Keywords
Bortezomib - BDR regimen - rituximab - Waldenström macroglobulinemia
Introduction
Waldenström macroglobulinemia (WM) is an indolent B-cell neoplasm, which is characterized
by the accumulation of lymphoplasmacytic cells in bone marrow. It is a lymphoproliferative
disorder in which a monoclonal immunoglobulin M (IgM) protein is produced. It is a
rare disease with an incidence of ~1%–2% of all hematologic cancers.[1],[2]
The clinical manifestations of WM include cytopenias, lymphadenopathy, hepatosplenomegaly,
and neurologic symptoms and hyperviscosity.[3],[4] WM usually occurs in the elderly with a median age of 63 years at presentation.[1],[2] The disease has an overall survival of 5–10 years.[3],[4] With the available treatments, WM is an incurable disease, and the patients are
generally managed with risk-adapted methods. In this report, we present the clinicopathological
profile and response to therapy in patients with WM.
Methodology
In this retrospective study, the records of patients were searched to detect cases
of WM from a single tertiary care referral center in Eastern India. Six such cases
were detected in 26 months, from October 2014 to December 2016, and their clinical
manifestations, diagnostic challenges, response to treatment, and outcomes were analyzed.
The Second International Workshop on WM (IWWM-2) proposed diagnostic criteria were
used to establish the diagnosis, and further clinical, biochemical, hematological,
and radiological investigations were analyzed.[5] The International Prognostic Scoring System (IPSS) was used for risk stratification.
The IWWM-6 criteria[6] was used for clinical response assessment, which was done after every two cycles
with serum protein electrophoresis (SPEP) and by immunofixation after the disappearance
of M band on SPEP.
Results
Clinicopathological profile
There was a predominance of male gender (5/83.3%), and four patients (66.7%) were
≥65 years of age, whereas the remaining two patients were <65 years. Transfusion-dependent
anemia was the predominant presenting complaint, whereas two patients (33.3%) had
symptoms of hyperviscosity as the chief complaint [Table 1]. All the six patients had anemia, and none of them was positive for direct antiglobulin
test. Two patients had leukopenia and thrombocytopenia in addition to anemia. Two
patients had hepatomegaly, whereas none had lymphadenopathy.
Table 1
Clinicopathological profile of six cases
|
Clinicopathological parameters
|
Patient characteristics
|
Number of patients, n (%)
|
|
Age (years)
|
<65
|
2 (33.3)
|
|
≥65
|
4 (66.7)
|
|
Sex
|
Male
|
5 (83.3)
|
|
Female
|
1 (16.7)
|
|
Hemoglobin (g/L)
|
<115
|
6 (100)
|
|
≥115
|
0
|
|
Platelet count (×109/L)
|
≤100
|
2 (33.3)
|
|
≥100
|
4 (66.7)
|
|
Absolute neutrophil
|
≤1.5
|
2 (33.3)
|
|
count (×109/L)
|
>1.5
|
4 (66.7)
|
|
Organomegaly
|
Absent
|
4 (66.7)
|
|
Present
|
2 (33.3)
|
|
Constitutional
|
Present
|
6 (100)
|
|
symptoms
|
Absent
|
0
|
|
Hyperviscosity
|
Present
|
2 (33.3)
|
|
symptoms
|
Absent
|
4 (66.7)
|
|
Serum monoclonal
|
≤70
|
4 (66.7)
|
|
protein (g/L)
|
>70
|
2 (33.3)
|
|
Serum albumin (g/L)
|
≤35
|
3 (50)
|
|
>35
|
3 (50)
|
|
Serum β2-microglobulin
|
≤3.0
|
2 (33.3)
|
|
(mg/L)
|
>3.0
|
4 (66.7)
|
|
Low risk
|
1 (16.7)
|
|
(0 or 1 except for age)
|
|
Bone marrow aspirate and trephine biopsy demonstrated hypercellularity and infiltration
by plasma cells, lymphocytes, and lymphoplasmacytoid cells. Dutcher bodies (periodic
acid–Schiff +, intranuclear pseudoinclusions) were present within the lymphoplasmacytic
cells. SPEP and immunofixation revealed IgM kappa in all the six cases. Quantitative
IgM levels were elevated at diagnosis in all patients, and one patient with an IgM
level of 113 g/L had immune paresis. Serum β2-microglobulin >3 mg/L was seen in 4
(66.7%) patients. None of these patients had evidence of hepatitis C virus infection.
