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1. nature
2. blood cancer journal
3. current treatment algorithm
4. article
Waldenström macroglobulinemia treatment algorithm 2018
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* Current Treatment Algorithm
* Open Access
* Published: 01 May 2018
WALDENSTRÖM MACROGLOBULINEMIA TREATMENT ALGORITHM 2018
* Morie A. Gertz1
Blood Cancer Journal volume 8, Article number: 40 (2018) Cite this article
* 12k Accesses
* 9 Citations
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A Correction to this article was published on 25 June 2019
This article has been updated
ABSTRACT
Waldenström macroglobulinemia is often an indolent disorder, and many patients
are candidates for observation with careful monitoring. For symptomatic
patients, one must distinguish between those patients whose symptoms are related
to immunologic manifestations associated with the IgM monoclonal protein and
those that have symptoms related to progressive marrow and nodal infiltration
with lymphoplasmacytic lymphoma. In Waldenström macroglobulinemia, the driver
for therapy in the majority of patients is progressive anemia, secondary to bone
marrow replacement by lymphoplasmacytic lymphoma. Recent introduction of MYD88
mutational analysis has been very useful for diagnostic purposes but is unclear
what effect it might have on the prognosis or response rate to therapy. An
algorithm is provided on the management of asymptomatic individuals and the
sequence used for chemotherapeutic intervention of symptomatic patients.
Download PDF
PATIENT 1
A 67-year-old male was first seen at Mayo Clinic in July of 2005. At that time,
he was found to have a hemoglobin of 15.2 g/dL associated with an M spike of
1.8 g/dL and a quantitative IgM of 2610 mg/dL. His bone marrow showed a B cell
chronic lymphoproliferative disorder with plasmacytic differentiation involving
15 to 20% of the bone marrow. Because he was asymptomatic, observation was
elected, and he was monitored on an annual basis. By September of 2016, his M
spike had increased to 4.5 g/dL, his IgM was 7270 mg/dL without symptoms, and
his hemoglobin declined to 11.3 g/dL without symptoms. Observation was continued
through July of 2017, at which time his hemoglobin had fallen to 9.3 g/dL with
his M spike and IgM unchanged from September 2016. A repeat bone marrow showed
90% involvement with lymphoplasmacytic lymphoma. The patient began rituximab and
bendamustine (now age 79) and had an excellent response. Comment: This patient
is not unusual and was observed for a total of 12 years before sufficient anemia
developed to warrant therapeutic intervention. Despite having an IgM level
>5000 mg/dL from August 2013 through July of 2017, the patient never developed
symptoms of hyperviscosity, fatigue, or lymphadenopathy.
INTRODUCTION
IgM monoclonal gammopathy represents 18% of all monoclonal proteins seen at Mayo
Clinic1, Waldenström macroglobulinemia represents only 2.5% of all M proteins
seen at Mayo Clinic. This represents between 1 and 2% of non-Hodgkin lymphoma
with an incidence of ~4 per million per year, making it approximately one-tenth
as common as multiple myeloma. The median age at diagnosis of Waldenström
macroglobulinemia is 73 years. It is familial in 4.3% of patients2. It appears
to be twice as common in men as in women and more than twice as common in
Caucasians as blacks. Because of the indolent nature of Waldenström and the
advanced age of patients, only approximately half of patients actually succumb
to Waldenström macroglobulinemia, and the remainder die of unrelated second
cancers and cardiovascular causes of death3. The fact that only half of patients
with the disorder will die of Waldenström is important in selecting therapies
that are unlikely to produce long-term toxicities and take into account the
comorbidities of this elderly population.
CLASSIFICATION OF IGM RELATED DISORDERS
Patients are usually divided into four groups:
1. (1)
Patients defined as having IgM MGUS have an IgM level <3 g/dL and a bone
marrow infiltration with lymphoplasmacytic lymphoma of <10%4.
2. (2)
Patients with smoldering Waldenström macroglobulinemia either have >10%
lymphoplasmacytic lymphoma in the bone marrow or an M spike >3 g/dL and, by
definition, cannot have any symptoms of tumor infiltration or IgM-mediated
symptoms5.
