Oral oncolytic treatment for chronic lymphocytic leukemia

Abstract

Objective

The objective of this article is to review the current supporting literature for the use of oral oncolytics in chronic lymphocytic leukemia, consideration for their use and management of adverse drug events that may limit use.

Data Sources

NCCN guidelines were utilized to determine available oral options for treatment of chronic lymphocytic leukemia. A literature review was carried out through PubMed to find relevant clinical trials that evaluated the efficacy and safety of Bruton's tyrosine kinase inhibitors, BCL-2 inhibitors and PI3K-δ inhibitors. Medication package inserts and primary literature regarding toxicity were used to determine appropriate adverse drug event management.

Data Summary

A total of 7 clinical trials were found for the evaluation the efficacy and safety of burton tyrosine kinase inhibitor, 1 clinical trial for the BCL-1 inhibitor venetoclax and 4 trials were for PI3K-δ inhibitors. The data from these studies suggest that ibrutinib can be used first line in previously untreated patients and relapsed/refractory patients as well as acalabrutinib. The data also support the use of venetoclax, idelalisib, and duvelisib in relapsed/refractory chronic lymphocytic leukemia patients.

Conclusions

The use of oral-only oncolytics could be a viable option for reducing the risk of infection due to limiting exposure to healthcare settings. Current literature suggests oral oncolytics may be an option, but there are several considerations to evaluate including medication adherence, drug-drug interactions, adverse events, and financial toxicity.

Keywords

Chronic lymphocytic leukemia CLL oral oncolytics adverse drug event adverse drug event management

The landscape of CLL treatment has evolved to include numerous oral oncolytics alongside or even in place of intravenous (IV) drugs. Oral-only treatment options have the benefit of potentially limiting a patient's exposure to the health care setting by decreasing the number of patient visits for routine treatment and monitoring. This yields an added benefit of reducing the risk of infection exposure in patients who are more susceptible to developing severe complications. However, there are important factors for the clinician to consider such as medication adherence, toxicities, increased cost, and drug-drug interactions. Despite having FDA indications for monotherapy, these agents are also used in combination with IV drugs, which require routine visits to an infusion centre for treatment. The purpose of this paper is to review the evidence for current oral treatment options for newly diagnosed and relapsed/refractory CLL patients.

Bruton Tyrosine Kinase (BTK) Inhibitors

BTK, an enzyme part of the B-cell receptor (BCR), is thought to play a vital role in survival of malignant B-cells when activated. Blocking the activation of this receptor leads to decreased proliferation and survivability of the B-cell. Ibrutinib is a BTK inhibitor that is FDA-approved for the treatment of CLL in previously untreated and previously treated patients with or without 17p deletion.¹ The recommended dosing of ibrutinib is 420 mg once daily and is continued until disease progression or unacceptable toxicity occurs.¹

Ibrutinib was evaluated as first line treatment in RESONATE-2, which was an open-label, randomized clinical trial that compared ibrutinib to chlorambucil in previously untreated patients with CLL.² Patients were randomized 1:1 to receive ibrutinib 420 mg daily (n = 136) or chlorambucil dosed at 0.5 mg/kg on days 1 and 15 of each 28-day cycle, which was increased to a maximum of 0.8 mg/kg up to 12 cycles (n = 133).² The median progression-free survival (PFS) was not reached in the ibrutinib arm and was 18.9 months in the chlorambucil arm. The overall survival (OS) was prolonged in the ibrutinib arm with an estimated survival rate at 24 months of 98% in the ibrutinib arm versus 85% in the chlorambucil arm. The overall response rate (ORR) was 86% in the ibrutinib arm versus 35% in the chlorambucil arm p < 0.001. In a 5 year follow-up of RESONATE-2, the estimated at 5 years progression free survival (PFS) was 70% in the ibrutinib arm compared to 12% in the chlorambucil arm. The estimated OS at 5 years was 83% in the ibrutinib arm and 68% in the chlorambucil arm. ORR for ibrutinib versus chlorambucil was 92% versus 32% respectively.³

