Secondary Immunodeficiency in Marginal Zone Lymphoma and Impact of Bruton Tyrosine Kinase Inhibitor

The availability of Bruton tyrosine kinase (BTK) inhibitors has brought about a paradigm shift in the treatment of patients with B-cell lymphomas and chronic lymphocytic leukemia. BTK was clinically validated as a target by the efficacy of the first-in-class inhibitor ibrutinib. The extended survival conferred by BTK inhibitors has brought long-term tolerability to the foreground. To minimize toxicities thought to be attributable to off-target kinase inhibition, a next generation of BTK inhibitors with greater selectivity was developed. In the United States, zanubrutinib, a next-generation BTK inhibitor, has been approved for treating adults with mantle cell lymphoma who have received at least one prior therapy, for adults with Waldenström macroglobulinemia, and for adults with relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20–based therapy. Because few head-to-head comparative trials of BTK inhibitors have so far been reported, no BTK ‘inhibitor of choice’ can be identified. Zanubrutinib has promising efficacy in its approved indications and appears to have reduced cardiac toxicities, particularly atrial fibrillation, which may influence the choice of BTK inhibitor treatment by prescribers. Further studies are needed to inform on optimal treatment sequencing of zanubrutinib and its combination with other agents. Here, we summarize existing clinical evidence for its efficacy and safety in mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and other B-lymphoproliferative indications.Plain Language Summary Zanubrutinib is a drug that was shown to effectively treat cancer of B cells without causing excessive serious side effects Patients with certain B-cell malignancies (cancers of white blood cells) benefit from treatment with Bruton tyrosine kinase (BTK) inhibitors, drugs that block the BTK protein and keep cancer from growing and spreading. Patients experience extended survival with ibrutinib, the first-generation BTK inhibitor approved by US Food and Drug Administration (FDA); however, one in five patients quit treatment because of harmful side effects. Ibrutinib-related side effects such as increased risk of bleeding, atrial fibrillation (abnormal heart rhythm), and high blood pressure are thought to be caused by ibrutinib blocking other proteins besides the intended target protein BTK. To reduce these side effects, zanubrutinib, a next-generation BTK inhibitor, was designed to block BTK more specifically than ibrutinib. Results of clinical studies on zanubrutinib treatment appear promising in patients with several types of B-cell malignancies, including mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), chronic lymphocytic leukemia, and small lymphocytic lymphoma. There are not yet enough clinical data to determine which BTK inhibitor is most effective in treating B-cell malignancies without causing harmful side effects. Early data from the phase 3 ALPINE clinical study suggest that zanubrutinib works better than ibrutinib, and fewer patients experience side effects and quit treatment. Zanubrutinib is currently approved for use for treatment of adult patients with MCL who have received at least one prior therapy, for adults with WM, and for adults with MZL who have received at least one anti-CD20–based therapy.

Introduction The development of Bruton tyrosine kinase (BTK) inhibitors has significantly changed the treatment landscape for patients with Waldenström macroglobulinemia (WM). Ibrutinib was the first BTK inhibitor to receive FDA approval for this disease, but in recent years additional more selective BTK inhibitors have become available. Zanubrutinib, the most recently FDA-approved therapy for WM, has demonstrated comparable efficacy regarding hematologic response, but with an improved side effect profile compared to other BTK inhibitors. Areas covered In this review, we highlight the pivotal studies that have formed the foundation for the use of zanubrutinib in WM, including safety and efficacy data from prospective clinical trials of the currently available BTK inhibitors. Expert opinion BTK inhibitors are very effective in WM and have an overall response rate higher than 90%. The side effect profile of these medications is manageable but does include a risk of atrial fibrillation, infection, and bleeding. The newer BTK inhibitors, such as acalabrutinib and zanubrutinib, are known to have less off-target effects and are potential treatment options. BTK inhibitors should be considered as a treatment option in treatment-naïve and previously treated disease depending on the individual patient preferences, comorbidities, and molecular profile.

