Acalabrutinib, a small-molecule inhibitor of Bruton's tyrosine kinase (BTK), is an antineoplastic agent.1, 19
Acalabrutinib is used for the treatment of adults with previously untreated mantle cell lymphoma who are ineligible for autologous hematopoietic stem cell transplantation (HSCT) in combination with bendamustine and rituximab.1, 19, 21 Acalabrutinib is also used for the treatment of mantle cell lymphoma in adults who have received at least 1 prior therapy.1, 2, 19 Acalabrutinib has been designated an orphan drug by FDA for the treatment of this cancer.3
Previously Untreated Mantle Cell Lymphoma
The use of acalabrutinib in previously untreated mantle cell lymphoma is based principally on the results of a randomized, double-blind, placebo-controlled, multicenter, phase III study (ECHO) in 598 patients who were ≥65 years of age with adequate organ function, radiologically measurable disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.21 The primary measure of efficacy was progression-free survival as assessed by an independent review committee based on the Lugano Classification.1, 21 The median age of patients enrolled in the study was 71 years (range: 65-86 years), 71% were male, 78% were white, 16% Asian, and 0.5% Black or African American; most patients (80%) had classic histology of mantle cell lymphoma, 7.7% had blastoid mantle cell lymphoma, and 5.5% had pleiomorphic mantle cell lymphoma.1 Most patients in the study had Ann Arbor stage IV disease (86%) and 38% had tumor bulk ≥5 cm.1
Patients were randomly assigned (1:1 ratio) to either acalabrutinib plus bendamustine and rituximab or placebo plus bendamustine and rituximab; induction dosing for both groups was given in 28-day cycles for 6 cycles.1, 21 In the active therapy group, acalabrutinib 100 mg orally twice daily was initiated on Cycle 1 Day 1.1, 21 Bendamustine was administered at 90 mg/m2 IV over 30 minutes on Days 1 and 2 of each of the 6 cycles and rituximab 375 mg/m2 IV was administered on Day 1 of each cycle for the 6 cycles.1, 21 If patients achieved a partial or complete response, acalabrutinib 100 mg twice daily was given continuously, in combination with rituximab 375 mg/m2 on Day 1 of every other cycle for a maximum of 12 additional doses up to Cycle 30.1, 21 After rituximab discontinuation, acalabrutinib 100 mg twice daily was continued until disease progression or unacceptable toxicity.1, 21 In the control group, patients received the same regimen except for placebo in place of acalabrutinib.1, 21 Patients in the placebo arm were allowed to crossover to acalabrutinib monotherapy at disease progression.1, 21
At the prespecified interim analysis, the median follow-up for progression-free survival was 49.8 months in both groups.1, 21 Median progression-free survival was significantly improved with acalabrutinib plus bendamustine and rituximab as compared to placebo plus bendamustine and rituximab (66.4 months versus 49.6 months).1, 21 The proportion of patients with an overall response was similar between the groups (91% acalabrutinib plus bendamustine and rituximab versus 88% placebo plus bendamustine and rituximab); complete responses were seen in 67% of the acalabrutinib group and 54% of the placebo group and partial responses occurred in 24% of the acalabrutinib group and 34% in the placebo group.1, 21 Median overall survival had not been reached in either group at the time of the analysis; 97 deaths occurred in the acalabrutinib group and 106 deaths occurred in the placebo group.1, 21
Previously Treated Mantle Cell Lymphoma
The use of acalabrutinib in previously treated mantle cell lymphoma is based principally on the results of an open-label, phase 2 study (ACE-LY-004 trial) in 124 patients with the disease who received at least one prior therapy.1, 2 The primary measure of efficacy was overall response rate (complete plus partial responses) based on the Lugano Classification.1, 2 The median age of patients enrolled in the study was 68 years (range: 42-90 years), 80% were male, and 74% were white; most patients (93%) had a baseline ECOG performance status of 0 or 1 and the median time since diagnosis of disease was approximately 46 months.1, 2 Patients in the study received a median of 2 (range: 1-5) prior therapies for their disease and 18% of patients had previously undergone a stem-cell transplant.1, 2 Patients who received prior therapy with a Bruton's tyrosine kinase (BTK) inhibitor (e.g., ibrutinib) were excluded from the study.1, 2 All patients received acalabrutinib 100 mg orally twice daily in 28-day cycles until disease progression or unacceptable toxicity occurred.1, 2 The median dose intensity was 98.5%.1
Effects of acalabrutinib on investigator-assessed overall response rate and independent review committee-assessed overall response rate were comparable.1, 2 At a median of 15.2 months follow-up, the investigator-assessed overall response rate in acalabrutinib-treated patients was 81%; 40% of patients receiving the drug achieved a complete response.1, 2 At the time of data analysis, the median time to best response was 1.9 months; however, estimated medians for duration of response, progression-free survival, and overall survival had not yet been reached.1, 2 Following initiation of acalabrutinib therapy, lymphocytosis (i.e., absolute lymphocyte count exceeding 5000/mm3 and an increase of at least 50% from baseline) occurred in 31% of patients; the median time to onset of lymphocytosis was 1.1 weeks1, 2 and the median duration of lymphocytosis was 6.7 weeks.1