Four patients (66.7%) were categorized as high risk based on IPSS WM scoring system,
whereas one patient each (16.7%) fell in the intermediate- and low-risk groups [Table 1].
Treatment and outcomes
All the patients were symptomatic and required therapy. Patients received different
combination therapies. Two patients (33.3%) who presented with symptoms of hyperviscosity
and high IgM levels underwent therapeutic plasma exchange along with cytoreductive
chemotherapy, whereas the rest of the patients received only chemotherapy. “IgM flare”
was seen in one patient (16.7%) who responded to further cycles of plasmapheresis,
and rechallenge with rituximab was tolerated well.
The most common regimen used was bortezomib, dexamethasone, and rituximab (BDR) for
6 cycles. Each 3-weekly treatment cycles consisted of:
-
Bortezomib 1.3 mg/m2 IV and dexamethasone 40 mg IV on days 1, 4, 8, and 11
-
Rituximab 375 mg/m2 IV on day 11.
Patients received four consecutive cycles as induction therapy, followed by four more
cycles as a maintenance therapy at 3-monthly intervals. Two patients (33.3%) also
received bendamustine in addition to the above three drugs as in 4-weekly cycles:
-
Bendamustine 90 mg/m2 IV on days 1 and 2 and
-
Rituximab 375 mg/m2 IV on day 1
-
Prophylactic granulocyte-colony-stimulating factor was also given.
All patients received antiviral prophylaxis for herpes zoster. Of the six patients,
one patient (16.7%) achieved a complete response (CR), one (16.7%) had a very good
partial response (VGPR), and three (50%) had a partial response (PR). One patient
(16.67%) had disease progression with transformation to diffuse large B-cell lymphoma
(DLBCL) [Table 2].
Table 2
Overall response to different chemotherapy regimens
|
Age (years)
|
Sex
|
Presenting symptom
|
Serum IgM level (g/L)
|
β2-microglobulin (mg/L)
|
IPSS score/risk group
|
Plasmapheresis
|
Chemotherapy Response
|
Current status
|
|
BDR – Bortezomib, dexamethasone, rituximab; CR – Complete response; BBD – Bendamustine,
bortezomib, dexamethasone; BBDR – BBD, rituximab; VGPR – Very good partial response;
R‑CVP – Rituximab, cyclophosphamide, vincristine, prednisolone; PR – Partial response;
MPS+R – Methylprednisolone, rituximab; PD – Progressive disease; IgM – Immunoglobulin
M; IPSS – International Prognostic Scoring System
|
|
56
|
Male
|
Pancytopenia
|
43.1
|
2.5
|
2 (intermediate)
|
No
|
BDR - 8 cycles PR
|
Died (sudden cardiac arrest)
|
|
49
|
Female
|
Constitutional symptoms
|
45.1
|
2.3
|
1 (low)
|
No
|
BDR - 8 cycles CR
|
Alive
|
|
80
|
Male
|
Transfusion -dependent anemia
|
27.2
|
5.5
|
3 (high)
|
No
|
Benda+dexa - 1 PR cycle BBD - 2 cycles BBDR - 3 cycles
|
Died (postmeasles)
|
|
70
|
Male
|
Hyperviscosity
|
113
|
4.6
|
4 (high)
|
Yes
|
Benda+dexa - 1 PD cycle
BBDR - 4 cycles
R-CVP - 4 cycles
|
Died (sepsis)
|
|
71
|
Male
|
Hyperviscosity
|
98
|
3.9
|
4 (high)
|
Yes
|
BDR - 8 cycles VGPR
|
Alive
|
|
66
|
Male
|
Pancytopenia
|
25.3
|
4.3
|
4 (high)
|
No
|
MPS+R - 1 PR cycle
|
Alive
|
Bone marrow biopsy after therapy was done in the patient with CR, which confirmed
the CR with no evidence of disease. One patient who received eight cycles of BDR chemotherapy
died due to sudden cardiac arrest with a PR of the disease at demise. The patient
with the progression of disease to non-Hodgkin lymphoma DLBCL after five cycles of
chemotherapy was treated with four cycles of rituximab, cyclophosphamide, vincristine,
and prednisolone (R-CVP) as the patient was elderly and had cardiac comorbidities.
