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WM Medical Practice Guidelines & Research Publications

Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia.  Dimopoulos MA, Tedeschi A, Trotman J, García‑Sanz R, Macdonald D, Leblond V, Mahe B, Herbaux C,  Tam C,  Orsucci L, Palomba ML, Matous JV,  Shustik C, Kastritis E, Treon SP,  Li J, Salman Z,  Graef T, and C. Buske, for the iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Among patients with Waldenström’s macroglobulinemia, the use of ibrutinib– rituximab resulted in significantly higher rates of progression-free survival than the use of placebo–rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib–rituximab, whereas infusion reactions and IgM flare were more common with placebo–rituximab.

Impact of Ibrutinib dose intensity on patient outcomes in previously treated Waldenström macroglobulinemia. Castillo JJ, Gustine JN, Meid K, Dubeau TE, Xu L, Yang G, Hunter ZR, Advani R,  Palomba L, and Treon SP. Haematologica May 2018: haematol.2018.191999; Doi:10.3324/haematol.2018.191999. This multicenter study suggests that, similar to CLL patients, low dose intensity adversely impacts progression free survival in WM patients. Ibrutinib therapy is indefinite and compliance should be strongly emphasized to optimize outcomes.

Ibrutinib Withdrawal Symptoms In Patients With Waldenström Macroglobulinemia. Castillo JJ, Gustine JN, Meid K, Dubeau T, Severns, P, Treon SP.  Haematologica February 2018 : haematol.2017.186908; Doi:10.3324/haematol.2017.186908. Ibrutinib is the first approved therapy for the treatment of patients with Waldenström macroglobulinemia (WM). The approval was based on results of a study in WM patients that showed overall response rate (ORR) of 91% and median time to response of 4 weeks. Temporary interruption of ibrutinib is sometimes needed to manage toxicities or perioperatively to minimize bleeding. Some WM patients developed withdrawal symptoms (fever, body aches, night sweats, arthralgias, chills, headache, fatigue) while holding ibrutinib, which then resolved promptly after ibrutinib reinitiation. A retrospective study shows that withdrawal symptoms develop in 20% of WM patients who hold ibrutinib therapy. The rate of withdrawal symptoms was lower in patients who started ibrutinib at serum IgM levels ≥4,000 mg/dl and CXCR4 mutated patients, and higher in patients who had achieved a very good partial response (VGPR) on ibrutinib. Symptoms ensue within 2 days of ibrutinib hold and resolve rapidly following reinitiation of therapy. In two thirds of the patients who experience withdrawal, there is no evidence of disease progression during ibrutinib hold. In the patients who progress during the hold, response is regained within 3 months of ibrutinib reinitiation.

A consensus project of the EBMT (European Society for Bone Marrow Transplantation) lymphoma working party (LWP)/ ECWM (European Consortium for Waldenstrom’s Macroglobulinemia)/IWMF (International Waldenstrom’s Macroglobulinemia Foundation) to define indications for hematopoietic stem cell transplantation in patients with Waldenstrom’s macroglobulinemia. Kyriakou C, et al. Oral Abstract OS1-1: EBMT 44th Annual Meeting, Lisbon, Portugal, March 19, 2018. Charalampia Kyriakou presents the outcomes of a consensus on the role of autologous stem cell transplantation (ASCT) and allogeneic stem cell transplantation (allo-SCT) in Waldenström’s macroglobulinemia (WM). The experts aimed to address a gap in the knowledge of the role of transplantation in WM however; the main challenge was the lack of evidence in such a rare disease. Eighteen statements were prepared and scored by the members and a consensus was successfully agreed on nine of the statements.

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound. Gustine JN, Meid K, Dubeau T, Severns P, Hunter ZR, Guang Y, Xu L, Treon SP, Castillo JJ.  American J. Hematol. 2018;93:511–517. doi.org/10.1002/ajh.25023. This is a retrospective review of patients with WM who discontinued ibrutinib and their subsequent outcomes. Reasons for discontinuation include: disease progression, toxicity, non-response, and other unrelated reasons. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4‐fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival. Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.