After a median follow-up period of 38.1 months, patients enrolled in ACE-LY-004 had an overall response rate of 81.5% and 47.6% of patients achieved a complete response.12 The median duration of response was 28.6 months and median progression-free survival was 22 months.12 Patients had an estimated median overall survival of 59.2 months and an estimated 5-year overall survival rate of 49.5%.12
Clinical practice guidelines from European experts provide recommendations for the treatment of mantle cell lymphoma, an uncommon type of B-cell non-Hodgkin lymphoma.13 Therapy is dependent on staging and/or age at time of diagnosis.13 In early disease, radiotherapy with conventional chemotherapy can be used in a small percentage of patients with limited tumor burden.13 For more advanced disease or in the presence of high tumor burden, immunochemotherapy (e.g., rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is recommended, with a dose-intensified regimen for patients ≤65 years of age and conventional dosing for patients >65 years, followed by autologous stem cell transplantation (≤65 years only) plus rituximab maintenance therapy.13 For patients with relapsed disease, immunochemotherapy or targeted therapies with BTK inhibitors or lenalidomide are recommended.13
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Acalabrutinib is used for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1, 10, 11, 19 Acalabrutinib has been designated an orphan drug by FDA for the treatment of CLL.3
Efficacy of acalabrutinib for the treatment of CLL and SLL is based principally on the results of 2 open-label, randomized, multicenter, actively controlled, phase 3 studies (ELEVATE-TN and ASCEND) in patients with CLL.1, 10, 11 Because of the similarities between CLL and SLL, efficacy and safety of acalabrutinib in patients with SLL is based on the ELEVATE-TN and ASCEND trials in patients with CLL.1
In the ELEVATE-TN study, 535 patients with previously untreated CLL were randomized in a 1:1:1 ratio to receive acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, or obinutuzumab plus chlorambucil.1, 10 Acalabrutinib 100 mg orally twice daily was continued until progressive disease or unacceptable toxicity occurred; obinutuzumab and chlorambucil were each given for a maximum of six 28-day cycles.1, 10 In the acalabrutinib plus obinutuzumab group, obinutuzumab was administered IV on days 1 (100 mg), 2 (900 mg), 8 (1 g), and 15 (1 g) of cycle 2 followed by 1 g on day 1 of cycles 3-7; acalabrutinib was given for one cycle before initiating obinutuzumab to reduce infusion-related reactions.1, 10 In the obinutuzumab plus chlorambucil group, obinutuzumab was administered IV on days 1 (100 mg), 2 (900 mg), 8 (1 g), and 15 (1 g) of cycle 1 followed by 1 g on day 1 of cycles 2-6, and chlorambucil 0.5 mg/kg was administered orally on days 1 and 15 of cycles 1-6.1, 10 Eligible patients were ≥65 years of age, or 18 to <65 years of age with a total Cumulative Illness Rating Scale (CIRS) >6 or creatinine clearance of 30-69 mL/minute; in addition, patients had serum aminotransferase concentrations ≤3 times the upper limit of normal (ULN), total bilirubin ≤1.5 times the ULN, ECOG performance status score ≤2, and adequate hematologic, hepatic, and renal function.1, 10 Patients with substantial cardiovascular disease or Richter's transformation were excluded, and concomitant use of warfarin or an equivalent vitamin K antagonist was prohibited.1, 10 Patients had a median age of 70 years (range: 41-91 years); 47% had Rai stage III or IV disease, 14% had 17p deletion or TP53 mutation, 63% of patients had unmutated IgVH , and 18% had 11q deletion.1, 10
At a median follow-up duration of 28.3 months, progression-free survival as assessed by an independent review committee (IRC) using the 2008 International Workshop Criteria for CLL (IWCLL) guidelines showed a hazard ratio of 0.1 (95% confidence interval: 0.06-0.17) in favor of acalabrutinib plus obinutuzumab compared with obinutuzumab plus chlorambucil.1, 10 In addition, progression-free survival showed a hazard ratio of 0.2 (95% confidence interval: 0.13-0.3) for acalabrutinib monotherapy compared with obinutuzumab plus chlorambucil (a secondary end point).1, 10 The median IRC-confirmed progression-free survival duration was 22.6 months in patients receiving obinutuzumab plus chlorambucil but had not been reached in patients receiving acalabrutinib monotherapy or acalabrutinib plus obinutuzumab.1, 10 Overall response rate was substantially higher with acalabrutinib plus obinutuzumab (94%) than with obinutuzumab and chlorambucil (79%); overall response rate with acalabrutinib monotherapy was 86%.1, 10 Substantially more patients had complete responses (as assessed by an IRC) with acalabrutinib plus obinutuzumab (13%) than with obinutuzumab and chlorambucil (5%); complete response with acalabrutinib monotherapy was 1%.1, 10 At the time of analysis, median overall survival had not been reached in either treatment group.1, 10
