NEW YORK CITY—An uncommon disease representing just 3% of all monoclonal gammopathies, Waldenström's macroglobulinemia (WM) may be difficult to manage in patients due to its sheer rarity and physicians' unfamiliarity with the malignancy. So said Asher Chanan-Khan, MD, Associate Professor and Attending Physician in the Division of Lymphoma/Myeloma in the Department of Medicine at Roswell Park Cancer Institute, speaking here at the National Comprehensive Cancer Network's 5th Annual Congress on Hematologic Malignancies.
“It is a very rare disease of five cases per one million, with approximately 1,500 new cases diagnosed each year in the US. This number is so low that it is very hard to do randomized trials with survival outcomes in these patients,” said Dr. Chanan-Khan, who is also Assistant Professor of Medicine at the State University of New York at Buffalo.
“This field is very early, because the number of patients who are available to investigate is very few, but now there is a very concerted effort across the globe to study this disease and make new headways defining new parameters for response, new categories, new symptoms, and new stages of the disease which are now starting to be implemented.”
A strong familial disposition to lymphoproliferative disorders may play a role in the development of Waldenström's. “We don't necessarily know what gene is involved, but there does seem to be this association,” he said.
The most common physical symptoms are cytopenias, fatigue, hepatosplenomegaly and lymphadenopathy, cryoglobulinemia, amyloidosis, and constitutional symptoms such as fever, night sweats, and weight loss. Hyperviscosty is another important feature, occurring when IGM, a large protein molecule produced by the disease, sticks together.
A characteristic cytogenetic finding using fluorescence in situ hybridization is deletion of chromosome 6 at q21, noted in one out of every two cases.
The incidence of these symptoms varies from patient to patient, Dr. Chanan-Khan said. “When you do see a patient with monoclonal gammopathy, especially with the IGM type, I recommend that you have a much more detailed neurological exam, because some patients will demonstrate some degree of peripheral neuropathy.”
The Waldenström consortium has tried to identify subcategories of the disease based on clinical characteristics in order to aid in diagnosis:
* IgM MGUS: Serum IgM less than 3 g/dL, less than 10% bone marrow lymphoplasmacytic infiltration, and no symptoms and/or physical findings.
* Smoldering/Indolent Waldenström's macroglobulinemia: Serum IgM of 3 g/dL or more, bone marrow lymphoplasmacytic infiltration of 10% or more, and no symptoms and/or physical findings.
* Waldenström's macroglobulinemia: Serum IgM of any concentration, greater than 10% bone marrow lymphoplasmacytic infiltration, symptoms and/or physical findings, and deletion of chromosome 6 at q21.
“The consortium has been able to do a number of important prospective clinical trials in Waldenström's that would be impossible to do in a single center,” noted Andrew Zelenetz, MD, Chair of the NCCN Congress and Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, in an interview following the presentation.
“Because it is a group of investigators who have a specific interest in Waldenström's, it's even in some ways more effective than a cooperative group for a rare disease because this is a self-selected group of people who are truly interested in the disease and therefore they get trials done faster so that we can get answers.”
An international prognostic staging system was also developed for WM, identifying five factors for determining low-, interim-, or high-risk disease: age older than 65, hemoglobin less than 11.5 g/dL, platelet count less than 100 × 109/L, β2 microglobulin greater than 3 mg/L, and an IgM level less than 7 g/dL.
The classifications directly translate into patient outcomes, Dr. Chanan-Khan noted. “If you have two of these characteristics, your survival is significantly compromised at five years, but if you have low-risk disease, which is one or no characteristics, survival at five years is approaching 90%.”
Overall, the median survival of WM patients ranges from five to 10 years, but only 10% of patients are alive after 15 years of follow up.
“It is very hard to study this disease and there aren't very many models available,” Dr. Chanan-Kahn said, adding that he and his colleagues are currently working on developing diagnostic models at their institution. He also noted that the Lymphoma and Leukemia Society has successfully been able to engage various investigators across the country to develop a program that would allow preclinical model development of the malignancy.
