Waldenström Macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the malignant accumulation of IgM-producing lymphoplasmacytic cells in the bone marrow and other organs.

 Recurrent somatic mutations in MYD88 and CXCR4 are observed in approximately 90% and 40% of patients with cancer, respectively, and give the malignant cells a survival advantage through apoptosis escape mechanisms.

The genomic profile impacts the clinical presentation of patients with WM. For example, patients with CXCR4-mutated disease typically present with high serum IgM levels, symptomatic hyperviscosity, and acquired von Willebrand disease.

 In contrast, patients with MYD88 wild-type disease have a higher risk of an aggressive transformation and experience inferior survival outcomes.

One-third of patients are diagnosed with WM in an asymptomatic phase, also known as smoldering or inactive WM. These patients have an overall survival similar to age-, sex-, and race-matched individuals of the general population.6 The asymptomatic WM risk scoring system uses the percentage of bone marrow involvement, serum IgM, albumin, and beta-2-microglobulin levels to identify patients at high, intermediate, and low risk of needing therapy.

 As WM is currently incurable using standard therapies, and the available therapies can induce adverse effects, therapy should be reserved for patients with symptomatic WM whose activities of daily living are impacted by the disease.


Approximately 80% of patients with asymptomatic WM will require therapy within 10 years of diagnosis.

 Criteria for treating WM include symptomatic anemia; constitutional symptoms such as fevers, drenching night sweats, or unintentional weight loss; symptomatic hyperviscosity; progressive neuropathy; and symptomatic lymphadenopathy or organomegaly. Other rare indications to treat include symptomatic cryoglobulinemia, cold agglutinin syndrome, systemic light chain amyloidosis, and the rare Bing-Neel syndrome, in which WM cells invade the central nervous system.

Several treatment options exist for patients with symptomatic WM, but no large, randomized studies have compared the commonly used regimens. Therefore, treatment selection is highly personalized and should consider the patient’s clinical presentation, comorbidities, concurrent medications, genomic profile, treatment objective, and personal preferences.

 The modified staging system for WM is an externally validated multi-institutional prognostic model to estimate the survival of patients with active, symptomatic WM and uses age, serum beta-2-microglobulin, lactate dehydrogenase, and albumin to classify patients into low-, low-intermediate, intermediate, and high-risk disease.


Rituximab (Rituxan)-containing regimens, also known as chemoimmunotherapy, are commonly used with a long track record and evidence of durable responses.

Beyond deep and durable responses, advantages of chemoimmunotherapy include a fixed duration, potentially allowing patients to be off therapy for years. However, chemoimmunotherapy can induce cytopenias, a higher risk of infections, and the development of myeloid neoplasms.

Over the past decade, Bruton tyrosine kinase (BTK) inhibitors have become a standard treatment option. Ibrutinib was highly effective in WM and induced deep and durable responses.

 The combination of ibrutinib (Imbruvica) and rituximab induced deeper and more durable responses than rituximab plus placebo in the phase 3 INNOVATE study (NCT02165397).

 Zanubrutinib was as effective as ibrutinib but was associated with lower rates of diarrhea, rash, and atrial fibrillation in the phase 3 ASPEN study (NCT03053440).

These findings supported the FDA approval of ibrutinib in 2015, ibrutinib and rituximab in 2018, and zanubrutinib in 2021 for the treatment of patients with WM. The advantages of BTK inhibitors include the ease of oral administration and the absence of risk of myeloid neoplasms. On the other hand, BTK inhibitors are associated with unique adverse events, such as an increased risk of bleeding, hypertension, and arrhythmia. The duration of therapy is indefinite and should continue until disease progression or unacceptable toxicity.

Beyond chemoimmunotherapy and BTK inhibitors, BCL2 antagonists such as venetoclax and noncovalent BTK inhibitors such as pirtobrutinib are safe and effective options.

 The National Comprehensive Cancer Network guidelines endorse both agents to treat patients with WM with previously treated disease. Tumor lysis monitoring is essential when ramping up the dose of venetoclax (

Clinical trial participation is essential to develop safer and more effective agents to treat WM. Any patient with WM should consider clinical trial participation at any stage of the disease.