Trial in Progress: A Phase 1b Study of AS-1763, an Oral, Potent and Selective Noncovalent BTK Inhibitor, in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or Non-Hodgkin Lymphoma

Zanubrutinib is well tolerated and effective in acalabrutinib-intolerant patients with B-cell malignancies: A long-term follow-up

Billion-Dollar Drugs with Misallocated Rewards

Preliminary Efficacy and Safety of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients with Relapsed or Refractory (R/R) Indolent NHL: Results from the Phase 1 CaDAnCe-101 Study

Starting with the first-in-class agent ibrutinib, the development of Bruton tyrosine kinase (BTK) inhibitors has led to dramatic improvements in the management of B-cell malignancies. Subsequently, more-highly selective second-generation BTK inhibitors (including acalabrutinib, zanubrutinib, tirabrutinib and orelabrutinib) have been developed, primarily with an aim to reduce off-target toxicities. More recently, third-generation agents including the non-covalent BTK inhibitors pirtobrutinib and nemtabrutinib have entered later-stage clinical development. BTK inhibitors have shown strong activity in a range of B-cell malignancies, including chronic lymphocytic leukaemia/small lymphocytic lymphoma, mantle cell lymphoma, Waldenström’s macroglobulinaemia and marginal zone lymphoma. The agents have acceptable tolerability, with adverse events generally being manageable with dosage modification. This review article summarises the evidence supporting the role of BTK inhibitors in the management of B-cell malignancies, including highlighting some differential features between agents.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00857-8.