A 4-year follow-up of the ELEVATE-TN study reported a median progression-free survival of 27.8 months for obinutuzumab plus chlorambucil, with the median progression-free survival not reached for the acalabrutinib-containing arms.14 Median overall survival was not reached in any of the treatment arms.14 Overall response rates were substantially higher with acalabrutinib plus obinutuzumab (96.1%) and acalabrutinib monotherapy (89.9%) than with obinutuzumab plus chlorambucil (82.5%).14
In the ASCEND trial, 310 patients with relapsed or refractory CLL after at least one prior systemic therapy were randomized in a 1:1 ratio to receive acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity, or the investigator's choice of either idelalisib (150 mg orally twice daily until disease progression or unacceptable toxicity occurred) plus rituximab (375 mg/m2 IV on day 1 of cycle 1, followed by 500 mg/m2 every 2 weeks for 4 doses and then every 4 weeks for 3 doses in 28-day cycles) or bendamustine (70 mg/m2 IV on day 1 and 2 of each 28-day cycle) plus rituximab (375 mg/m2 IV on day 1 of cycle 1, followed by 500 mg/m2 on day 1 of subsequent 28-day cycles for up to 6 cycles).1, 11 In the investigator's choice group, 119 or 36 patients received idelalisib-rituximab or bendamustine-rituximab, respectively.1, 11 Eligible patients were ≥18 years of age, had an ECOG performance status score ≤2, and had adequate hematologic, hepatic, and renal function.1, 11 Patients with substantial cardiovascular disease were excluded, and concomitant use of warfarin or an equivalent vitamin K antagonist was prohibited.11 Patients who had received prior therapy with a Bruton's tyrosine kinase (BTK) inhibitor (e.g., ibrutinib), a B-cell chronic lymphoma 2 (BCL-2) inhibitor (e.g., venetoclax), a phosphoinositide 3-kinase isoform delta (PI3Kδ) inhibitor (e.g., idelalisib), or a spleen tyrosine kinase (SYK) inhibitor (e.g., fostamatinib) were excluded from the study.11 Patients had a median age of 67 years (range: 32-90 years); 42% had Rai stage III or IV disease, 28% had 17p deletion or TP53 mutation, 78% had an unmutated IgVH , and 27% had a 11q deletion.1, 11 Patients in the acalabrutinib group had received a median of one prior therapy (range: 1-8), with 47% having received at least two prior therapies; patients in the investigator's choice group had received a median of two prior therapies (range: 1-10), with 57% having received at least two prior therapies.1, 11 Median treatment duration was 15.7 or 8.4 months in the acalabrutinib or investigator's choice group, respectively.1 With a median follow-up of 16.1 months (range: 0.03-22.4 months), the primary end point of progression-free survival as assessed by an IRC using the 2008 IWCLL guidelines showed a hazard ratio of 0.31 (95% confidence interval: 0.20-0.49) in favor of acalabrutinib compared with idelalisib-rituximab or bendamustine-rituximab.1, 11 The median IRC-confirmed progression-free survival duration was 16.5 months for idelalisib-rituximab or bendamustine-rituximab but had not been reached for the acalabrutinib group.1, 11 No difference in overall response rates between the two treatment arms was observed, and median overall survival had not been reached in either treatment group.1, 11
Acalabrutinib was also compared to ibrutinib, another BTK inhibitor, in previously treated patients with CLL in a phase 3, randomized, open-label, noninferiority trial (ELEVATE-RR).15, 16 A total of 533 adult patients were randomly assigned (at a 1:1 ratio) to acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity.15 The primary endpoint was time from randomization to disease progression or any cause death.15 Enrolled patients were a median 66 or 65 years of age for acalabrutinib or ibrutinib, respectively; 92% had an ECOG performance status score of 0 to 1, with a median of 2 prior therapies.15 Patients with prior exposure to BTK inhibitors were excluded.15 At a median follow-up of 40.9 months, acalabrutinib was found to be noninferior to ibrutinib, with a median progression-free survival of 38.4 months for both BTK inhibitors.15
Guidelines for CLL are available from the National Cancer Institute, with treatment individualized based on disease stage and behavior.17 Observation may be an option for asymptomatic or minimally symptomatic patients.17 For symptomatic patients or patients with progressive CLL, first line agents include the BTK inhibitors acalabrutinib, zanubrutinib, or ibrutinib; venetoclax with initial use of obinutuzumab or rituximab; bendamustine and rituximab; fludarabine, cyclophosphamide, and rituximab; and the BTK inhibitors (ibrutinib or acalabrutinib) plus venetoclax.17 Treatment recommendations are similar in guidelines on CLL from European experts.18, 22
Acalabrutinib is available as capsule and tablet formulations.1, 19 The capsule and tablet formulations are bioequivalent; however, the tablets can be concurrently administered with gastric-reducing agents (e.g., antacids, H2-receptor antagonists, proton pump inhibitors).20
Acalabrutinib is administered orally twice daily, with doses given approximately 12 hours apart; the drug can be taken without regard to meals.1, 19
Acalabrutinib tablets and capsules should be swallowed whole with water.1, 19 Patients should not chew, crush, dissolve, or cut the tablets and should not open, break, or chew the capsules.1, 19
If a dose of acalabrutinib is missed by more than 3 hours, the dose should be skipped and the next dose should be taken at the regularly scheduled time.1, 19 Patients should not take extra tablets or capsules of the drug to make up for the missed dose.1, 19