Comparatively, RESONATE-17 was an open-label, single arm study that evaluated the use of ibrutinib in 145 previously treated CLL patients with 17p deletion.⁴ The 24-month PFS was 63%, the 24 month OS was 75% and the ORR was 75% with a median follow up of 27.6 months.⁴ In an extended study (18 months), median PFS was not reached in the ibrutinib arm with a PFS rate of 74% and was 8.1 months in the ofatumumab arm. The estimated 18 month OS was 86% in the ibrutinib which was similar amongst the subgroups.⁵

In another study by Byrd et al., patient with relapsed or refractory CLL or SLL were randomized to receive daily ibrutinib or ofatumumab. Patients enrolled in the study were specifically at risk for poor outcomes. The median follow-up was 9.4 months and the median PFS was not reached in the ibrutinib group with a rate of PFS of 88% at 6 months compared to 8.1 months in the ofatumumab group. The OS at 12 months was 90% in the ibrutinib group and versus 81% in the ofatumumab group. The ORR was 42.6% in the ibrutinib group versus 4.1% in the ofatumumab group p < 0.001.⁶

The second BTK inhibitor, acalabrutinib, is a second generation BTK inhibitor FDA-approved for use in previously untreated or relapsed/refractory CLL patients.⁷ The recommended dosing as monotherapy is 100 mg twice daily and is continued until disease progression or unacceptable toxicity occurs.⁷

ELEVATE TN was an open-label study evaluating the use of acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for previously untreated CLL patients.⁸ 535 patients were randomized to receive acalabrutinib-obinutuzumab, acalabrutinib alone, or obinutuzumab-chlorambucil. Estimated PFS at 24 months was 93% in the acalabrutinib-obinutuzumab group, 87% with acalabrutinib monotherapy, and 47% with the obinutuzumab-chlorambucil group (p < 0.0001).⁸ The OS was not reached in any group and the best overall response rate was 95% in the acalabrutinib-obinutuzumab arm versus 79% in the obinutuzumab-chlorambucil arm.⁸

Acalabrutinib's role in therapy for relapsed/refractory CLL patients was evaluated in the ASCEND study, which was a phase 3 randomized clinical trial that compared acalabrutinib monotherapy versus investigator's choice (idelalisib and rituximab or bendamustine and rituximab).⁹ The median PFS was not reached in the acalabrutinib arm compared to 16.5 months in the investigator choice arm p < 0.001.⁹ Estimated 12-month PFS was 88% in the acalabrutinib arm and 68% for investigator's choice.⁹

Toxicities Of BTK inhibitors

Hemorrhage/Atrial Fibrillation

Major and minor bleeding has been associated with the use of BTK inhibitors.^2,7,10 The risk of bleeding can be increased based on specific patient risk factors such as age, gender, comorbidities, and the use of antiplatelet or anticoagulation therapy. There should be careful consideration prior to initiation of concomitant anticoagulants or antiplatelets.⁹ Recommendations regarding antiplatelet therapy are summarized in Table 1.¹⁰A summary of VTE, bleeding and cardiac arrhythmias management can be found in Figure 1.

Table 1.

Antiplatelet considerations around BTK inhibitors.¹⁰

Caution with non-steroidal anti-inflammatory drugs (NSAIDs), fish oils, vitamin E and other aspirin-containing products

Stopping aspirin in patients with low or moderate cardiovascular risk

Using a maximum dose of 81 mg of aspirin for myocardial infarction or stroke

Delaying or holding BTKi when dual antiplatelet therapy (DAPT) is needed due to a metal cardiac stent or drug eluting stent placement

Hypertension

Although hypertension can be seen with both BTK inhibitors, real-world observations suggest this is far more common with ibrutinib.¹¹ A retrospective study published in 2019 showed more than 75% of patients on ibrutinib developed hypertension or experienced worsening of hypertension.¹² Optimal hypertension management for BTKi-induced hypertension is not known. Until further evidence emerges, we recommend managing hypertension in these patients include standard antihypertensive therapy directed per the ACC/AHA hypertension guidelines that has been optimized for the specific patient.^11,13 The patient's primary care provider can play a crucial role in monitoring and treating the hypertension; however, care should be taken to not prescribe antihypertensives such as diltiazem and verapamil given their CYP-3A4 mediated interaction with ibrutinib.

