatment.25,26 That’s why AstraZeneca is also focusing on education that aims to increase the level of understanding and awareness around the potential benefits of targeted therapies in blood cancer. We believe by increasing awareness in medical communities among practicing physicians and oncologists, as well as across the community of individuals affected by it, we could ultimately improve the lives of patients and caregivers.
We recognize that different patients have different needs.27 For blood cancer patients, many factors play an important role in treatment selection, including compliance, convenience, comorbidities, toxicity and duration of therapy, among others.28,29
In CLL specifically, we know that tolerability is particularly important, as patients tend to be older and may have other comorbidities.2,28,30-35 So, in addition to living free from disease progression, an effective option that is also tolerable becomes crucial.2,30-34 As we head into 2022, we’re expecting even more safety and tolerability data from our Phase III ASSURE trial with CALQUENCE in untreated and relapsed or refractory CLL, including those previously on a BTK inhibitor therapy, which will further build on the knowledge we have gained from our established clinical trial program.36
On top of this, we also must acknowledge the significant impact the COVID-19 pandemic has had on blood cancer patients over the past two years – more so than some other communities.37 We know that for people living with blood cancers, there is a higher risk of prolonged infection and death from COVID-19 because patients often have abnormal or depleted levels of immune cells that produce antibodies against viruses.37 Although vaccination is an important measure to help prevent COVID-19 infections, additional precautions may also be necessary for individuals who are either ineligible for immunization or who have comorbidities that could contribute to a reduced immune response to a vaccine.37
During this time, AstraZeneca has also been using patient insights in real time to adapt to a changing healthcare delivery infrastructure and ensure continuity of care. For example, we have been exploring orally administered therapies, which may offer more convenience and ease of administration.38 To maintain the pace and progress of our clinical trial programs during COVID-19, we became more flexible and adaptable, making it easier for patients to participate through telehealth, delivering medications directly to their homes, and fast-tracking the implementation of digital technologies to closely monitor trials in real time.
A brighter future, together
Finally, and perhaps most importantly, coming together with medical colleagues at ASH always reminds me that we cannot do this alone. While we will continue to take bold approaches and push the boundaries of science to transform patient care in hematology, we recognize that outsmarting cancer requires a collective and collaborative approach.
The future of hematology requires a deep commitment to partnering with patients, healthcare providers, payers and policymakers. By doing this, we can ensure the best progress in the care of patients with hematologic malignancies, targeting those blood cancers with remaining high unmet need and focusing on making meaningful improvements in patient outcomes.
For more information, visit www.calquencehcp.com
INDICATION AND USAGE
CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) capsules
Serious and Opportunistic Infections
Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.
Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.
Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.
Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.
Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.
Second Primary Malignancies
Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.
Atrial Fibrillation and Flutter
Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.
The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, * neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea.
*Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions.
In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).
Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.
In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.
Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dose interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 1.3% of patients who received CALQUENCE.
Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.
Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.
Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg approximately every 12 hours.
Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.
Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.
Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE.
It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.
Avoid administration of CALQUENCE in patients with severe hepatic impairment. Dose modifications are not required for patients with mild or moderate hepatic impairment.
Please see full Prescribing Information, including Patient Information.
- Smith J, Milnthorpe J. Haematological malignancies: a guide to novel therapies. Prescriber. 2020;31:9-15.
- Patel K, Pagel JM. Current and future treatment strategies in chronic lymphocytic leukemia. J Hematol Oncol. 2021;14(1):69. doi:10.1186/s13045-021-01054-w.
- Scheffold A, Stilgenbauer S. Revolution of chronic lymphocytic leukemia therapy: the chemo-free treatment paradigm. Curr Oncol Rep. 2020 Feb 5;22(2):16.
- 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 [published correction appears in Lancet. 2020 May 30;395(10238):1694]. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2.
- Rozovski U, Hazan-Halevy I, Keating MJ, Estrov Z. Personalized medicine in CLL: current status and future perspectives. Cancer Lett. 2014;352(1):4-14. doi:10.1016/j.canlet.2013.07.013
- American Cancer Society. What Is chronic lymphocytic leukemia. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html. Accessed November 2021.
- Mato AR, Barrientos JC, Ghosh N, et al. Prognostic testing and treatment patterns in chronic lymphocytic leukemia in the era of novel targeted therapies: results from the inform CLL Registry. Clin Lymphoma Myeloma Leuk. 2020;20(174–183):e173.
