Received: 1 December 2021 Revised: 13 June 2022
DOI: 10.1111/hae.14648
REVIEW ARTICLE
Acquired von Willebrand syndrome and lymphoid neoplasms:
A review of malignancy management, and propositions of
practical recommendations
Christophe Nicol1
1
Service d’Onco-Hématologie, Centre
Hospitalier des Pays de Morlaix, Morlaix,
France
2
Service d’Hématologie Clinique, Institut de
Cancéro-Hématologie, CHRU de Brest, Brest,
France
3
Centre de ressources et de compétence des
maladies hémorragiques, CHRU de Brest,
Brest, France
Correspondence
Dr Christophe Nicol, MD, Service
d’Onco-Hématologie, CH des Pays de Morlaix,
15 rue Kersaint Gilly, Morlaix, 29762 Cedex,
France.
Email: cnicol@ch-morlaix.fr
Haemophilia. 2022;1–12.
Accepted: 17 July 2022
Brigitte Pan-Petesch2,3 Jean-Christopher Ianotto2
Abstract
Introduction: Acquired von Willebrand syndrome (AWS) is a rare and potentially life-
threatening bleeding disorder. AWS is primarily associated with lymphocyte-related
disorders (AWS-LRD), such as lymphoma and IgM monoclonal gammopathy of unde-
termined significance (MGUS), and plasmocyte-related disorders (AWS-PRD), such as
non-IgM MGUS and myeloma. Symptomatic treatments are important to control and
prevent bleeding, but AWS-LRD and AWS-PRD can only be cured by targeting the
responsible clonal cell. No reviews exist on this specific subgroup of AWS.
Aim: We performed a literature review to help manage these rare cases.
Method: Thirty-two AWS-PRD and 43 AWS-LRD cases with data on malignancy
treatment were reported in 56 articles from the Medline database.
Results: LRDs were exclusively indolent and primarily associated with IgM monoclonal
compounds. LRDs and PRDs may be treated because of severe bleeding symptoms, but
severe VWF deficiency did not necessarily correlate with severe bleeding. Immuno-
suppressive drugs in AWS-PRD, including rituximab, provided an overall response rate
of AWS (AWS-ORR) of 30% (3/10), including short responses. Anti-myeloma drugs pro-
vided an AWS-ORR of 71.4% (20/28), with long-lasting remissions. Bortezomib was the
most commonly used drug and provided an AWS-ORR of 66.7% (6/9), including ther-
apeutic associations with other anti-myeloma drugs. Autologous and allogeneic stem
cell transplantation was performed in eight and two patients, respectively, and some
details on the management of AWS during these procedures were provided. Rituximab
in AWS-LRD provided an AWS-ORR of 60% (3/5), and a chemotherapy + rituximab
regimen increased the AWS-ORR to above 50%. Bleeding syndrome in AWS-PRD and
AWS-LRD generally improved prior to AWS biological improvement.
Conclusion: Long term remission of AWS due to lymphoid neoplasms is attainable by
treating the underlying clonal cell. Some data and recommendations are provided to
help answer difficult questions, including treatment timing, choice of drug, and the
timing of evaluations and treatment changes.
KEYWORDS
acquired von Willebrand, guideline, lymphoma, lymphoproliferative disease, MGUS, myeloma
wileyonlinelibrary.com/journal/hae © 2022 John Wiley & Sons Ltd. 1
2 NICOL ET AL .
1 INTRODUCTION
Acquired von Willebrand syndrome (AWS) is a rare bleeding dis-
order, that is primarily associated with lymphoid neoplasms.1 Half
of these cases are frequently called monoclonal gammopathies of
undetermined significance (MGUS), although they could be labelled
monoclonal gammopathies of clinical significance.2 Other conditions
are also diagnosed: myeloproliferative neoplasms (15%), cardiovascu-
lar diseases (21%–40%), solid tumours (5%), hypothyroidism, drugs,
autoimmune diseases (2%–6% each),1,3–6 and miscellaneous causes
(e.g. sarcoidosis and diabetes).7 The physiopathology of lymphoprolif-
erative diseases involves several mechanisms: increased shear stress,
autoantibodies5 and/or adsorption of von Willebrand factor (VWF) by
tumoral cells.8,9
Distinguishing AWS from congenital von Willebrand disease (VWD)
is challenging because laboratory tests and clinical presentations
are similar.10 A lack of personal and family bleeding history, old
age, existence of underlying disease, unusual inefficiency of desmo-
pressin or VWF-containing concentrates raise suspicions for AWS.3
decrease in high-molecular-weight multimers of VWF or an increased
VWF:pp/VWF:Ag ratio suggests AWS.10 Anti-VWF antibodies may
help clinicians link AWS to the suspected aetiology but are hard
to detect, and no standardised test exists.10 Clinical severity and
biological exams do not necessarily correlate with AWS.
AWS treatments start with symptomatic actions for the prevention
and control of bleeding, which is similar but not identical to congenital
VWD management,3 and may be cured with treatment of the underly-
ing cause. Some of these indolent haematological malignancies do not
require treatment, but the presence of AWS may be the reason to start
treatment of the hemopathy. Evidence-based guidelines for the treat-
ment of lymphoid neoplasms responsible for AWS are lacking, and only
case reports have been published.
To address this void, we reviewed the literature on AWS treat-
ments for lymphoid neoplasms and their impact. Major key points of
the management of these rare patients are also discussed.
2 METHODS
2.1 Review of the literature
A PubMed search for articles was performed with no initial target date,
up to May 2021 using the following keywords: acquired von Willebrand
AND myeloma, MGUS, lymphoma, lympho-proliferative disorders, dif-
fuse large B cell lymphoma, mantle cell lymphoma, marginal zone
lymphoma, chronic lymphocytic leukaemia, lymphocytic lymphoma,
T lymphoma, Hodgkin lymphoma, Waldenström macroglobulinemia.
Reviews with unreleased data and case-reports were collected, and
the relevant references of these articles were also searched. Articles
were analysed if the treatment of the cause of AWS was described, and
clinical and/or biological information of the AWS response. Other arti-
cles related to congenital von Willebrand disease or only concerning
haemostatic drugs for AWS were excluded.
