BTK Inhibitors, Other Blood Cancer Drugs Are Being Tapped for COVID-19

The Bruton tyrosine kinase (BTK) inhibitor acalabrutinib demonstrated benefit in a small uncontrolled case series of hospitalized patients with severe COVID-19, reducing measures of inflammation and improving oxygenation.

The results support the idea that BTK inhibitors might effectively combat the hyperimmune reaction, or cytokine storm, that occurs in patients with severe COVID-19 and have led to larger confirmatory controlled trials.

These studies are among many exploring the use of BTK inhibitors, such as acalabrutinib (Calquence, AstraZeneca), and other immunomodulating agents approved for the treatment of hematologic malignancies in the treatment of COVID-19. In these studies, researchers are honing in on the role of immune cells involved in the hyperinflammatory response in patients with COVID-19 and trying to uncover treatments to mitigate that response. Some of these agents target specific cytokines, such as interleukin (IL)-6, whereas others are more broadly immunosuppressive.

We understand how these agents work and their safety profiles, which is “critically important for a repurposed drug,” Lee Greenberger, PhD, the chief science officer at the Leukemia & Lymphoma Society, told Clinical Oncology News.

However, cautioned R. Donald Harvey, PharmD, the director of the Phase I Clinical Trials Section at Emory University’s Winship Cancer Institute, in Atlanta, “although we know how these agents work and their adverse event profiles, we won’t really know how effective they are until randomized controlled trials are performed. Single-arm or case series of patients treated with any drug or intervention do not take into account the natural course of COVID-19 infection, which can be highly variable.”

Early Results With BTK Inhibitors

That variability can range from no symptoms to severe multiorgan system failure and death. In some patients SARS-CoV-2 causes extensive inflammation in the lungs, which is “about the worst thing … when you are trying to get oxygen into the body,” Dr. Greenberger noted. Preclinical data and a positive report on patients with COVID-19 taking ibrutinib (Imbruvica, Pharmacyclics/Janssen) for Waldenstrom’s macroglobulinemia (Blood 2020;35[21]:1912-1915) suggested that BTK inhibitors can reverse this inflammation, he added.

To evaluate this hypothesis, the acalabrutinib case series investigators, led by Wyndham Wilson, MD, PhD, and Louis Staudt, MD, PhD, from the National Cancer Institute, in Bethesda, Md., tested the drug in 19 hospitalized patients with COVID-19 and severe hypoxia (Sci Immunol 2020 Jun 5. [Epub ahead of print]). Eleven of the patients were receiving supplemental oxygen, and eight were on mechanical ventilation. All but one had increasing oxygen demands at the start of treatment. The patients also had evidence of inflammation (C-reactive protein [CRP] >10 mg/dL and/or ferritin >500 ng/mL) and/or lymphopenia (absolute lymphocyte count <1,000 cells/mcL). They were a median of 61 years of age (range, 45-84 years), and 13 (68%) were men. The patients had a median of two comorbidities including hypertension in 84%, a body mass index greater than 30 kg/m² in 68%, and diabetes in 37%.

The patients received the 100-mg dose of acalabrutinib that is approved for chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle cell lymphoma. The drug was administered orally or via feeding tube twice daily for either 10 days (in patients receiving supplemental oxygen) or 14 days (in patients on mechanical ventilation). Additional treatments included steroids and/or hydroxychloroquine (HCQ). No patients received an anti-IL-6 receptor blocker or the investigational antiviral remdesivir (Gilead).

Over the treatment course, acalabrutinib improved oxygenation in most patients, often within one to three days, with no evident toxicity. Measures of inflammation and lymphopenia “normalized quickly in most patients … in correlation with improved oxygenation,” the investigators noted. After acalabrutinib treatment, eight of 11 (72.7%) patients in the supplemental oxygen group had been discharged on room air, and four of eight (50%) patients receiving mechanical ventilation had been successfully extubated, with two (25%) discharged on room air. Among the 12 patients who achieved room air status with acalabrutinib, none had symptom recurrence, “suggesting that a short course of acalabrutinib was sufficient to quell the disease clinically,” they noted.

“If these results are confirmed by a randomized, controlled clinical trial, this therapy may play an important role in the control of severe COVID-19,” noted Dr. Wilson in a National Institutes of Health press release about the study.

Commenting on the case series, Andrea LeVoir, PharmD, a clinical pharmacy specialist in lymphoma at Memorial Sloan Kettering Cancer Center in New York City, said, “While this case series is good for hypothesis generation, I think it is important to have a larger peer-reviewed, randomized controlled clinical trial to see if there is benefit to the regimen.”

