Waldenström Macroglobulinemia – Symptoms, Treatment

Waldenström Macroglobulinemia (WM) is a low-grade B-cell clonal disorder characterized by lymphoplasmacytic bone marrow involvement associated with monoclonal immunoglobulin M (IgM). Although WM remains to be an incurable disease with a heterogeneous clinical course, the recent discovery of mutations in the MYD88 and CXCR4 genes further enhanced our understanding of its pathogenesis. Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton’s tyrosine kinase inhibitors have made the management of WM increasingly complex. Treatment should be tailored to the individual patient while considering many clinical factors. The clinical outcomes are expected to continue to improve given the emergence of novel therapeutics and better understanding of the underlying pathogenesis.

Other Names for This Condition

  • macroglobulinemia of Waldenstrom
  • Waldenstrom macroglobulinemia
  • Waldenstrom’s macroglobulinemia
  • WM

Causes of Waldenström Macroglobulinemia

Waldenström macroglobulinemia is thought to result from a combination of genetic changes. The most common known genetic change associated with this condition is a mutation in the MYD88 gene, which is found in more than 90 percent of affected individuals. Another gene commonly associated with Waldenström macroglobulinemia, CXCR4, is mutated in approximately 30 percent of affected individuals (most of whom also have the MYD88 gene mutation). Other genetic changes believed to be involved in Waldenström macroglobulinemia have not yet been identified. Studies have found that certain regions of DNA are deleted or added in some people with the condition; however, researchers are unsure which genes in these regions are important for development of the condition. The mutations that cause Waldenström macroglobulinemia are acquired during a person’s lifetime and are present only in the abnormal blood cells.

The proteins produced from the MYD88 and CXCR4 genes are both involved in signaling within cells. The MyD88 protein relays signals that help prevent the self-destruction (apoptosis) of cells, thus aiding in cell survival. The CXCR4 protein stimulates signaling pathways inside the cell that help regulate cell growth and division (proliferation) and cell survival. Mutations in these genes lead to production of proteins that are constantly functioning (overactive). Excessive signaling through these overactive proteins allows survival and proliferation of abnormal cells that should undergo apoptosis, which likely contributes to the accumulation of lymphoplasmacytic cells in Waldenström macroglobulinemia.

Symptoms of Waldenström Macroglobulinemia

WM is a heterogenous disease and patients can present with a broad spectrum of symptoms and signs [,]. Most patients with the diagnosis of WM have symptoms attributable to tumor infiltration, to circulating IgM, to tissue deposition of IgM, and to autoantibody activity of IgM. The most common clinical presentations are related to cytopenias, specifically anemia related to replacement of the bone marrow with tumor cells. Fatigue is a very common presentation of WM that is multifactorial, due at least in part to the underlying degree of cytopenia. Patients may also present with symptoms of hyperviscosity related to elevate IgM levels including headache, blurring of vision, and epistaxis. Hepatosplenomegaly and lymphadenopathy occur in 20% of the patients, and some patients may present with B symptoms including night sweats, fever, and weight loss. Other presentation features include peripheral neuropathy, cryoglobulinemia, skin rash (Shnitzler’s syndrome is the term for IgM monoclonal gammopathy associated with urticarial skin lesions, fever, and arthralgia), cold-agglutinin hemolytic anemia, and amyloidosis. Anti-myelin-associated glycoprotein (MAG) antibody has been implicated in the demyelinating neuropathy found in WM [].

Besides these problems, you may also get symptoms like:

  • Headaches
  • Night sweats
  • Lack of appetite and weight loss without trying
  • Frequent infections
  • Fevers
  • Swollen belly or lymph nodes
  • Confusion, dizziness, and clumsiness
  • Shortness of breath
  • Changes in vision, such as blurriness
  • Numbness or tingling in your hands or feet

Waldenström’s may start with a very early condition, called a precursor condition.