Articles were separated into two categories depending on the
underlying disorders: plasma-cell-related disorders (PRDs), including
non-IgM MGUS and multiple myeloma; and lymphocyte-related disor-
ders (LRDs), including all lymphomas, B-cell monoclonal lymphocytosis
and IgM MGUS.11
2.2 Analysis of treatment success
There is no consensus on the definition of response in AWS.
The was notable heterogeneity in the description of AWS response in the
different articles.
We created two simple categories:
- ‘Overall response’ was proposed when VWF tests normalised, when
VWF tests improved enough to be considered a response by the author,
or when clinical bleeding was chronically stopped (e.g. >3 months without
significant episode). Any of these criteria were independent from the use
of haemostatic drugs such as VWF-containing concentrates, intravenous
A immunoglobulins (IVIg) or desmopressin, because the authors generally
described their use, and bleeding control was considered linked to underlying
disease treatment depending on the author.
- ‘No response’ was defined when the first definition was not applicable.
The time to response was also evaluated depending on these
definitions and author conclusions.
3 RESULTS
3.1 Global analysis of the cases
The selection process identified 288 potentially eligible articles. After
review using the prespecified inclusion and exclusion criteria, 56 arti-
cles were ultimately selected for further analysis (Figure 1). These
articles described 32 cases of AWS (26 articles) associated with PRD
(AWS-PRD) (Table 1) and 43 cases of AWS (30 articles) associated with
LRD (AWS-LRD) (Table 2).
Some cases described discordant responses of AWS and PRD/LRD,
such as the absence of AWS-ORR despite improvement of LRD/PRD
(an alternative cause, prostate cancer12 or angiodysplasia,13,14 must
be considered). Conversely, one patient curiously achieved an overall
response of AWS despite a stable WM.15
3.2 Analysis of the AWS-PRD cases
Twenty-six articles described 32 cases of AWS-PRD (Table 1). Indolent
PRD represented 68.7% of cases (non-IgM MGUS in 53.1% and smoul-
dering multiple myeloma in 15.6%), and confirmed and unclear symp-
tomatic multiple myeloma represented 28.1% of the cases. Monoclonal
isotypes were primarily IgG (71.9%), and the usual representation of
kappa/lambda light chain isotype was 69.2%/30.8%.
For AWS-PRD treatment solely because of AWS, authors often
used immunosuppressive drugs, and the AWS-ORR was 30% (3/10
NICOL ET AL .
F I G U R E 1 Flow chart of article selection for this review of acquired von Willebrand disease, lymphoproliferative disease, and causal
treatment. MGUS: monoclonal gammopathy of undetermined significance
patients).16–18 Steroids alone produced one response in two stud-
ied cases in three weeks, but no data on the duration of response
were provided.16,19 Rituximab with prednisone and IVIg produced
a response in one case.17 Rituximab was used six times in other
cases20–23 without efficacy, including an association with melphalan.24
One article reported a significantly longer response with the addition
of mycophenolate mofetil to IVIg and dexamethasone (2 months vs. 10
days), and a loss of response correlated with a decrease in mycopheno-
late mofetil dose.18 In contrast, the use of anti-myeloma drugs provided
an AWS-ORR of 64.7% (11/17) in patients who were only symptomatic
because of AWS. Among the drugs used, some combinations are no
longer used that way in a usual symptomatic myeloma, such as alky-
lating agents + steroids (melphalan, four cases, cyclophosphamide, one
case), and provided an AWS-ORR of only 20% (1/5). The use of IMID
(thalidomide, one case, and lenalidomide, two cases) was efficient in
100% (3/3) of cases. The use of proteasome inhibitors (bortezomib)
was efficient in 60% (3/5) of cases, including one case associated
with melphalan. The use of anti-CD38 (daratumumab) was efficient in
100% (2/2) of cases, including one case with an autologous stem cell
transplant following several months of daratumumab.
For all AWS-PRD, the use of antimyeloma drugs produced to an
AWS-ORR of 71.4% (20/28 patients)13,19,22,23,25–37 (Table 3), including
three ASCT used as the sole treatment. Notably, bortezomib steroid-
based regimens were used nine times with an AWS-ORR of 66.7%
(6/9),19,22,23,25–27,29,30 including associations with thalidomide,27
melphalan,25 cyclophosphamide26,27 and lenalidomide.30 For ASCT,
nine lines of treatment included autologous haematopoietic stem cell
transplantation (HSCT) with an AWS-ORR of 88.9%.25–27,30,31,33,34
3
Autologous HSCT was performed immediately33,34 or was preceded
by induction therapy. Among the recently available antimyeloma
drugs, daratumumab was successfully used twice,23,25 and carfilzomib
was described once with an unclear overall response.30 No articles
described the use of pomalidomide.
Responses in PRD (PRD-R) were rarely provided, but when
the drug used to treat AWS-PRD was an anti-myeloma drug,
the AWS-ORR matched the PRD-R for 20/21 lines of treatment
(95.2%).22,23,25–31,33,34,38
The median and mean times to normalise VWF levels in PRD were 6
and 8.1 months (1–20 months), respectively.17,22,23,25,26,28,36 Notably,
several cases described an improvement of bleeding syndrome prior to
the biological improvement of AWS.25,31 The overall response for AWS
was several months to up to two years after the initial improvement of
VWF levels and/or clinical bleeding.23,25
Data on the recurrence of AWS and PRD are scarce.23,25 A relapse
of AWS with severe VWF deficiency without clinical impact for two
additional years was also decribed.25
3.3 Analysis of the AWS-LRD cases
Thirty articles described 43 cases of AWS-LRD (Table 2). The most fre-
quently identified lymphoid neoplasms were Waldenström macroglob-
ulinemia (32.6%), chronic lymphocytic leukaemia/lymphocytic lym-
phoma (23.3%) and marginal zone lymphoma (16.3%). Eight cases
(18.6%) were labelled ‘B-cell lymphoproliferative disease’ or ‘lym-
phoma’ without additional details. Ten of the 43 cases benefited from
4 NICOL ET AL .