Dose Modification for adverse events

BTKi therapy should be interrupted for any grade 3 or greater non-hematological, neutropenia with infection or fever or grade 4 hematological toxicities.^1,7 After recovery of the toxicity to grade 1 or baseline, ibrutinib can be restarted. Dose adjustments for recurrent toxicities can be found in Table 2.

Table 2.

BTK inhibitor dose modification for toxicity Occurrences.^1,7

Ibrutinib
Toxicity occurrence	Dose modification
First	Restart at 420 mg daily
Second	Restart at 280 mg daily
Third	Restart at 140 mg daily
Fourth	Discontinue
Acalabrutinib
Toxicity occurrence	Dose modification
First	100 mg twice daily
Second	100 mg twice daily
Third	100 mg daily
Fourth	Discontinue

Table 3.

Ibrutinib dose modification for concomitant use with azole antifungals.¹

Co-administered drug	Recommend dose adjustment
Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily	140 mg once daily
Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole DR tablets 300 mg once daily	70 mg once daily

These dosing modifications are recommended after recovery of toxicity to grade 1 or baseline. 420 mg daily is the starting dose for ibrutinib and 100 mg twice daily for acalabrutinib.

Acalabrutinib therapy should be interrupted for any grade 3 or greater non-hematologic toxicity, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, or grade 4 neutropenia lasting longer than 7 days.⁷

Drug-Drug Interactions

Ibrutinib

The concurrent use of strong CYP3A inhibitors should be avoided as ibrutinib is a major CYP3A4 substrate.² However, if the use of a strong CYP3A4 inhibitor is required and will be used short-term, consider holding ibrutinib. Examples of recommended dose adjustments for ibrutinib when used with specific azole antifungals can be found in the table below. When ibrutinib is used concurrently with a moderate CYP3A4 inhibitor, the recommended dose is 280 mg daily.¹ Further dose modification can be found in Table 3.

Acalabrutinib

Similar to ibrutinib, the concurrent use of strong CYP3A inhibitors or inducers should be avoided. But if the use of a CYP3A inhibitor/inducer is needed short-term, acalabrutinib can be held until treatment with the offending agent is complete. For concurrent use with a moderate CYP3A inhibitor, reduce the dose to 100 mg once daily.⁷ Increase the dose of acalabrutinib to 200 mg twice daily for concomitant use with a strong CYP3A inducer.⁷ Also, the use of proton pump inhibitors (PPIs) should be avoided as they may decrease the serum concentration of acalabrutinib due to its absorption dependence on stomach pH. If therapy with PPIs are required concurrently with acalabrutinib, one can consider taking acalabrutinib with cola to maintain bioavailability.¹⁴ If using H2-receptor antagonists (H2RA), the H2RA should be dosed once daily and acalabrutinib should be taken 2 hour before the H2RA. Acalabrutinib should be separated by at least 2 hour from antacids.⁷

BCL-2 Inhibitors

Venetoclax

Venetoclax is an oral B-cell lymphoma 2 (BCL-2) inhibitor that is FDA-approved for CLL and is one of the preferred therapies in relapsed or refractory CLL in patients with del(17p)/TP53 mutation.¹⁵ In a phase 2 trial, venetoclax was evaluated in relapsed/refractory patients with del(17p).¹⁶ A total of 158 patients were enrolled in the study which included five patients who were previously untreated. Estimated PFS at 24 months was 54% and the investigator-assessed ORR was 77% and 30% of patients achieved a minimal residual disease (MRD) below the cutoff of 10⁻⁴.¹⁶ The target dose for venetoclax after 5 weeks of the ramp-up phase is 400 mg daily and is continued until disease progression or unacceptable toxicity occurs. The ramp-up schedule can be found in Table 4.¹⁵

Table 4.