  • Smoldering Waldenström’s Macroglobulinemia (SWM): In this precursor condition, high concentrations of abnormal lymphocytes and plasma cells are found in the bone marrow and secrete M proteins of IgM type. SWM is characterized by the absence of end organ damage; M protein concentrations of 3 g/dL or greater; 10 percent or more abnormal lymphocytes and plasma cells in the bone marrow; or a combination of all of these factors.
  • Monoclonal Gammopathy of Undetermined Significance (MGUS): In this type of plasma cell neoplasm, there are abnormal plasma cells in the bone marrow – but there is no cancer. The abnormal plasma cells produce monoclonal (M) proteins. In most patients, the amount of M protein stays the same and there are no symptoms or problems. In some patients, MGUS may later become a more serious condition or cancer, such as Waldenström’s.

Diagnosis of Waldenström Macroglobulinemia

Tests and procedures used to diagnose Waldenstrom macroglobulinemia include:

  • Blood tests – Your doctor takes a sample of your blood and sends it to a lab, where technicians look at it under a microscope. Blood tests show if you have low levels of healthy blood cells. They can also check the amount of immunoglobulin M proteins in your blood. Blood tests also measure how well your organs are working.

    Bone marrow aspiration and biopsy – To confirm that you have Waldenstrom’s macroglobulinemia, your doctor tests your bone marrow for cancer cells. Bone marrow aspiration and biopsy are done at your doctor’s office or in a hospital. In an aspiration, your doctor numbs part of your hip and puts in a thin needle. It sucks out a small sample of liquid bone marrow. Your doctor usually then does a biopsy. Another needle removes some of your bone marrow tissue. Your doctor sends the samples to a lab, where technicians check for cancer cells. They also test your bone marrow for markers of Waldenstrom’s macroglobulinemia.Imaging tests. Your doctor may want to see if the cancer has spread. These tests include X-rays and a CT scan, which is a powerful kind of X-ray. They’re often combined with PET scans, which use a weak radioactive material to look for cancer cells.

  • Blood tests – Blood tests may reveal low numbers of healthy blood cells. Also, blood tests are used to detect the IgM proteins produced by the cancer cells. Blood tests may also measure your organ function, which can tell your doctor whether the IgM proteins are affecting your organs, such as your kidneys and your liver.
  • Collecting a sample of bone marrow for testing – During a bone marrow biopsy, your doctor uses a needle to extract some of your bone marrow from your hipbone. The sample is examined to look for cancer cells. If any are detected, advanced laboratory analysis can help your doctor understand the cancer cells’ characteristics, including their genetic mutations.
  • Imaging tests  Imaging tests can help your doctor determine whether cancer has spread to other areas of your body. Imaging tests may include computerized tomography (CT) scans or positron emission tomography (PET) scans.

Treatment of Waldenström Macroglobulinemia

WM is an insidious lymphoproliferative disease that shares many similarities with low grade NHLs. Its indolent manner, therefore, lends itself to close monitoring before any active treatment is needed.

