What Is Lymphoplasmacytic Lymphoma?

Lymphoplasmacytic lymphoma (LPL) is a rare, slow-growing cancer of white blood cells that sits at the border between B-cell lymphoma and plasma cell disease. It affects roughly three to four people per million each year, making it one of the least common blood cancers.

¹ The vast majority of LPL cases fall under a clinical entity called Waldenström macroglobulinemia, defined by bone marrow involvement and an abnormal IgM protein in the blood. A single genetic mutation, MYD88 L265P, turns up in over 90 percent of cases and has reshaped how the disease is understood, diagnosed, and treated.²

Who Gets LPL and What Raises the Risk

LPL is overwhelmingly a disease of older adults, with most people diagnosed in their sixties or seventies. Men are affected more often than women. A large pooled analysis of risk factors found several conditions and exposures tied to higher odds of developing the disease. People with autoimmune disorders stood out: those with Sjögren syndrome had roughly fourteen times the risk of the general population, and those with systemic lupus had about eight times the risk. A positive hepatitis C test roughly doubled the odds. Having a first-degree relative with any blood cancer was also linked to modestly higher risk. Long-duration cigarette smoking (forty years or more) raised the odds as well.

The same analysis turned up a few unexpected associations, including a significantly elevated risk among medical doctors and a mildly protective effect from hay fever. Higher adult body weight was actually associated with lower risk, which runs counter to the pattern seen in many other cancers. These associations come from observational data and do not prove causation, but they suggest that chronic immune stimulation and genetic predisposition are central to how LPL develops.

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The MYD88 Mutation and How the Disease Starts

If there is one genetic event that defines LPL, it is the MYD88 L265P mutation, a single amino acid swap that turns on a signaling pathway promoting cell survival and growth. This mutation shows up in more than 90 percent of LPL cases.⁵ For years, researchers assumed this mutation arose inside the cancerous cells themselves. A 2022 study upended that view by finding the MYD88 L265P mutation in normal, non-cancerous precursor B cells of patients with LPL. The mutation appears to be a “pre-cancerous” event, accumulating in healthy cells long before any lymphoma develops. The researchers modeled the disease in mice by combining MYD88 L265P with overexpression of BCL2 (a protein that blocks cell death), and that combination was enough to produce lymphoma.

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This discovery has implications beyond LPL. If the mutation can be detected in normal blood cells before cancer appears, it opens a theoretical window for early detection, though no screening program exists for this at present.

LPL and Waldenström Macroglobulinemia

The terms “lymphoplasmacytic lymphoma” and “Waldenström macroglobulinemia” are used almost interchangeably in everyday conversation, but they are not identical. LPL is the pathological diagnosis describing the type of cancer cell. Waldenström macroglobulinemia (WM) is a clinical diagnosis that requires two things: LPL primarily involving the bone marrow, plus a measurable IgM monoclonal protein (a single type of antibody mass-produced by the cancer cells) circulating in the blood.⁷ Most LPL is WM, but a small fraction of cases involve non-IgM proteins or lack a measurable paraprotein. When you read about treatments and outcomes, the data almost always come from WM cohorts, which is worth knowing if your particular case does not fit the standard WM definition.

Symptoms and Complications

Many people with LPL/WM are diagnosed before they feel sick at all, through routine blood work that catches an abnormal protein or low blood counts. When symptoms do appear, they tend to fall into two broad categories: those caused by the tumor cells themselves crowding the bone marrow, and those caused by the IgM protein circulating in the blood.

Bone marrow infiltration leads to the same problems seen in other blood cancers: anemia (fatigue, shortness of breath), low platelets (easy bruising, bleeding), and sometimes an enlarged spleen or lymph nodes. The IgM protein, however, produces a distinctive set of complications. Because IgM is a very large molecule, high levels can thicken the blood, a condition called hyperviscosity syndrome. Symptoms include blurred vision, headaches, nosebleeds, and dizziness. In the eyes, hyperviscosity can cause retinopathy with changes visible on examination, including dilated veins and retinal hemorrhages.⁸

The IgM protein can also behave as an autoantibody, attacking the body’s own tissues. In cold agglutinin disease, the IgM causes red blood cells to clump together at low temperatures, leading to anemia and painful circulation problems in the fingers and toes. In mixed cryoglobulinemia, the IgM forms complexes that clog small blood vessels, causing skin rashes, joint pain, and kidney problems. These autoantibody-driven syndromes are sometimes the very first sign that brings a patient to medical attention.⁹

Nerve Damage and the IgM Connection

Peripheral neuropathy is one of the more disabling complications of WM. In many cases, the IgM protein targets a component of the nerve’s insulating sheath called myelin-associated glycoprotein (MAG). This produces a slowly progressive sensory neuropathy: numbness, tingling, and balance problems that typically start in the feet and work upward. Electron microscopy studies of nerve biopsies from affected patients show characteristic widening of the myelin layers, with some fibers showing dramatically abnormal spacing between layers.¹⁰ This kind of neuropathy can be present even when the underlying lymphoma is very indolent, and it does not always improve when the blood cancer is treated.