Venetoclax ramp-up dosing.¹⁵

Week	Venetoclax daily dose
1	20 mg
2	50 mg
3	100 mg
4	200 mg
5	400 mg

Venetoclax Toxicities

Tumour Lysis Syndrome

It is highly recommended that venetoclax is ramped-up to its target dose due to the risk of tumour lysis syndrome (TLS). The release of intracellular contents from malignant lymphocytes can cause hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. If severe, these metabolic changes can lead to multiple clinical complications, such as renal insufficiency, cardiac arrhythmias, seizures, and death.^17,18 Management of abnormal electrolytes can be found in Table 5.¹⁹

Table 5.

Abnormal electrolyte management.¹⁹

Electrolyte Abnormalities	Management Recommendation
Hyperphosphatemia	Avoid IV phosphate Administration of a phosphate binder such sevelamer or calcium acetate Dialysis in severe cases
Hyperkalemia	Avoid IV and PO potassium EKG and cardiac rhythm monitoring Calcium gluconate 100–200 mg/kg for life-threatening arrhythmias followed by: – Regular insulin 5–10 units with dextrose or albuterol followed by: – Furosemide 20–40 mg IV or sodium polystyrene 15–60 mg – Hemodialysis
Hypocalcemia	No therapy if asymptomatic Calcium gluconate 50–100 mg/kg IV if symptomatic

In addition to ramp-up dosing, TLS is prevented using prophylaxis with both hydration and urate-lowering therapy (allopurinol). The degree of monitoring is dependent on the tumour burden, as defined by lymph nodes (LN) and absolute lymphocyte count (ALC). Recommendations based on tumour burden can be found in Table 6.^15,17

Table 6.

TLS management.¹⁵

Tumour burden
Low: LN < 5 cm and ALC < 25 × 10⁹/L	Medium: LN 5 cm to < 10 cm or ALC ≥ 25 × 10⁹/L	High: LN ≥ 10 cm or ALC ≥ 25 × 10⁹/L and LN ≥ 5 cm
Prophylaxis: 1.5–2 L oral hydration Allopurinol 300 mg started 2–3 days prior to starting venetoclax	Prophylaxis: 1.5–2 L oral hydration and consider additional IV fluids Allopurinol 300 mg started 2–3 days prior to starting venetoclax	Prophylaxis: 1.5 to 2 L orally and IV fluid 150–200 mL/hr as tolerated Allopurinol 300 mg started 2–3 days prior to starting venetoclax Rasburicase 6 mg, can be repeated based on response
Blood Chemistry monitoring: Outpatient setting: a blood chemistry pre-dose, 6–8 h after the dose, 24 h at first dose of 20 mg and 50 mg and pre-dose at subsequent ramp-up doses	Blood Chemistry monitoring: Same for a patient with a low tumour burden Patients with CrCl < 80 mL/min can be considered for hospitalization	Blood Chemistry monitoring: Hospital monitoring: a blood chemistry pre-dose, 4, 8, 12, and 24 h Outpatient monitoring: blood chemistry at subsequent ramp-up doses including pre-dose, 6–8 h, and 24 h

For high tumour burden, allopurinol can still be used, but rasburicase as a single dose can be considered if serum uric acid level is elevated at baseline. It should be noted that allopurinol does not actively decrease the uric acid level.²⁰ It works by inhibiting xanthine oxidases which reduces the production of uric acid. Rasburicase is a recombinant urate-oxidase enzyme that actively decreases the uric acid level by converting uric acid to allantoin which is a soluble metabolite. The FDA approved dose of rasburicase is 0.2 mg/kg daily for up to 5 days pending the patient's response. However, a meta-analysis of 15 studies has shown that a single flat dose of rasburicase 6 mg is as efficacious and cost effective compared with traditional weight-based dosing.²¹ Initiation of rasburicase should only be considered on a case-by-case basis based on distinct factors (i.e. baseline organ dysfunction, cost, the patient's risk of TLS, baseline uric acid-level and adverse event consideration).