  • Observation – If IgM proteins are found in your blood, but you don’t have any signs or symptoms, you may choose to wait before beginning treatment. Your doctor may recommend blood tests every few months to monitor your condition. You may go years without needing further treatment.
  • Plasma exchange – If you experience signs and symptoms related to having too many IgM proteins in your blood, your doctor may recommend plasma exchange (plasmapheresis) to remove the proteins and replace them with healthy blood plasma.
  • Targeted therapy – Targeted therapy drugs kill cancer cells by focusing on the specific abnormalities present in the cancer cells that allow them to survive. Targeted therapy drugs may be used alone or combined with other medications, such as chemotherapy or biological therapy, as an initial treatment for Waldenstrom macroglobulinemia or in cases where the cancer returns despite treatment.
  • Biological therapy – Biological therapy drugs use your immune system to kill cancer cells. Biological therapy drugs can be used alone or in combination with other medications as an initial treatment or as a treatment for recurrent Waldenstrom macroglobulinemia.
  • Bone marrow transplant – In certain highly selected situations, a bone marrow transplant, also known as a stem cell transplant, may be used to treat Waldenstrom macroglobulinemia. During this procedure, high doses of chemotherapy are used to wipe out your diseased bone marrow. Healthy blood stem cells are infused into your body where they can rebuild healthy bone marrow.
  • Chemotherapy – Chemotherapy is a medicine that destroys cells in the body that grow quickly. You can get this treatment as a pill or intravenously, which means through your veins. Chemotherapy for Waldenstrom’s disease is designed to attack the abnormal cells producing the excess IgM.
  • Plasmapheresis – Plasmapheresis, or plasma exchange, is a procedure in which excess proteins called IgM immunoglobulins in the plasma are removed from the blood by a machine, and the remaining plasma is combined with donor plasma and returned to the body.
  • Biotherapy – Biotherapy, or biological therapy, is used to boost the immune system’s ability to fight cancer. It can be used with chemotherapy.

Surgery

It’s possible your doctor may recommend surgery to remove the spleen. This is called a splenectomy. People who have this procedure may be able to reduce or eliminate their symptoms for many years. However, the symptoms of the disease often return in people who’ve had a splenectomy.

In frontline

The use of alkylator drugs (such as chlorambucil, cyclophosphamide, and melphalan), nucleoside analogs (such as fludarabine or cladribine), the monoclonal antibody rituximab, as well as combinations of these agents have resulted in response rates of 30–90% in the frontline. Notable, however, has been the lack of complete responses with the use of these agents or regimens in the frontline setting, with CR rates of 8–10% observed []. However, the panel recommended that for patients who may be eligible for autologous transplants, exposure to alkylator agents, and nucleoside analogs should be limited in view of reports suggesting depletion of stem cells by these agents [,].

Chlorambucil (0.1 mg/kg, Qid, oral) was the first agent used, with response rates varying between 31% and 92% []. The most common complication of therapy with alkylating agents is the development of myelodysplasia and acute nonlymphocytic leukemia from therapy-induced chromosomal breakage []. Cladribine (0.1 mg/kg, for 5 to 7 days, IV) has shown response rates in the range of 44–90% [,]. Response rates to fludarabine (25–30 mg/m2, 3 days, IV) as initial therapy range from 38% to 100% [,]. Fludarabine and cladribine are cross-resistant. The principal dose limiting toxicity of both these agents is bone marrow suppression and immunosuppression, predisposing patients to infections.

Response rates to rituximab (375 mg/m2, 4 weekly injections IV) vary between 20% and 50% [–]. Rituximab may be regarded as a reasonable choice for treating patients with IgM autoantibody-related neuropathies []. Patients with polyneuropathy associated with anti-MAG antibodies treated with high-dose rituximab have shown clinical improvement as well as improvement of nerve conduction velocities and decreased anti-MAG antibody titers []. The response to rituximab is delayed in most patients with a median time to partial response of 4 months and a median time to best response of 17 months []. Polymorphisms in the FcγRIIIA (CD16) receptor gene may affect response to rituximab []. Transient increases in IgM titers have been reported in 54% of patients after initiation of rituximab therapy. These levels may persist for up to 4 months and do not indicate treatment failure, but they may necessitate plasmapheresis to reduce hyperviscosity, which may result in the loss of the therapeutic antibody [,]. Patients who had initial IgM flares had worse response rates compared to those with lower IgM lvels (28% vs 80%). Some patients receive maintenance therapy with rituximab. Although the impact of this regimen on the time to progression has not been determined specifically in WM, it has prolonged time to progression in patients in patients with other low-grade lymphomas who received rituximab maintenance compared to those who did not []. The use of radioimmunotherapy such as iodine 131I-tositumomab radioimmunotherapy in WM has been limited since the high level of bone marrow involvement precludes their use. However, case reports have shown that these therapies may be effective in patients with WM who have <25% bone marrow involvement [].