3. (3)
The third group is those patients whose symptoms are directly related to
immunologic effects of the IgM monoclonal protein and not to the tumor mass
of lymphoplasmacytic lymphoma. These include patients with type 2 mixed
cryoglobulinemia6, cold agglutinin hemolytic disease7, peripheral neuropathy
associated with IgM monoclonal gammopathy8,9, IgM amyloidosis10, and IgM
POEMS syndrome11.
4. (4)
The final group is those patients who have symptoms that are due to marrow,
liver, spleen, and lymph nodal infiltration with lymphoplasmacytic lymphoma
causing anemia, hyperviscosity, hepatosplenomegaly, and significant
lymphadenopathy, and these patients are defined as Waldenström
macroglobulinemia.
The most important prognostic factor predicting survival in patients with
Waldenström macroglobulinemia from SEER data is age. Patients under the age of
70 have a median survival in excess of 10 years; those 70 to 79, ~7 seven years;
and those 80 or older, ~4 years3. The MYD88 mutation has a prevalence in
Waldenström macroglobulinemia of anywhere from 87 to 100%12. In a Mayo Clinic
study of 557 patients, 79% had MYD88 positivity13. Those that expressed MYD88
mutations did not demonstrate differences in median overall survival, time to
next therapy from frontline treatment, or median time to progression to active
disease in those with smoldering Waldenström macroglobulinemia. There was a
significantly higher frequency of transformation to large-cell lymphoma and for
the development of myelodysplastic syndrome in the MYD88 wild-type cohort (16%
versus 4%). Others have found a survival difference between those with mutant
and those with wild-type MYD88. The estimated 10-year survival was 73% (95%
confidence interval [CI] 52–86%) for MYD88WT versus 90% (95% CI 82–95%) for
mutated MYD88MUT14,15. The MYD88 mutation failed to distinguish Waldenström
macroglobulinemia from IgM MGUS, and this distinction remains dependent on
clinical criteria16. The international staging system for Waldenström
macroglobulinemia includes five features: age >65, hemoglobin <11.5 g/dL,
platelets <100,000 per mcL, β2 microglobulin >3 mg/dL, and an IgM concentration
>717.
IGM MGUS
Most patients who have an IgM MGUS are found incidentally because of an
elevation in serum total protein on a multi-channel chemical analyzer test.
These patients have no fatigue. Imaging, if performed, will show only modest
enlargement of lymph nodes. These patients have no oronasal bleeding
(hyperviscosity), and they have no symptoms consistent with amyloidosis (Fig.
1). These patients do not require treatment. They should begin a routine
monitoring schedule for changes in hemoglobin, IgM level, and M spike. Among
patients with IgM MGUS, the presence of two adverse risk factors (abnormal serum
free light chain ratio and a serum monoclonal protein level >1.5 g/dL) was
associated with a risk of progression at 20 years of 55% compared with 41% in
those who had one risk factor and 19% who had neither risk factor. Patients with
IgM MGUS require life-long monitoring for the development of Waldenström
macroglobulinemia18.
Fig. 1
Recommended approach to patients with IgM MGUS and patients with immunologic
disorders associated with an IgM monoclonal protein
Full size image
PATIENT 2
A 67-year-old male was referred with an IgM Κ monoclonal protein. His
quantitative IgM was 376 mg/dL, which had been followed for 17 years, rising to
1330 mg/dL. His hemoglobin had fallen to 9.6 g/dL. Chemotherapy for Waldenström
was recommended. A bone marrow showed 15–20% lymphoplasmacytic lymphoma. His
hemoglobin was 10.2 g/dL. He had a reticulocyte count of 3% with a haptoglobin
that was unmeasurable. Total bilirubin was 1.6 mg/dL, with a direct bilirubin of
0.3 mg/dL. The direct antiglobulin test was 2+ positive, anti-complement was 2+
positive, and a cold agglutinin titer was 1:131,072. Observation was
recommended. Three years later, he developed acute bronchitis while on a cruise
ship. His hemoglobin fell to 6.5 g/dL, and he received rituximab and steroids.
Comment: This patient was felt to have active Waldenström, but anemia below 10 g
with only 20% marrow infiltration is unusual. This patient turned out to have
cold agglutinin disease that was responsive to rituximab.