If laboratory TLS does occur, the next dose of venetoclax should be held. If resolved within 24 to 48 h after the last dose, then venetoclax can be resumed at the same dose. However, if TLS takes more than 48 h for resolution, or if clinical TLS (defined as suspected TLS based on laboratory abnormalities along with acute renal failure, cardiac arrhythmias, or sudden death and/or seizures) occurs, venetoclax should be resumed at a reduced dose (dose modifications found in Table 7).¹⁵

Table 7.

Venetoclax dose modifications for adverse Events.¹⁵

Dose at interruption (mg)	Restart dose (mg)
400	300
300	200
200	100
100	50
50	20
20	10

Dose modifications for adverse events

Venetoclax therapy should be interrupted for grade 3 or 4 non-hematologic toxicities, grade 3 or 4 neutropenia with infection or fever, or grade 4 hematologic toxicities (except lymphopenia).¹⁵ For non-hematologic toxicities and grade 3 or 4 hematologic toxicities, venetoclax can be resumed at the same dose after resolution of the toxicity for the 1^st occurrence.¹⁵ If neutropenic, consider giving granulocyte-colony stimulating factor (G-CSF) with venetoclax to reduce the risk of prolonged neutropenia and infection. If the patient's venetoclax dose is reduced to less than 100 mg for 2 weeks, consider discontinuing venetoclax.¹⁵

Venetoclax drug-drug interactions

The concurrent use of strong CYP3A inhibitors such as ritonavir, posaconazole and other triazole antifungals are contraindicated during the initiation and ramp-up phase of venetoclax as it is a major CYP3A4 substrate and CYP3A inhibitors have been shown to increase the AUC and Cmax of venetoclax. A pharmacokinetic study showed that co-administration of venetoclax and posaconazole resulted in a Cmax increase of 53% and AUC increase of 76%. This increase in serum exposure of venetoclax, especially during the ramp-up phase, can increase the risk of adverse events, such as TLS and neutropenia.¹⁵ Strong CYP3A inhibitors should ideally be avoided during the post ramp-up phase as well.¹⁴ If this is not possible, the dose of venetoclax should be decreased by at least 75%.²² For moderate CYP3A inhibitors and P-gp inhibitors, the venetoclax dose should be decreased by at least 50%.

PI3K-δ Inhibitors

Idelalisib

Idelalisib is an oral inhibitor of phosphatidylinositol 3-kinase delta (PI3K-δ) that is indicated for the treatment of relapsed/refractory CLL.²³ Inhibition of PI3K-δ signaling, which is thought to promote B-cell proliferation in B-cell cancers, leads to apoptosis of tumour cells. In a previous phase 2 study, idelalisib plus rituximab in previously untreated CLL patients showed an ORR of 97%.²⁴ Preliminary results from a phase 2 study evaluating idelalisib as monotherapy in the treatment of CLL and SLL have shown activity in treatment-naïve patients and has been well tolerated in the treatment group.²⁵ Another phase 2 study by Lampson et al. evaluated the use of idelalisib as a first line agent in combination with ofatumumab.²⁶ The study was terminated early due to unacceptable safety profile due to an increased rate of death from infection.²⁶ At this time, both idelalisib monotherapy and idelalisib plus rituximab are not recommended in the first line setting by the National Comprehensive Cancer Network (NCCN) guidelines.²⁷ The recommended dose is 150 mg twice daily and is continued until disease progression or unacceptable toxicity occurs.²³

Duvelisib

Duvelisib is a dual inhibitor of δ and gamma (γ) (PI3K-δ,γ) that is FDA approved for relapsed or refractory CLL.²⁸ In the phase 3 DUO trial, patients were randomized 1:1 to receive duvelisib 25 mg twice daily monotherapy or ofatumumab monotherapy 300 mg IV on day 1, followed by 1000 mg on day 8.²⁹ Subsequent cycles were 1000 mg on day 1 every 28 days for a maximum of 6 cycles. The ORR was higher in the duvelisib arm regardless of del17p status and PFS. The PFS was 13.3 months in the duvelisib arm and 9.9 months and in the ofatumumab arm (P < .0001).²⁹ The recommended dose is 25 mg twice daily and is continued until disease progression or unacceptable toxicity occurs.²⁸

