BR J Haematol - 2012
BR J Haematol - 2012
BR J Haematol - 2012
Waldenström macroglobulinaemia (WM) is a distinct B-cell Second International Workshop on WM (Weber et al, 2003)
lymphoproliferative disorder characterised by the presence of and these were further revised following the Third
immunoglobulin M (IgM) monoclonal gammopathy and International Workshop (Kimby et al, 2006). The emergence
bone marrow infiltration by lymphoplasmacytic lymphoma of additional clinical data has resulted in a need to re-evaluate
(Owen et al, 2003; Swerdlow et al, 2008). Criteria for the the current criteria. These data include the increasing fre-
formal assessment of response were proposed following the quency of high quality responses with newer combinations as
Table I. Categorical response definitions. that clinical benefit can be obtained in the absence of high
quality categorical responses.
Response category Definition
and that confirmation with a second immunofixation assay considerably from patient to patient (Owen et al, 2001;
should also be performed. Morice et al, 2009; Pasricha et al, 2011). Emerging data how-
The serum free light chain assay (sFLC) has been widely ever has demonstrated there can be discrepancies between
applied in multiple myeloma and has proved particularly serum IgM and bone marrow responses. IgM responses are
informative in patients with non-secretory and light-chain typically slow with purine analogue and monoclonal antibody-
only disease. Limited data is available in WM but the assay based therapy, as it appears these agents selectively deplete the
appears to be informative in the majority of patients and CD20+ B-cell component with sparing of the CD138+ plasma
may provide an earlier indication of both response and pro- cell component (Varghese et al, 2009; Barakat et al, 2011). In
gression (Itzykson et al, 2008; Leleu et al, 2008, 2011a). A this context it is possible to demonstrate significant B-cell
similar assay (heavy chain/light chain assay, HLC), which depletion in the marrow but suboptimal IgM responses.
allows the quantification of IgM kappa and IgM lambda, has Satisfactory IgM responses are subsequently documented in
recently been developed and is based upon the unique junc- the majority of patients with maximum responses documented
tional epitopes that exist between heavy and light chains and at a median of 6 months following the completion of therapy
initial reports have suggested a potential role in WM in fludarabine-treated patients, for instance (Varghese et al,
response assessment (Leleu et al, 2011b; Manier et al, 2011). 2009). Conversely, bortezomib-containing regimens and other
The panel however considered there were insufficient data at novel agents, such as the mammalian target of rapamycin
this time to incorporate sFLC and HLC assessments into inhibitor everolimus, may demonstrate excellent IgM
the revised criteria and further prospective evaluation is responses but discordant bone marrow responses (Chen et al,
encouraged. 2007; Treon et al, 2007, 2011a).
It should be noted that these response criteria are applica- Serial bone marrow assessment is encouraged for all
ble only to patients with symptomatic WM and that the patients enrolled in clinical trials irrespective of their IgM
assessment of response in patients with IgM-related disorders response. Similarly, repeat marrow assessment can provide
such anti-myelin-associated glycoprotein neuropathy, cryo- significant value in the routine management of individual
globulinaemia and cold agglutinin disease will probably patients. In order to make a detailed assessment of residual
require specific criteria to assess clinical benefit. infiltrates it is recognized that both bone marrow aspirate
and trephine biopsies should be obtained and that these
should be routinely supplemented by flow cytometric and
Relapse and progression criteria
immunohistochemistry studies. Attempts should be made to
These criteria were also reviewed in light of the increasing characterise residual infiltrates with respect to their B-cell
incidence of CR and VGPR reported with newer therapeutic and plasma cell content and immunohistochemical assess-
combinations (Treon et al, 2009; Laszlo et al, 2010; Tedeschi ment of trephine biopsy sections currently provides the opti-
et al, 2012). It is again stressed that progression, when this is mal method (Morice et al, 2009; Varghese et al, 2009;
defined solely on the basis of increasing IgM concentrations, Barakat et al, 2011). CD138 and/or IRF4 (also known as
is not necessarily an indication to reintroduce treatment. MUM1) may be used to demonstrate residual plasma cells
Relapse from CR is defined by the reappearance of monoclo- while CD20 may be used to define residual B-cell infiltration
nal IgM protein and/or recurrence of bone marrow involve- although additional markers may be necessary in rituximab-
ment, lymphadenopathy/splenomegaly or symptoms treated patients due to masking of the antigenic site, which
attributable to active disease. may be seen in post-treatment specimens (Treon et al, 2001).
Progression from PR is defined by 25% increase in IgM PAX5 is a potentially useful marker in this context as expres-
level from lowest recorded value and confirmed by a repeat sion will be confined to the B-cell component but CD19 and
assessment. The development of new signs and symptoms of CD79 may be difficult to interpret as expression is seen in
disease, including Bing Neel syndrome and histological trans- both B-cells and plasma cells (Morice et al, 2009; Varghese
formation, is also considered as evidence of disease progres- et al, 2009; Barakat et al, 2011).
sion. An absolute increase of at least 5 g/l is required to The most appropriate time point at which to assess bone
define progression when the IgM level is the only applicable marrow response following the completion of treatment is
criterion. unknown and may vary with the type of treatment given. A
standardized approach is desirable, as this will facilitate mean-
ingful comparisons of future clinical trial data. It is therefore
Bone marrow assessment
suggested that bone marrow responses be formally assessed
The previous response criteria mandated morphological 4–6 weeks from the completion of induction therapy. It is
assessment of the bone marrow for the confirmation of CR however recognized and encouraged that assessment at addi-
but it was not considered necessary in patients achieving less tional time points may be desirable in some clinical protocols,
than a CR. Bone marrow appearances in WM are, by defini- particularly those examining maintenance therapies.
tion, heterogeneous and the extent and pattern of infiltration The panel also recognized the potential value and impact of
as well as the extent of plasma cell differentiation can vary minimal residual disease (MRD) studies in WM. Numerous
Table II. Efficacy measure definitions. It is recognized that progression in WM, as defined, does
not always result in the reintroduction of treatment and the
Endpoint Definition
collection of data relating to the time of next treatment
Overall survival Time from the initiation of treatment to death (TTNT) is strongly encouraged. Similarly, it is also acknowl-
from any cause edged that deaths can occur in WM due to co-morbid condi-
Cause-specific Time from the initiation of treatment to death tions and the reporting of cause-specific survival (CSS) is
survival censoring for deaths from unrelated causes
also encouraged. The proposed efficacy measures are defined
Progression-free Time from the initiation of treatment to disease
in detail in Table II.
survival (PFS) progression or death from any cause
Time to Time from the initiation of treatment to disease
progression progression with deaths due to unrelated Haemopoietic recovery
(TTP) causes censored
Disease-free Time from the first documentation of complete Incomplete or suboptimal haemopoietic recovery remains a
survival (DFS) response to disease progression with deaths difficult issue in WM response assessment because treatment
due to unrelated causes censored itself often impacts haemopoietic recovery. The presence of
Duration of Time from the first documentation of response persistent cytopenias is clearly relevant in the management of
response (DOR) to disease progression with deaths due to individual patients but the panel reaffirmed their view that
unrelated causes censored haemopoietic recovery should not be included as a criterion
Time to next Time from the initiation of treatment to next
in response assessment. Repeat bone marrow assessment is
treatment therapy
however encouraged in those patients with adequate IgM
(TTNT)
response but poor haemopoietic recovery in order to fully
exclude refractory disease.
quantification: implications for monitoring Morice, W.G., Chen, D., Kurtin, P.J., Hanson, C.
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