Store acalabrutinib tablets or capsules at 20-25ºC (excursions permitted between 15-30°C).1, 19
For the treatment of mantle cell lymphoma in adults who have received at least 1 prior therapy, the recommended dosage of acalabrutinib is 100 mg approximately every 12 hours.1, 19 Acalabrutinib therapy should be continued until disease progression or unacceptable toxicity occurs.1, 19
Acalabrutinib in Combination with Bendamustine and Rituximab
For the treatment of previously untreated mantle cell lymphoma in adults who are ineligible for autologous hematopoietic stem cell transplantation (HSCT), the recommended dosage of acalabrutinib is 100 mg approximately every 12 hours in combination with bendamustine and rituximab.1, 19
Acalabrutinib should be initiated on Day 1 of Cycle 1 (each cycle is 28 days) and given until disease progression or unacceptable toxicity occurs.1, 19 Administer bendamustine 90 mg/m2 on Days 1 and 2 and rituximab 375 mg/m2 on Day 1 of Cycle 1 and continue for a total of 6 cycles.1, 19 If a patient achieves a partial or complete response after the initial 6 cycles, maintenance rituximab may be continued on Day 1 of every other cycle for a maximum of 12 additional doses, starting on Cycle 8 up to Cycle 30.1, 19
Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults, the recommended dosage of acalabrutinib is 100 mg approximately every 12 hours.1, 19 Acalabrutinib therapy should be continued until disease progression or unacceptable toxicity occurs.1, 19
Acalabrutinib in Combination with Obinutuzumab
For the treatment of previously untreated CLL or SLL in adults, the recommended dosage of acalabrutinib is 100 mg approximately every 12 hours.1 Continue acalabrutinib therapy until disease progression or unacceptable toxicity occurs.1 Initiate acalabrutinib at cycle 1 and obinutuzumab at cycle 2, for a total of six 28-day cycles.1, 19
Consult prescribing information for obinutuzumab for recommended dosage.1, 19 When given on the same day, administer acalabrutinib prior to obinutuzumab.1, 19
Dosage Modification for Toxicity
Acalabrutinib therapy should be withheld for the occurrence of grade 3 or higher nonhematologic toxicity, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, or grade 4 neutropenia lasting longer than 7 days in patients receiving acalabrutinib monotherapy or acalabrutinib in combination with obinutuzumab.1, 19 Upon resolution or improvement of the toxicity (i.e., return to baseline or resolution to grade 1), acalabrutinib therapy may be resumed (or discontinued) as described in Table 1.1, 19 Consult prescribing information for obinutuzumab for additional information for management of toxicities.1, 19
When acalabrutinib is administered in combination with bendamustine and rituximab, dosage modifications may also be necessary (Table 2).1, 19 Consult prescribing information for bendamustine and rituximab for additional information for management of toxicities.1, 19
Toxicity Occurrence | Recommended Dosage after Recovery from Toxicity (Starting Dosage = 100 mg approximately every 12 hours) |
|---|---|
First | Restart at 100 mg approximately every 12 hours |
Second | Restart at 100 mg approximately every 12 hours |
Third | Restart at 100 mg once daily |
Fourth | Discontinue acalabrutinib |
Adverse Reaction | Severity | Dosage Modification (Starting Dosage = 100 mg approximately every 12 hours |
|---|---|---|
Neutropeniaa | ANC <500 cells/mm3 for >7 days | Acalabrutinib : interrupt therapy; resume at starting dosage once toxicity has resolved to grade ≤2 Upon second or third occurrence, reduce dosage to 100 mg once daily b Discontinue therapy at fourth occurrence Bendamustine : interrupt therapy; resume therapy and consider dose reduction to 70 mg/m2 once toxicity has resolved to grade ≤2 c d |
Thrombocytopeniae | Platelet count 25,000 to 50,000 cells/mm3 with clinically significant bleeding or platelet count <25,000 cells/mm3 | Acalabrutinib : interrupt therapy; resume at starting dosage once toxicity has resolved to grade ≤2 or baseline If recurrence, reduce dosage to 100 mg once daily b Consider discontinuing therapy with third occurrence Bendamustine e: interrupt therapy; resume therapy and consider dose reduction to 70 mg/m2 once toxicity has resolved to grade ≤2 or baselined |
Non-hematologic adverse reactions | Grade 3 or higher | Acalabrutinib : interrupt therapy; resume at starting dosage once toxicity has resolved to grade ≤2 or baseline If recurrence, reduce dosage to 100 mg once dailyb Discontinue therapy with third recurrence of grade 4 toxicity; for grade 3 toxicity, consider risks and benefits of continuing therapy Bendamustine : interrupt therapy; resume therapy and consider dose reduction to 70 mg/m2 once toxicity has resolved to grade ≤2 or baselined |
aFor neutropenia with ANC <1000 cells/mm3, consideration for bendamustine dose interruption and dosage reduction to 70 mg/m2 may be appropriate in certain circumstances.
bDose may be re-escalate at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks.
cConsider use of myeloid growth factors before bendamustine dose reduction.
dConsider discontinuing bendamustine if additional dosage reduction is required.
eFor thrombocytopenia, a platelet count <50,000 cells/mm3 should prompt bendamustine dose interruption even in the absence of clinically significant bleeding.
Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of acalabrutinib and drugs that are strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A (CYP3A) should be avoided.1, 19 If short-term (e.g., anti-infective therapy for up to 7 days) therapy with a strong CYP3A inhibitor is necessary, acalabrutinib should be withheld during such therapy.1, 19 After discontinuance of the strong CYP3A inhibitor for at least 24 hours, resume previous dosage of acalabrutinib.1
If acalabrutinib is used concomitantly with a moderate CYP3A inhibitor, the manufacturer recommends reducing the dosage of acalabrutinib to 100 mg once daily.1, 19
Concomitant use of acalabrutinib and drugs that are strong inducers of CYP3A should be avoided.1, 19 If therapy with a strong CYP3A inducer is unavoidable, the manufacturer recommends increasing the dosage of acalabrutinib to 200 mg every 12 hours.1, 19
Dosage adjustments are not required in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.1, 19 Avoid use in patients with severe (Child-Pugh class C) hepatic impairment.1, 19
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1, 19
Serious and Opportunistic Infections
Serious and sometimes fatal infections, including bacterial, fungal, viral, or other opportunistic infections, have been reported in acalabrutinib-treated patients.1, 2, 19 Serious or grade 3 or higher infections occurred in 19% of patients receiving acalabrutinib for hematologic malignancies in clinical trials.1 The most commonly reported grade 3 or 4 infections were respiratory tract infections, including pneumonia.1, 2 Opportunistic infections reported in patients receiving acalabrutinib have included hepatitis B reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML).1, 19
Patients receiving acalabrutinib therapy should be monitored for the development of signs and symptoms of infection and treated promptly if infection occurs.1, 19 In addition, anti-infective prophylactic therapy should be considered in patients who are at increased risk for opportunistic infections.1, 9, 19
Serious hemorrhagic events, including fatal events, have occurred in patients with hematologic malignancies treated with acalabrutinib in clinical trials.1, 2, 19 Major hemorrhage (serious or grade 3 or higher bleeding or any CNS bleeding) was reported in 3% of these patients, with fatal hemorrhage occurring in 0.1% of patients.1, 2 Overall, hemorrhagic events, excluding bruising and petechiae, of any grade of severity occurred in 22% of patients receiving acalabrutinib1
Concomitant use of acalabrutinib with antithrombotic agents may further increase the risk of hemorrhagic events; in clinical trials, major hemorrhage occurred in 2.7% of patients taking acalabrutinib without antithrombotic agents and 3.6% of patients taking acalabrutinib with antithrombotic agents.1 Consider the risks and benefits of antithrombotic agents when used concomitantly with acalabrutinib, and monitor patients for signs of bleeding.1, 19
Because of the risk of bleeding, the potential benefits and risks of withholding acalabrutinib therapy for 3-7 days prior to and following surgery (based on the type of surgery and bleeding risk) should be considered.1, 19
Cytopenias, including neutropenia, anemia, thrombocytopenia, and lymphopenia, have been reported in patients receiving acalabrutinib.1, 2, 19 Grade 3 or 4 cytopenias included reduced absolute neutrophil count (26%), decreased platelets (10%), decreased hemoglobin (10%), and reduced absolute lymphocyte count (10%) in patients treated with acalabrutinib alone or in combination with obinutuzumab.1, 19 Grade 4 neutropenia developed in 14% of patients.1, 19
Complete blood cell (CBC) counts should be monitored regularly during acalabrutinib therapy.1, 19 Temporary interruption of acalabrutinib therapy, dosage reduction, or discontinuance of therapy may be necessary.1, 19
Second primary malignancies, including skin cancers and other solid tumors, have occurred in 18% of patients with hematologic malignancies treated with acalabrutinib in clinical trials.1, 19 Non-melanoma skin cancer was the most frequently reported second primary malignancy, occurring in 10% of acalabrutinib-treated patients, followed by other solid tumors (including melanoma, lung cancer, GI cancers, and genitourinary cancers) in 9% and hematologic malignancies in 1% of patients.1, 19 Patients receiving the drug should therefore be monitored for the development of second cancers and advised to avoid sun exposure.1, 19
Serious cardiac arrhythmias have been reported with acalabrutinib therapy.1, 19 Atrial fibrillation or atrial flutter of any grade was reported in 4.1% of patients.1 Grade 3 atrial fibrillation or flutter occurred in 1.1% of patients.1 Ventricular arrhythmias (grade 3 or higher) were reported in 0.9% of patients.1
The risk for an arrhythmia may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, or acute infection.1, 19
Patients receiving acalabrutinib should be monitored for symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) and managed appropriately should they occur.1, 19
Hepatotoxicity, Including Drug-induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury, have occurred with acalabrutinib therapy.1, 19