Following the fourth cycle of R-CVP, the patient developed Fournier gangrene and died
of septicemia. With a follow-up of 26 months, four of six patients (66.7%) remained
free of disease progression. The combined proportion of patients achieving CR, VGPR,
and PR was seen in 83.3% of our patients.
One patient received methylprednisolone and rituximab as the first cycle due to high
IPSS score and Eastern Cooperative Oncology Group performance of >3. However, his
clinical condition improved, and subsequently, he received three more cycles of BDR.
Patients' follow-up done in December 2019 revealed the current status of the patients
as alive in three (one patient each had CR and PR and the third patient had relapsed
disease after 7 months) and death in three patients (one due to sudden cardiac arrest
with PR at demise, one due to sepsis who had progressive disease, and the third patient
died post measles with PR at demise). The patient who had progressive disease after
7 months was further treated with six cycles of dexamethasone/rituximab/cyclophosphamide
(DRC) and reported VGPR.
Peripheral neuropathy was the most common toxicity. However, bortezomib was better
tolerated with reduced toxicity on weekly subcutaneous administration. Bendamustine
therapy was associated with episodes of febrile neutropenia.
Discussion
WM, also known as lymphoplasmacytic lymphoma (LPL), is a rare indolent non-Hodgkin
lymphoma (incidence: 1%–2% of hematologic malignancies). It is characterized by excessive
proliferation of lymphoplasmacytic cells in the bone marrow and is associated with
the presence of serum monoclonal IgM antibody.[7] We report here a retrospective analysis of six cases of WM and provide the details
pertaining to the clinicopathological profile and response to therapy.
WM occurs mostly in elderly population, with a median age of diagnosis of 63–68 years.[8] The mean age of the patients was 65 years in our study, similar to the aforementioned
evidence. A higher age-adjusted incidence rate of WM was reported in males as compared
with females in the US and EU populations.[8] A similar trend of male preponderance was reported in our study too.
Anemia, fatigue, and weakness are the most common early symptoms of WM.[5] Other common symptoms include decreased weight, fever, night sweats, lymphadenopathy,
splenomegaly, hepatomegaly, peripheral neuropathy, hyperviscosity syndrome, and hemolytic
anemia.[9],[10] All the patients (100%) in our study had symptomatic anemia, whereas two of the
six (33.3%) had symptoms of hyperviscosity and 1 (16%) patient had B symptoms. The
high IgM serum levels (>50 g/L) correspond to the increased risk of hyperviscosity
syndrome, a very common clinical feature of WM.[11] The two patients with hyperviscosity in our study had serum IgM levels of >70 g/L.
According to the IWWM-2, the diagnosis of WM is exclusively based on the presence
of LPL and an IgM monoclonal protein. The requirement for a threshold for marrow involvement
by LPL or serum IgM concentration was removed for WM diagnosis.[12] In the present study, all the six patients (100%) had bone marrow involvement and
had IgM monoclonal gammopathy. Approximately 10%–15% of WM patients transform into
aggressive DLBCL type with extramedullary involvement.[13] One of the six patients (16.7%) in this study progressed to DLBCL.
Therapy is not indicated in all the patients of WM; it is required only in patients
with symptomatic disease.[4],[14] Alkylating agents and nucleoside analogs had been used for WM for several decades
in the past[4],[10],[15] but are associated with only a transient response. Rituximab has a low toxicity
profile and is currently used extensively for WM treatment.[10],[16] “IgM flare” (transient increase in serum IgM levels) is reported in a large population
of patients (30%–80%) treated with rituximab. The IgM flare may cause a worsening
of the disease and may lead to hyperviscosity syndrome.[4] Hence, in majority of the regimens, rituximab is used after chemotherapy to avoid
the IgM flare. A better treatment response with combination therapy (such as DRC regimen)
with rituximab is reported as compared to rituximab monotherapy. However, it is associated
with an infrequent response profile and a high time to response (median: 4 months).[17] The more intensive chemotherapy regimens with rituximab (including rituximab, cyclophosphamide,
doxorubicin, vincristine, and prednisone or nucleoside analogs [fludarabine/rituximab,
fludarabine/cyclophosphamide/rituximab, and rituximab/cladribine]) may yield a better
response, but the associated morbidity and mortality are also increased. Furthermore,
an increase in the cost of supportive therapy is also observed.[10],[17]
The combination of rituximab with dexamethasone and bortezomib (the BDR regimen) is
an active, chemotherapy-free regimen, which has reported a durable efficacy and long-term
favorable toxicity profile for the treatment of WM in clinical studies.[18] The BDR was the most commonly used regimen in our study. All the three patients
treated with BDR regimen in our study had a response (CR/VGPR/PR), which is comparable
to the results reported in a previous long-term (6-year follow-up) Phase 2 study (response:
85%).[18] Overall, in our study, 83.3% of the patients had response. The median time to the
first response was 4 months in our study, similar to earlier reports.[19],[20]
[Table 3] provides a comparison of previous studies with different regimens used for WM with
the current study.
