Director, Lymphoma Research Program
Sarah Cannon Research Institute/Tennessee Oncology
Ian Flinn, MD, PhD, has disclosed that he has received consulting fees form AbbVie, Seattle Genetics, TG Therapeutics, and Verastem; funds for contracted research from AbbVie, Acerta, Agios, ArQule, AstraZeneca, BeiGene, Calithera, Celgene, Constellation, Curis, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, Incyte, Infinity, Janssen, Juno, Karyopharm, Kite, Merck, Morphosys, Novartis, Pfizer, Pharmacyclics, Portola, Roche, Takeda, Teva, TG Therapeutics, Unum, and Verastem; and he and his spouse have less than 5% ownership interest in Johnson & Johnson.
In this commentary, I present my thoughts on using BTK inhibitors to treat patients with newly diagnosed chronic lymphocytic leukemia (CLL). Let’s start with a patient. He is a 71-year old man who presents with weight loss and increasing fatigue. He has well-controlled hypertension. On physical examination, he has axillary lymphadenopathy and a palpable spleen. He appears well but he has cut back on his activity level. He has a WBC of 47,000/mL, with 76% lymphocytes, platelets are 115,000/mL with a hemoglobin of 9.3 g/dL. Peripheral blood flow cytometry reveals a monoclonal CD5+ CD20+ B-cell population consistent with CLL, and FISH analysis detects an 11q deletion. Molecular analysis shows an unmutated immunoglobulin heavy chain.
Choice of Therapy
This patient is a candidate for chemotherapy, or a BTK inhibitor such as ibrutinib or acalabrutinib, or a venetoclax-based therapy (which I will discuss later). So how do we treat him? My first choice for this patient would be ibrutinib, based on the results of 3 randomized trials that show that ibrutinib, either alone or in combination with an anti-CD20 antibody, is superior to any of the chemotherapy alternatives.
The phase III iLLUMINATE trial randomized patients aged 65 years or older, or younger than 65 years of age with comorbidities (N = 229), to receive ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116). A clear PFS advantage was demonstrated for patients who received ibrutinib plus obinutuzumab (HR: 0.23; 95% CI: 0.15-0.37; P < .0001), including patients with high-risk cytogenetics, including del(17p), TP53 mutation, del(11q), and/or unmutated IGHV or bulky disease status.
The phase III ALLIANCE trial compared ibrutinib with or without rituximab vs bendamustine plus rituximab and showed that ibrutinib alone or with rituximab is superior to bendamustine and rituximab in terms of PFS. However, at 2 years there was no significant difference in OS, with allowance for crossover complicating it further. Of interest, ibrutinib plus rituximab did not provide benefits over ibrutinib alone. For this reason, when I treat patients with ibrutinib in the frontline setting, I use it as single-agent therapy and not in combination with rituximab.
The phase III ECOG 1912 trial compared ibrutinib plus rituximab vs fludarabine/cyclophosphamide/rituximab in treatment-naive patients younger than 70 years of age with CLL requiring therapy (N = 529). The results demonstrated an advantage in PFS and OS for patients treated with ibrutinib plus rituximab vs the control. Based on results of this trial, the FDA recently gave an expanded approval to ibrutinib plus rituximab in adult patients with CLL. This study did not examine if the addition of rituximab to ibrutinib was beneficial, but given the overlapping curves from the ALLIANCE trial, my interpretation is that I would use single-agent ibrutinib rather than combined with rituximab. Together, these 3 studies clearly show the superiority of ibrutinib vs chemoimmunotherapy, especially in patients with high-risk CLL.
Alternative BTK Inhibitors
Ibrutinib is the most thoroughly studied of BTK inhibitors, but there are second-generation BTK inhibitors available as well. The FDA recently approved acalabrutinib, a covalent BTK inhibitor with increased selectivity, for the treatment of adult patients with CLL/small lymphocytic lymphoma (SLL). In the phase III ELEVATE TN trial, acalabrutinib given alone or in combination with obinutuzumab was compared with obinutuzumab plus chlorambucil in treatment-naive CLL patients who were 65 years of age or older, or younger than 65 years with comorbidities (N = 535). Both acalabrutinib arms demonstrated superiority over chlorambucil plus obinutuzumab, with significantly prolonged median PFS (not reached with both acalabrutinib arms vs 22.6 months for chlorambucil plus obinutuzumab) and a reduction in the risk of disease progression or death. The 24-month PFS was 93% for acalabrutinib plus obinutuzumab and 87% for single-agent acalabrutinib vs 47% for chlorambucil plus obinutuzumab, a dramatic difference. The marginal improvement of adding obinutuzumab to acalabrutinib comes with an increased risk of cytopenias and other adverse events vs acalabrutinib alone. For our patient above, acalabrutinib is a reasonable treatment option.