Clinicians should evaluate bilirubin and transaminases at baseline and throughout acalabrutinib treatment.1, 19 For patients who develop abnormal liver tests after acalabrutinib therapy, clinicians should monitor for liver test abnormalities and clinical signs and symptoms of hepatotoxicity more frequently.1, 19 Clinicians should withhold acalabrutinib if drug-induced liver injury is suspected and discontinue therapy entirely if confirmed.1, 19
There are no available data regarding the use of acalabrutinib in pregnant females.1, 19 However, based on animal findings, acalabrutinib may cause fetal harm and dystocia if administered to pregnant females.1, 19 In animal reproduction studies, administration of acalabrutinib during the period of organogenesis resulted in dystocia in rats and embryofetal toxicity (e.g., decreased fetal body weight, delayed skeletal ossification) in rabbits at maternal exposures 2 times those in humans at the recommended dosage of 100 mg twice daily.1, 19
Pregnancy testing is recommended for females of reproductive potential prior to initiating acalabrutinib therapy.1, 19 If acalabrutinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.1, 19
Acalabrutinib and its active metabolite ACP-5862 are distributed into milk in rats.1, 19 It is not known whether the drug or its active metabolite distributes into human milk or if the drug has any effect on milk production or the nursing infant.1, 19 Because of the potential for adverse reactions to acalabrutinib in nursing infants, females should be advised not to breast-feed while receiving acalabrutinib and for at least 2 weeks after the last dose of the drug.1, 19
Females and Males of Reproductive Potential
Pregnancy testing is recommended for females of reproductive potential prior to initiating acalabrutinib therapy.1, 19 Advise female patients of reproductive potential to use effective contraception during treatment with acalabrutinib and for ≥1 week following the last dose of the drug.1, 19
Safety and efficacy of acalabrutinib have not been established in pediatric patients.1, 19
In clinical studies evaluating acalabrutinib in patients with previously treated mantle cell lymphoma or chronic lymphocytic leukemia, 67% of patients were 65 years of age or older and 22% were 75 years of age or older.1, 19 No clinically important differences in efficacy were observed between geriatric patients and younger adults in these studies.1, 19
Among patients 65 years of age or older, 74% had grade 3 or higher adverse reactions and 58% had serious adverse reactions.1, 19 Among patients younger than 65 years of age, 61% had grade 3 or higher adverse reactions and 39% had serious adverse reactions.1, 19
In clinical studies evaluating acalabrutinib in patients with previously untreated mantle cell lymphoma, 72% of patients were 65 to 74 years of age and 28% were 75 years of age or older.1, 19 No clinically important differences in efficacy or safety were observed between patients 65 to 74 years of age and those 75 years of age and older.1, 19
Population pharmacokinetic analysis suggests that age does not have a clinically important effect on the pharmacokinetics of acalabrutinib and its active metabolite ACP-5862.1, 19
In a hepatic impairment study, acalabrutinib exposure increased by 1.9-fold in individuals with mild (Child-Pugh class A) hepatic impairment, 1.5-fold in individuals with moderate hepatic impairment (Child-Pugh class B), and 5.3-fold in individuals with severe hepatic impairment (Child-Pugh class C).1, 19
No clinically relevant differences in the pharmacokinetics of ACP-5862 (active metabolite) were observed in subjects with severe hepatic impairment compared to subjects with normal liver function.1, 19 No clinically important difference in the pharmacokinetics of acalabrutinib or ACP-5862 was observed in individuals with mild or moderate hepatic impairment (defined as total bilirubin concentrations that are less than or equal to the upper limit of normal [ULN] with AST concentration greater than ULN or total bilirubin concentrations that are greater than ULN with any AST concentration) compared with individuals with normal hepatic function.1, 19
The safety of acalabrutinib has not been studied in patients with moderate or severe hepatic impairment.1, 19 Avoid use in patients with severe hepatic impairment.1, 19
There are no clinically important differences in the pharmacokinetics of acalabrutinib and its active metabolite, ACP-5862, based on mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] of at least 30 mL/minute per 1.73 m2 and eGFR less than 89 mL/minute per 1.73 m2).1, 19 The manufacturer states that the effects of severe renal impairment (eGFR less than 29 mL/minute per 1.73 m2) or renal impairment requiring dialysis on acalabrutinib pharmacokinetics are unknown.1, 19
Adverse effects reported in at least 30% of patients receiving acalabrutinib in clinical trials include diarrhea, upper respiratory tract infection, headache, musculoskeletal pain, lower respiratory tract infection, and fatigue.1 The most common Grade 3 or 4 laboratory abnormalities (≥10%) include decreased absolute neutrophil count, absolute lymphocyte count, platelets, and hemoglobin.1
Acalabrutinib is principally metabolized by cytochrome P-450 (CYP) isoenzyme 3A and, to a minor extent, by glutathione conjugation and amide hydrolysis.1, 19 Metabolism of acalabrutinib to the principal active metabolite, ACP-5862, is mediated principally by CYP3A.1, 19