IBRUTINIB-INDUCED SINUS NODE DYSFUNCTION: A RARE CLINICAL ENTITY

Recent changes to the commissioned regimens and the COVID-19 pandemic necessitate an update of the 2018 British Society of Haematology guidance on chronic lymphocytic leukaemia (CLL).1 Here we discuss: (1) considerations prior to treatment; (2) front-line treatment recommendations; (3) management of relapsed or refractory disease; (4) management of intolerance to Bruton tyrosine kinase inhibitors (BTKi); and (5) guidance for vaccinations and prophylaxis. We focus particularly on therapies approved for use in the UK at the time of writing. Guidance on initial approach to patient management, indications for treatment, molecular assessment prior to treatment, assessment of response to treatment, supportive care, and autoimmune cytopenia remain unchanged. In addition to this CLL treatment update, we have published recent guidance on management of cardiovascular complications secondary to treatment with BTKi2 and Good Practice Guidance on the management of Richter transformation (RT) of CLL.3 These guidelines were compiled according to the BSH process (https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf). The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the literature using Medline/Pubmed. Search terms included; CLL treatment, randomised, clinical trial, FCR, TP53 disruption, Bruton tyrosine kinase inhibitor, BCL2 inhibitor, rituximab, obinutuzumab, vaccination, Covid19. The search was limited to English-language publications and conference abstracts from the date of publication of the previous CLL guideline in 2018 to July 2021. Titles/abstracts obtained were curated and manually reviewed by the writing group who conducted additional searches, using subsection heading terms. Review of the manuscript was performed by the BSH Guidelines Committee Haemato-Oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of the BSH. It was also posted on the members section of the BSH website for comment. This guideline has also been reviewed by patient representatives from the UK CLL Support Association (https://www.cllsupport.org.uk) and Leukaemia Care (https://www.leukaemiacare.org.uk). Choosing the optimal therapy for a patient with CLL requires consideration of both patient-related factors (such as comorbidities, concomitant medication, patient preference) and disease-related factors (prognostic and predictive). In addition, previous responses and toxicities from prior therapies and the impact of treatment on cellular and humoral immunity will also influence therapy choices. The availability of targeted agents provides effective therapy for older patients for whom palliative chemoimmunotherapy was previously the only option. However, differences in the side effect profiles of first- and second-generation BTKi and B-cell lymphoma-2 inhibitors (BCL2i), phosphoinositide 3-kinase inhibitors (PI3Ki), and the option of fixed-duration venetoclax-including regimens versus continuous BTKi therapy all impact on the choice of therapy for individual patients. Screening for TP53 disruption (i.e. del 17p13.1 and/or TP53 mutation) prior to each line of treatment is recommended as patients with these genetic abnormalities remain a high-risk group, even in the era of targeted therapy. IGHV gene mutation analysis should be performed to identify a subgroup of patients who often fare particularly well and may be functionally cured with fludarabine, cyclophosphamide and rituximab (FCR) (fit, younger patients) and have excellent, durable responses with 12 months' fixed-duration venetoclax–obinutuzumab (VenO) (older patients). Since the last BSH CLL guidelines were published in 2018, targeted pathway inhibitors have challenged the role of chemoimmunotherapy (CIT) and represent a paradigm shift in front-line treatment. Criteria for initiating treatment remain as defined by the iwCLL.4 Given the natural CLL age distribution, the majority of patients fall into the category of 'less fit', with almost 90% having comorbidities.5 Prior to the approval of targeted agents, the German CLL Study Group (DCLLSG) CLL11 trial established chlorambucil with obinutuzumab (CO) as an international standard of care for this patient cohort.6 Three major randomised clinical trials in unfit patients7-9 have since shown an improved progression-free survival (PFS) with targeted inhibitors using either a BTKi or BCL2i in combination with obinutuzumab, compared to CO (Table 1), but no overall survival benefit to date. Ibrutinib Chlorambucil 73 72 136 133 92/30 37 NR (78% 6.5 years) NR (68% 5 years) – – Ibrutinib: Hypertension (26%) AF (16%) Major haemorrhage (11%) Ibrutinib Ibrutinib-Rituximab Bendamustine-Rituximab 71 71 70 182 183 183 93 94 81 NR (87% 2 years) NR (88% 2 years) NR (74% 2 years) 0.38 (0.250–0.59) IR vs BR 1.00 (0.62–1.62) I vs IR NR (90% 2 years) NR (94% 2 years) NR (95% 2 years) – – – 1 4 8 ≥G3 neutropenia-I (15%), IR (21%), BR (40%) AF-I (9%), IR (6%), BR (3%) Hypertension >G3-I (29%), IR (34%), BR (15%) Ibrutinib-obinutuzumab Chlorambucil-obinutuzumab 70 72 113 116 88 73 NR (76% 36 m) 22 m 0.251 (0.160–0.395) NR (86% 40 m) NR (85% 30 m) – – 35 25 Acalabrutinib Acalabrutinib-obinutuzumab Chlorambucil-obinutuzumab 70 70 71 179 179 177 86 94 79 NR (78% 4 years) NR (87% 4 years) 27.8 m – – – NR (88% 4 years) NR (93% 4 years) NR (88% 4 years) – – – – – – AF-A (4%), AO (3%), CO (1%) Hypertension ≥G3 A (2%), AO (3%), CO (3%) Bleeding >G3 A & AO (2%) Venetoclax-obinutuzumab Chlorambucil-obinutuzumab 72 72 216 216 85 71 NR (74% 4 years) 36.4 m NR (85.3% 4 years) NR (83.1% 4 years) 76 35 ECOG-ACRIN E1912 Ibrutinib-rituximab FCR 56.7 56.7 354 175 96 81 NR (89% 3 years) NR (73% 3 years) NR (99% 3 years) NR (92% 3 years) 8 59 Neutropenia ≥G3 IR (25.6), FCR (44.9%) AF-IR (7.4%), FCR (3.2%) Ibrutinib was the first-in-class BTKi to be licensed in CLL. The phase 3 RESONATE-2 study compared indefinite ibrutinib with ≤12 cycles of chlorambucil in untreated patients over 65 years old without del17p13.1.10 After seven years of follow-up, the ibrutinib arm displayed superior survival: PFS 61% vs 9%, and overall survival (OS) at five years of 83% vs 68% (78% of ibrutinib-treated patients were estimated to be alive at 6.5 years). Ibrutinib was well tolerated in