Bing-Neel Syndrome

A rare but serious complication occurs when the LPL cells themselves invade the central nervous system, a condition called Bing-Neel syndrome. This can happen even when the lymphoma in the rest of the body is well controlled. In a review of 44 cases, Bing-Neel syndrome was actually the first sign of WM in about a third of patients. For those already diagnosed, the median gap between the original WM diagnosis and development of Bing-Neel was nearly nine years.¹¹

Symptoms are wildly variable. The most common are balance problems and difficulty walking, seen in roughly half of cases, followed by cranial nerve involvement in about a third. Headaches, cognitive changes, weakness, and even psychiatric symptoms have all been reported.¹² Because of this diversity, the diagnosis can be missed or delayed. Diagnosis relies on MRI of the brain and spinal cord along with spinal fluid analysis, including testing the fluid for the MYD88 L265P mutation, which has proven useful for confirming central nervous system involvement.¹³

Diagnosis and Telling LPL Apart from Its Look-Alikes

LPL can resemble other low-grade B-cell lymphomas and plasma cell disorders under the microscope, so diagnosis relies on putting together the clinical picture, pathology, and molecular testing. The MYD88 L265P mutation is especially helpful: it is found in over 90 percent of LPL cases but is uncommon in marginal zone lymphoma, chronic lymphocytic leukemia, and multiple myeloma, the conditions most frequently confused with LPL.

Another diagnostic challenge is separating true WM from its precursor state, IgM monoclonal gammopathy of undetermined significance (IgM MGUS). Both conditions feature the IgM protein, but MGUS involves a smaller clone and does not require treatment. Bone marrow examination helps draw this line. Studies suggest that a cutoff of about 20 percent lymphoplasmacytic cells by morphology, or about 5 percent by flow cytometry in the marrow aspirate, can help distinguish MGUS from smoldering or symptomatic WM when a tissue biopsy is not available.¹⁴

When and How Treatment Begins

Not everyone diagnosed with LPL/WM needs treatment right away. People with smoldering disease, meaning no symptoms and preserved blood counts, are typically monitored without therapy. This “watch and wait” approach is standard because the disease is slow-growing and treatment carries its own side effects.¹⁵ Treatment is generally started when symptoms arise, such as significant anemia, hyperviscosity, neuropathy, or organ enlargement.

For most people who do need treatment, the first line is chemoimmunotherapy built around rituximab (an antibody that targets the CD20 protein on the cancer cells) combined with agents like cyclophosphamide and dexamethasone, bendamustine, or bortezomib and dexamethasone.¹⁶ The choice among these combinations depends on individual factors such as age, kidney function, and whether the patient might need stem cell collection for a future transplant.

BTK Inhibitors and Why CXCR4 Mutations Matter

The discovery that MYD88 L265P drives LPL growth through a protein called Bruton tyrosine kinase (BTK) made BTK inhibitors a logical treatment. Ibrutinib was the first to gain approval for WM, and zanubrutinib followed as a more selective alternative. These oral drugs have transformed care, especially for patients who cannot tolerate chemotherapy or whose disease has relapsed.

However, not everyone responds equally. About 30 to 40 percent of WM patients carry mutations in a second gene called CXCR4.¹⁷ These mutations blunt the effectiveness of BTK inhibitors. In a large cohort of 319 patients treated with ibrutinib alone, those with CXCR4 mutations had a major response rate of about 67 percent compared with 86 percent in patients without the mutation. Progression-free survival was also significantly shorter: a median of roughly four and a half years with CXCR4 mutations, versus not yet reached in patients without them.¹⁸

The type of CXCR4 mutation also matters. Nonsense mutations (which truncate the CXCR4 protein) are associated with significantly worse response and survival on ibrutinib, while frameshift mutations may not carry the same penalty.¹⁹ This is one reason genomic testing of tumor samples is increasingly recommended before choosing therapy.