Plasma exchange (1–1.5 volume) is indicated for the acute management of patients with symptoms of hyperviscosity because 80% of the IgM protein is intravascular. Splenectomy is rarely indicated, but limited case reports suggest that it may be helpful for managing symptomatic painful splenomegaly and hypersplenism [,].

Several combinations including these agents have been studied (Table 4). The addition of alkylating agents to nucleoside analogues is active against WM. For example, the combination of oral cyclophosphamide with subcutaneous cladribine in 37 newly diagnosed patients achieved 84% PR or more, with a median duration of response of 36 months []. The combination of fludarabine and intravenous cyclophosphamide resulted in 55–78% overall response, with median time to treatment failure of 27 months []. Hematologic toxicity was commonly observed. A phase II clinical trial of 60 patients with WM treated with cyclophosphamide, rituximab and dexamethasone (DRC) demonstrated an overall response rate of 70%, with 7% complete remission []. Treatment was well tolerated and the main toxicity observed was grade 3–4 neutropenia in 20% of the patients. The combination of rituximab, cladribine and cyclophosphamide was tested in 17 previously untreated patients with WM and achieved at least a partial response in 94% of the patients, with complete response in 18% [,]. The combination of rituximab and fludarabine was evaluated in WM patients, with an overall response rate of 91% and CR of 7% []. In another study, the combination of fludarabine, cyclophosphamide and rituximab (FCR) was tested in WM patients with an overall response rate was 52%, with 5% complete remissions [].

Combination therapies in WM

Study Regimen No. of patients Phase of study ORR %
Tam [] Fludara/CTX 9 II 88
Tamburini [] Fludara/CTX 49 II 78
Weber [] Cladribine/CTX 37 II 84
Leblond [] Fludarabine vs CAP 92 III 30 vs 11%
Owen [] Fludara/rituximab 43 II 82
Tam [] Fludara/CTX/rituximab 5 II 80
Weber [] Cladribine/CTX/rituximab 27 II 94
Hensel [] Pentostatin/CTX/rituximab 17 II 90
Dimopoulos [] Dex/CTX/rituximab 72 II 83
Treon [] CHOP/rituximab 13 II 77
Dimopoulos [] CHOP/rituximab vs CHOP 72 II 94

The combination of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) together with rituximab (CHOP-R) has been tested in patients with WM. The German Low-Grade Lymphoma Study Group (GLSG) performed a randomized upfront study of CHOP-R vs CHOP in 72 patients with low-grade lymphoma (71% of who had lymphoplasmacytic lymphoma). The response rate in the CHOP-R arm was 94% compared to 69% in the CHOP arm (Buske et al. unpublished). These results were confirmed in a small retrospective study of patients with relapsed WM []. A prospective study of CHOP-R in newly diagnosed patients with WM is ongoing in the Eastern Cooperative Oncology Group.

For patients with relapsed disease

The use of alternate first-line agents, re-use of a first-line agent, use of combination myelotoxic chemotherapy, and the use of thalidomide as a single agent or in combination therapy were recommended [–].

High-dose chemotherapy with autologous stem cell rescue in primary refractory or relapsed disease should be considered for eligible patients. However, allogeneic and ‘‘nonmyeloablative allogeneic” transplantations should be cautiously approached, given the associated high mortality and/or morbidity risks, and should be undertaken only in context of a clinical trial [–]. As such, the development of novel and stem cell sparing agents has been prioritized in the treatment of WM.