In the frontline setting, a series of randomized European trials are comparing chemoimmunotherapy regimens, such as cyclophosphamide, dexamethasone, and rituximab vs ibrutinib plus rituximab in the phase 2/3 RAINBOW trial (NCT04061512) or vs venetoclax plus rituximab in the phase 2 VIWA-1 study (NCT05099471). Single-arm studies are evaluating BTK inhibitors in combination to provide fixed-duration therapy, including acalabrutinib (Calquence), bendamustine (Bendeka), and rituximab in the phase 2 BRAWM trial (NCT04624906); zanubrutinib (Brukinsa), bendamustine, and rituximab in the phase 2 ZEBRA trial (NCT06561347); and zanubrutinib and sonrotoclax in another phase 2 trial (NCT05952037).

In the relapsed setting, the phase 2 CLOVER-WaM study (NCT02952508) evaluating the radioconjugate iopofosine I-131 has completed accrual of patients, and results are expected soon. A number of other agents are under active clinical development and assessment in trials, including the following: pirtobrutinib plus venetoclax in a phase 2 study (NCT05734495), the second-generation BCL2 inhibitor sonrotoclax as monotherapy and in combination with zanubrutinib in a phase 2 study (NCT05952037), and the BTK degrader BGB-16673 in a phase 1/2 study (NCT05006716). Others include NX-5498 in a phase 1a/1b trial (NCT05131022), NX-2127 in another phase 1a/1b trial (NCT04830137), the anti-CD19 antibody-drug conjugate loncastuximab tesirine in a phase 2 study (NCT05190705), and the anti-CD20 bispecific antibody epcoritamab (Epkinly) in another phase 2 trial (NCT06510491). Additionally, chimeric antigen receptor T-cell therapy will soon enter clinical trials for patients with WM.

Clinical trials for special WM populations include a phase 2 study (NCT05065554) evaluating the combination of acalabrutinib and rituximab for patients with IgM monoclonal gammopathy of undetermined significance or WM with predominantly demyelinating neuropathy. Given WM’s rarity, clinical trials are essential to advance the field, and multi-institutional collaboration is crucial.


In Europe, the European Consortium for Waldenström’s Macroglobulinemia (ECWM), under the direction of Christian Buske, MD, was formed to improve the understanding of the biology of WM and develop therapies to enable patients with WM to live a life without compromise, with the final goal of achieving a cure. Dana-Farber Cancer Institute, in Boston, Massachusetts, under the direction of Jorge Castillo, MD, and in partnership with the International Waldenström’s Macroglobulinemia Foundation, created a US-based think tank to advance clinical research in WM, known as the WM-NET.

The WM-NET comprises more than 20 academic institutions in the US and will help design and support scientifically driven multi-institutional clinical trials in the US (

Other projects include the development of an academic prospective database aimed at answering questions that are unlikely to be answered by clinical trials and establishing a biorepository for blood and marrow samples from clinical trial participants to enhance WM-specific research efforts further (

). A cross talk between the ECWM and the WM-NET is being planned.

Swerdlow SH, Cook JR, Sohani AR, et al. Lymphoplasmacytic lymphoma. In: 

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

. Swerdlow SH, Campo, E, Harris NL, et al, eds. IARC Publications; 2017:232-235.

Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. 

. 2012;367(9):826-833. doi:10.1056/NEJMoa1200710

Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. 

. 2014;123(11):1637-1646. doi:10.1182/blood-2013-09-525808

Castillo JJ, Xu L, Gustine JN, et al. CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib. 

. 2019;187(3):356-363. doi:10.1111/bjh.16088

Treon SP, Gustine J, Xu L, et al. MYD88 wild-type Waldenstrom macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival. 

. 2018;180(3):374-380. doi:10.1111/bjh.15049

Zanwar S, Abeykoon JP, Ansell SM, et al. Disease outcomes and biomarkers of progression in smouldering Waldenström macroglobulinaemia. 

. 2021;195(2):210-216. doi:10.1111/bjh.17691

Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, et al. Progression risk stratification of asymptomatic Waldenström macroglobulinemia. 

. 2019;37(16):1403-1411. doi:10.1200/JCO.19.00394

8.Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. 

. 2003;30(2):116-120. doi:10.1053/sonc.2003.50038

Castillo JJ, Advani RH, Branagan AR, et al. Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia. 