Idelalisib/Duvelisib Toxicities

Infection

Idelalisib and duvelisib require Pneumocystis Jiroveci Pneumonia (PJP) prophylaxis with trimethoprim/sulfamethoxazole.^23,28 Options for patients with a sulfa allergy include dapsone, atovaquone and pentamidine. PJP prophylaxis should be continued until absolute CD4 + T cell count is greater than 200 cells/µ after completion of duvelsib therapy.²⁸ CMV prophylaxis should be considered after monitoring CMV and presence of CMV viremia. Options for CMV prophylaxis include oral valganciclovir 900 mg daily.

Pneumonitis

According to package insert recommendations, idelalisib should be discontinued in patients with symptomatic pneumonitis.²³ Duvelisib, on the other hand, should be held and the patient should be treated with systemic steroid therapy for moderate symptomatic or grade 2 pneumonitis. If the pneumonitis recovers to grade 0 to 1, duvelisib can be resumed at 15 mg twice daily. For severe or life-threatening pneumonitis, recurrent pneumonitis, or if the patient does not respond to systemic steroid therapy, duvelisib should be discontinued.²⁸

Diarrhea

For mild to moderate diarrhea, the package insert recommends idelalisib dose to be maintained with close monitoring. If the patient experiences severe diarrhea (defined as 7 or more stools from baseline or hospitalization), idelalisib should be held until diarrhea is resolved and can be restarted at a reduced dose of 100 mg twice daily. If the patient experiences life-threatening diarrhea, idelalisib should be discontinued.²³

For diarrhea unresponsive to antidiarrheal agents (such as loperamide or bismuth subsalicylate), hold duvelisib and start supportive therapy with enteric acting steroids as the mechanism of diarrhea is immune-mediated. Once resolved, duvelisib can be restarted at a reduced dose of 15 mg twice daily. For diarrhea associated with abdominal pain, stool with mucus or blood, or severe diarrhea (defined as more than 6 stools), duvelisib should be held and supportive therapy with enteric acting or systemic steroids should be started with weekly monitoring. Once resolved, duvelisib can be restarted at the reduced dose. For recurrent severe diarrhea, recurrent colitis, or life threatening diarrhea, discontinue duvelisib permanently.²⁸

Cutaneous Reactions

For grade 1–2 cutaneous reactions, start supportive care with emollients, antihistamines or topical steroids and monitor closely. For grade 3 cutaneous reactions, duvelisib should be held and can be resumed at a reduced dose upon the resolution of the cutaneous reaction. For life threatening cutaneous reactions (i.e. Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), discontinue duvelisib.²⁸

PI3K-δ Inhibitors drug-drug interactions

Both idelalisib and duvelisib are major CYP3A4 substrates. Therefore, co-administration with strong CYP3A4 inducers should be avoided with idelalisib and if a strong CYP3A4 inhibitor is used with duvelisib the dose should be reduce to 15 mg. Dose adjustments for toxicities for idelalisib and duvelisib can be found in Tables 8 and 9 respectively. A summary of dose modifications can be found Table 10.

Table 8.

Idelalisib Lab abnormality Management.²³

Lab Abnormality
ALT/AST	> 3–5x ULN continue 150 mg twice daily with once weekly monitoring until ALT/AST ≤1 X ULN	If > 5–20X ULN, hold idelalisib and monitor weekly until ALT/AST are ≤ 1x. At this point idelalisib can be restarted at 100 mg twice daily	If ALT/AST is >20x ULN idelalisib should be discontinue permanently

Bilirubin	>1.5–3x ULN continue 150 mg twice daily with once weekly monitoring until bilirubin is ≤ 1 x ULN	If bilirubin is > 3–10x ULN, hold idelalisib and monitor once weekly until bilirubin is ≤1 and then restart at 100 mg twice daily	If bilirubin is >10 x ULN, discontinue idelalisib permanently