Noting that “45% of the supplemental oxygen cohort (5/11 patients) had received steroids and/or [HCQ],” she said “the concomitant experimental treatments could have impacted the results of the case series.” Dexamethasone, in particular, was shown in an arm of the UK RECOVERY trial to have efficacy in treating COVID-19 (bit.ly/394TOjv), and the NIH now recommends its use in COVID-19 patients who require supplemental oxygen or are mechanically ventilated (www.covid19treatmentguidelines.nih.gov/ dexamethasone/). (In contrast, most studies have shown that HCQ is not beneficial [bit.ly/30pnVy8]).

Another point Dr. LeVoir raised is that according to the package insert, acalabrutinib should only be given whole and should not be crushed. Given that eight of the patients were intubated, she said she wondered how the drug was administered to those patients. In addition, she said, “acalabrutinib should not be given with proton pump inhibitors [PPIs], as it can lower the absorption of acalabrutinib,” but PPIs often are used in intubated patients as stress ulcer prophylaxis. “If they were administered together, this could impact the efficacy of the treatment,” she said, adding, “I think we would need to study the pharmacokinetics/pharmacodynamics of acalabrutinib when it is administered in a way that has not been studied.”

Two ongoing open-label, phase 2, randomized controlled trials may help confirm the role of acalabrutinib in the treatment of COVID-19. These trials (called CALAVI) will evaluate the safety and efficacy of acalabrutinib plus best supportive care (BSC) versus BSC alone in approximately 200 patients hospitalized with respiratory complications of COVID-19 who are not receiving mechanical ventilation (Table). The U.S. arm of CALAVI is expected to be completed in September.

Trials also are evaluating two other BTK inhibitors, ibrutinib and zanubrutinib (Brukinsa, BeiGene), in this setting. Steven P. Treon, MD, PhD, the director of Dana-Farber Cancer Institute’s Bing Center for WaldenstrÖm’s Macroglobulinemia, in Boston, and his colleagues are following up on a report on their experience with six patients who fared well after contracting SARS-CoV-2 while receiving treatment with ibrutinib for WaldenstrÖm’s macroglobulinemia (Blood 2020;35[21]:1912-1915). In the Pharmacyclics (AbbVie)-sponsored phase 2 iNSPIRE trial, they and investigators from other U.S. centers will prospectively investigate ibrutinib in approximately 46 patients hospitalized for COVID-19 infection within 10 days of diagnosis. Patients included in the study will require supplemental oxygen (≤6 L per minute), but those requiring mechanical ventilation will be excluded. Zanubrutinib is being assessed in a phase 2, randomized, double-blind, placebo-controlled trial. In this BeiGene-sponsored study, investigators will enroll approximately 52 adults with severe COVID-19 respiratory disease.

Targeting IL-6

Directly targeting IL-6 is another approach to stave off the cytokine storm in patients with COVID-19. Multiple studies are examining use of the IL-6 receptor blockers, such as tocilizumab (Actemra, Genentech), which is approved to treat cytokine release syndrome (CRS) associated with chimeric antigen receptor T-cell therapy.

“COVID-19 is associated with an intense inflammatory response resulting in pulmonary edema, exudate and cellular infiltrates in severe cases, which may be mediated by a dysregulated host immune/cytokine response. As tocilizumab is an inhibitor of the pro-inflammatory cytokine IL-6, it is hypothesized that it could be beneficial in addressing the cytokine storm seen in some patients with COVID-19,” noted Mark Wilcox, MD, a consultant and the head of microbiology research and development at Leeds Teaching Hospitals NHS Trust, in England.

Dr. Wilcox and his colleagues are studying tocilizumab as part of the multiarm RECOVERY trial that is evaluating various potential therapies in patients with COVID-19 in the United Kingdom.

Although an Italian study ended early because the researchers did not find a benefit from tocilizumab, that study focused on patients with less severe disease who may not derive as much benefit from IL-6 inhibition as patients with more severe disease, he noted. That multicenter open-label, randomized study aimed to assess the efficacy of tocilizumab administered at an early stage compared with standard therapy in patients with COVID-19 pneumonia, with a primary end point of severe clinical aggravation (worsening respiratory failure, ICU admission or death). Reporting the results, the Agenzia Italiana del Farmaco noted that an intermediate analysis of 123 patients showed a similar percentage of clinical aggravation in the first two weeks in patients who received tocilizumab compared with those who received standard therapy (28.3% vs. 27.0%) (bit.ly/2ZF2kTn).