In vitro studies indicate that acalabrutinib is an inhibitor of CYP isoenzymes 3A4/5, 2C8, and 2C9; does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, and 2D6; and is an inducer of CYP isoenzymes 3A4, 1A2, and 2B6.1, 19
In vitro studies also indicate that acalabrutinib's active metabolite, ACP-5862, is an inhibitor of CYP isoenzymes 2C8, 2C9, and 2C19; does not inhibit CYP isoenzymes 3A4/5, 1A2, 2B6, or 2D6; and is an inducer of CYP3A4.1, 19
Acalabrutinib and ACP-5862 do not inhibit uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1 or UGT2B7.1, 19
In vitro studies indicate that acalabrutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, and organic anion transport proteins (OATP) 1B1 and OATP1B3.1, 19 Acalabrutinib is an inhibitor of BCRP.1, 19 Acalabrutinib does not inhibit P-gp, multidrug and toxin extrusion transporter (MATE) 1, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, or MATE2-K.1, 19
ACP-5862 is a substrate of P-gp and BCRP but is not a substrate of OATP1B1 or OATP1B3.1, 19 ACP-5862 inhibits MATE1 but does not inhibit BCRP, P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, or MATE2-K .1, 19
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of acalabrutinib with strong or moderate inhibitors of CYP3A may result in substantially increased peak plasma concentrations and systemic exposure (AUC) of acalabrutinib and result in increased toxicity.1, 19
When the strong CYP3A inhibitor itraconazole was administered concomitantly with acalabrutinib in healthy individuals, peak plasma concentration and AUC of acalabrutinib increased by 3.9- and 5.1-fold, respectively.1, 19
Concomitant use of acalabrutinib and a moderate inhibitor of CYP3A (e.g., diltiazem, erythromycin, fluconazole) is predicted to increase peak plasma concentration and AUC of acalabrutinib by approximately two- to three-fold.1, 19
Concomitant use of acalabrutinib with strong CYP3A inhibitors should be avoided.1, 19 If short-term therapy with a strong CYP3A inhibitor is required, the manufacturer recommends withholding acalabrutinib therapy during administration of the strong CYP3A inhibitor.1, 19 After discontinuance of the strong CYP3A inhibitor for at least 24 hours, resume previous dosage of acalabrutinib.1
If acalabrutinib is used concomitantly with a moderate CYP3A inhibitor, the manufacturer recommends reducing the dosage of acalabrutinib to 100 mg once daily.1, 19
Concomitant use of acalabrutinib with strong inducers of CYP3A may result in decreased peak plasma concentrations and systemic exposure (AUC) of acalabrutinib and therefore reduce its efficacy.1, 19
When the strong CYP3A inducer rifampin was administered concomitantly with acalabrutinib in healthy individuals, peak plasma concentration and AUC of acalabrutinib decreased by 68 and 77%, respectively.1, 19
Concomitant use of acalabrutinib with strong CYP3A inducers should be avoided; if such concomitant use cannot be avoided, the manufacturer recommends increasing the dosage of acalabrutinib to 200 mg approximately every 12 hours.1, 19
When acalabrutinib tablets were administered concomitantly with the proton-pump inhibitor rabeprazole, no clinically important differences in acalabrutinib pharmacokinetics were observed.1
When acalabrutinib capsules were administered with gastric acid reducing agents (e.g., calcium carbonate, omeprazole), solubility decreased with increasing pH.19
Anticoagulants and Antiplatelet Agents
In the principal efficacy trial (ACE-LY-004 trial), 43% of the patients were concurrently receiving anticoagulants.2 Because of the increased risk of hemorrhagic events, patients concurrently receiving acalabrutinib and anticoagulants or antiplatelet agents should be monitored for signs of bleeding and hemorrhage.1, 19
Acalabrutinib is a selective, irreversible, small-molecule inhibitor of Bruton tyrosine kinase (BTK); the drug is an antineoplastic agent.1, 2, 4, 5 Acalabrutinib and its active metabolite (ACP-5862) bind covalently with a cysteine residue in the BTK active site, which results in inhibition of BTK enzymatic activity.1 BTK is an essential signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.1 Within B cells, BTK signaling results in activation of pathways involved in cell proliferation, trafficking, chemotaxis, and adhesion.1 In nonclinical studies, acalabrutinib inhibited the BTK-mediated activation of downstream signaling proteins CD86 and CD69 resulting in decreased malignant B-cell proliferation and tumor growth in mouse xenograft models.1, 4, 5 Inhibition of BTK also reduces plasma concentrations of cytokines and chemokines, which may lead to decreased cell adhesion and mobilization of cells from tissues;2 this redistribution of cells from tissues to peripheral blood may contribute to the transient increase in absolute lymphocyte count (lymphocytosis) that has been observed in patients receiving BTK inhibitors (e.g., acalabrutinib, ibrutinib).2, 6 Unlike ibrutinib (another BTK inhibitor used to treat mantle cell lymphoma), acalabrutinib does not appear to irreversibly target kinases other than BTK, including epidermal growth factor receptor (EGFR), tyrosine kinase expressed in hepatocellular carcinoma (TEC), and interleukin 2-inducible T-cell kinase (ITK).2, 4, 5 The selective targeting of BTK by acalabrutinib may help explain, at least in part, some of the tolerability differences between acalabrutinib and ibrutinib observed in clinical studies to date.2, 4, 5