Zanubrutinib may partially overcome CXCR4-related resistance. In the ASPEN trial, a head-to-head comparison with ibrutinib, patients with CXCR4 nonsense mutations treated with zanubrutinib had a numerically higher major response rate (about 86 percent versus 54 percent with ibrutinib), though the sample sizes were small. Zanubrutinib also showed better outcomes in patients with TP53 mutations, another marker of harder-to-treat disease.²⁰ Beyond efficacy, zanubrutinib was associated with better quality of life, with patients reporting less diarrhea, nausea, and fatigue compared with ibrutinib.²¹

Options When the Disease Comes Back

LPL/WM is generally not curable with current treatments, so most patients will eventually need a new line of therapy. For those whose disease progresses after BTK inhibitors, venetoclax has emerged as a promising option. This drug works by blocking BCL2, the cell-survival protein that appears to cooperate with MYD88 L265P in driving LPL. In a phase II trial of 32 previously treated patients, including half who had already been on BTK inhibitors, the major response rate was about 81 percent with a median progression-free survival of 30 months.²²

A larger real-world analysis of 76 patients at nine U.S. centers confirmed these findings in a more diverse, heavily pretreated population. The overall response rate was 70 percent and the major response rate was 63 percent, with a median progression-free survival of about 28 months.²³ One caveat from the phase II trial: patients with truly refractory disease (meaning no response to their most recent therapy) fared worse, with a major response rate of only 50 percent, compared with 95 percent in those whose disease had simply relapsed after a prior response.²⁴

Prognosis and How Doctors Estimate Risk

Survival with WM varies enormously depending on age, blood markers, and disease burden. The original International Prognostic Scoring System for WM (IPSSWM), based on 587 patients, identified five risk factors: age over 65, hemoglobin at or below 11.5 g/dL, low platelets, elevated beta-2 microglobulin, and a high IgM level. Patients were split into low, intermediate, and high risk, with five-year survival rates of about 87, 68, and 36 percent respectively.²⁵

As treatments improved, a revised version was developed using a cohort of over 490 patients treated in the chemoimmunotherapy era. The revised system uses age (broken into three tiers rather than a single cutoff), beta-2 microglobulin, serum albumin, and LDH to sort patients into five risk groups. Ten-year survival ranged from 84 percent in the very-low-risk group down to 9 percent in the very-high-risk group.²⁶ These scoring systems help doctors and patients set expectations, though they were developed before BTK inhibitors became standard, so outcomes today may be somewhat better than the numbers suggest.

Transformation to Aggressive Lymphoma

A small fraction of LPL/WM cases undergo histological transformation, where the indolent cancer changes into an aggressive large-cell lymphoma. This is one of the most feared complications. A French multi-center study of 77 transformed cases found a median overall survival of only 16 months after transformation, and patients who had a longer interval (more than five years) between the original WM diagnosis and transformation paradoxically fared worse.²⁷

A prognostic index for transformed WM (the tWIPI) was subsequently developed. It uses three factors: elevated LDH, low platelet count, and whether the patient had been treated for WM before transformation. The two-year survival for low-risk patients (none or one of these factors) was 81 percent, while high-risk patients (all three factors) had a two-year survival of just 21 percent.²⁸ Transformation calls for aggressive treatment, often using regimens designed for diffuse large B-cell lymphoma rather than the gentler approaches used for indolent WM.

CAR T-Cell Therapy in LPL and Transformed Disease

Chimeric antigen receptor (CAR) T-cell therapy, where a patient’s own immune cells are engineered to attack the cancer, is being explored in WM. An early report described three WM patients treated with CD19-targeting CAR T cells. All three responded, including one who achieved a complete response with no detectable residual disease, though all eventually relapsed between 3 and 26 months later. Treatment was well tolerated, with no severe cytokine release syndrome or neurotoxicity.²⁹

The most encouraging results come from transformed WM, where the disease behaves aggressively and options are limited. A collaborative study of 22 patients with transformed WM/LPL treated with CAR T cells reported a best overall response rate of 95 percent and a complete response rate of 82 percent. At one year, roughly 70 percent of patients remained progression-free and 84 percent were alive. Toxicities were manageable, though blood count suppression was common and severe in many patients.³⁰ These numbers are striking for a disease where median survival after transformation had historically been measured in months rather than years. CAR T is not yet standard for WM, but for patients with transformed disease who have run out of other options, it represents a real advance.