TA B L E 1 Description of AWS associated with plasmocyte-related disorders (PRD): neoplasm treatment, response, and distribution of
subtypes of plasma-cell related disorders and monoclonal compound isotypes (32 reported cases)

PRD treated only because of AWS Patient(s) Underlying disease treatment and best response of AWS
First line of treatment
IgG Kappa MGUS14 1 Azathioprine (150 mg/d): No response
Free light chain MGUS64 1 Prednisone (60 mg/d): Overall response.
65
IgG Kappa MGUS 1 Dexamethasone (4d): No response
IgG Lambda MGUS18 1 Dexamethasone (40 mg/d d1-4) + MMF (1000 mg BID) + IVIG: Overall
response
IgG Kappa MGUS20 1 Rituximab (375 mg/m2 /w – 4 injections): No response
2 IgG Kappa MGUS21 2 Rituximab (350 mg/m2 /w ; one patient had two infusions, one had four): No
response
IgG Lambda MGUS17 1 Rituximab (1 dose) + Prednisone + IVIG (2 injections): Overall response
IgG Kappa MGUS22 1 Rituximab (375 mg/m2 /w – 6 injections): No response
23
IgG Lambda MGUS 1 Rituximab 375 mg/m2 , four infusions weekly: No response described
IgG Kappa MGUS24 1 Rituximab + Melphalan + Prednisone : No response
IgG Kappa MGUS 35
1 Melphalan + Prednisone (4 cycles): No response
2 IgG Kappa MGUS 32
2 Melphalan + Prednisone (1 mg/kg): No response
IgA Lambda SMM36 1 Melphalan + Prednisone (12 cycles): Overall response.
IgG SMM 37
1 Cyclophosphamide + Steroids (3 cycles): No response
IgG Kappa MGUS65 1 Bortezomib + Dexamethasone (1 cycle): No response
IgG Lambda SMM 29
1 Bortezomib (1.3 mg/m2 /w) + Dexamethasone (40 mg/d d1-2) (8 cycles):
Overall response
IgG Kappa SMM25 1 Bortezomib + Melphalan + Dexamethasone (3 cycles): Overall response
13
IgG MGUS 1 Thalidomide (50 mg/d): Overall response
28
IgG Kappa MGUS 1 Lenalidomide (25 mg/d d1-d21, 15 mg/d after 8 cycles): Overall response
IgA Kappa SMM28 1 Lenalidomide (25 mg/d d1-d21, 15 mg/d after 8 cycles) + Dexamethasone
(40 mg/w): Overall response
IgA Lambda MGUS + AL Amyloidosis33 1 ASCT/High Dose Melphalan: Overall response
Second and subsequent lines of treatment
IgG Kappa MGUS22 1 (bis) Bortezomib (1.3 mg/m2 /d d1-d21) + Dexamethasone (40 mg bi-weekly) (6
cycles): Overall response
IgG Lambda MGUS23 1 (bis) Bortezomib + Dexamethasone four cycles: No response
IgG Kappa SMM25 1 (bis) Thalidomide: Overall response
23
IgG Lambda MGUS 1 (ter) Daratumumab six infusions weekly: Overall response
IgG Kappa SMM 25
1 (ter) Daratumumab + Dexamethasone + ASCT/Melphalan: Overall response