- 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. Epub 2020 May 27.
- American Cancer Society. Targeted therapy drugs for chronic lymphocytic leukemia. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/treating/targeted-therapy.html. Accessed November 2021.
- Kipps TJ, Choi MY. Targeted therapy in chronic lymphocytic leukemia. Cancer J. 2019;25(6):378-385. doi:10.1097/PPO.0000000000000416.
- Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223.
- Brown JR, Hillmen P, O’Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32:83–91.
- Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–2437.
- Robak T, Burger JA, Tedeschi A, et al. Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia: a cross-trial comparison of phase 3 studies. Am J Hematol. 2018;93:1402–1410.
- Fraser G, Cramer P, Demirkan F, et al. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019;33:969–980.
- Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007.
- Zelenetz AD, Barrientos JC, Brown JR, et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. doi:10.1016/S1470-2045(16)30671-4.
- Sharman JP, Coutre SE, Furman RR, et al. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402.
- Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042.
- CALQUENCE® (acalabrutinib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.
- Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9:21.
- Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017 Nov;363(2):240-252. doi: 10.1124/jpet.117.242909. Epub 2017 Sep 7. PMID: 28882879.
- Jurczak W, Pluta A, Wach M, et al. Three-year follow-up of the ASCEND trial: acalabrutinib vs rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia [presentation]. Presented at: 63rd American Society of Hematology (ASH) Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia.
- Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN 4-year follow-up [abstract and poster]. Presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021 (Virtual Meeting). Accessed November 2021.
- Williamette Valley Cancer Institute and Research Center. Targeted therapy. https://www.oregoncancer.com/targeted-therapy. Accessed November 2021.
- American Cancer Society. How is chemotherapy used to treat cancer. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-is-chemotherapy-used-to-treat-cancer.html. Accessed November 2021.
- National Cancer Institute. Chronic lymphocytic leukemia treatment (PDQ®)–health professional version. https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq/. Accessed November 2021.
- Strati P, Parikh SA, Chaffee KG, et al. Relationship between co-morbidities at diagnosis, survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. Br J Haematol. 2017;178(3):394-402. doi:10.1111/bjh.14785.
- Eek D, Krohe M, Mazar I, et al. Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: a review of the literature. Patient Prefer Adherence. 2016;10:1609-1621.
- Frey S, Blankart CR, Stargardt T. Economic burden and quality-of-life effects of chronic lymphocytic leukemia: a systematic review of the literature. Pharmacoeconomics. 2016;34:479–498.
- Hewison A, Atkin K, McCaughan D, et al. Experiences of living with chronic myeloid leukaemia and adhering to tyrosine kinase inhibitors: a thematic synthesis of qualitative studies. Eur J Oncol Nurs. 2020;45:101730.
- Patel K, Sudhir VS, Kabadi S, et al. Impact of dosing frequency (once daily or twice daily) on patient adherence to oral targeted therapies for hematologic malignancies: a retrospective cohort study among managed care enrollees. J Oncol Pharm Pract. 2019;25:1897–1906.
- Kabadi SM, Goyal RK, Nagar SP, et al. Treatment patterns, adverse events, and economic burden in a privately insured population of patients with chronic lymphocytic leukemia in the United States. Cancer Med. 2019;8:3803–3810.
- Farooqui AA, Ashraf A, Farooq TB, et al. Novel targeted therapies for chronic lymphocytic leukemia in elderly patients: a systematic review. Clin Lymphoma Myeloma Leuk. 2020;20(7):e414–e426.
- American Society of Clinical Oncology. Leukemia – chronic lymphocytic – CLL: statistics. https://www.cancer.net/cancer-types/leukemia-chronic-lymphocytic-cll/statistics. Accessed November 2021.
- AstraZeneca. Acalabrutinib safety study in untreated and relapsed or refractory chronic lymphocytic leukemia patients (ASSURE). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT04008706. Accessed November 2021.
- National Cancer Institute. Coronavirus: what people with cancer should know. https://www.cancer.gov/about-cancer/coronavirus/coronavirus-cancer-patient-information. Accessed November 2021.
- Sharma S, Pepin X, Burri H, et al. New acalabrutinib formulation enables co-administration with proton pump inhibitors and dosing in patients unable to swallow capsules (ELEVATE-PLUS) [abstract]. Blood. 2021. Abs 4365.