The Italian researchers acknowledged that selected patient subgroups may have a better response to the drug, and suggested that larger studies of cases and/or studies targeting specific subgroups at various stages of disease are needed.

Dr. Wilcox told Clinical Oncology News that “the timing of onset of tocilizumab [treatment] could well be critical in obtaining a therapeutic response. Studying large patient cohorts with differing illness severities and stage of disease is needed to determine if tocilizumab has a role in some patients at certain stages of COVID-19.”

In a study of patients at later stages with more severe COVID-19, the results to date are more positive, albeit preliminary. Investigators in China, in a retrospective study, treated 21 adults (average age, 57 years) with severe or critical COVID-19 disease with tocilizumab (Proc Natl Acad Sci U S A 2020;117[20]:10970-10975). All patients presented with fever and lung abnormalities on CT; other symptoms included cough, fatigue and dyspnea. All but one had elevated levels of CRP, and 17 had abnormally low lymphocyte percentages. Twenty of 21 had received oxygen therapy before treatment, including assisted ventilation in three patients. The patients were given a 4- to 8-mg/kg dose of tocilizumab. (The recommended dose was 400 mg, up to a maximum of 800 mg.) If fever persisted, patients were permitted a second dose.

The investigators found that “symptoms, hypooxygenemia and CT opacity changes were improved immediately after the treatment with tocilizumab in most of the patients.” Temperatures returned to normal on day 1 of treatment and remained stable. Fifteen patients reduced their oxygen intake by day 5. Among the three patients who required a ventilator, one was taken off the noninvasive ventilator the first day after tocilizumab, one was extubated and regained consciousness on day 5, and the third one on day 11. Lymphocyte percentages and CRP had returned to normal in 10 and 16 patients, respectively, by day 5. Lung lesions were absorbed in 19 patients after treatment. All patients were discharged between 10 and 31 days after treatment, and there were no obvious adverse events associated with tocilizumab.

Acknowledging the preliminary nature of the data, the investigators nevertheless suggested that tocilizumab “is a treatment to reduce mortality” in patients with severe COVID-19.

However, Genentech released disappointing results from its randomized, placebo-controlled, phase 3 COVACTA study in late July. Genentech reported that the study evaluating tocilizumab in hospitalized adults with severe COVID-19–associated pneumonia did not meet its primary end point of improved clinical status or key secondary end points, including a difference in patient mortality at week 4.The company plans to submit the study to a peer-review publication and it also is sponsoring three additional randomized trials of tocilizumab in patients with COVID-19, including one evaluating tocilizumab with remdesivir in hospitalized patients with severe COVID-19 pneumonia.

Additional concerns have been raised related to limitations of focusing only on IL-6. Radbel et al reported two cases of COVID-19 patients who progressed from CRS to secondary hemophagocytic lymphohistiocytosis despite being treated with tocilizumab and having decreased levels of CRP (Chest 2020;158[1]:e15-e19). They noted that this suggests that other cytokines in addition to IL-6 contribute to CRS in COVID-19 and that effective treatments may need to take a broader immunosuppressive approach and “target multiple cytokines.” They underscored that the cases they presented “highlight the need for clinical trials to determine optimal patient selection and timing for the use of tocilizumab during this disease process.”

Dr. Wilcox agreed that blocking one cytokine might not be enough. “While there is a theoretical potential benefit of using a drug that can interfere with cytokine release,” he told Clinical Oncology News that “it may be that the severe inflammation seen in some COVID-19 cases is not amenable to a single inhibitor approach.”

Other Treatments Being Explored

Among the more broadly immunosuppressive anticancer agents being studied in this setting are JAK inhibitors, which work downstream of the IL-6 pathway but can work independently of it to reduce inflammation. Ruxolitinib (Jakafi, Incyte), a JAK inhibitor used for myeloproliferative neoplasms and graft-versus-host disease, is being evaluated in several trials, including the randomized, placebo-controlled, phase 3 RUXCOVID-DEVENT trial (also called 369 DEVENT), designed to evaluate the safety and efficacy of ruxolitinib for the treatment of COVID-19-associated acute respiratory distress syndrome requiring mechanical ventilation.

Ruxolitinib also is available through an expanded access program for emergency treatment of the COVID-19 cytokine storm in patients aged 12 years and older (ClinicalTrials.gov Identifier: NCT04355793).