this older population with 47% of patients remaining on treatment at this timepoint. Continued ibrutinib also improved depth of response with complete remission/complete remission with incomplete count recovery (CR/CRi) increasing from 11% at 18 months to 34% after a median follow-up of seven years.11, 12 The ALLIANCE A041707 study demonstrated an improved two-year PFS for ibrutinib with or without rituximab, compared to bendamustine–rituximab (87% vs 88% vs 74%, hazard ratio [HR] 0.38; 95% confidence interval [CI] 0.25–0.59).13 Notably, there was no additional benefit in adding rituximab to ibrutinib. Most common/clinically relevant adverse events (AEs) are included in Table 1. In the ELEVATE-TN study, acalabrutinib, the second-generation BTKi, in combination with obinutuzumab or as monotherapy improved the four-year PFS compared to chlorambucil–obinutuzumab (87% vs 78% vs 25%). An ad hoc analysis showed the addition of obinutuzumab to acalabrutinib improved PFS, but at the expense of an increased rate of ≥grade 3 infection (23.6% vs 16.2%, compared with 8.3% with chlorambucil–obinutuzumab), neutropenia rate (30.9% vs 11.2% vs 41.4%), and infusion-related reactions (2.8% vs 0 vs 5.9%)14 (see Table 1 for more information on AEs). The DCLLSG CLL14 study, which compared venetoclax in combination with obinutuzumab (VenO) to CO, showed improved four-year PFS (74% vs 35%).15 The improved PFS of CO, compared to that in the CLL11 study,6 is possibly explained by longer chlorambucil treatment (12 vs 6 cycles). VenO has some potential advantages over BTKi combinations, offering a fixed-duration treatment of one year, and high rates of minimal residual disease (MRD)-negative (<10−4) response (75.5% MRD-negative in peripheral blood and 56.9% in bone marrow). Additionally, there was a significantly lower incidence of subsequent clonal evolution than in the CO arm. Specific mutations associated with venetoclax resistance were not detected, such as mutations in BCL2, BIM, BAX, BCL-XL and MCL1). Grade ≥3 neutropenia occurred in 52.8% of VenO-treated patients, but precautions (use of adequate prophylaxis, initial debulking with obinutuzumab, and the well-established weekly venetoclax ramp-up dosing schedule) resulted in significant reduction of tumour lysis syndrome (TLS). FCR was previously the standard of care for front-line treatment of fit patients with CLL and intact TP53. The phase 3 ECOG-ACRIN 1912 trial randomised patients to receive either ibrutinib and rituximab (IR) for six cycles, followed by ibrutinib until disease progression or unacceptable toxicity, or six cycles of FCR.16 The IR cohort had a superior survival compared to FCR (three-year PFS 89.4% vs 72.9%, HR 0.35; 95% CI 0.22–0.56, with three-year OS 98.8% vs 91.5% HR 0.17; 95% CI 0.05–0.54). A subgroup analysis of patients with unmutated IGHV showed a PFS of 90.7% vs 62.5% at three years in favour of IR; whereas among those with mutated IGHV, PFS was comparable (87.7% vs 88.0%). The overall incidence of grade ≥3 AEs was similar; however, grade ≥3 infections were less common (10.5% vs 20.3%) in the IR group. Acalabrutinib Investigator's choice (BR/IdelaR) 68 67 155 155 81/0 76/2 NR (88% 1 year) 16.5 (68% 1 year) NR (90% 1 year) NR (88% 1 year) N/A N/A MURANO (Seymour et al.35) (Kater et al.37) VenR BR 64 66 194 195 92.3/26.8a 72.3/8.2a 53.6 17 NR (82% 5 years) NR (62% 5 years) X°62.4 13.3 Ibrutinib Ofatumumab 67 71 195 196 44.1 8.1 67.7 65.2 N/A N/A GS-US-312-0116 (Furman et al.31) (Sharman et al.82) IdelaR Rituximab 71 71 110 110 85.5/0 17/0 19.4 6.5 40.6 34.6 N/A N/A Among patients with mutated IGHV who receive front-line FCR and obtain a MRD-negative remission, extremely durable responses can be achieved leading to 'functional cure' in about 50% of patients with mutated IGHV,17 while the very long-term durability of responses to targeted inhibitors is as yet unknown. FCR therefore remains a viable option for fit, younger patients with mutated IGHV and intact TP53. However, this indication for FCR may change once longer-term follow-up data exist for the targeted inhibitors. Currently, front-line BTKi with ibrutinib or acalabrutinib does not have NICE approval for use in fit, younger patients without TP53 disruption, although the E1912 study showed an OS advantage of ibrutinib compared to FCR in this patient group. Prospective data from a phase 1b study of 32 patients indicates that VenO may be equally effective in fit patients.18 NICE TA633 permits use, via the Cancer Drugs Fund (CDF) in England and Northern Ireland, and through a different funding stream in Wales, of up-front VenO for fit patients lacking TP53 disruption, while more data are collected in this group. NICE-approved front-line treatment options for all patients with CLL and TP53 disruption include VenO, ibrutinib, acalabrutinib and venetoclax monotherapy where BTKi is contra-indicated (Figure 1). A growing body of evidence suggests that BTKi and BCL2i with or without anti-CD20 antibodies are highly effective front-line combination treatment. The phase 2 CAPTIVATE19 trial of venetoclax combined with ibrutinib (VI) in previously untreated CLL, included patients who were fit, under 65 years, but had at least one of: del(17p), TP53 mutation, del(11q) or unmutated IGHV. After 12 cycles of combined treatment, 88% of patients had CR/CRi, and 61% were MRD-negative in bone marrow, leading to FDA approval. The most common grade 3/4 AE across cohorts was neutropenia.20 In the less fit populations (over 65 years old or younger patients with a cumulative illness rating scale (CIRS) score of >6 or creatinine clearance <70 ml/min) efficacy and safety of fixed-duration VI is being evaluated in a phase 3 trial, GLOW. Improved PFS with VI (76% at 27.7 months) compared with CO (29%) (HR for progression or death 0.216; 95% CI 0.131–0.357) was consistent across predefined subgroups, including patients with unmutated IGHV. High-risk patients with known TP53 disruption were excluded. Undetectable bone-marrow (BM) MRD rates by next-generation sequencing (NGS) were significantly higher for VI at three months after the end of treatment compared with CO (51.9% vs 17.1% respectively, p = 0.0259). The most common grade 3/4 AE in both treatment groups was neutropenia (VI 34.9% vs CO 