It is important to consider the differences in BTK inhibitors. Acalabrutinib is given twice daily vs once daily for ibrutinib. Acalabrutinib also requires an acidic stomach for its pharmacokinetics, so you would not want to treat a patient with gastroesophageal reflux disease requiring a proton pump inhibitor such as omeprazole with acalabrutinib. Preclinical studies demonstrated that acalabrutinib is more selective compared with ibrutinib in targeting off-target kinases, resulting in a cleaner profile and a potentially improved adverse event profile. For example, acalabrutinib showed fewer cardiac and bleeding events in clinical trials than did ibrutinib, but acalabrutinib can cause headaches that can last for 10-14 days, typically addressed with caffeine.
Zanubrutinib is another second-generation BTK inhibitor, with a mechanism of action similar to ibrutinib and acalabrutinib, that is currently indicated only for adult patients with mantle cell lymphoma who have received ≥ 1 previous therapy. The randomized, open-label, head-to-head phase III ALPINE trial comparing zanubrutinib vs ibrutinib in patients with relapsed/refractory CLL/SLL is ongoing but data are not yet available (NCT03734016).
Venetoclax would be the third choice for our patient; it functions as a BH3 mimetic to inhibit BCL-2 and induce apoptosis. The phase III CLL14 study compared a combination of obinutuzumab and venetoclax vs obinutuzumab and chlorambucil in previously untreated patients with CLL (N = 432). At 24 months, PFS was significantly improved with venetoclax, with 88% in the venetoclax plus obinutuzumab arm vs 64% in the chlorambucil plus obinutuzumab arm (HR: 0.35; 95% CI: 0.23-0.53; P < .001). I think this regimen is attractive because it is a 1-year time-limited therapy when given in frontline therapy with obinutuzumab, and it has high response, CR, and negative measurable residual disease rates. So the venetoclax combination may be an attractive option for some patients. However, it is more cumbersome to give because you have to do a dose ramp up and monitor for tumor lysis syndrome, a potentially fatal adverse event.
When to Halt Ibrutinib
So the big question is: When do you stop ibrutinib? Patients with CLL are often on long-term ibrutinib therapy, and if they develop an adverse event such as atrial fibrillation, ibrutinib can be discontinued. But if you discontinue ibrutinib, the atrial fibrillation resolves, and the cardiologist does not think anticoagulation is needed, then what do you do the next time atrial fibrillation occurs? I probably would not put the patient back on ibrutinib, but I might try acalabrutinib or zanubrutinib, if it becomes available. Otherwise, I think you need to switch to a venetoclax-based treatment, which has not been associated with atrial fibrillation. If the patient remains on ibrutinib, the requirement for anticoagulation in the setting of a BTK inhibitor that causes bleeding is a problem. I would take the patient off the BTK inhibitor and switch to venetoclax.
There are little head-to-head data comparing adverse events with BTK inhibitors in CLL. For ibrutinib, studies show a range of 3% to 15% for the incidence of atrial fibrillation, so it is difficult to determine what rates to compare between trials. The large, ongoing phase III ELEVATE-RR study comparing acalabrutinib vs ibrutinib in previously treated patients with high-risk CLL (N = 533) should help to provide clarity on the differences in adverse events such as atrial fibrillation between these 2 BTK inhibitors (NCT02477696).
Returning to Our Case
Our patient decided to go with single-agent ibrutinib and he tolerated it well, with the exception of easy bruising and myalgias and arthralgias. These are common adverse events that can be managed with a treatment break until they resolve, and by slowly increasing the ibrutinib dose, the patient was able to continue ibrutinib without difficulty. As expected with this treatment class, he did not achieve a CR, but after 3 years he remains in remission. Although exacerbation of hypertension is common with small molecule BTK inhibitors—and this patient has a history of hypertension—it has not worsened with ibrutinib thus far, although we will need to monitor his hypertension as time goes on.
In conclusion, in most cases, ibrutinib is my first choice for many patients with CLL; should adverse events become a concern, acalabrutinib may offer less toxicity. If the patient is on anticoagulants or atrial fibrillation occurs, I think that venetoclax plus obinutuzumab is a better option.
What questions do you have about treating your patients with CLL with BTK inhibitors? And what challenges are you facing managing your patients with CLL during the COVID-19 pandemic? I invite you to join the conversation below.
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