IMMUNOLOGIC DISORDERS ASSOCIATED WITH MONOCLONAL IGM PROTEINS
There are a number of disorders where symptoms develop not due to tumor mass but
due to unusual immunologic properties of the IgM protein. The most common among
these would be immunoglobulin light chain amyloidosis, in which 5% have an IgM
monoclonal protein19. IgM amyloidosis results from intrinsic properties of the
immunoglobulin, leading it to misfold, rendering it insoluble, and then
depositing in tissues. Patients with IgM amyloid have a higher prevalence of
pulmonary involvement and peripheral nerve involvement and a lower incidence of
cardiac involvement20.
Cold agglutinin hemolytic anemia results from the ability of the IgM to fix
complement to the red cell surface. Eventually, C3b fixes to the red cell
surface, and these sensitized red cells are removed by the liver and spleen,
resulting in chronic extravascular hemolysis21. Type 2 (mixed) cryoglobulinemia
results when an IgM monoclonal protein binds to polyclonal IgG and acts as an
immune complex that deposits in the endothelium of vessels22. There is a high
association with hepatitis virus infection23,24. There are patients with POEMS
syndrome who can develop sclerotic lesions or Castleman disease with an IgM
monoclonal protein25. These patients present with peripheral neuropathy,
hepatosplenomegaly, and endocrinopathy25.
IgM-associated neuropathy is a common problem in practice. In most instances,
the pathophysiology involves an IgM monoclonal protein that binds to the myelin
sheath and causes demyelination and widened myelin lamellae26. The IgM has
antiganglioside antibody activity in 35% of patients; 40–50% have an IgM that
binds to myelin-associated glycoprotein. Pathogenesis is a direct effect of M
proteins on the peripheral nerve, leading to demyelination27.
These syndromes are unique insofar as significant reduction in the IgM protein
may have little or no impact on the clinical manifestations of the disease. In
Waldenström macroglobulinemia, a 50% reduction in the IgM protein can result in
dramatic reversal of anemia, lymphadenopathy, and hyperviscosity28. In
cryoglobulinemia, cold agglutinin disease, and IgM neuropathy, a 50% reduction
in the M protein may not result in clear-cut benefit. Moreover, the optimal
reduction of the IgM protein is unknown. The endpoint of peripheral neuropathy
is very difficult to evaluate. Even when the IgM is suppressed, the best that
can be expected may be stabilization of the neuropathy. Long-term damage to the
myelin sheath can result in irreversible axonal damage8,29. Nerve regrowth and
recovery may not be a realistic endpoint and it is, thereby, difficult to
distinguish therapeutic failure from what may be stabilization of disease. In
most instances, a trial of rituximab is justified and has been reported to
provide benefit in patients with IgM-associated neuropathy8,29, cold agglutinin
hemolysis30, and cryoglobulinemia31.
THERAPY OF WALDENSTRÖM MACROGLOBULINEMIA
In Waldenström macroglobulinemia, the lack of comparative trials amongst
regimens makes it difficult to provide high-quality recommendations based on
level A evidence. The long survival and age range of affected individuals
requires long-term follow-up to assess full therapeutic benefit. A significant
proportion of patients with Waldenström macroglobulinemia die of large-cell
transformation32 or myelodysplastic syndrome33,34, which needs to be considered
when choosing regimens, particularly for younger patients. Because of the low
quality of evidence, much of the therapy reported in this paper relies heavily
on long-term experience and is largely opinion-based. Rituximab alone as a
single agent has consistently been shown to be an inferior regimen in
meta-analyses with PR rates of <50% compared to combination chemotherapy
regimens where response rates are in the 80% range35. Therefore, for patients
where therapy is indicated due to progressive marrow infiltration or for
symptoms for hyperviscosity, multi-agent chemotherapy is to be preferred over
single-agent rituximab.
Hyperviscosity is an uncommon manifestation of Waldenström macroglobulinemia.
The most common presentation is nasal or gingival bleeding36. Because of the
risk of retinal and central nervous system hemorrhage, emergency therapy is
required in conjunction with immediate initiation of systemic chemotherapy. The
viscosity level should always be measured in patients with suspect
hyperviscosity syndrome37. The therapy of choice is plasma exchange. A single
plasma exchange can normalize the viscosity and allow chemotherapy to
successfully reduce the tumor mass38. Single-agent rituximab is known to
precipitate hyperviscosity and should either be omitted from the first cycle of
therapy in at-risk patients or combined with an agent that reduces the risk of
flare, such as bendamustine or bortezomib39.