Phase I study of an active immunotherapy for asymptomatic phase lymphoplasmacytic lymphoma with DNA vaccines encoding antigen-chemokine fusion: study protocol. Thomas SK, Cha S, Smith DL, Kim KH, Parshottam SR, Rao S, Popescu M, Lee VY, Neelapu SS, Kwak LW. BMC Cancer 2018 18:187 doi.org/10.1186/s12885-018-4094-2. There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Asymptomatic patients with lymphoplasmacytic lymphoma (LPL) are currently managed by a “watchful waiting” approach, as available therapies provide no survival advantage if started before symptoms develop. Tumor-specific markers and effective vaccination was demonstrated in a positive controlled phase III trial for LPL patients. This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and aid the development of other personalized approaches.

Long-term follow-up of monoclonal gammopathy of undetermined significance. Kyle RA, Larson DR, Therneau TM, et al., N Engl J Med 2018: 378:241-249.
MGUS affects more than 5% of persons older than seventy years and shortens survival, as compared to age-matched controls. In a long term study involving more than 1000 patients, those with IgM GUS had a higher rate of progression to B-cell cancer than those with IgG MUS.

How I manage monoclonal gammopathy of undetermined significance. Go, RS, Rajkumar SV.  Blood 2018 131:163-173; doi.org/10.1182/blood-2017-09-807560 Monoclonal gammopathy of underdetermined significance (MGUS) is, in many ways a unique hematologic entity. MGUS is considered an obligate precursor to several lymphoplastic malignancies, including immunoglobulin light-chain amyloidoisis, multiple myeloma, and Waldenstrom macroglobulinemia. The authors present 7 vignettes to illustrate common clinical management questions that arise during the course of MGUS. They describe how they practice provide a rationale for their approach. They also discuss the portnetial harms associated with MGUS diagnosis, a topic rarely broached between patients and providers.

Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenstrom macroglobulinaemia. Gustine JN, Meid K, Dubeau T, Hunter ZR, Xu L, Yang G, Ghobrial IM, Treon SP and Castillo JJ. British Journal of Haematology, 2017, 177, 717–725; DOI: 10.1111/bjh.14743. Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenstrom macroglobulinaemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. A large retrospective study showed the odds of developing symptomatic hyperviscosity were 370-fold higher with serum IgM levels >60 g/l, and showed an association with CXCR4 mutational status. Symptomatic hyperviscosity did not impact overall survival. The findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.

Diagnosis and Management of Waldenström Macroglobulinemia Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. Kapoor P, Ansell SM, Fonseca R, et al. JAMA Oncol.2017;3(9):1257–1265. i:10.1001/jamaoncol.2016.5763. The Mayo Clinic Cancer Center Myeloma, Amyloidosis and Dysproteinemia and Lymphoma Disease-Oriented Groups have updated their evidence-based recommendations for the management of WM. Important advances have led to a broader understanding of the biology of WM since their initial risk stratification–based approach was published in 2010. Clinical and observational studies published or presented through December 2015 are reviewed to provide consensus recommendations for clinicians. The guidelines are formulated using a grading system of evidence and grades of recommendations

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and WM. Chen C, Siegel D, Gutierrez M, et al, Blood, 2017, doi:10.1182/blood-2017-08-797886. The XPO1 inhibitor selinexor is an oral agent with a completely novel mechanism of action and anti-MM/WM activity in combination with dexamethasone that could provide a new option for patients with relapsed or refractory disease.

Acquired mutations associated with ibrutinib resistance in Waldenstrom macroglobulinemia. Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, Kofides A, Patterson CJ, Meid K, Gustine J, Dubeau T, Palomba ML, Advani R, Castillo JJ, Furman RR, Hunter ZR, Treon SP,Blood 2017 129:2519-2525; doi.org/10.1182/blood-2017-01-761726  Ibrutinib produces high response rates and durable remissions in Waldenstrom macroglobulinemia (WM) that are impacted by MYD88 and CXCR4WHIM mutations. Disease progression can develop on ibrutinib, although the molecular basis remains to be clarified. This study showed that Bruton tyrosine kinase (BTK) mutations are common in WM patients with clinical disease progression while on ibrutinib, and are associated with mutated CXCR4.