49.5%), infections (17% vs 11.4%), and diarrhoea (10.4% vs 1%); 22.6% participants discontinued VI.21 The relatively high incidence of early treatment-related mortality in VI patients compared with the control arm and VI patients in the CAPTIVATE trial suggests this combination should be used with caution in older/more comorbid patients and should be limited to fit patients with high-risk CLL. The pivotal studies described above have demonstrated superior long-term efficacy and tolerability of targeted therapy over CIT in the front-line setting for patients over 65 or with CIRS scores of >6. As result, both continuous therapy with acalabrutinib monotherapy and 12 months' fixed-duration VenO are now NICE-approved in the UK. The decision on which regimen to choose has to be based on a number of different factors including CLL-specific risk factors, past medical history, concomitant medication and patients' choice. Front-line ibrutinib monotherapy is NICE-approved and funded in the UK for patients with TP53 disruption but not routinely for all other front-line patients at the time of writing. There is no evidence directly comparing targeted agents in TP53 aberrant to recommend one over the other. Long-term follow-up of CLL14 shows that the small proportion of patients with TP53 disruption have a shorter PFS compared to those with wild-type (WT) TP53 following fixed-duration VenO. A similar patient population receiving continuous ibrutinib plus obinutuzumab in the Illuminate trial had a PFS of 72% at 36 months (HR 0.162; 95% CI 0.096–0.275).22 There is long-term benefit with ibrutinib monotherapy despite lack of undetectable MRD: Ahn et al. reported a six-year PFS in CLL patients with TP53 aberrations of 61% (95% CI 46–80) and an OS of 79% (95% CI 67–94).23 Zanubrutinib, a selective, second-generation covalent BTK inhibitor, had been tested in 109 TP53-deleted naïve patients with overall response rates of 94.5%, 18-months PFS of 88.6% (95% CI, 79.0–94.0) and an OS of 95.1% (95% CI, 88.4–98).24 With respect to IGHV mutational status, ibrutinib and acalabrutinib with or without anti-CD20 showed broadly equal responses for IGHV-mutated and unmutated patients,7, 13, 16 whereas IGHV-unmutated patients have an inferior PFS compared to those with mutated IGHV following VenO in CLL14.9 Whether IGHV status should be used to determine use of BTKi- or BCL2i-based treatment remains unclear. Longer-term sequencing studies may provide further guidance in this area in the future. Impact of past medical history such as cardiovascular comorbidities, use of anticoagulation, and bleeding risk on choice of front-line therapy is covered by related guidance.2 Here, the use of a more selective BTKi, such as acalabrutinib, with fewer cardiovascular side effects may be preferable.25 Alternatively, a combination is a for this patient group. with a history of disease should be obinutuzumab also treatment with BCL2 inhibitors requires adequate and patients with clearance and ml/min) should only be for venetoclax benefit with for the increased risk of for patients with high tumour and/or chronic BTKi may be a option. on the of treatment, medication should be with to or inhibitors which should be or by other of for all targeted inhibitors is are with and inhibitors. to the of for guidance on management of therapy to the BSH on management of cardiovascular complications of Bruton tyrosine kinase A of the and of fixed-duration therapy and continuous therapy should patient age patients, fixed-duration treatment may be and the effect of treatment on of should be In addition, the long-term of secondary should be with younger patients with mutated IGHV, CLL where FCR is being and side effects is treatment but is particularly relevant in the months following of a data demonstrated a rate of ibrutinib with subsequent also a rate of at 17 Acalabrutinib rates were for acalabrutinib with obinutuzumab and for acalabrutinib Most side effects with time with the of and The licensed therapies in relapsed CLL are BTKi and BCL2i monotherapy or in combination with and phosphoinositide 3-kinase inhibitors and After one or cycles of and BCL2 or in combination with anti-CD20 standard treatment options for relapsed CLL, of or of TP53 randomised evidence has compared BTKi versus in CLL after are into patient and There are also data on the sequencing patients following targeted agents (Table a patient is on a targeted treatment should be for as as the patient clinical benefit until the subsequent targeted therapy is as there is a risk of progression once therapy is Acalabrutinib monotherapy demonstrated benefit in relapsed CLL over choice or in the With a median follow-up of patients with acalabrutinib showed an overall response rate of and a PFS of 88% compared to 68% on the choice. Acalabrutinib also improved PFS in and unmutated IGHV There were no safety for acalabrutinib and the rate of to AEs was fixed-duration venetoclax and rituximab for CLL demonstrated PFS and OS benefit compared to BR in MURANO with a four-year PFS of and (HR 95% CI A proportion of patients peripheral blood MRD at the end of treatment vs 37 patients had previously been to VenR was in unmutated IGHV patients and in those with TP53 Ibrutinib showed superior efficacy in CLL compared to in follow-up demonstrated an of and a rate of of therapy was months with on ibrutinib at study PFS was 44.1 months for the ibrutinib arm and 8.1 months for the arm. and were in and In a phase 3 trial of patients unfit for standard IdelaR demonstrated an of a PFS of 19.4 months and an OS of 40.6 months compared to rituximab The IdelaR subgroup of showed a similar median PFS of However, IdelaR remains a less used treatment option to and data exist to the sequencing of targeted with pivotal randomised trials performed in targeted patients after A phase 2 35 of venetoclax monotherapy in patients an of and a progression-free survival of patients who prior showed an of and a estimated PFS of patients demonstrated an of 50% and a of monotherapy is further by studies provide evidence for sequencing with Recent evidence suggests that BTKi provide high in patients including those previously to and more than in this monotherapy is licensed for relapsed CLL patients who have or are for monotherapy