One of the earliest combination chemotherapy regimens used with rituximab was
dexamethasone and cyclophosphamide40. An updated report on 72 patients with
newly diagnosed Waldenström gave an overall response rate of 83%, a >PR of 75%,
a three-year progression-free survival of 45%, and a median time to next therapy
of 51 months. The rate of myelodysplasia was 3%, diffuse large B-cell lymphoma
10%, and the median overall survival was 95 months. This was a well-tolerated
regimen and the cyclophosphamide was given orally. In this trial at 100 months,
mortality due to Waldenström and unrelated to Waldenström was virtually
identical at ~20%. Moreover, there was no improvement in survival based on the
depth of response. Patients who achieved a VGPR or better had the same outcome
as patients who achieved a partial or minor response. It is imperative not to
judge the efficacy of therapy based on percentage reduction of IgM but on the
endpoint through which therapy was initiated, such as anemia or lymphadenopathy.
One of the few randomized phase 3 trials in Waldenstrom was conducted in Europe.
Unfortunately neither arm was rituximab-containing, which is standard of care in
the United States. The trial compared chlorambucil, which is now used
infrequently, versus oral fludarabine41. In this trial, fludarabine was superior
to chlorambucil in terms of progression-free and overall survival. In addition,
the frequency of secondary malignancies was substantially lower in the
fludarabine arm, and the cumulative incidence of high-grade lymphoma at 100
months was <10%.
For younger patients with Waldenström macroglobulinemia,
fludarabine-cyclophosphamide-rituximab, as used in chronic lymphatic leukemia,
has been reported to produce an overall response rate of 79%, with an event-free
survival of responders of 48 months42. In a subsequent trial of 40 patients, 25
of whom were untreated, with a median age of 61 years, the overall response rate
was 85.4%, with a >PR rate of 77%, and median time to best response of 10.8
months. At 48 months, the progression-free survival was 67%; at 3 years, the
overall survival was 90%43. There were two patients who developed myelodysplasia
and three patients who developed diffuse large-cell lymphoma. Prolonged
cytopenia was a common problem44. Other purine nucleoside analogs, including
cladribine and pentostatin, have both been used in the management of Waldenström
in combination with rituximab with very similar results. Cladribine results in
an overall response rate of 88%, with no difference in risk categories45.
Pentostatin produced a two-year, progression-free survival of 83.6%46.
Proteasome inhibitors are highly active in Waldenström macroglobulinemia.
Bortezomib-rituximab-dexamethasone with bortezomib given in a 1, 4, 8, 11
schedule IV with rituximab and dexamethasone given in cycles 2 and 5 produced a
response rate of 85% and an IgM flare in 11%47,48. Unfortunately, 46% of
patients developed peripheral neuropathy, and it appears that patients with IgM
monoclonal gammopathies have a predisposition to peripheral neuropathy, as
screening EMG in this population demonstrates latent neuropathy in a high
proportion of patients49. Progression-free survival with this regimen is ~40
months, with a median survival in excess of 5 years. A combination of rituximab
cyclophosphamide-bortezomib-dexamethasone has been reported. Among 15 patients,
only one patient failed to respond, with progressive disease, and six had a
minor response (25–50% reduction in the level of the M protein). The risk of
progression appears to be lower in patients treated with bendamustine-rituximab
or bortezomib-dexamethasone-rituximab when compared to
cyclophosphamide-dexamethasone-rituximab50,51,52.
A non-neurotoxic epoxyketone proteasome inhibitor, carfilzomib, has also been
reported in the treatment of Waldenström macroglobulinemia. Carfilzomib,
starting at 20 mg/m2 and escalating to 36 mg/m2, was given days 1, 2, 8, 9 of
each cycle, rituximab and dexamethasone on days 2 and 9 of each cycle, and a
maintenance treatment every 8 weeks for eight cycles was given. The overall
response rate in 31 patients was 87%; 36% achieved a ≥VGPR with a median time to
response of 2.1 months and no peripheral neuropathy >grade 1. This is a useful
alternative for the management of Waldenström53. This combination has also been
used for the management of relapsed disease54.