Novel therapeutics agents

Proteasome inhibitor

Proteasomal degradation is involved in physiological protein turnover and is the main mechanism accounting for intracellular protein degradation, such as signal transduction, cell cycle, and apoptosis. Proteasome inhibitors such as bortezomib have become the focus of clinical research in many malignancies including WM. The prototype 26S protea-some inhibitor bortezomib (Velcade, PS-341) selectively binds to the catalytic domain of the proteasome and prevents its activity [,]. Proteasome inhibitor bortezomib induces apoptosis of primary WM lymphoplasmacytic cells, as well as the BCWM.1 and WM-WSU WM cell lines at pharmacologically achievable levels. Based on its activity in MM, single agent bortezomib (1.3 mg/m2, J1, 4, 8, 11; cycles 21 days, IV, 8 cycles) was tested in WM in phase II trials and achieved 40–80% responses [–]. As part of an NCI-Canada study, Chen et al. [] treated 27 patients with both untreated (44%) and previously treated (56%) disease.

The addition of rituximab as well as steroids to bortezomib has been the subject of both preclinical as well as clinical investigation in various B-cell malignancies. In a trial by the WMCTG, bortezomib has been combined with dexamethasone and rituximab (BDR) for the primary therapy of patients with WM. The regimen proposed IV bortezomib at 1.3 mg/m2 and IV dexamethasone 40 mg on days (1, 4, 8, and 11), and rituximab at 375 mg/m2 (day 11). Patients received four consecutive cycles, followed by a three-month pause, and then 4 more cycles, each given three months apart. The development of peripheral neuropathy occurs in up to half of patients and are concerning using this schedule []. In addition, 4 of the first 7 patients receiving BDR in this study developed herpes zoster necessitating prophylaxis. In addition, Ghobrial et al. at the Dana-Farber Cancer Institute are examining the use of weekly intravenous bortezomib at 1.6 mg/m2 along with rituximab (at 375 mg/m2) in patients with relapsed/refractory WM with an overall response rate of over 80% in the first 17 evaluable patients (out ASH abstract). This study has been expanded to also include an arm of newly diagnosed patients to determine the toxicity and efficacy of once a week bortezomib therapy in patients with WM.

The immunomodulatory agents (IMIDs)

In view of their success in the treatment of patients with Multiple Myeloma, IMIDs were tested in patients with WM, although their experience is limited. Thalidomide is nonmyelosuppressive, immunomodulatory, and antiangiogenic and may be a reasonable choice for patients for whom first-line therapies have failed, those who have had disease relapse and are not candidates for alkylating or nucleoside analogue therapy, or patients with pancytopenia []. Lenalidomide has been studied in Multiple Myeloma and myelodysplastic syndrome and found to be more potent and also to lack the neurotoxic and prothrombotic adverse effects of thalidomide [].

Thalidomide

A study to evaluate thalidomide alone showed a partial response in 5 of 20 previously untreated and treated patients (25%) who received single-agent thalidomide. Adverse effects were common and prevented the dose escalation of thalidomide in 75% of patients []. However, a follow-up study of 10 patients with higher doses of thalidomide (200 mg daily) showed only 20% overall response rate (Treon et al. unpublished). Thalidomide (50 mg daily) in combination with dexamethasone (40 mg orally once a week) and clarithromycin (250 mg orally twice a day) induced partial response in 10 of 12 (83%) previously treated patients [].

In a previous study, the immunomodulators thalidomide significantly augmented rituximab mediated antibody dependent cell-mediated cytotoxicity (ADCC) against lymphoplasmacytic cells []. Moreover, an expansion of natural killer cells has been shown to be associated with rituximab response. A phase II study of the combination of thalidomide and rituximab in 23 patients triggered response in 15 patients. No patients with stable disease or better have progressed with a median follow-up of 10 months (range 6–13 months) []. Intended therapy for patients on the phase II study of thalidomide plus rituximab consisted of thalidomide administered at 200 mg daily for 2 weeks, followed by 400 mg daily thereafter for one year. Patients received four weekly infusions of rituximab at 375 mg/m2 beginning one week after initiation of thalidomide, followed by four additional weekly infusions of rituximab at 375 mg/m2 beginning at week 13. Twenty three patients were evaluable in this study, overall and major response rates were of 78% and 70%, respectively. With a median follow-up of 42+ months, the median TTP for responders was 38+ months. Dose reduction of thalidomide occurred in all patients and led to discontinuation in 11 patients. Among 11 patients experiencing grade >2 neuroparesthesias, 10 demonstrated resolution to grade 1 (n = 3) or complete resolution (n = 7) at a median of 6.7 (range 0.4–22.5 months).