New developments in the management of Waldenstrom macroglobulinemia. Abeykoon, J. P., Yanamandra, U., & Kapoor, P. (2017), Cancer Management and Research, 9, 73–83. doi.org/10.2147/CMAR.S94059 The management of WM is evolving, with a deeper understanding of the disease pathophysiology and introduction of new drugs. In this excellent review article, the authors discuss new developments in the management of WM based on data published over the past 15 years, with an emphasis on the role of Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib.

Once-weekly ofatumumab in untreated or relapsed Waldenström’s macroglobulinaemia: an open-label, single-arm, phase 2 study. Furman RR, Eradat HA, DiRienzo CG, Hofmeister CC, Hayman SR, Leonard JP, Coleman M, Advani R, Chanan-Khan A, Switzky J, Liao QM, Shah D, Jewell RC, Lisby S,and Lin TS, Lancet Haematol 2017; 4: e24–3, dx.doi.org/10.1016/S2352-3026(16)30166-1. The aim of the study was to assess the safety and clinical activity of intravenous ofatumumab monotherapy for untreated and relapsed Waldenström’s macroglobulinaemia. They found a high proportion of patients achieved an overall response with ofatumumab as a single therapy and this treatment was well tolerated, with a low incidence of IgM flare. This therapy might be a non-chemotherapeutic treatment option for patients with Waldenström’s macroglobulinaemia, especially those with high IgM concentrations.

How I treat cryoglobulinemia. Muchtar E, Magen H and Gertz MA, Blood. 2017;129(3):289-298. Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Found in some patients with Waldenstrom’s macroglobulinemia, the authors explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients, including one with WM.

Dexamethasone, rituximab and cyclophosphamide for relapsed and/or refractory and treatment-naïve patients with Waldenström macroglobulinaemia. Paludo J, Abeykoon JP, Kumar S, et al.  Br J Haematol. 2017 Aug 8. doi: 10.1111/bjh.14826. The management of Waldenstrom macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab, and cyclophosphamide (DRC) as upfront treatment . The authors report on the efficacy of DRC, focusing on relapsed/refractory patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88WT genotype. They additionally report on the activity of DRC based on the MYD88L265P mutation status. They conclude that in contrast to ibrutinib, DRC offers a less expensive, fixed-duration option, with preliminary data suggesting efficacy independent of the patients' MYD88 status.

Waldenstrom's Macroglobulinemia. 1st ed, Leblond V, Treon S, Dimoploulos M (eds.), Springer International Publishing, Switzerland. 2017. With the  participation of many widely-recognized experts, this comprehensive book sheds new light on clinical, biological, and therapeutic data on Waldenstrom's macroglobulinemia. The book is divided into seven parts; tumor cells and microenvironment, epidemiology and genetic predisposition, clinical features, laboratory investigations, response, prognostic factors, and treatment options and recommendations.

Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenstrom macroglobulinemia. Gustine, J. N., Meid, K., Dubeau, T., Hunter, Z. R., Xu, L., Yang, G., Ghobrial, I. M., Treon, S. P. and Castillo, J. J. (2017), Br J Haematol, 177: 717–725. doi:10.1111/bjh.14743. Symptomatic hyperviscosity is a common clinical manifestation in patients with Waldenstrom macroglobulinemia (WM) and high serum IgM levels. Prompt intervention is required to prevent catastrophic events, such as retinal or central nervous system bleeding. Identifying patients at high risk of symptomatic hyperviscosity might support the decision to treat asymptomatic patients before irreversible damage occurs. They carried out a large retrospective study in newly diagnosed WM patients, Their findings support the use of serum IgM level >60 g/l as a criterion for initiation of therapy in an otherwise asymptomatic WM patient.