. 2020;7(11):e827-e837. doi:10.1016/S2352-3026(20)30224-6

Zanwar S, Le-Rademacher J, Durot E, et al. Simplified risk stratification model for patients with Waldenström macroglobulinemia. 

. 2024;42(21):2527-2536. doi:10.1200/JCO.23.02066

Kastritis E, Gavriatopoulou M, Kyrtsonis MC, et al. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenström macroglobulinemia: final analysis of a phase 2 study. 

. 2015;126(11):1392-1394. doi:10.1182/blood-2015-05-647420

Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. 

. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2

Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. 

. 2009;27(23):3830-3835. doi:10.1200/JCO.2008.20.4677

Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström’s macroglobulinemia. 

. 2014;124(4):503-510. doi:10.1182/blood-2014-03-566273

Castillo JJ, Meid K, Flynn CA, et al. Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up. 

. 2020;4(16):3952-3959. doi:10.1182/bloodadvances.2020001963

Castillo JJ, Meid K, Gustine JN, et al. Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia. 

. 2022;36(2):532-539. doi:10.1038/s41375-021-01417-9

Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. 

. 2015;372(15):1430-1440. doi:10.1056/NEJMoa1501548

Buske C, Tedeschi A, Trotman J, et al. Ibrutinib plus rituximab versus placebo plus rituximab for Waldenström’s macroglobulinemia: final analysis from the randomized phase III iNNOVATE study. 

. 2022;40(1):52-62. doi:10.1200/JCO.21.00838

Dimopoulos MA, Opat S, D’Sa S, et al. Zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: final analysis from the randomized phase III ASPEN study. 

. 2023;41(33):5099-5106. doi:10.1200/JCO.22.02830

Castillo JJ, Allan JN, Siddiqi T, et al. Venetoclax in previously treated Waldenström macroglobulinemia. 

. 2022;40(1):63-71. doi:10.1200/JCO.21.01194

Palomba ML, Patel MR, Eyre TA, et al. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in relapsed / refractory Waldenström Macroglobulinemia: results from the phase 1/2 BRUIN study

. 2022;140(suppl 1):557-560. doi:10.1182/blood-2022-159123

Articles

Waldenström Macroglobulinemia (WM) is a rare non-Hodgkin lymphoma subtype characterized by IgM-producing lymphoplasmacytic cells. Key mutations in MYD88 and CXCR4 influence clinical presentation and treatment response. Asymptomatic WM patients have survival rates similar to the general population, but 80% require treatment within 10 years. Treatment options include chemoimmunotherapy and BTK inhibitors, with personalized regimens based on patient profiles. Clinical trials are crucial for advancing WM treatment, with ongoing studies exploring various drug combinations and novel therapies. Collaborative efforts aim to enhance understanding and develop curative strategies.

Understanding Waldenström Macroglobulinemia, and genomic profiles influencing clinical presentation and treatment strategies.

New Advances in Waldenström Macroglobulinemia

Jorge J. Castillo, MD, discusses the rationale for evaluating the iopofosine I 131 in Waldenström macroglobulinemia.

Dr Castillo on the Rationale for Evaluating Iopofosine I 131 in Waldenström Macroglobulinemia

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, institute physician, Dana-Farber Cancer Institute, associate professor, medicine, Harvard Medical School, discusses the rationale for evaluating the efficacy of iopofosine I 131 (previously CLR 131) in the phase 2 COLVER WaM trial (NCT02952508) evaluating patients with Waldenström macroglobulinemia.

In Waldenström macroglobulinemia, current treatment options such as chemoimmunotherapy and BTK inhibitors have shown high effectiveness and generated durable responses, Castillo begins. However, as Waldenström macroglobulinemia is an incurable disease, there is a need for additional treatment options, Castillo explains. He adds that this is especially important with patients living longer. The single-arm, multicenter, multinational CLOVER WaM study addresses this need by investigating the use of iopofosine I 131 for patients with relapsed/refractory Waldenström macroglobulinemia who have received at least 2 prior lines of therapy, including BTK inhibitors, Castillo states.