Selective inhibitor of nuclear export compounds, such as selinexor (Xpovio, Karyopharm), which is approved to treat relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma, work by a different, two-pronged approach. These agents have been shown to exhibit potent anti-inflammatory activity by inhibiting nuclear factor kappa B, leading to reductions in IL-6 and other cytokines, but they also have antiviral activity (bit.ly/3jaeFXd; bit.ly/30gOCoK).

In April, investigators initiated the randomized, multicenter, placebo-controlled, phase 2 XPORT-CoV-1001 study in hospitalized patients with severe COVID-19 to assess the activity and safety of low-dose selinexor (20 mg three times per week for two weeks). Patients who are tolerating therapy well and experiencing clinical benefit may be eligible to continue treatment for an additional two weeks at the discretion of the treating physician.

Karyopharm reported that after a planned interim analysis, the Data Safety Monitoring Board (DSMB) for the study concluded that the trial was likely to show a benefit in a subpopulation of patients <75 years old who have a COVID-GRAM non-high risk score for disease severity, which represented approximately 75% of the study population, but not in the entire heterogenous patient population studied. The study is expected to be completed in August, and the company reported that it may be able to report some initial efficacy results by September or October.

Potential Safety and Access Concerns

If these agents pan out as successful treatments for COVID-19, clinicians will need to be aware of potential adverse effects and drug interactions associated with them, experts warned.

“These drugs are not side effect free,” Dr. Greenberger said. Noting that BTKs are associated with atrial fibrillation (AFib), he said this would be a concern in a COVID-19 patient, who potentially could have cardiovascular disease. “This is something that physicians have to pay attention to,” he said. “If we know that these drugs cause atrial fibrillation, even to a small degree,” it will be critical “to find out what the safety would be in a COVID-19 patient.”

Dr. Harvey agreed, and further noted that “the increase in bleeding risk with BTK inhibition also has to be considered, particularly since venous thromboembolism prophylaxis has been recommended in all COVID-19 patients (www.hematology.org/ covid-19/ covid-19-and-vte-anticoagulation). He said many of these immunomodulating agents also cause cytopenias, “potentially further complicating care of these critically ill patients.”

Dr. LeVoir pointed out some of the monitoring that might be needed for patients taking these agents:

• Acalabrutinib—cardiac complications, including AFib, as well as infections and bleeding.
• Ruxolitinib—thrombocytopenia, anemia, neutropenia and liver toxicity.
• Selinexor—In larger studies of patients with multiple myeloma, selinexor was associated with “significant thrombocytopenia (along with other cytopenias), fatigue, nausea and anorexia.” Noting that “nausea can be a big problem” with selinexor, she said prophylactic antiemetics and adequate fluids should be given before administration.

In addition, some of these agents require “dose adjustments based upon renal or hepatic function” that would need to be considered in critically ill patients with COVID-19, who often “present with organ damage to multiple systems,” Dr. LeVoir said. “Inappropriate dosing of the oral chemotherapy could potentially exacerbate toxicities,” she cautioned.

“Similarly, in patients with other comorbidities,” she said, “many of these drugs have numerous drug–drug interactions that could impact the efficacy or toxicity of the therapies as well.” Dr. Harvey noted that IL-6 signaling inhibition, specifically, “can cause increased CYP [cytochrome P450] enzyme activity, particularly CYP3A, potentially leading to decreased effectiveness of drugs cleared through these enzymes.”

An additional issue that could arise if one or more of these agents becomes more widely used in the treatment of COVID-19 is ensuring that there are adequate supplies to treat COVID-19 patients and those who need ongoing cancer therapy. “If these therapies gain FDA approval for treatment of COVID-19, we will likely need to address access to these therapies,” Dr. LeVoir noted.

The NIH recommendation on use of dexamethasone in patients with COVID-19 (www.covid19treatmentguidelines.nih.gov/ dexamethasone/ ) underscores the potential for access issues when agents are used for COVID-19 in addition to their standard uses, Dr. Harvey cautioned. “There will be an impact on general cancer care if widespread adoption of dexamethasone is employed, leading to a shortage in availability for use as a supportive care agent, for example, as an antiemetic or to reduce edema in brain tumor patients.”

Confirmatory Trials Needed

Preliminary results and “anecdotal observations have set the stage,” said LLS’s Dr. Greenberger, “but comparative trials will really tell us if these drugs will be efficacious and safe…that’s really critical. Until we have the comparative control, we’re never going to know for sure.”

With results from many of these confirmatory trials expected by the fall, it may become clearer whether these immunomodulating agents indicated for hematologic malignancies will fulfill their promise for the treatment of COVID-19.