Single vs Combination Therapy
The current stance regarding treatment of IgM MGUS patients is that they should be monitored only until symptoms become present, whereas plasmapheresis remains the standard practice for addressing symptomatic hyperviscosity.
“When I address viscosity, I don't look at the viscosity number. It is the symptoms of the patient that define whether or not you should start plasmapheresis,” Dr. Chanan-Khan said.
Rituximab has demonstrated efficacy in WM, playing a similar role as in indolent lymphomas due to its anti- cd20 monoclonal antibody effect. Ofatumumab is also demonstrating responses in an ongoing clinical trial that will answer the question of whether the agent will also be an important therapy to use in these patients.
An important thing to remember, though, he said, is that none of the patients have had complete responses (CRs).
“In contrast to the situation with multiple myeloma or lymphoma, CR has not had a major impact in WM. We actually don't know whether CR means anything or if we can just control the disease for a very long time. Those studies are hard to do, but hopefully some day we will get that question answered.”
Of equal significance is the flare reaction seen in approximately one out of every two patients treated with rituximab, Dr. Zelenetz said.
“In general, most patients will respond, but early on in the treatment it's very common to see a rise in the IGM level, and this paradoxical rise can lead to significant symptoms related to Waldenström's like viscosity and neuropathy. If you are unaware of this and not looking for it, you can miss something that can potentially harm your patients.”
For patients in whom flare is a significant concern or who already have hyperviscosity syndrome, bortezomib has been able to show rapid response in controlling the disease, although a precaution is that it tends to induce neuropathy on its own. Chlorambucil has also shown promise, but is limited in that it cannot be used in transplant candidates and has a longer duration of response.
Combination therapy is another viable route. The combined regimen of bortezomib, dexamethasone, and rituximab demonstrated a 96% overall response rate with a time to response of just one month in a clinical trial conducted by the Waldenström's Macroglobulinemia Clinical Trials Group. Rituximab-related flare was seen in only 9% of patients. In another trial of 26 patients treated with bortezomib and rituximab, the overall response rate was 88%.
In terms of deciding whether to use monotherapy or a combined regimen, Dr. Chanan-Khan said that there are no randomized trials to say that one is better than the other: “You have to use your own clinical judgment to determine which is best for your patients or which path you're obligated to take—to control disease immediately with a multi-drug regimen or if you have time to induce one at a time.”
In terms of relapse, Dr. Chanan-Kahn, said the answer is common sense: If there is a history of more than two years of response with a particular agent, then you can use the same strategy again.
“I have a patient I've followed for six or seven years and have never given anything but rituximab. Every time symptoms start to come back and neuropathy happens, I go back and give a couple of cycles of rituximab. The patient then goes back into a stable state, and then I don't see him again until the symptoms come back.”
Several novel therapeutic agents are showing promise in Waldenström's, including sildenafil (overall response rate of 17%), the combined regimen of lenalidomide and rituximab (67%), and even more so R-CHOP (94%), and bendamustine and rituximab (94%).
Several clinical trials are also under way or planned such as protein kinase C inhibitors like enzastaurin, and the proteasome inhibitor carlfilzomib.
“There is much less neuropathy here and if bortezomib works, carlfilzomib should show similar efficacy because the target remains the same,” Dr. Chanan-Khan said.
The largest cohort study of WM patients treated with ofatumumab is coming to a close and there is also potential for HDAC inhibitors like panabinostat or a combined regimen of everolimus, rituximab, and/or bortezomib.
“There are a number of agents that are active, but how to apply them, and how to use them, and what the risks are is something that if you don't do it frequently, you're not going to know,” Dr. Zelenetz said.
When possible, patients should be referred to a center with expertise in treating Waldenström's, he added. “That's not going to be true for all patients—not everyone is going to have access to specialized experts, and that is in fact why we have guidelines for these patients.”
In the face of limited research data, personal experience is clinicians' best guide for managing the disease, Dr. Chanan-Kahn said.
“What we are left with in terms of conclusions as to what to do next for this very rare disease is that these patients have to make us pause and think strategically based on the amount of disease and the associated symptoms.”