Iopofosine I 131 is a potential first-in-class, targeted radioligand therapy, Castillo continues. It is administered intravenously over 4 doses spaced several months apart, offering a finite treatment course for patients, he details. What sets Iopofosine I 131 apart is its unique mechanism of action compared with existing therapies in Waldenström macroglobulinemia, Castillo says. As a radioisotope and phospholipid-drug conjugate, iopofosine I 131 presents a novel approach that may provide alternative benefits and outcomes for patients with Waldenström macroglobulinemia, he says.

 demonstrated an overall response rate (ORR) of 75.6% and a major response rate (MRR) of 61% (95% CI, 44.50%-75.80%; 2-sided 

 < .0001) with the agent in the efficacy-evaluable population (n = 41).

Moreover, the agent produced a disease control rate of 100% and the median duration of response (DOR) has not yet been reached at a median follow-up of 8 months.

 by the FDA for patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.

Videos

Dr Castillo on Acalabrutinib Plus Rituximab in Patients With Anti-MAG IgM Peripheral Neuropathy

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, institute physician, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses preliminary data from a phase 2 study (NCT05065554) of acalabrutinib (Calquence) plus rituximab (Rituxan) in patients with Waldenström’s Macroglobulinemia or IgM symptomatic anti-myelin associated glycoprotein (MAG)–mediated peripheral neuropathy.

The prospective, single-arm study was designed to evaluate the efficacy of BTK inhibition plus CD20 directed therapy as a novel treatment for patients with anti-MAG peripheral neuropathy, Castillo begins. Patients with an anti-MAG antibody and an IgM monoclonal gammopathy or Waldenström’s Macroglobulinemia; and a predominantly sensory demyelinating PN with a modified Rankin score of 1 or more with progressive symptoms or a score of 2 or more were enrolled onto the study. Treatment consisted of 100 mg of continuous oral acalabrutinib administered twice daily, plus weekly rituximab in cycles 1 and 4. The first 8 patients enrolled onto the study were included in this analysis. Interestingly, MYD88 mutations occurred in 6 patients but none were CXCR4 mutated, Castillo notes.

Results showed that the combination of acalabrutinib and rituximab demonstrated early activity in patients with IgM-related anti-MAG peripheral neuropathy, Castillo reports. Among the 7 evaluable patients, the overall response rate based on IWWM-11 criteria was 86%, he details. Categorical responses included 2 very good partial responses, 1 partial response, 3 minor responses, and 1 occurrence of stable disease. Additionally, 57% of patients showed improvement in their I-RODS score, with a median improvement of 0.5 points, he adds. The median time on treatment was 175 days (range 28-510), indicating a favorable duration of response.

Regarding safety, the treatment regimen was deemed well tolerated. However, 1 patient had to be removed from the trial after 28 days due to a grade 3 elevation in ALT. Two other grade 3 adverse effects occurred, including a rituximab-related infusion reaction and syncope unrelated to treatment, but these were deemed reversible.

Overall, these findings may provide a framework for the development of novel and more effective therapeutics in anti-MAG peripheral neuropathy, Castillo says. Additional data from more detailed neurologic assessments are expected to provide further insights, Castillo states, adding that long-term data will hopefully show that this regimen can induce responses to improve patients' quality of life. The trial is ongoing and enrollment continues.

Jorge J. Castillo, MD, discusses preliminary data from a phase 2 study of acalabrutinib plus rituximab in patients with IgM symptomatic anti-MAG peripheral neuropathy.

Dr Castillo on the Efficacy of Iopofosine I 131 in Waldenström Macroglobulinemia

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, institute physician, Dana-Farber Cancer Institute, associate professor, medicine, Harvard Medical School, discusses the efficacy of treatment with iopofosine I 131 (previously CLR 131) in patients with Waldenström macroglobulinemia.

Topline data from the phase 2 CLOVER WaM trial

 (NCT02952508) were shared on January 8, 2024, showing that the agent elicited an overall response rate (ORR) of 75.6% and a major response rate (MRR) of 61% (95% CI, 44.50%-75.80%; 2-sided 

 < .0001), meeting the trial’sprimary end point. Furthermore, the disease control rate was 100% and at a median follow-up of 8 months, the median duration of response (DOR) has not yet been reached. Notably, these data continue to support the 

, which was granted by the FDA to patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.