PRD with AWS and other treatment

criterion Patient(s)
First line of treatment
IgG Lambda SyMM66 1 “Aetiological treatment” (sic): Overall response
38
IgD Lambda SyMM 1 “Chemotherapy” with maintenance: Initial overall response and secondary
relapse without response
IgG Kappa MM + AL Amyloidosis33 1 Melphalan + Prednisone: No response.
67
MM 1 ASCT: Overall response
Free Lambda light chain MM + AL 1 ASCT/High Dose Melphalan (twice): Overall response
Amyloidosis33
IgG Kappa SyMM31 1 Thalidomide + Dexamethasone (4 cycles): Overall response, then ASCT
(Melphalan 200 mg/m2 ): Improved response
(Continues)
NICOL ET AL . 5

TA B L E 1 (Continued)

PRD with AWS and other treatment

criterion Patient(s)
SyMM 30
1 Bortezomib + Lenalidomide + Dexamethasone (4 cycles), then ASCT
(Melphalan 140 mg/m2 ): Overall response
IgG Kappa SyMM26 1 Bortezomib + Cyclophosphamide + Dexamethasone (4 cycles), then
Cyclophosphamide + Adriamycin + Dexamethasone (1 cycle), then
ASCT/Melphalan, then “consolidation therapy”: Overall response
IgA Kappa SyMM39 1 Bortezomib + Cyclophosphamide + Dexamethasone: Overall response
Second and subsequent lines of treatment
IgA Kappa SyMM39 1 (bis) Bortezomib + Thalidomide + Dexamethasone: No response
30
SyMM 1 (bis)
Carfilzomib + ASCT (Melphalan): Unclear response
IgA Kappa SyMM39 1 (ter) Lenalidomide + Dexamethasone + ASCT: No response
39
IgA Kappa SyMM 1 (quad) Allogeneic SCT: Overall response
Disease type
Confirmed symptomatic Multiple 6 (18,7%)
myeloma
Unclear symptomatic multiple myeloma 3 (9,4%)
Smoldering multiple myeloma 5 (15,6%)
Non-IgM MGUS 17 (53,1%)
Total patients 32
Monoclonal protein isotypes
IgG Kappa 16 (50%)
IgG Lambda 5 (15,6%)
Unprecised IgG 2 (6,3%)
Ig A Kappa 2 (6,3%)
Ig A Lambda 2 (6,3%)
Free light chains 2 (6,3%)
Ig D Lambda 1 (3,1%)

Abbreviations: ASCT, autologous stem cell transplant; AWS, acquired von Willebrand syndrome; IVIG, intravenous immunoglobulin; MGUS, monoclonal
gammopathy of undetermined significance; MMF, mycophenolate mofetil; Nb, number; PRD, plasmocyte related disorders; SyMM, symptomatic multiple
myeloma; SMM, smoldering multiple myeloma. Cases coloured in grey (full) means there was an overall response of AWS to indicated therapy.