The mTOR inhibitor, everolimus, active in the treatment of renal cell cancer,
has been used to treat Waldenström macroglobulinemia. In one trial, 60 patients
were treated that were relapsed or refractory, with an overall response rate of
50% and a clinical benefit rate of 73%. The median time to response for patients
who achieved a PR was 2 months. The median progression-free survival was 21%.
Unfortunately, grade 3 or higher toxicities were observed in 67% of patients55.
Everolimus has also been combined with bortezomib and rituximab in a phase 1–2
trial where six cycles were given, followed by maintenance everolimus; 57% of
patients had prior bortezomib, 98% prior rituximab, yet the overall survival
rate at 1 year was 89%, the >PR rate was 53%, and the median progression-free
survival was 21 months56.
For younger patients with Waldenström macroglobulinemia, autologous stem cell
transplant and rarely allogeneic transplantation can be highly efficacious. As
indicated in Fig. 2, younger patients at Mayo Clinic have stem cells collected
in first plateau to be used at the time of first progression. A multi-center
study from the European Bone Marrow Transplant Registry has demonstrated that in
patients with chemosensitive disease, 75% achieve a response, and
progression-free survival exceeds 4 years56. When BEAM is used for conditioning
in Waldenström macroglobulinemia, the survival at 5 years was 71%, in 25
reported patients57.
Fig. 2
Approach to the therapy of Waldenström macroglobulinemia
Full size image
The East German Lymphoma Study Group conducted a randomized trial of R-CHOP
versus bendamustine-rituximab in patients with low-grade lymphoma. A subset
analysis demonstrated 41 patients among the entire group had Waldenström, 22
received R-bendamustine, and 19 received R-CHOP. In both groups, the response
rate was 95%, but the median progression-free survival was 36 months for R-CHOP
versus not reached for bendamustine and rituximab. At the time this was
reported, there were four relapses in the bendamustine group and 11 relapses in
the R-CHOP group. In addition, toxicity was lower in the bendamustine group58.
This led to the adoption of R-bendamustine as the preferred first-line therapy
in the treatment of Waldenström macroglobulinemia. A PFS hazard ratio of
bendamustine-rituximab versus R-CHOP was 0.33. Median progression-free survival
for rituximab-bendamustine was 69.5 months compared to 28.1 for R-CHOP. A trial
of bendamustine-rituximab in relapsed refractory Waldenström macroglobulinemia
was reported in 71 patients, with a median age of 72. The bendamustine dose
ranged from 50 to 90 mg/m2 on two consecutive days every 28. The overall
response rate was 80%, the >PR rate was 75%, 13% of patients had grade 3–4
neutropenia, and the progression-free survival at 36 months was 60%59. Because
the primary toxicity of bendamustine is long-term myelosuppression, it is often
wise, particularly in elderly patients, to scale back the first cycle to 50%
dosing to ensure that excessive myelosuppression does not occur.
Lenalidomide is active in Waldenström macroglobulinemia but can aggravate the
anemia60. In a phase 1–2 trial, the maximum tolerated dose was 15 mg/day 21 days
out of 28 and, in a heavily pretreated population, produced an overall response
rate of 29%, with a time to progression of 16 months61. When lenalidomide was
combined with rituximab-cyclophosphamide-dexamethasone, response rate was 80%,
median progression-free survival was 25 months, overall survival at 2 years was
86%, and >grade 2 anemia was seen in 40%62.
BTK INHIBITION
Ibrutinib is the only drug that is FDA approved for the treatment of Waldenström
macroglobulinemia, and it is approved for administration both in treated and
untreated patients63. In the first report of patients who had one prior
treatment, planned therapy was 420 mg of oral ibrutinib daily for 2 years. The
median time to response was 4 weeks. The median IgM fell from 3610 to 1340, and
the hemoglobin rose from 10.5 to 12.6 g/dL. The two-year progression-free
survival was 69%64. However, ibrutinib must be given indefinitely65,66 and can
cause diarrhea, thrombocytopenia, rash, joint pain, atypical bleeding, and
occasional pneumonia67. Atrial fibrillation occurs in 10.6% of patients68,69.
