Management of Waldenström macroglobulinemia (WM), an indolent lymphoplasmacytic lymphoma with circulating IgM monoclonal protein, is evolving. In recent years, there has been a marked shift in our approach to treating patients with WM, particularly in the relapsed/refractory setting, wherein the Bruton’s tyrosine kinase BTK inhibitor, ibrutinib, has been a game changer. In this commentary, I discuss the latest information pertaining to the role of BTK inhibitors in the management of WM.

Important Mutations in WM
The primary driver behind the expansion of therapeutics in WM is the discovery that somatic gain‑of‑function mutations in the MYD88 gene are present in 95% to 97% of patients with WM. MYD88 mutations lead to leucine to proline (L265P) substitution in the vast majority and are non-L265P type in a very small proportion of WM patients. The mutated MYD88 protein, with its constitutive activation and  predisposition to dimerize and serve as a scaffold for other proteins, including BTK and IRAK4/IRAK1, triggers the Myddosome assembly and ultimately downstream pro-survival signals through activation of the transcription factor, NF-κB, which in turn leads to increased growth and proliferation of WM cells. This discovery led to the investigation of BTK inhibitors in WM.

Although this specific point mutation is not a disease-defining feature of WM, it is useful in differentiating WM from other low‑grade lymphomas, such as marginal zone lymphoma, which infrequently harbor mutated MYD88. Likewise, multiple myeloma, with high levels of IgM can be misdiagnosed as WM, and if MYD88 mutations are not evident during evaluation of an IgM lymphoplasmacytic malignancy, the possibility of myeloma should be entertained, and work-up including cytogenetic and imaging studies may offer additional clues. In our clinic, we assess patients’ bone marrow for this mutation, which is preferable to checking peripheral blood as it can be difficult to detect low levels of circulating clonal B‑cells and plasma cells, particularly in patients who have been previously treated with lymphodepleting agents, potentially giving a false-negative reading for the presence of this mutation.

Another notable somatic genetic alternation encountered in WM is the CXCR4^WHIM mutation, carried by approximately 30% to 40% of patients. In contradistinction to MYD88 mutations, nearly all of which are L265P type, more than 40 nonsense and frameshift mutations in the C-terminal domain of CXCR4 have been identified. Mutated CXCR4 results in sustained CXCL12-mediated AKT and ERK pathway activation, and usually occurs only in patients who also have a co-existing MYD88 mutation. Similar to the MYD88 mutation, CXCR4 mutations have  also been noted in a few cases of marginal‑zone lymphoma and diffuse large B‑cell lymphoma. The most interesting aspect of CXCR4 in WM is its impact on BTK inhibitor-based treatment: Patients with a CXCR4 mutation have shown lower rates of response and shorter PFS with ibrutinib treatment than those without the mutation.

Patient Case: Woman With WM After Multiple Previous Therapies
So how do we treat patients with BTK inhibitors in WM? Let’s consider an illustrative case. Seven years ago, a 40‑year‑old woman presented to my clinic with complaints of severe fatigue, bulky intra-abdominal and cervical lymphadenopathy, low‑grade fever, and intermittent drenching night sweats. Upon further evaluation, there was evidence of anemia and circulating monoclonal IgM immunoglobulin. We established the diagnosis of WM and she was enrolled in a phase II clinical trial of lenalidomide plus rituximab, dexamethasone, and cyclophosphamide, but unfortunately was intolerant of lenalidomide and ultimately taken off the study. She was then switched to bendamustine with rituximab but progressed at 18 months and was then given cyclophosphamide, bortezomib, and dexamethasone, followed by BEAM conditioning and taken for autologous stem cell transplantation. She achieved a deep response and maintained it for approximately 2 years before her disease progressed again. Her WM cells genotyping had previously revealed the MYD88^L265P mutation and wild-type CXCR4. She was started on ibrutinib and for the past 2 years, and her disease has been well controlled—she reports feeling much better and her anemia has resolved.