Lenalidomide

Similarly, based on the potent activity of lenalidomide in MM and the lack of neuropathy with this agent, a phase II study of lenalidomide 25 mg daily in combination with rituximab is ongoing in patients with relapsed or relapsed/refractory WM. Lenalidomide was administered for 3 weeks, followed by a one week pause for an intended duration of 48 weeks. Patients received one week of therapy with lenalidomide, after which rituximab (375 mg/m2) was administered weekly on weeks 2–5, then 13–16 []. Twelve patients were evaluable for an overall and a major response rate of 67% and 33%, and a median TTP of 15.6 months. Acute decreases in hematocrit were observed during first 2 weeks of lenalidomide therapy in 13/16 (81%) patients with a median hematocrit decrease of 4.4% (1.7–7.2%), resulting in hospitalization in 4 patients. Despite reduction of initiation doses to 5 mg daily, anemia continued to be problematic without evidence of hemolysis or more general myelosuppression. Therefore, the mechanism for pronounced anemia in WM patients receiving lenalidomide remains to be determined and the use of this agent among WM patients remains investigational. A phase I/II escalade dose single agent lenalidomide relapse/refractory WM clinical trial should open in 2008 in France in order to address the best tolerated dose.

Monoclonal antibodies and blocking proteins

Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody which targets CD52, an antigen widely expressed on bone marrow LPC in WM patients, as well as on mast cells which are increased in the BM of patients with WM []. A phase II study of alemtuzumab was conducted in 25 patients with relapsed WM or newly diagnosed untreated []. Patients received 3 daily test doses of alemtuzumab (3, 10, and 30 mg IV) followed by 30 mg alemtuzumab IV three times a week for up to 12 weeks. All patients received acyclovir and bactrim or equivalent prophylaxis for the duration of therapy plus 8 weeks following the last infusion of alemtuzumab. All patients tolerated test dosing, and completed a median of 33 infusions (range 10–36) post test-dosing. WM patients showed an overall response rate of 76%, including 8 (32%) partial responses and 11 (44%) minor responses. Hematological toxicities were common among previously treated (but not untreated) patients and included grade 3/4 neutropenia (39%); thrombocytopenia (18%); anemia (7%). G3/4 non-hematological toxicity for all patients included dermatitis (11%); fatigue (7%); and infection (7%). Cytomeglovirus (CMV) reactivation and infection was commonly seen among previously treated patients. Three patients died due to therapy-related complications. With a median follow-up of 8.5+ months, 11/19 responding patients remain free of progression. High rates of response with the use of alemtuzumab as salvage therapy have also been reported by Owen et al. [], but opportunistic infections were common in this heavily pretreated population.

TACI-Ig, atacicept (ZymoGenetics) contains a soluble receptor fusion protein comprised of the extracellular domain of TACI and the Fc portion of a human IgG binds to both APRIL (A Proliferation-Inducing Ligand) and BLYS (B-Lymphocyte Stimulator), members of the tumor necrosis factor family that promotes B-cell survival [,]. An open-label, dose-escalation phase 1b study enrolled 16 patients with refractory or relapsed MM or active progressive WM []. Sequential cohorts received one cycle of 5 weekly subcutaneous injections of atacicept at 2, 4, 7 or 10 mg/kg. A total of 16 patients (12 MM and 4 WM) entered the trial, treatment with atacicept was well tolerated, and no dose limiting toxicity was observed. A biological response was observed in this heavily treated refractory population, with disease stabilization in 75% of the patients with WM.