remains a option for following venetoclax evidence for this approach remains 1). The BTKi has efficacy in patients to both covalent BTKi and but is not yet approved in The majority of data on BTKi intolerance from of with ibrutinib and small clinical demonstrated that acalabrutinib is effective in patients ibrutinib to A phase 2 trial of found an of and a two-year PFS of AEs were diarrhoea and Prospective trial data that long-term are for patients who a BTKi for intolerance than but there are no data on responses to subsequent In subgroup 95% CI of 30 patients who had discontinued ibrutinib therapy of AEs had an overall response with compared with 95% CI of patients who had discontinued ibrutinib of disease of acalabrutinib and ibrutinib showed that acalabrutinib is tolerated with similar efficacy to ibrutinib in previously patients, but has lower of common AEs and treatment In cardiovascular events were less A phase 2 trial has demonstrated that the selective is and effective in BTKi and British Society of and and indications for in CLL remain as defined in This therapy to be an option for patients with high-risk such as TP53 disruption and treatment The decision to patients with high-risk disease should be based on remission status, patient status, and patient status and availability of Given the evolution of targeted treatment options the of treatment that indicates remains unclear. the time of patients who are refractory to CIT and/or TP53 disruption, and following at least one targeted should be targeted inhibitors not to impact the safety of and survival are similar of number of agents prior chemoimmunotherapy or targeted inhibitors prior to therapies to are including therapy which has been evaluated in clinical trials the last years following initial reported in A of and with ibrutinib have been or are in phase 1 and 2 response rates of to 95% of patients have been with rates of to in patients. These may be to of has also limited the use of to the of patients with CLL who not have Long-term follow-up data are lacking and such treatment remains an option only through clinical It is of that a number of trials of cellular licensed for other B-cell have either been using or are not using remains a very of CLL for which therapy may have a the management of to the recent BSH is a treatment option for patients with high-risk CLL defined by A of CLL is by responses to vaccination, including and We patients to a (see the is followed at least months by the response to should be in those with a history of or The is and should not be should with who have the for seven The is for patients with and is in the UK for those years of age should be for all patients with a history of or Most patients with disease from secondary patients BTKi is recommended either therapy or for at least the 12 months the risk of infection to be patients on fixed-duration regimen may be for at least six months after the end of treatment or until from the and on in patients with BTKi in a front-line setting and use of is We recommend for the of BTKi therapy in those on combination therapy or for patients with significant and a history of or of infection are and limited to those with is not routinely recommended with BTKi or BCL2i to potential There are of infections on patients receiving BTKi and the and of with targeted therapy should be each other on the individual risk is a common in patients with therapy is for patients (1) or infections despite six months of continuous (2) have a and (3) have to to of therapy that can be may be more for patients and can be used as an to A of is recommended with according to the In a small the resulted in higher levels and patient of improved in to In addition, a reduction in the number of AEs were with This information on to for the information found The COVID-19 pandemic has for patients with CLL and It is that the secondary associated with CLL a higher risk of COVID-19 disease but no data exist to the risk compared with An early the of COVID-19 in patients with CLL was similar to that in the population but associated with a high mortality rate in those with infection to be and rates were similar patients and those on including those on In a where CLL patients were for COVID-19 infection the mortality was lower but this included a number of who have from COVID-19 infection have lower rates in without and this is most in those with The of to patients with CLL by the COVID-19 is lower than that of An initial study from found responses to the COVID-19 of compared with for The response rate for untreated patients was compared with in those on BTKi therapy. patient 12 months of anti-CD20 therapy a response to The UK study patients who had either the and vaccination, with an interval the Here, an response rate of was compared to in This increased to 79% those on and response rates were in those on BTKi therapy or with Notably, the which was in the UK at the time of study, were compared to a further in those with The of from COVID-19 disease with levels remains unknown. response to COVID-19 is and cellular which are to in However, recent that cellular responses to are also in CLL compared to and compared to rates and to with subsequent of should be recommended to all patients and particularly for those to the inferior response rates patients with CLL, a followed at least three months by a is now patients who COVID-19 treatment options have been and are now for patients with CLL in the has been shown to the risk of and death in high-risk patients by to is to patients who for infection and have the last five are for use as a treatment option. an is associated with a reduction in the risk of or and is with the criteria and where of therapy is not or contra-indicated CLL Support Association Leukaemia Care and other groups provide to CLL patients. After of and initial we recommend that patients are to these and also of the where can receive on a treatment patients should be using the or to the writing of the The to members of the UK CLL for and review of the to to Richter and who reviewed the and to the members of the BSH The BSH the the writing of this have a of to the BSH and Task which may be on The is not for the or of information by the than should be to the for the