Investigation and management of IgM and Waldenström-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel. D'Sa, S., Kersten, M. J., Castillo, J. J., Dimopoulos, M., Kastritis, E., Laane, E., Leblond, V., Merlini, G., Treon, S. P., Vos, J. M. and Lunn, M. P. (2017), Br J Haematol. doi:10.1111/bjh.14492
The International Workshops on Waldenström Macroglobulinaemia (IWWM) have proposed criteria for diagnosis and therapy (Owen et al, 2003), response (Owen et al, 2013), and treatment (Dimopoulos et al, 2014) in WM patients. As part of its latest consensus deliberations (IWWM8, London 2014), the panel reviewed the management of peripheral neuropathies associated with IgM monoclonal gammopathies, including WM.  Importantly, a consensus regarding the use of clinical outcome measures and recommended models of care for this group of patients is discussed, as well as appropriate treatment interventions.

Genomics, Signaling, and Treatment of Waldenström Macroglobulinemia. Zachary R. Hunter, Guang Yang, Lian Xu, Xia Liu, Jorge J. Castillo, and Steven P. Treon Journal of Clinical Oncology  2017, 35(9):994-1001. Next-generation sequencing studies have identified highly recurrent somatic mutations in MYD88, CXCR4, ARID1A, and CD79, and other genes, as well as copy number alterations effecting important regulatory genes in chromosome 6q and elsewhere. Transcriptional changes, disease presentation, therapeutic outcome, and overall survival are affected by mutations in MYD88 and/or CXCR4. (Article provided with permission of the Bing Center for Waldenstrom's Macroglobulinemia.)

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Dimopoulos, Meletios A et al. The Lancet Oncology, 2017,18(2):241 - 250. In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. This study assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. (Article provided with permission of the Bing Center for Waldenstrom's Macroglobulinemia.)

Waldenstrom Macroglobulinemia: 2017 Update on Diagnosis, Risk Stratification, and management. Gertz, MA, Am. J. Hematol. 92:209–217, 2017. This Mayo Clinic clinician provides a technical clinical update of WM, as part of the Annual Clinical Updates in Hematological Malignancies Series from the American Journal of Hematology.

Guidelines for the diagnosis, treatment and response criteria for Bing-Neel syndrome. Minnema  MC. et al. Haematologica, 2017 Volume 102(1):43-51 obtained from the Haematologica Journal website. Bing Neel syndrome is a rare disease manifestation of Waldenstrom’s macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. These technical guidelines describe the clinical symptoms, as well as, the appropriate laboratory and radiological studies that can aid in the diagnosis. A discussion of prospective clinical trials and protocols that employ uniform treatment for delineating treatment outcomes is included.

Prospective, multicenter clinical trial of everolimus as primary therapy in Waldenstrom macroglobulinemia (WMCTG 09-214). Treon SP, Meid K, Christina Tripsas C, Heffner L, Eradat H, Badros AZ, Xu L, Hunter ZR, Yang G, Patterson CJ, Gustine J, Castillo JJ,  Matous J, Ghobrial IM. Blood Dec. 2016 128(22):4487. Everolimus inhibits mTOR, a component of PI3K/AKT pro-survival signaling triggered by MYD88 and CXCR4 activating mutations in Waldenstrom’s Macroglobulinemia (WM). They evaluated everolimus in a prospective, multicenter study of symptomatic, previously untreated WM patients. They found that everolimus is active in previously untreated WM. Serum IgM discordance with bone marrow disease burden was common and treatment cessation often lead to rapid serum IgM rebound. Pneumonitis also appeared more pronounced in untreated versus previously treated WM patients. They concluded that risks and benefits of everolimus should be carefully weighed against other primary WM therapy options.

Treatment Recommendations for Waldenström Macroglobulinemia from the Eighth International Workshop on WM. Leblond, V., et al. Blood, September 8, 2016, Volume 128, Number 10. These are updated treatment recommendations from the August 2014 International Workshop in London, England. (Article provided with permission of Dr. Steven Treon of the Bing Center for Waldenstrom's Macroglobulinemia.)

Paraproteinemic neuropathy: a practical review.  Rison RA, Beydoun SR, BMC Neurology 2016 16:13 doi.org/10.1186/s12883-016-0532-4 The term paraproteinemic neuropathy describes a heterogeneous set of neuropathies characterized by the presence of homogeneous immunoglobulin in the serum. An abnormal clonal proliferation of B-lymphocytes or plasma cells produces the immunoglobulins in excess. In this review, the authors provide a clinically practical approach to diagnosis and management of patients with this condition.