Signaling pathways inhibitors

Perifosine

Perifosine (KRX-0401, Keryx Biopharmaceuticals, NY) is a novel Akt inhibitor that belongs to a class of lipid-related compounds called alkylphospholipids []. It has shown activity in phase II trials in MM. Our previous studies have shown that the activity of the survival protein Akt is upregulated in patients with WM compared to normal B cells, and that downregulation of Akt leads to significant inhibition of proliferation and induction of apoptosis in WM cells in vitro []. These results were confirmed in vivo in a xenograft mouse model where perifosine have shown significant cytotoxicity and inhibition of tumor growth []. Based on this preclinical activity, a phase II trial of single agent perifosine in patients with relapsed or relapsed/refractory disease was initiated using 150 mg oral daily dosing []. Thirty seven patients were enrolled on the study and of the first 27 evaluable patients, the overall response rate was 31%. These preliminary results indicate that perifosine is a well tolerated and promising agent to be used in combination in future studies in WM.

RAD001

Based on the preclinical data showing increased activity of the PI3K/mTOR pathway in WM [,], rapamycin (mTOR inhibitor) has been studied in vitro in WM and showed cytotoxicity in WM cell lines []. A phase II trial of single agent RAD001 (orally at 10 mg daily) was initiated in patients with relapsed or refractory WM. To date, 25 patients have been enrolled with an overall response rate of 40%, indicating promising activity for further evaluation of this agent in WM.

Bcl-2 inhibitor, G3139 (Oblimersen sodium; Genasense, Genta Inc, Berkeley Heights, NJ)

Bcl-2 regulates apoptosis and resistance to chemotherapeutic agents; it has therefore become an attractive target for anticancer therapy in a number of malignancies including WM []. In vitro studies have shown that Bcl-2 is expressed in WM cells, and that downregulation of Bcl-2 and increased cytotoxicity in WM cells may be achieved with G3139 []. A phase I/II clinical trial of G3139 was conducted in patients with relapsed or relapsed/refractory WM showed favorable tolerability but minimal activity [].

Imatinib mesylate (Gleevec)

Imatinib targets the microenvironment of WM through inhibition of stem cell factor signaling through CD117, which is expressed on WM tumor cells []. A phase II trial of single agent imatinib as performed in patients with relapsed or refractory WM []. Imatinib was given at 400 mg daily, with dose escalation to 600 mg after one month of therapy, for up to 2 years. After 3 months of therapy, 6/13 (46.2%) of patients achieved MR. Responses were prompt, and occurred at a median of 2.5 months. The main toxicities observed included cytopenias, edema, and hyperglycemia, leading to dose reductions in 31% patients and cessation of therapy in 23% patients. The preliminary results of this study therefore demonstrate that imatinib mesylate has potential activity, but there are concerns regarding toxicity.

Management of hyperviscosity

Hyperviscosity syndrome secondary to elevated IgM leads to decreased blood flow, compromising microcirculation including the central nervous system and heart. In patients with hyperviscosity related symptoms such as blurry vision, headache, papilledema, stupor/coma, chest pain, or ischemic changes, plasmapheresis should be initiated promptly for IgM removal from the serum. Red blood cell transfusion should be avoided since it can increase blood viscosity and precipitate symptoms. Plasmapheresis is only a temporary measure and patients should proceed to systemic treatment to prevent the recurrence of symptoms.

Bortezomib also demonstrated clinical efficacy in refractory or relapsed WM patients. In a study by Dimopoulos et al., 60% patients achieved PR with bortezomib. Also, bortezomib significantly reduced the median serum IgM level (4460mg/dL vs. 2092mg/dL) as well as BM involvement (30% vs. 20%) as shown in a study by Treon et al. In this study, ORR and MRR were 48% and 85%, respectively, and 6 of the 23 responding patients remained progression free (PFS rate 26%) with median follow-up of 18.2 months. Moreover, bortezomib combined with rituximab in 37 relapsed patients showed ORR 62%, 1-year PFS 58%, and 1-year OS 94%.

