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research paper

Response assessment in Waldenström macroglobulinaemia:


update from the VIth International Workshop

Roger G. Owen,1 Robert A. Kyle,2 Summary


Marvin J. Stone,3 Andy C. Rawstron,1
This report represents a further update of the consensus panel criteria for
Veronique Leblond,4 Giampaolo Merlini,5
Ramon Garcia-Sanz,6 Enrique M. Ocio,6 the assessment of clinical response in patients with Waldenström macro-
Enrica Morra,7 Pierre Morel,8 Kenneth globulinaemia (WM). These criteria have been updated in light of further
C. Anderson,9 Christopher J. Patterson,9 data demonstrating an improvement in categorical responses with new
Nikhil C. Munshi,9 Alessandra Tedeschi,7 drug regimens as well as acknowledgement of the fact that such responses
Douglas E. Joshua,10 Efstathios are predictive of overall outcome. A number of key changes are proposed
Kastritis,11 Evangelos Terpos,11 Irene M. but challenges do however remain and these include the variability in
Ghobrial,9 Xavier Leleu,12 Morie A. kinetics of immunoglobulin M (IgM) reduction with different treatment
Gertz,2 Stephen M. Ansell,2 William modalities and the apparent discrepancy between IgM and bone marrow/
G. Morice,2 Eva Kimby13 and Steven tissue response noted with some regimens. Planned sequential bone mar-
P. Treon9
1
row assessments are encouraged in clinical trials.
St James’s University Hospital, Leeds, UK,
2
Mayo School of Medicine, Rochester, MN, Keywords: Waldenström macroglobulinaemia, trials, residual disease.
3
Baylor Sammons Cancer Center, Dallas, TX,
4
Hopital Pitie Salpetriere, Paris, France, 5IRCCS
Policlinico San Matteo and University of Pavia,
Pavia, Italy, 6Hospital Universitario de Salam-
anca, Salamanca, Spain, 7Niguarda Ca’Granda
Hospital, Milan, Italy, 8Hospitalier Schaffner,
Lens, France, 9Dana Farber Cancer Institute,
Harvard Medical School, Boston, MA, USA,
10
Royal Prince Alfred Hospital, Sydney, NSW,
11
Australia, University of Athens School of
12
Medicine, Athens, Greece, Hopital Huriez,
13
Lille, France and Karolinska Institute and
Karolinska University Hospital, Stockholm,
Sweden

Received 14 August 2012; accepted for


publication 20 September 2012
Correspondence: Dr Roger G. Owen,
HMDS Laboratory, Level 3, Bexley Wing,
St James’s University Hospital,
Beckett Street, Leeds LS9 7TF, UK.
E-mail: rogerowen@nhs.net

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

ª 2012 Blackwell Publishing Ltd First published online 15 November 2012


British Journal of Haematology, 2013, 160, 171–176 doi:10.1111/bjh.12102
13652141, 2013, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.12102 by ESCP Europe, Wiley Online Library on [27/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
R. G. Owen et al

Table I. Categorical response definitions. that clinical benefit can be obtained in the absence of high
quality categorical responses.
Response category Definition

Complete response Absence of serum monoclonal IgM protein by


(CR) immunofixation Categorical response definitions
Normal serum IgM level The categorical response definitions proposed are provided
Complete resolution of extramedullary disease,
in detail in Table I. A number of key changes are proposed.
i.e., lymphadenopathy and splenomegaly if
Categorical responses may now be determined either by
present at baseline
IgM M protein quantitation by densitometry or by total
Morphologically normal bone marrow aspirate
and trephine biopsy serum IgM quantitation by nephelometry, given that they
Very good partial Monoclonal IgM protein is detectable appear to provide similar levels of correlation with bone
response (VGPR)  90% reduction in serum IgM level from marrow response (Tripsas et al, 2012). It should however
baseline* be noted that IgM values as assessed by nephelometry are
Complete resolution of extramedullary disease, systematically higher than M protein values determined by
i.e., lymphadenopathy/splenomegaly if present densitometry (Riches et al, 1991; Murray et al, 2009). It is
at baseline crucial that sequential response assessments for individual
No new signs or symptoms of active disease patients are performed in the same laboratory using the
Partial response Monoclonal IgM protein is detectable
same methodology. Further considerations include the
(PR)  50% but<90% reduction in serum IgM level
knowledge that the biological variability for M protein
from baseline*
quantitation by densitometry and immunoglobulin quantita-
Reduction in extramedullary disease, i.e.,
lymphadenopathy/splenomegaly if present at tion by nephelometry are 8% and 13%, respectively
baseline (Katzmann et al, 2011).
No new signs or symptoms of active disease A new category of Very Good Partial Response (VGPR) is
Minor response Monoclonal IgM protein is detectable also proposed, which is defined by the presence of monoclo-
(MR)  25% but<50% reduction in serum IgM level nal IgM on immunofixation and/or  90% reduction in
from baseline* serum IgM levels from baseline along with complete resolu-
No new signs or symptoms of active disease tion in extramedullary disease, i.e., lymph node and splenic
Stable disease Monoclonal IgM protein is detectable disease, if present at baseline. This category is supported by
(SD) <25% reduction and <25% increase in serum
numerous data demonstrating improved depth of responses
IgM level from baseline*
with newer therapeutic combinations, such as bortezomib
No progression in extramedullary disease, i.e.,
containing regimens and purine analogue/alkylator/monoclo-
lymphadenopathy/splenomegaly
No new signs or symptoms of active disease nal antibody combinations (Treon et al, 2009; Laszlo et al,
Progressive disease  25% increase in serum IgM level* from 2010; Tedeschi et al, 2012). Similarly, it has become clear
(PD) lowest nadir (requires confirmation) and/or that categorical response predicts outcome, at least in terms
progression in clinical features attributable the of progression-free survival (PFS) and rituximab-based thera-
disease pies. In this context, patients who achieve a VGPR have an
outcome similar to those patients achieving complete
*Sequential changes in IgM levels may be determined either by M
responses (CR) (Treon et al, 2011b). Similarly, the minor
protein quantitation by densitometry or total serum IgM quantita-
tion by nephelometry. response (MR) category has been further validated by new
data demonstrating an improved outcome compared to those
patients with stable (SD) or progressive disease (PD) (Gertz
well as the confirmation that categorical response is predic- et al, 2009).
tive of outcome (Gertz et al, 2009; Treon et al, 2009, The panel reiterated the value of sequential assessment of
2011a; Laszlo et al, 2010; Tedeschi et al, 2012). Similarly, it response following the completion of therapy given the
is becoming clear that discrepancies can exist between IgM delayed IgM responses seen particularly in the context of
responses and bone marrow/tissue responses, which has led purine analogue and monoclonal antibody-based therapy
to a re-evaluation of the value of repeat bone marrow (Del Giudice et al, 2005; Varghese et al, 2009; Tedeschi et al,
assessment (Chen et al, 2007; Treon et al, 2007, 2011b; 2012). It is essential therefore that the categorical responses
Varghese et al, 2009; Barakat et al, 2011). These current reported in clinical trials be the best-recorded response, irre-
proposals represent a consensus report produced following spective of the time point at which those responses were doc-
the Sixth International Workshop on WM. It is acknowl- umented. The reporting of time to best response is also to be
edged that the principal role of these criteria is to promote encouraged in clinical trials as this is a particularly meaning-
uniform reporting of clinical trial data. The principles out- ful criterion for those patients with high IgM concentrations
lined may also aid physicians in the routine clinical man- and hyperviscosity syndrome. It was further affirmed that CR
agement of individual patients although it is recognized be confirmed by morphological assessment of the marrow