Adverse events overall occurred in 94% of patients. In an open-label sub-study
that was multi-center and phase 3, 31 patients, all of whom were rituximab
refractory with a median age of 67, were enrolled. Overall response rate was
71%, progression-free survival at 18 months was 86%, and overall survival was
97%70. Hemoglobin rose from 10.3 to 11.4 g/dL and, at 49 weeks, was 12.7 g/dL.
There was improved quality of life, and serious adverse events were reported in
32% of patients. The overall response rate in this trial, including minor
responders, was 100%.
Current trials underway include acalabrutinib, a second-generation BTK inhibitor
that appears to be more potent and selective than ibrutinib (NCT02180724). It
appears to lack some of the off-target effects on epidermal growth factor
receptors and the ITK and TEC family kinases. Acalabrutinib is used now for
second-line treatment of mantle cell lymphoma, and a trial of acalabrutinib in
combination with pembrolizumab has been launched (NCT02362035). There is a phase
3 randomized, open-label, multi-center study comparing the safety and efficacy
of the BTK inhibitor, BGB-3111, and ibrutinib (NCT03053440); 75 subjects with
MYD88-positive Waldenström macroglobulinemia will receive ibrutinib, and the
other arm will receive BGB-3111 until progressive disease.
A trial of 30 patients who were newly diagnosed and received ibrutinib was
recently reported. The major response rate was 80% with no difference between
patients with mild-type or mutated CXCR4. Atrial arrhythmias were seen in 10%71.
Venetoclax in a trial of relapsed-refractory non-Hodgkin lymphoma was reported.
Four of the patients had Waldenström macroglobulinemia72. Toxicity included
diarrhea, fatigue, nausea, and vomiting. BCL2 was expressed in all three
patients measured. A partial response or better was seen in all four patients,
with one patient still on therapy at 42 months. The PI3kδ inhibitor, idelalisib,
was investigated in Waldenström, but the trial was closed due to
hepatotoxicity73. It is for these reasons, illustrated in Fig. 2, that the
treatment of choice recommended for first line therapy of Waldenström is
rituximab with bendamustine. For patients who respond to this regimen and have
response duration in excess of 36 months, this regimen can be repeated. Younger
patients at Mayo Clinic have their stem cells collected and cryopreserved for
later use. Patients who are primary failures to R-bendamustine or who relapse
within 3 years should be considered for a bortezomib-based regimen or ibrutinib.
Active third-line therapies in Waldenström macroglobulinemia will include
second-generation BTK inhibitors, purine nucleoside analogs, everolimus, and
lenalidomide.
CONCLUSION
It is important to ensure that patients with an IgM monoclonal protein need
treatment. If there is doubt, it would be wise to recheck the patient in 1–2
months by repeating the serum protein electrophoresis, IgM, and CBC to see if
there is evidence of disease progression. Asymptomatic patients can often be
followed for many years. It is important to distinguish patients whose symptoms
are related to the IgM protein and those whose symptoms are due to progressive
lymphoplasmacytic lymphoma, where the IgM monoclonal protein is simply a
surrogate for disease activity. Rituximab-bendamustine should be considered
first-line therapy. There are multiple choices for treatment at relapse.
CHANGE HISTORY
* 25 JUNE 2019
An amendment to this paper has been published and can be accessed via a link
at the top of the paper.
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CAS Article Google Scholar
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cases of mixed cryoglobulinemia: a 6-year observational study. Am. J.
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CAS Article Google Scholar
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cases from the French Innovative Leukemia Organization (FILO). Br. J.
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multiple myeloma, Waldenstrom macroglobulinemia and monoclonal gammopathy
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PubMed Google Scholar
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AUTHOR INFORMATION
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1. Division of Hematology, Mayo Clinic, 200 First Street, SW, Rochester, MN,
55905, USA
Morie A. Gertz
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Gertz, M.A. Waldenström macroglobulinemia treatment algorithm 2018. Blood Cancer
J. 8, 40 (2018). https://doi.org/10.1038/s41408-018-0076-5
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* Received: 15 February 2018
* Revised: 01 March 2018
* Accepted: 08 March 2018
* Published: 01 May 2018
* DOI: https://doi.org/10.1038/s41408-018-0076-5
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CURRENT TREATMENT ALGORITHMS
* Sections
* Figures
* References
* Abstract
* Patient 1
* Introduction
* Classification of IgM related disorders
* IgM MGUS
* Patient 2
* Immunologic disorders associated with monoclonal IgM proteins
* Therapy of waldenström macroglobulinemia
* BTK inhibition
* Conclusion
* Change history
* References
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CAS Article Google Scholar
14. Treon, S. P. et al. MYD88 wild-type Waldenstrom macroglobulinaemia:
differential diagnosis, risk of histological transformation, and overall
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CAS Article Google Scholar
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macroglobulinemia has distinct clinical and pathological features as
compared to its mutation negative counterpart. Leuk. Lymphoma 56, 420–425
(2015).