Ibrutinib has also been studies in WM, as data with MYD88L265P leads to constitutively active BTK signaling. In a recent phase II trial with 66 WM patients with prior treatments, ibrutinib showed ORR 73%, 2-year PFS rate 69.1%, and OS rates 95.2% Also, the median BM involvement (60% vs. 25%) and serum IgM levels (3520mg/dL vs. 880mg/dL) significantly improved upon ibrutinib treatment. The best serum IgM and hemoglobin responses were achieved in MYD88L265P/CXCR4WT patients whereas the least responses in MYD88WT/CXCR4wt patients. Based on these results, FDA has approved ibrutinib for WM patients. Common adverse reactions associated with ibrutinib include cytopenia, fatigue, diarrhea, bruising, and rash. It is also shown to increase the risk of atrial fibrillation and bleeding although the incidence is low.

Current studies are assessing the prognostic impact of MYD88 and CXCR4 mutations and correlative outcomes. A larger study evaluating 175 WM patients showed significantly higher BM involvement and serum IgM levels in patients harboring MYD88L265P and CXCR4 nonsense mutation compared to the ones with MYD88L265P and CXCR4 frameshift mutation or MYD88L265P and CXCR4WT52. Surprisingly, patients with MYD88L265P showed significantly worse OS compared to MYD88WT patients despite their lower disease burden. In a recent study comparing whole genome sequencing in 57 WM patients vs. healthy donors, MYD88 and CXCR4 expression levels were shown to be inversely correlated, which is also affected by mutation status. In most of WM patients, DNTT, RAG1, and RAG2 that are involved in VDJ recombination and BCL2 were found to be highly upregulated, and BAX expression was low. Further, in comparison to MYD88L265P, MYD88WT patient showed increased expression of PI3K signaling genes, but low NFκB response genes as well as increase promoter methylation in PRDM5 and WNK2 genes. Collectively, these findings suggest that BCL2, PI3K inhibitors and hypomethylating agents may be effective in WM.

Immunomodulatory agents and mTOR inhibitors have also been studied in WM. Combination therapy of lenalidomide and rituximab showed ORR 50% and PFS rate 25% with significant improvement in serum IgM level (2980mg/dL vs. 1775mg/dL, p=0.015). One of the caveats in the study was that tolerance was a limiting factor for treatment as lenalidomide causes noticeable toxicities including cytopenia from myelosuppression. The mTOR inhibitors were shown to be effective in NHLs–, and preclinical study showed that PI3K/AKT/mTOR pathway is activated in WM. In a phase II study with everolimus 10mg/day, 42% and 28% patients achieved PR and MR, respectively, with ORR 70%. The estimated PFS rates at 6 and 12 months were 75% and 62%, respectively, although 56% patients experienced grade≥3 toxicities, requiring dose reduction or treatment delay,. In a subsequent phase I/II trial with 46 patients, combination regimen of everolimus, bortezomib, and rituximab followed by everolimus maintenance therapy showed CR in 6% and MR in 89% patients. In this study, 82% of patients completed 6 cycles of combination therapy; however, 52% of patients required everolimus dose reduction or interruption during treatment. In patients who did not have dose alteration and received the full dose during their treatment cycles, the median PFS was 21 months. Of note, there are significant discordance between IgM and BM responses, indicating the importance of BM exam for the treatment response when treated with everolimus.

Stem cell transplantation

Although there is not enough data, SCT could be an option for patients with refractory disease as salvage therapy. Autologous SCT in European Bone Marrow Transplant Registry (EBMTR) study with 155 WM patients showed 5-yr PFS and OS rates of 49% and 69%, respectively, and non-relapsed mortality (NRM) of 5.6%. Allogeneic SCT reported by EBMTR showed 5-yr PFS and OS rates of 56% and 62% in patients who received myeloablative conditioning vs. 49% and 64% in reduced-intensity conditioning regimens.