172 ª 2012 Blackwell Publishing Ltd


British Journal of Haematology, 2013, 160, 171–176
13652141, 2013, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.12102 by ESCP Europe, Wiley Online Library on [27/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Response Assessment in WM

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

ª 2012 Blackwell Publishing Ltd 173


British Journal of Haematology, 2013, 160, 171–176
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R. G. Owen et al

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.

studies in myeloma and chronic lymphocytic leukaemia (CLL)


Imaging studies
have demonstrated that MRD is demonstrable in a significant
proportion of patients in conventional CR and that this is It was reaffirmed that computerised tomography (CT) scanning
highly predictive of outcome (Rawstron et al, 2002; Moreton (of chest, abdomen and pelvis) be performed in all patients prior
et al, 2005; Paiva et al, 2008). Currently, flow cytometry to commencing therapy and that repeat scanning be used in
appears to be the most appropriate technique as it is applicable determining categorical response for those with measurable
to the vast majority of patients with myeloma and CLL and disease. It is recognized that the precise measurement of nodal
has a reproducible sensitivity of 001%. Categories incorporat- disease was problematical in many cases, particularly in those
ing MRD-negative remissions have therefore been introduced patients with multifocal nodal involvement and complex nodal
in both myeloma and CLL (Hallek et al, 2008; Rajkumar et al, masses. It was therefore proposed that complete resolution of
2011). There is encouraging, but limited MRD data in WM extramedullary disease be required for attainment of CR and
(Garcı́a-Sanz et al, 2011) and, given the heterogeneity in cellu- VGPR and reduction in nodal and splenic involvement was
lar content and the differential responses seen with various needed for the attainment of a PR, assuming that the IgM
therapies, additional data is required before MRD assessment criteria were met. Positron emission tomography (PET) appears
can be included in the consensus criteria. to be informative for the presence of extramedullary disease in
approximately 80% of patients with active WM but further
prospective studies are needed (Banwait et al, 2011).
Efficacy measures for clinical trials
It is recognized that there is very limited randomised clinical
Conclusions and future directions
trial data in WM and the assessment of the efficacy of differ-
ent regimens frequently involves the comparison of non- It is recommended that these criteria be adopted in
randomised phase II trials. It is therefore essential that all prospective clinical trials, as meaningful comparisons of non-
clinical trials report their efficacy results in a standardized randomised data can only be made in the context of uniform
manner. In this context the crucial parameters to report are reporting of overall response and efficacy outcomes.
overall survival (OS), PFS and time to progression (TTP). Similarly, the prospective evaluation of novel serological,
Given the improvement in categorical responses and increas- immunophenotypic and imaging methods in the context of
ing rates of CR it is also encouraged that disease-free survival clinical trials protocols is also encouraged.
(DFS) is reported for patients achieving CR and duration of
response (DOR) is reported for all responding patients.
Acknowledgements
Given the variability in kinetics of monoclonal IgM reduc-
tion with different treatments, determining the time taken to RGO and SPT conceived of the project and wrote the paper.
achieve best response is also considered a worthwhile efficacy All authors were involved in consensus discussions and
measure. reviewed the manuscript.

174 ª 2012 Blackwell Publishing Ltd


British Journal of Haematology, 2013, 160, 171–176
13652141, 2013, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.12102 by ESCP Europe, Wiley Online Library on [27/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Response Assessment in WM

quantification: implications for monitoring Morice, W.G., Chen, D., Kurtin, P.J., Hanson, C.
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