The data presented on January 8th, 2024, exceeded expectations, Castillo begins. The ORR was also high, and the clinical benefits observed in these patients was substantial, he emphasizes. From a clinical research standpoint, these data support the continued evaluation of therapies to address unmet needs in Waldenström macroglobulinemia, particularly the lack of complete responses (CRs) seen in this disease, he emphasizes. Achieving CRs has been a challenge in Waldenström macroglobulinemia, contrasting with the efficacy of therapies for patients with other hematological conditions, in whom deep responses and minimal residual disease–negative treatment outcomes are more attainable, he states.

In the presented data, an 8% stringent CR rate with iopofosine I 131 was observed, a noteworthy development given that traditional treatments, such as chemotherapy, are the primary inducers of CRs in Waldenström macroglobulinemia clinical trials, Castillo expands.

The efficacy of the regimen is especially interesting considering the targeted patient population, which includes those previously exposed to rituximab (Rituxan)–containing regimens and BTK inhibitors, Castillo continues. This subset of patients has limited treatment options. In the trial, patients underwent a median of 4 prior treatments, according to Castillo. Notably, iopofosine I 131 demonstrated effectiveness in patients regardless of their mutational status, adding an intriguing dimension to this agent’s potential application in clinical practice, he concludes.

Jorge J. Castillo, MD, discusses the efficacy of treatment with iopofosine I 131  in patients with Waldenström macroglobulinemia.


Ongoing Areas of Investigation in Waldenström Macroglobulinemia

Dr Castillo on Ongoing Areas of Investigation in Waldenström Macroglobulinemia

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, institute physician, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the ongoing investigation into potential treatment options for patients with Waldenström macroglobulinemia, including iopofosine I-131 (previously CLR 131).

In the treatment of patients with Waldenström macroglobulinemia, there are several highly effective and safe regimens available, Castillo begins. Presently, the standard approaches involve either chemoimmunotherapy or BTK inhibitors. However, for patients who have undergone prior exposure to both chemoimmunotherapy and BTK inhibitors, determining the optimal third-line treatment remains uncertain, he explains. In this context, there are various options worth considering. Pirtobrutinib (Jaypirca), a noncovalent BTK inhibitor, demonstrated promising efficacy based on previous data that were presented at the 2022 ASH Annual Meeting, with patients benefiting from this approach, Castillo says. Additionally, venetoclax (Venclexta), has shown efficacy in this setting, with encouraging a progression-free survival.

Castillo goes on to explain that other agents are currently under investigation, such as iopofosine, Castillo states. Iopofosine is a novel phospholipid drug conjugate which received 

 in May 2020. This  agent is administered intravenously over 4 infusions within a 71-day interval, and final results from the CLOVER-WaM trial (NCT02952508) are eagerly anticipated, Castillo emphasizes.

Furthermore, additional agents, such as BTK degraders, constitute another category of interest and work differently than BTK inhibitors by attaching to the molecule in an alternative manner to block BTK signaling, Castillo continues. Notably, they appear effective even in patients who have received covalent and noncovalent BTK inhibitors, emphasizing their critical role. Another facet of research involves immunotherapy, he states.

Looking ahead, the future appears promising with targeted agents and immunotherapy, Castillo expands. Although the extent of their benefits to patients is yet to be fully understood, ongoing investigations in other lymphomas suggest a potential avenue for development, he says. As investigators continue to observe these advancements, the prospect of combining targeted agents with immunotherapy emerges as an area warranting further exploration, Castillo concludes.

Jorge J. Castillo, MD, discusses the ongoing investigation into potential treatment options for patients with Waldenström macroglobulinemia, including iopofosine I-131.

Jorge J. Castillo, MD, associate professor of medicine, Harvard Medical School, clinical director, senior physician, Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, discusses the phase 2 CLOVER WaM trial (NCT02952508) in Waldenström macroglobulinemia (WM).

CLOVER-WaM is the pivotal expansion portion of the CLOVER-1 trial, which investigated the small-molecule radiotherapeutic iopofosine I-131 (CLR 131) in patients with select B-cell malignancies, including WM. 

CLOVER-WaM will enroll patients who have received at least 2 prior lines of therapy with exposure to a BTK inhibitor, and the trial will feature a population without many treatment options remaining, Castillo says. 