Neutropenia	If ANC is between 1–1.5 × 10⁹/L, continue 150 mg twice daily	For ANC 0.5 to < 1.0 × 10⁹/L, continue 150 mg twice daily and monitor ANC at least weekly	For ANC < 0.5 × 10⁹/L, hold idelalisib and monitor ANC weekly until ANC is ≥ 0.5 × 10⁹/L or greater. At this point, idelalisib can be restarted at 100 mg twice daily

Thrombocytopenia	If platelets 50–75 × 10⁹/L, continue 150 mg twice daily	For platelets 25–50 × 10⁹/L, continue 150 mg twice daily and monitor at least once weekly	If platelets <25 × 10⁹/L, hold idelalisib and monitor weekly until platelets is ≥25 × 10⁹/L or greater and restart idelalisib at 100 mg twice daily

Table 9.

Duvelisib Lab abnormality Management.²⁸

Lab Abnormality
AST/ALT	For ALT/AST 3–5x ULN, continue 25 mg twice daily and monitor weekly until ALT/AST < 3x ULN	For ALT/AST >5–20x ULN, duvelisib should be held and ALT/AST should be monitor at least weekly until ALT/AST <3x ULN. For the first occurrence, continue 25 mg twice daily if subsequent reduced to 15 mg twice daily	For ALT/AST >20x ULN, discontinue duvelisib

Neutropenia	For ANC 0.5–1.0 × 10⁹/L, continue 25 mg twice daily and monitor ANC weekly	If ANC less than 0.5 × 10⁹/L, hold duvelisib until ANC is greater than 0.5 × 10⁹/L and continue duvelisib at 25 mg twice dailyIf this is the first occurrence for subsequent occurrence, reduce duvelisib to 15 mg twice daily

Thrombocytopenia	For a platelet count 25–50 × 10⁹/L with grade 1 bleeding, continue duvelisib 25 mg twice daily and monitor platelets weekly	For platelet counts 25–50 × 10⁹/L with grade 2 bleeding or platelet count < 25 × 10⁹/L, hold duvelisib and monitor platelet count until platelets are 25 or greater and bleeding resolves.Restart at 25 mg twice daily for the first occurrence and for subsequent occurrences, decrease the dose to 15 mg twice daily

Table 10.

Duvelisib dose Modification.²⁸

Dose level	Dose
Initial dose	25 mg twice daily

Dose reduction	15 mg twice daily

Subsequent dose modification	Discontinue if patients are unable to tolerate 15 mg twice daily

A comprehensive review of toxicities and management resource can be found in a review by Hanlon and Brander.³⁰

Adherence and access considerations

As outlined in this paper, oral-only therapy may be an option for CLL patients. However, there are several factors to consider when determining if the patient is an ideal candidate for oral-only therapy, as well as determining the appropriate oral therapy for patients. Adherence to the medication is of the uppermost importance when treating CLL. A 2017 study showed that patients missing 8 or more consecutive days of ibrutinib had a shorter mean PFS of 10.9 months compare to patients who missed 8 or less consecutive days where the PFS was not reached.³¹ One of the most common reasons for poor adherence is toxicities associated with treatment. A further consideration is that while clinic visits may be minimized with oral therapy, there is decreased interaction with the patient's care team, which can lead to poorer adherence and monitoring of therapy unless a proactive plan is in place. Telemedicine can play a role in bridging this gap to evaluate patient adherence, counselling for common adverse effects of these drugs, and assessing tolerance of therapy.

Cost

Cost is another common barrier to adherence, as many oral oncolytic medications can be expensive, even with insurance. Major manufacturers of these drugs provide various medication assistance programmes. For example, ibrutinib has the IMBRUVICA copay programme, acalabrutinib has the AstraZeneca Access 360 programme, and venetoclax has the Genentech access solution patient assistance tool. A major limitation to these medication assistance programmes are the increased difficulty in enrolling patients with Medicare due to their inability to use copay cards. Other barriers may include communication between the patient and manufacturer pharmacies and the ability to appropriately track adherence. Diagnosis-based assistance programmes can be found in Table 11 from needymeds.org and other resources for Medicare patients can be found at healthwellfoundations.org.

Table 11.

Diagnosis-Based assistance programme.