Following oral administration, the mean absolute bioavailability of acalabrutinib is 25%.1, 19 The median time to achieve peak plasma concentrations is 0.5 hours for the parent drug and 0.75 hours for ACP-5862, its active metabolite, for oral tablets.1 For oral capsules, the median time to peak plasma concentration is 0.9 hours for the parent drug and 1.6 hours for ACP-5862.19 Administration of a high-fat, high-calorie meal did not substantially alter the area under the plasma concentration-time curve (AUC) of acalabrutinib (100 mg single dose); peak plasma concentrations decreased by 54 to 73% and time to achieve peak concentrations was delayed by 1-2 hours compared with administration of the drug under fasting conditions.1, 19 Acalabrutinib exhibits dose-proportionality; exposures of both acalabrutinib and ACP-5862 increase with dose over a dosage range of 75-250 mg.1, 19 Accumulation of the drug does not appear to occur with repeated dosing.5 In patients with B-cell malignancies receiving acalabrutinib at a dosage of 100 mg twice daily, median steady-state binding of the drug to BTK (BTK occupancy) of 95% or more was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval of the drug.1, 2
Acalabrutinib is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by CYP3A, and, to a minor extent, by glutathione conjugation and amide hydrolysis.1, 19 The principal active metabolite, ACP-5862, is approximately 50% less potent as a BTK inhibitor than acalabrutinib.1, 19 Acalabrutinib and ACP-5862 are 97.5 and 98.6% bound to plasma proteins, respectively.1, 19 Following administration of a single radiolabeled dose of acalabrutinib, 84% of the dose was recovered in feces and 12% was recovered in urine; unchanged drug in urine and feces accounted for less than 2% of the recovered dose.1, 19 The mean elimination half-life of acalabrutinib is 1.4 hours.1 The mean elimination half-life of ACP-5862 is 6.4 hours.1 The pharmacokinetics of acalabrutinib do not appear to be affected by age (range: 32-90 years), sex, race, or body weight.1, 19
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of acalabrutinib is restricted.8 Consult manufacturer's website [Web] for specific availability information.8
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 100 mg | ||
Tablets, film-coated | 100 mg | Calquence® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. AstraZeneca Pharmaceuticals LP. Calquence® (acalabrutinib) film-coated tablets prescribing information. Wilmington, DE; 2025 Jan. [Web]
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; 391:659-67. [PubMed 29241979]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 Jan 17. [Web]
4. 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; 363:240-52.
5. Byrd JC, Harrington B, O'Brien S et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med . 2016; 374:323-32.
6. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210259Orig1s000: Multi-discipline review(s). From FDA website. [Web]
8. AstraZeneca Pharmaceuticals LP. Calquence® (acalabrutinib) distribution card. 2022. From the Calquence® Healthcare Professionals website. Accessed 2024 Jan 8. [Web]
9. Awan FT, Jurczak W. Use of acalabrutinib in patients with mantle cell lymphoma. Expert Rev Hematol . 2018; 11:495-502. [PubMed 29737219]
10. Sharman JP, Egyed M, Jurczak W et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet . 2020; 395:1278-91. [PubMed 32305093]
11. 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; 38:2849-61. [PubMed 32459600]
12. Le Gouill S, Długosz-Danecka M, Rule S, et al. Final results and overall survival data from a phase II study of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma, including those with poor prognostic factors. Haematologica . 2024;109(1):343-350.
13. Dreyling M, Campo E, Jerkeman M, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol . 2017;28(suppl 4):iv62-iv71.
14. Sharman J, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia . 2022;36:1171-1175.
15. Byrd J, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol . 2021;39:3441-3452.
16. Seymour J, Byrd J, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood . 2023;142(8):687-699.
17. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ)-Health Professional Version. Accessed 2025 Jun 2. [Web]
18. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol . 2021;32(1):23-33.
19. AstraZeneca Pharmaceuticals LP. Calquence® (acalabrutinib) gelatin-coated capsules prescribing information. Wilmington, DE; 2025 Jan.
20. AstraZeneca. News release. Calquence formulation approved in the US across current indications. August 5, 2022. [Web]
21. Wang M, Salek D, Belada D, et al. Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma. J Clin Oncol . Epub 2025 May 1.
22. Eichhorst B, Ghia P, Niemann CU, et al. on behalf of the ESMO Guidelines Committee. ESMO clinical practice guideline interim update on new targeted therapies in the first line and at relapse of chronic lymphocytic leukemia. Ann Oncol . 2024;35:762-768.