CAS Article Google Scholar
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not restricted to, Waldenstrom’s macroglobulinemia. Leukemia 27, 1722–1728
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CAS Article Google Scholar
17. Kastritis, E. et al. Validation of the International Prognostic Scoring
System (IPSS) for Waldenstrom’s macroglobulinemia (WM) and the importance
of serum lactate dehydrogenase (LDH). Leuk. Res. 34, 1340–1343 (2010).
CAS Article Google Scholar
18. Kyle, R. A. et al. Long-term follow-up of monoclonal gammopathy of
undetermined significance. N. Engl. J. Med. 378, 241–249 (2018).
CAS Article Google Scholar
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single center retrospective study of 377 patients. Leuk. Res. 46, 85–88
(2016).
Article Google Scholar
20. Sachchithanantham, S. et al. European collaborative study defining clinical
profile outcomes and novel prognostic criteria in monoclonal immunoglobulin
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CAS Article Google Scholar
21. Swiecicki, P. L., Hegerova, L. T. & Gertz, M. A. Cold agglutinin disease.
Blood 122, 1114–1121 (2013).
CAS Article Google Scholar
22. Galli, M. et al. HCV-unrelated cryoglobulinaemic vasculitis: the results of
a prospective observational study by the Italian Group for the Study of
Cryoglobulinaemias (GISC). Clin. Exp. Rheumatol. 35(Suppl 103(1)), 67–76
(2017).
PubMed Google Scholar
23. Mazzaro, C. et al. Hepatitis B virus related cryoglobulinemic vasculitis: a
multicentre open label study from the Gruppo Italiano di Studio delle
Crioglobulinemie–GISC. Dig. Liver. Dis. 48, 780–784 (2016).
Article Google Scholar
24. Gill, K., Ghazinian, H., Manch, R. & Gish, R. Hepatitis C virus as a
systemic disease: reaching beyond the liver. Hepatol. Int. 10, 415–423
(2016).
Article Google Scholar
25. Dispenzieri, A., Kourelis, T. & Buadi, F. POEMS syndrome: diagnosis and
investigative work-up. Hematol. Oncol. Clin. North. Am. 32, 119–139 (2018).
Article Google Scholar
26. Franciotta, D. et al. Diagnostics of anti-MAG antibody polyneuropathy.
Neurol. Sci. 38(Suppl 2), 249–252 (2017).
Article Google Scholar
27. D’Sa, S. et al. Investigation and management of IgM and
Waldenstrom-associated peripheral neuropathies: recommendations from the
IWWM-8 consensus panel. Br. J. Haematol. 176, 728–742 (2017).
Article Google Scholar
28. Gertz, M. A. et al. Clinical value of minor responses after 4 doses of
rituximab in Waldenstrom macroglobulinaemia: a follow-up of the Eastern
Cooperative Oncology Group E3A98 trial. Br. J. Haematol. 147, 677–680
(2009).
CAS Article Google Scholar
29. Mauermann, M. L. Paraproteinemic neuropathies. Contin. (Minneap. Minn.). 20
(5 Peripheral Nervous System Disorders), 1307–1322 (2014).
Google Scholar
30. Reynaud, Q. et al. Efficacy and safety of rituximab in auto-immune
hemolytic anemia: a meta-analysis of 21 studies. Autoimmun. Rev. 14,
304–313 (2015).
CAS Article Google Scholar
31. Roccatello, D. et al. Improved (4 plus 2) rituximab protocol for severe
cases of mixed cryoglobulinemia: a 6-year observational study. Am. J.
Nephrol. 43, 251–260 (2016).