CancerCare - Co-Payment Assistance Foundation (CCAF)

Leukemia & Lymphoma Society - Chronic Lymphocytic Leukemia (CLL) Co-Pay Assistance Programme

Patient Access Network (PAN) Foundation - Chronic Lymphocytic Leukemia

Table 12.

Review of commonly used agents and considerations.

Drug	FDA Approval	Monotherapy Data	Important consideration
Ibrutinib	Frontline: YesRelapsed/Refractory: Yes	Yes, based on data from RESONATE-2 and RESONATE-17	AdherenceHypertensionHemorrhageCardiac arrhythmiasInfections
Acalabrutinib	Frontline: YesRelapsed/Refractory: Yes	Yes, based on data from ELEVATE TN and ASCEND	AdherenceHemorrhageCardiac arrhythmiasInfections
Venetoclax	Frontline: NoRelapsed/Refractory Yes:	Yes, based on data from Phase 2 trial	AdherenceInfectionsTumour lysis syndrome

Emerging Therapies

Umbralisib

Umbralisib, an inhibitor of PI3K-δ, was assessed in a phase 2 study evaluating its efficacy and safety in patients with relapsed or refractory marginal zone lymphoma.³² Monotherapy use of umbralisib was found to be active and well tolerated in this patient population. In this small study, the median time to response was 2.7 months and the 12-month PFS was 71%. In UNITY-CLL, a phase 3 randomized trial with a median follow up of 36.2 months, the median PFS was 31.9 months in the umbralisib + ublituximab arm compared to 17.9 months in the obinutuzumab plus chlorambucil arm.³³

Zanubrutinib

Zanubrutinib is a BTK inhibitor that is FDA approved for relapsed or refractory mantle cell lymphoma. Results from arm C of the Sequoia trial evaluated its used as monotherapy dosed 160 mg twice daily in CLL patients with del17p.³⁴ The ORR was 92.2% and the preliminary results suggest that zanubrutinib was active in CLL patients and tolerated well. A review of all agents discussed can be found in Table 12.

Ibrutinib/venetoclax Combination

The combination of ibrutinib and venetoclax in the treatment of CLL is not yet FDA approved. However, a phase 2 study (CAPTIVATE) explored the combination in untreated high-risk CLL patients that had a median age of 65 with 30% of the patient being older than 70 years old. Patients received ibrutinib daily monotherapy for three 28-day cycles. Venetoclax was started in combination with ibrutinib at cycle 4. 74% of patients had complete remission or complete remission with incomplete count recovery as their best response. Estimated 1-year PFS was 98% and OS was 99%.³⁵ After 12 cycles of venetoclax-ibrutinib the percentage of patients who had remission with undetectable minimal residual disease (MRD) was 61%. The rate of remission with undetectable MRD increased over time.³⁵ There is an ongoing phase 3 clinical trial comparing triple therapy with ibrutinib, venetoclax, and obinutuzumab versus ibrutinib and obinutuzumab in treatment-naive CLL patients (NCT03701282.)³⁶

Conclusion

Previous data support the use of various oral oncolytics in the treatment of previously untreated and relapsed/refractory CLL. Adherence and toxicity management must be considered when determining if oral-only treatment is appropriate for these patients. Oral-only options add the benefit of minimizing in-person interactions with the health care team when needed (i.e. during the COVID-19 pandemic), but may decrease face to face opportunities to address adherence and toxicities. Treatment of CLL with certain regimens, such as venetoclax or acalabrutinib in combination with obinutuzumab, will require frequent in-person visits for both drug administration and toxicity monitoring, which may place CLL patients at higher risk of contracting an infection, such as COVID-19, due to increased exposure with the health care system. More studies looking at oral oncolytics as monotherapy compared to combination therapy with a monoclonal antibody are required to determine the precise benefit of combination treatment in the treatment of CLL and if that benefit differs across different risk groups.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

ORCID iD

Vincent Harris

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Ibrutinib and Obinutuzumab With or Without Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia ClinicalTrials.gov identifier: NCT03701282 Updated May 5th 2021 Accessed June 6th 2021.