Treating WM With Ibrutinib
This case is one of many we have seen where the use of ibrutinib in the relapsed/refractory setting produced sustained remission in patients with WM who previously had few options. Ibrutinib is an oral agent that inhibits BTK activity by covalently binding with a cysteine residue of active site in the BTK enzyme. It received accelerated approval by the FDA for adult patients with WM based on phase II data showing high rates of overall (91%) and major (73%) responses with ibrutinib as single agent in previously treated patients. My colleagues and I conducted a retrospective review of 80 consecutive patients with WM (13 treatment naive and 67 relapsed/refractory) who were treated with ibrutinib following its approval and evaluated at the Mayo Clinic. Our data gathered from outside of a clinical setting confirmed the original findings that had previously led to its approval: an ORR of 91%, with a median duration of response of 32 months. At 18 months, the PFS rate was 82% in our study. The confirmation of the original phase II results in the community-based setting was very reassuring. However, similar to results from the clinical trials of ibrutinib, we saw no evidence of complete remission (CR). Achieving a CR with ibrutinib or the other BTK inhibitors has been elusive in WM.

It is difficult to accurately say how long a patient’s remission may last, but the response rate is heavily dependent on the patient’s MYD88 mutation status. Results from the extended follow-up study of ibrutinib monotherapy in patients with relapsed/refractory WM harboring the MYD88 mutation at baseline showed a 75% PFS rate at a follow-up of nearly 5 years vs a median PFS of only 5 months with wild-type MYD88 and 3.5 years in the presence of both MYD88 and CXCR4 mutations. Therefore, prior to initiating ibrutinib therapy, clinicians must perform genotyping of WM to determine if their patient is likely to respond to this oral therapy (typically, 420 mg/day until disease progression or intolerance). Ibrutinib has shown impressive activity in the frontline setting as well, but once again, the requirement of continuous instead of a finite duration of therapy is perceived as a barrier by many patients despite its attractiveness as an oral agent compared to fixed-duration alternatives. However, this becomes less of an issue in patients who tolerate it well and experience results, with amelioration of symptoms and improvement in anemia soon after starting this therapy.

Mutated CXCR4 is associated with a delayed response to ibrutinib monotherapy; patients with this mutation can take up to 4-5 months to achieve a major response. Initially, researchers believed that the addition of rituximab to ibrutinib would help to overcome this effect. However, in extended follow-up data from the phase III iNNOVATE trial (which led to the approval of ibrutinib plus rituximab in WM), the presence of this mutation still conferred an adverse prognosis that was not overcome by adding rituximab to the regimen. In addition, recent data have demonstrated that only patients with nonsense CXCR4 mutations have a poor prognosis, with lower odds of achieving a major response to ibrutinib in comparison to patients without a CXCR4 mutation (HR: 4.02), or with those with frameshift CXCR4 mutations. CXCR4^S338X is the most common sub-clonal nonsense CXCR4 mutation, and similar to the clonal MYD88^L265P mutation, can be detected by allele-specific polymerase chain reaction (PCR) assay. The CXCR4^S338X cancer cell fraction ≥ 25% (determined as the ratio of cells expressing CXCR4^S338X/MYD88^L265P) is associated with adverse long-term outcome with ibrutinib. Although all these findings, highlighting the differential impact of the CXCR4 mutations, need to be confirmed in other studies, they also emphasize the importance of genotyping patients with WM prior to initiating ibrutinib‑based therapy.

Interestingly, the iNNOVATE trial also reported reduced rates of infusion-related reactions (IRR) with rituximab when combined with ibrutinib, likely resulting from suppression of IRR-inducing cytokines with the concomitant use of ibrutinib. Unfortunately, the trial does not inform us whether the efficacy of ibrutinib-rituximab is superior to ibrutinib alone as rituximab instead of ibrutinib monotherapy was used as the control arm in this trial.