CAS Article Google Scholar
32. Durot, E. et al. Transformed Waldenstrom macroglobulinaemia: clinical
presentation and outcome. A multi-institutional retrospective study of 77
cases from the French Innovative Leukemia Organization (FILO). Br. J.
Haematol. 179, 439–448 (2017).
CAS Article Google Scholar
33. Castillo, J. J. & Gertz, M. A. Secondary malignancies in patients with
multiple myeloma, Waldenstrom macroglobulinemia and monoclonal gammopathy
of undetermined significance. Leuk. Lymphoma 58, 773–780 (2017).
CAS Article Google Scholar
34. Ricci, F., Tedeschi, A., Montillo, M. & Morra, E. Therapy-related myeloid
neoplasms in chronic lymphocytic leukemia and Waldenstrom’s
macroglobulinemia. Mediterr. J. Hematol. Infect. Dis. 3, e2011031 (2011).
Article Google Scholar
35. Santos-Lozano, A. et al. Response rate to the treatment of Waldenstrom
macroglobulinemia: a meta-analysis of the results of clinical trials. Crit.
Rev. Oncol. Hematol. 105, 118–126 (2016).
CAS Article Google Scholar
36. Kapoor, P. et al. Diagnosis and management of Waldenstrom
macroglobulinemia: Mayo Stratification Of Macroglobulinemia and
Risk-adapted Therapy (mSMART) Guidelines 2016. JAMA Oncol. 3, 1257–1265
(2017).
Article Google Scholar
37. Kwaan, H. C. Hyperviscosity in plasma cell dyscrasias. Clin. Hemorheol.
Microcirc. 55, 75–83 (2013).
PubMed Google Scholar
38. Stone, M. J. & Bogen, S. A. Evidence-based focused review of management of
hyperviscosity syndrome. Blood 119, 2205–2208 (2012).
CAS Article Google Scholar
39. Chen, C. et al. Bortezomib in relapsed or refractory Waldenstrom’s
macroglobulinemia. Clin. Lymphoma Myeloma 9, 74–76 (2009).
CAS Article Google Scholar
40. Kastritis, E. et al. Dexamethasone, rituximab, and cyclophosphamide as
primary treatment of Waldenstrom macroglobulinemia: final analysis of a
phase 2 study. Blood 126, 1392–1394 (2015).
Article Google Scholar
41. Leblond, V. et al. Results of a randomized trial of chlorambucil versus
fludarabine for patients with untreated Waldenstrom macroglobulinemia,
marginal zone lymphoma, or lymphoplasmacytic lymphoma. J. Clin. Oncol. 31,
301–307 (2013).
CAS Article Google Scholar
42. Tedeschi, A. et al. Fludarabine plus cyclophosphamide and rituximab in
Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to
be offered to patients with advanced disease. Cancer 118, 434–443 (2012).
CAS Article Google Scholar
43. Tedeschi, A. et al. Fludarabine, cyclophosphamide, and rituximab in salvage
therapy of Waldenstrom’s macroglobulinemia. Clin. Lymphoma Myeloma Leuk.
13, 231–234 (2013).
CAS Article Google Scholar
44. Souchet, L. et al. Efficacy and long-term toxicity of the
rituximab-fludarabine-cyclophosphamide combination therapy in Waldenstrom’s
macroglobulinemia. Am. J. Hematol. 91, 782–786 (2016).
CAS Article Google Scholar
45. Laszlo, D. et al. Rituximab and subcutaneous 2-chloro-2’-deoxyadenosine as
therapy in untreated and relapsed Waldenstrom’s macroglobulinemia. Clin.
Lymphoma Myeloma Leuk. 11, 130–132 (2011).
CAS Article Google Scholar
46. Herth, I. et al. Pentostatin, cyclophosphamide and rituximab is a safe and
effective treatment in patients with Waldenstrom’s macroglobulinemia. Leuk.
Lymphoma 56, 97–102 (2015).
CAS Article Google Scholar
47. Gavriatopoulou, M. et al. BDR in newly diagnosed patients with WM: final
analysis of a phase 2 study after a minimum follow-up of 6 years. Blood
129, 456–459 (2017).
CAS Article Google Scholar
48. Treon, S. P. et al. Primary therapy of Waldenstrom macroglobulinemia with
bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J.
Clin. Oncol. 27, 3830–3835 (2009).
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