Table 3
Comparison of therapies in Waldenstrom macroglobulinemiia
|
Reference
|
Number of patients
|
Regimen
|
Median number of cycles
|
CR (%)
|
VGPR
|
PR (%)
|
MR (%)
|
SD (%)
|
PD (%)
|
ORR (%)
|
|
CR – Complete response; VGPR – Very good partial response; PR – Partial response;
MR – Minimal response; SD – Stable disease; PD – Progressive disease; ORR – Overall
response rate; DRC – Dexamethasone, rituximab, cyclophosphamide; BDR – Bortezomib,
dexamethasone, rituximab
|
|
Dimopoulos et al.[17]
|
72
|
DRC
|
6
|
7
|
-
|
67
|
9
|
-
|
-
|
83
|
|
Treon et al.[19]
|
23
|
BDR
|
7
|
CR
3 (13)
Near
CR
2 (8)
|
3 (13)
|
11 (47)
|
3 (13)
|
-
|
-
|
96
|
|
Dimopoulos et al.[20]
|
59
|
BDR
|
5
|
2 (3)
|
4 (7)
|
34 (58)
|
10 (17)
|
3 (5)
|
6 (10)
|
85
|
|
Benevolo et al.[21]
|
13
|
Bendamustine ± rituximab
|
4
|
1 (7)
|
-
|
11 (85)
|
-
|
1 (7)
|
-
|
92
|
|
Treon et al.[22]
|
30
|
Bendamustine + rituximab (24)
Bendamustine (4), bendamustine + ofatumumab (2)
|
5
|
-
|
5 (17)
|
20 (67)
|
-
|
-
|
-
|
83.3
|
|
Current series
|
6
|
BDR ± bendamustine
|
8 (17)
|
1 (17)
|
1
|
3 (50)
|
-
|
-
|
1 (17)
|
83.3
|
Two patients received bendamustine in combination with BDR regimen in our study. Previous
studies have established the efficacy of bendamustine and rituximab combination for
WM. The response rate with DRC, BDR, and rituximab-bendamustine was reported to be
76%, 85%, and 96% for WM.[23]
As majority of the patients with WM are elderly in general, the therapy-related tolerability
and toxicity profile should be considered carefully. The risk of myelotoxicity is
limited with the use of BDR regimen as evidenced in previous clinical studies.[19],[20] Hence, this regimen can be used in patients presenting with cytopenia, as reported
in our study. The twice-weekly administration of bortezomib-based regimen in our series
was well tolerated, with peripheral neuropathy being the most common adverse event.
However, none of the patients in our study on BDR discontinued therapy due to neuropathy.
These results are similar to the previously published studies.[19],[20] Furthermore, most of our patients had reversible neuropathy. The use of bendamustine
in WM has resulted in a good overall response rate; however, occasional myelosuppression
is reported.[10]
Overall, DRC and BDR regimens are effective with an established satisfactory toxicity
profile for the treatment of WM. The preferred regimen for WM depends on the patient
characteristics. The DRC regimen can be preferred in patients with less pronounced
cytopenias, low IgM levels, or poor regimen compliance, whereas BDR can be preferred
in patients with high IgM levels and presenting symptoms of severe cytopenia or hyperviscosity.
Conclusions
WM is a rare disease, and there is no single established standard of care. Clinical
presentation varies widely, and selection of chemotherapeutic protocols should aim
at optimizing response, reducing toxicity, and leaving future treatment options open.
Our experience in these six cases supports the use of BDR as the primary frontline
therapy in most cases of WM, and clinical response and PFS rates correlate well with
earlier cohort studies. However, multi-institutional prospective cohort studies of
WM are required to get a clearer picture of the disease and its management in India,
as majority of the patients here present to physicians at advanced stage when they
become symptomatic.