Another mutation to be aware of in WM is the BTK^Cys481 mutation. This alteration is acquired with ibrutinib use (particularly in patients with preexisting CXCR4 mutations) at the site where ibrutinib covalently attaches to the BTK enzyme. A mutation at this site can make patients refractory to ibrutinib. In addition, new data have also suggested that WM cells with this BTK mutation can also harness the neighboring WM cells with wild-type BTK by cytokine-mediated cross-talk, thereby adversely affecting any benefit from ibrutinib, even on clones with wild-type BTK that are typically responsive to ibrutinib. Some of the newer BTK inhibitors can potentially overcome BTK^Cys481 mutation–associated resistance.

Although clinicians should generally avoid sudden disruption in ibrutinib therapy, a major practice point is to transiently stop ibrutinib at least 3 days before any minor surgical procedure and at least 7 days prior to a major surgery due to its antiplatelet effects. Clinicians should be mindful of the IgM rebound phenomenon, which refers to a sudden increase in the IgM level that we observe upon abrupt discontinuation of ibrutinib in a subset of our patients at Mayo Clinic. Of importance, this phenomenon should not be regarded as treatment failure because most patients who temporarily stop ibrutinib will respond again after we reinitiate therapy. Sudden cessation of ibrutinib has also been associated with arthralgias, fatigue, and headaches. Notably, the rebound phenomenon and the effects of ibrutinib withdrawal suggest that rather than abruptly discontinuing the treatment in patients who are actively relapsing on ibrutinib, it should be continued until the next agent or regimen is started.

Other BTK Inhibitors
Two other BTK inhibitors, acalabrutinib and zanubrutinib, are approved for other lymphomas and have shown promise in WM. Zanubrutinib is a next-generation oral BTK inhibitor that is approved for mantle cell lymphoma and has shown considerable activity in early phase studies in WM. Zanubrutinib is also an irreversible inhibitor of BTK like ibrutinib with similar in vitro binding affinity to BTK (IC₅₀: 0.5 vs 1.5, respectively) and has presumably fewer off-target effects on other enzymes (eg, EGFR, ITK, JAK3, HER2, and TEC). This may contribute to a slightly different adverse event profile with zanubrutinib than ibrutinib. Cytopenias are present, as expected, along with hemorrhage, as seen with ibrutinib. The difference here is that although patients with zanubrutinib typically have significant bleeding or contusion, major bleeding rates are very low.

Bleeding management with BTK inhibitor use is complex and is often dictated by individual patient characteristics. Atrial fibrillation is a known adverse effect resulting from the use of BTK inhibitors and as such may become the primary reason to commence an anticoagulant. Atrial fibrillation has been seen in up to 12%-15% of patients receiving ibrutinib long term. Consultation with the patient’s cardiologist to determine bleeding risk and need for an anticoagulant is required. Because the study follow‑up for zanubrutinib is short, we do not have sufficient data to compare the rates of atrial fibrillation with that seen with ibrutinib.

A direct comparison of zanubrutinib (160 mg orally, twice daily) and ibrutinib (420 mg orally daily) in WM is being conducted through the phase III ASPEN trial (planned N = 229). This is a 3-arm, 2-cohort, open-label study: patients with mutated MYD88 were randomized to zanubrutinib or ibrutinib (cohort 1), whereas patients with wild-type MYD88 (cohort 2) were assigned only to zanubrutinib, as historically, patients with wild-type MYD88 respond poorly to ibrutinib. The primary endpoint was achievement of VGPR or deeper response. Based on a recent press release, we expect results from this study to be reported at an upcoming meeting.

Another BTK inhibitor with promising activity in WM is the second-generation agent acalabrutinib, which is approved for mantle cell lymphoma and chronic lymphocytic leukemia/small cell lymphoma at 100 mg twice daily, and has shown promising activity in WM. Results from a phase II study of acalabrutinib monotherapy in 106 patients with WM (14 treatment naive and 92 relapsed/refractory) showed that at a median follow-up of more than 2 years, the ORR was 93%, regardless of previous treatment. The major response rate (ie, PR or better) was approximately 79%, with a smaller proportion achieving a VGPR. The 2‑year PFS rate was 82% (relapsed/refractory) to 90% (treatment naive).