Future therapeutic options for Waldenstrom macroglobulinemia. Castillo JJ, Hunter ZR, Yang G, Argyropoulos K, Palomba ML, Treon SP. Best Practice & Research Clinical Haematology 29 (2016) 206-215. This review focuses on potential therapies that could change the landscape of treatment of patients with WM, specifically focusing on inhibitors 

Waldenström's Macroglobulinemia: Subtype Review. Lymphoma Coalition, August 2016. This is an overview of the disease prepared by the Lymphoma Coalition with review and editing assistance provided by the IWMF. It covers the basic biology of WM, along with current treatment recommendations from NCCN and from Dr. Steven Treon of the Bing Center for WM. Special sections of this report look at treatment availability and clinical trial activity in multiple countries and discuss the patient experience in terms of physical symptoms and psychological and social factors that impact the patient's sense of well being.

Waldenstrom macroglobulinemia: biology, genetics, and therapy. Paludo J, Ansell SM, Blood and Lymphatic Cancer: Targets and Therapy, 2016, 6:49-58. An excellent review that covers the pathophysiologic understanding of WM in light of the discovery of MYD88 and CXCR4, as well as treatment regimens with a focus on ibrutinib.

Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia. Jorge J. Castillo et al, British Journal of Haematology, 2016. A multi-institutional task force was formed during the 8th International Workshop for WM in London to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, recommendations are provided for history-taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis, and imaging studies. Guidance is also provided on the initial evaluation of special situations, such as anemia, hyperviscosity, neuropathy, Bing-Neel syndrome, and amyloidosis. (Article provided with permission of Jorge J. Castillo of the Bing Center for Waldenstrom's Macroglobulinemia.)

How I Treat Waldenstrom Macroglobulinemia. Treon, S. P., Blood. First Edition Paper, prepublished online May 22, 2015, DOI 10.1182. Treatment recommendations published by Dr. Steven Treon of the Dana-Farber Cancer Institute in 2015. (Article provided with permission of the Bing Center for Waldenstrom's Macroglobulinemia.)

Biology, Prognosis, and Therapy of Waldenstrom Macroglobulinemia. Castillo JJ, Ghobrial IM, Treon SP,  in Non-Hodgkin Lymphoma, Cancer Treatment and Research 165, Springer International Publishing, Switzerland, 2015, A.M. Evens and K.A. Blum (eds.), DOI 10.1007/978-3-319-13150-4_7. In this chapter, the authors review the recent advances in the biology of WM and the current therapeutic options for untreated and relapsed WM patients. They also discuss the role of prognostic factors and current evidence supporting an improvement in the survival of WM patients in the last decade.

NCCN Clinical Practice Guidelines in Oncology for Macroglobulinemia/Lymphoplasmacytic Lymphoma. The NCCN is a non-profit alliance of 27 cancer centers in the U.S. whose goal is to improve the quality and effectiveness of care provided to cancer patients. They provide updated guidelines based on the most current and up-to-date diagnosis and treatment guidelines available. You must establish an account on the NCCN website to login and view these guidelines.

Systemic Light Chain Amyloidosis: an update for treating physicians. Merlini G, Wechalekar AD, Palladini G, Blood. 2013;121(26):5124-5130. In immunoglobulin light chain amyloidosis a small, indolent plasma cell clone synthesizes light chains that cause devastating organ damage. Early diagnosis, based on prompt recognition of “red-flags” before advanced cardiomyopathy ensues, is essential for improving outcomes, such as recovery of organ function and prolonged survival.

MYD88 L265P Somatic Mutation in Waldenström’s Macroglobulinemia. Steven P. Treon et al, Dana-Farber Cancer Institute, Boston MA. This article, published in the New England Journal of Medicine in 2012, outlines the seminal discovery of the prevalence of the MYD88 L265 P mutation in WM patients. The research leading to this discovery was funded in part with the support of the IWMF.

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