Unlike other treatments for WM, iopofosine I-131 has demonstrated central nervous system (CNS) penetration, Castillo adds. Patients with WM with CNS involvement have typically been excluded from past clinical trials, and CLOVER-WaM represents the chance to include this specific subset of patients, Castillo concludes.

Jorge J. Castillo, MD, discusses the phase 2 CLOVER WaM trial in Waldenström macroglobulinemia.

Dr. Castillo on the CLOVER-WaM Trial in Waldenström Macroglobulinemia

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, senior physician, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the integration of BTK inhibitors in Waldenström macroglobulinemia. 

Historically, the treatment of patients with Waldenström macroglobulinemia consisted of rituximab (Rituxan)-containing regimens, such as rituximab plus chemotherapy or proteasome inhibitors, Castillo says. Although these therapies are efficacious in this patient population, they conferred significant toxicity to patients. 

For example, rituximab-containing regimens are associated with an increased risk of infection, as well as a lowered response to vaccines, Castillo continues. Chemotherapy is associated with an additional risk of secondary leukemia in this patient population because of bone marrow damage, Castillo adds. Moreover, proteasome inhibitors can cause neuropathy. As such, the integration of BTK inhibitors, which are less toxic comparatively, have transformed the management of Waldenström macroglobulinemia, Castillo concludes.

Jorge J. Castillo, MD, discusses the integration of BTK inhibitors in Waldenström macroglobulinemia.  


Dr. Castillo on the Integration of BTK Inhibitors in Waldenström 

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, physician, associate professor of medicine, Harvard Medical School, Dana-Farber Cancer Institute, discusses the results of a multicenter, prospective, phase II study of venetoclax in patients with previously treated Waldenstrom macroglobulinemia.

Dr. Castillo on the Use of Venetoclax in Waldenstrom Macroglobulinemia

Jorge J. Castillo, MD, clinical director, Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, highlights ongoing research with emerging treatment approaches in Waldenström macroglobulinemia.

There are several novel approaches under investigation in the realm of Waldenström macroglobulinemia, says Castillo. For example, there are newer proteasome inhibitors, such as ixazomib (Ninlaro), that are emerging in the paradigm. This agent is being explored in combination with rituximab (Rituxan) and dexamethasone and will be added to the National Comprehensive Cancer Network guidelines in the future. Oprozomib (ONX 0912) is another agent that has been investigated in multiple myeloma and Waldenström, says Castillo.

BTK inhibitors, such as acalabrutinib (Calquence) and zanubrutinib (BGB-3111), have also shown promise in this space. Acalabrutinib has already received FDA approval for use in mantle cell lymphoma, and zanubrutinib is currently being compared head-to-head against ibrutinib (Imbruvica) in clinical trials. Both of these agents are more selective to BTK, explains Castillo, and unlike ibrutinib, they do not tend to have other off-target effects. However, these agents must be taken twice daily, while the dosing for ibrutinib is only once daily. How this dosing might affect patient compliance remains to be seen.

Venetoclax (Venclexta), a BCL-2 inhibitor previously FDA approved for use in chronic lymphocytic leukemia and acute myeloid leukemia, is another agent that is currently being evaluated in 30 patients with Waldenström macroglobulinemia. Preliminary data have shown that the agent is efficacious, says Castillo. Specifically, half of the patients who had progressed on ibrutinib and were given venetoclax responded to the agent.

Resistance to ibrutinib is mediated by a mutation in the BTK, explains Castillo, and the hope is that new BTK inhibitors will be able to overcome that resistance and rescue patients in whom ibrutinib is failing. Beyond this effort, ibrutinib is also being investigated in combination with ulocuplumab (BMS-936564), an antibody against CXCR4, in what is potentially the first genomically-driven clinical trial in patients with Waldenström, says Castillo. This trial is currently undergoing accrual. Another trial opening in the future will examine a small molecule targeting CXCR4 in these patients as well, he adds.

Lastly, investigators will be examining ibrutinib in combination with venetoclax in a trial that is slated to be launched later this year, concludes Castillo. In the trial, the combination will be given to 50 treatment-naïve patients for a limited duration of time, about 2 years.

Jorge J. Castillo, MD