Unlike the toxicities reported with ibrutinib and zanubrutinib, headaches are a prominent adverse event with acalabrutinib (seen in approximately 40% of patients). These typically resolve with the use of caffeine and generally do not lead to treatment discontinuation. As with zanubrutinib, bleeding is a major risk of acalabrutinib, but typically manifests as only mild bruises or contusions and not major hemorrhages. The most common serious adverse events in the phase II trial included lower respiratory tract infections, pneumonia, and pyrexia. Approximately 5% of patients had atrial fibrillation, similar to rates with zanubrutinib, although it was grade 3/4 in only 1 patient, and 5% of patients experienced hypertension, which is another class effect of BTK inhibitors and has been seen with ibrutinib and zanubrutinib as well.

Acalabrutinib and zanubrutinib are currently commercially available for indications that are outside of WM, and conceivably clinicians might consider them as off-label alternatives to ibrutinib in patients who are responding to BTK inhibition, but not tolerating ibrutinib well. Also, it is plausible that zanubrutinib may have a role specifically in the MYD88 wild-type WM patient population that responds poorly to ibrutinib.

Clinicians should remember that BTK inhibitors can interact with certain foods and other drugs. Patients should be instructed not to take NSAIDs or fish oil supplements due to their antiplatelet effects, and to avoid Seville oranges, grapefruit, and star fruit, all of which affect activity of the enzyme CYP3A4, involved in the metabolism of BTK inhibitors. In addition, clinicians should be aware of the potential for drug–drug interactions with warfarin or other anticoagulants. Ideally, a consultation with a pharmacist to run over the list of patients’ current medications that could potentially interact with the proposed BTK inhibitor is recommended prior to their initiation.

Notably, patients with WM are inherently at an increased risk of second primary malignancies. High rates of nonmelanomatous skin cancers such as basal and squamous cell carcinomas have been observed with BTK inhibitors, so in addition to their regular skin examinations, patients need to be counseled regarding sun protection with sunscreens.

Investigational BTK Inhibitors in WM
Tirabrutinib (ONO/GS-4059) is an investigational, highly selective, irreversible, second-generation BTK inhibitor with phase II data from a recent study in 27 patients with treatment-naive or relapsed/refractory WM. In this study, patients received tirabrutinib 480 mg once daily (unlike the twice-daily dosing for zanubrutinib and acalabrutinib). The primary endpoint was a response rate of PR or better, which was achieved in 77.8% of treatment-naive patients and 88.9% of relapsed/refractory patients, with an ORR of 94.4% and 100%, respectively. Of importance, a rash was noted in 41% of patients in this trial (3.7% grade 3 rash, including erythematous rash and erythema multiforme).

CXCR4 inhibitors such as ulocuplumab and mavorixafor are in development for use as partners to ibrutinib to overcome resistance to ibrutinib monotherapy in patients with CXCR4 mutations. Additionally, a strategy to reduce the duration of therapy with simultaneous inhibition of BTK and BCL-2 (a protein which is also overexpressed in MYD88 mutant WM cells) is being evaluated by pairing ibrutinib with venetoclax, a BCL-2 inhibitor that has already demonstrated remarkable single-agent activity in relapsed/refractory WM.

Various reversible, noncovalent BTK inhibitors are being investigated for WM, including vecabrutinib (SNS‑062), ARQ 531, and LOXO-305. Vecabrutinib (SNS 062), is a reversible BTK inhibitor that binds noncovalently, and like zanubrutinib, it has a restricted kinase inhibition profile. Importantly, vecabrutinib is active against both wild-type BTK and Cys481S mutated BTK. A phase Ib/II study is currently evaluating vecabrutinib in patients with CLL/SLL or and non-Hodgkin lymphomas, including WM. 

These data highlight the exciting changes in the field of WM treatment, with more to come.

Click HERE to access CCO’s online Interactive Decision Support Tool, “Minimizing and Managing Toxicities to Maintain Patients on BTK Inhibitor Therapy.”

How do you use BTK inhibitors in your clinical management of patients with WM? Share your thoughts in the comment box below.