The effects of bruton tyrosine kinase inhibitors on the waldenstrom macroglobulinemia microenvironment

The treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed over the last few years with the introduction of novel targeted agents. Physicians are now faced with several equally effective therapy options when treating patients with CLL. Here, we review the role of Bruton tyrosine kinase (BTK) inhibitors in treating patients with treatment-naïve and relapsed or refractory CLL. We review recent approvals of BTK inhibitors as well as reported and ongoing clinical trial data. The approval of ibrutinib rapidly led to a paradigm shift in the management of CLL. Randomized trials have now compared ibrutinib to several chemoimmunotherapy approaches, which were in favor of ibrutinib. Second-generation more selective BTK inhibitors, including acalabrutinib and zanubrutinib, have been developed, and recent data have led to the approval of acalabrutinib in CLL. Ongoing and future studies focus on either combining BTK inhibitors with other novel agents (e.g., venetoclax, obinutuzumab, or ublituximab) or developing next-generation non-covalent reversible BTK inhibitors that may be effective in treating patients with CLL harboring BTK-resistant mutations. The field of CLL continues to evolve rapidly with new and evolving combination treatments and novel BTK agents, which will continue to change the standard of care for CLL.

The Selective Bruton Tyrosine Kinase (BTK) Inhibitor TG-1701 As Monotherapy and in Combination with Ublituximab and Umbralisib (U2) in Patients with B-Cell Malignancies

Inhibitors of phosphatidylinositol 3-kinase (PI3K) and Bruton tyrosine kinase (BTK) represent a recognized option for the treatment of patients affected by indolent B cell lymphomas. However, small molecules as single agents show limited success in their ability in inducing complete responses, with only partial remission achieved in most patients, suggesting the need for combination therapies. IRAK4 is a protein kinase downstream of the Toll-like receptor signaling (TLR), a driver pathway of secondary tumor° resistance in both hematological and solid tumor malignancies. Activation of IRAK4 upon TLRs and IL-1 receptor (IL-1R) stimulation and through the adaptor protein MYD88 initiates a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NF-κB. MYD88-L265P encoding mutations occur in diffuse large B-cell lymphomas, in lymphoplasmacytic lymphomas and in few marginal zone lymphomas (MZL). The IRAK4 inhibitor emavusertib (CA-4948) has shown early safety and clinical activity in lymphoma and leukemia patients. In this preclinical study, we assessed emavusertib effectiveness in MZL, both as single agent and in combination with targeted agents, with a particular focus on its capability to overcome resistance to BTK and PI3K inhibitors. We showed that the presence of MYD88 L265P mutation in bona fide MZL cell lines confers sensitivity to the IRAK4 inhibitor emavusertib as single agent. Emavusertib-based combinations improved the sensitivity of MZL cells to BTK and PI3K inhibitors, including cells with a secondary resistance to these agents. Emavusertib exerted its activity via inhibition of NF-κB signaling and induction of apoptosis. Considering the early safety data from clinical trials, our study identifies the IRAK4 inhibitor emavusertib as a novel compound to be explored in trials for patients with MYD88-mutated indolent B cell lymphomas as single agent and as combination partner with BTK or PI3K inhibitors in unselected populations of patients.

Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1H-imidazole-5-carboxamide as a hinge binder. The most potent BTK inhibitor 26 demonstrates impressive selectivity, favorable pharmacokinetic properties, and robust antitumor efficacy in vivo, which indicates its potential as a novel therapeutic option for B-cell lymphomas. Importantly, to the best of our knowledge, this is the first example of a 1-amino-1H-imidazole-5-carboxamide scaffold used as the hinge binder of kinase inhibitors, which will largely expand the chemical diversity of kinase inhibitors.

Waldenström’s macroglobulinemia (WM) is a rare B-cell malignancy characterized by monoclonal immunoglobulin M (IgM) hypersecretion and invasion of B cells in the bone marrow (BM) and lymphoid tissues. &amp;gt;90% of WM cases show mutations in MYD88 and 30-40% show mutations in the carboxyl terminus of CXCR4.The CXCR4/CXCL12 axis is crucial for the homing/retention of WM cells in the BM. Emerging clinical trial data (NCT04274738; ongoing) suggest that mavorixafor, a CXCR4 antagonist, in combination with ibrutinib results in clinically meaningful changes in levels of IgM and hemoglobin in patients with MYD88L265P CXCR4WHIM WM. However, the effects of mavorixafor with ibrutinib and other Bruton tyrosine kinase (BTK) inhibitors on WM cells harboring only the single mutation (MYD88L265P without CXCR4 mutation) have not been evaluated. This study was designed to test the ability of mavorixafor to sensitize WM cells carrying MYD88L265P CXCR4WT to BTK inhibitors in a WM/BM stromal cell (BMSC) co-culture model. The effects of mavorixafor on Ca2+ mobilization, cell migration, and adhesion to BMSC were also measured. WM cells (MWCL-1 cell line, MYD88L265PCXCR4WT) pretreated with mavorixafor and BTK inhibitors (ibrutinib, zanubrutinib, evobrutinib, LOXO-305, ARQ 531) were co-cultured with established BMSCs (HS27a cells). Cell viability, apoptosis, and IgM release were measured after 72 hours. BTK inhibitors, but not mavorixafor, decreased tumor cell viability and increased apoptosis of WM cells in the absence of BMSCs. Co-culture with BMSCs enhanced CXCR4 expression and protected WM cells from the effects of BTK inhibitors. BMSCs also significantly increased IgM secretion 2- to 5-fold compared with WM cells grown in the absence of BMSCs. Mavorixafor alone inhibited CXCL12-stimulated Ca2+ mobilization and migration of WM cells and disrupted the adhesion of WM cells to BMSCs. Combination of mavorixafor with BTK inhibitors overcame the protective effect of BMSCs on tumor cells, decreasing cell viability and/or increasing apoptosis compared with BTK inhibitors alone. Mavorixafor also reduced IgM secretion, which was further decreased when combined with BTK inhibitors.This study is the first to show in vitro that the protection of WM cells against BTK inhibitors conferred by BMSCs can be overcome by inhibition of the CXCR4/CXCL12 axis. The observations and responses to mavorixafor suggest a contribution of CXCR4WT to the pathogenicity of WM cells carrying only the MYD88L265P mutation. Mavorixafor addition enhanced the efficacy of not only ibrutinib but the other BTK inhibitors tested, supporting the greater potential of this combination therapeutic strategy in WM patients with or without CXCR4WHIM mutations. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings. Citation Format: Chi Nguyen, Halenya Monticelli, Tom Kruitwagen, Matteo Tardelli, Barbara Maierhofer, Thalia Martins Rebelo, Sabine Maier-Munsa, Katarina Zmajkovicova, Lukas Dillinger, Adriana Badarau, Arthur G. Taveras. Mavorixafor enhances efficacy of Bruton tyrosine kinase inhibitors by overcoming the protective effect of bone marrow stroma on tumor cells in Waldenström’s macroglobulinemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6093.