treatment of the underlying disease only because of the presence of
AWS, but many cases did not provide sufficient data to assert the
indication of treatment. The AWS-ORR in the LRD is presented in
Table 4. The treatments used and underlying disorders were more
heterogeneous than in PRD. In contrast to AWS-PRD, the use of ritux-
imab in AWS-LRD produced a seemingly higher AWS-ORR of 60% (3/5
patients), including three MZLs.39–43
The immunochemotherapy used in some disseminated indolent lym-
phomas, such as bendamustine-rituximab, CVP-rituximab and CHOP-
rituximab was associated with AWS-ORRs of 66.7% (4/6)44–49 , 66.7%
(2/3)50,51 and 75% (3/4), respectively.44,46,52,53 Older drugs, such as
chlorambucil, provided an AWS-ORR of 50% (2/4),14,54,55 and more
recent drugs, such as, showed an AWS-ORR of 75% (3/4),47, 51 includ-
ing one inefficient combination with rituximab.47 Several regimens
were only used once in various diseases.
The most important point is that the AWS-ORR also matched
the LRD-R for most lines of treatment (43 patients, 55 lines
of treatment). The median and mean times to normalise VWF
levels in LRD were 4.75 and 7.6 months (.2–24 months),
respectively.15,40,42,46–48,51–53,55–57 Several cases described
an improvement of bleeding syndrome prior to the biological
improvement of AWS.48,51
The overall response for AWS was from several months to up to
two years after the initial improvement of VWF levels and/or clini-
cal bleeding.48,51 Two articles provided some data on AWS and LRD
recurrence.44,51
Four authors described an AWS diagnosis prior to LRD diagnosis:
‘few months before’, 10, 15 or 24 months before the diagnosis of LRD
(one CLL, one small lymphocytic lymphoma, one mantle cell lymphoma,
and one without precision).39,53,54,58
6 NICOL ET AL .

TA B L E 2 Description of AWS associated with lymphocyte-related disorders: neoplasm treatment, responses, and distribution of lymphoid
neoplasm subtypes (43 reported cases)

LRD treated only because of AWS Patient(s) Underlying disease treatment and best response of AWS
First line of treatment
“Lymphoproliferative diseases”68 2 Chemotherapy: Overall response (“Spectacular result” (sic))
SLL54 1 Chlorambucil + prednisone (6 months) : No response
CLL57 1 Prednisone (.75 mg/kg/day, six weeks): no response (initially diagnosed as
acquired hemophilia)
SLL + Sjögren Syndrome48 1 R-Bendamustine (6 cycles): Overall response
50
WM 1 R-CVP: Overall response
WM15 1 Carfilzomib + Rituximab + Dexamethasone: Overall response
40
Monoclonal B Cell lymphocytosis 1 Rituximab (375 mg/m2 , 4 infusions weekly, then 1 every 3 months over two
years): Overall response
B-cell lymphoproliferative disorder39 1 Rituximab (8 weekly injections, then every 3 months): Overall response
45
IgM MGUS 1 R-Bendamustine : Overall response
Second line of treatment
IgM MGUS45 1 Lenalidomide (25 mg/d): Overall response
57
CLL 1 Obinutuzumab-chlorambucil x6: Overall response

LRD with AWS and possible/confirmed

other treatment criterion Patient(s)
First line of treatment
WM69 2 Chlorambucil: Overall response
12
WM 3 “Chemotherapy”: overall responses
50
WM 1 R-CVP: Overall response
WM51 2 R-CVP (4 cycles): No response
WM52 1 R-CHOP: Overall response
WM70 1 Bortezomib + Thalidomide + Dexamethasone: Overall response
49
WM 1 Plasmapheresis (4 times), then R-Bendamustine (6 cycles): Overall response
51
WM 1 Idelalisib (24 months): Overall response
CLL14 1 Chlorambucil (2 mg/d then 6 mg/d): No response
CLL58 1 Fludarabine: Overall response
CLL32 1 Chemotherapy: Overall response
CLL 71
1 Cyclophosphamide + Dexamethasone: Overall response
CLL 44
1 Rituximab + Lenalidomide: No response
CLL47 1 R-Bendamustine: No response
46
CLL then Richter’s transformation of CLL 1 R-Fludarabine (4 cycles): No response
Richter’s transformation of CLL44 1 R-CHOP : Overall response
9
MZL, Splenic 1 Splenectomy: Overall response.
MZL, Splenic 58
1 Splenectomy + Chemotherapy: Overall response
MZL, Splenic43 1 Rituximab (375 mg/m2 /w - 8 cycles): No response
MZL, Thymic MALT + Sjögren Syndrome41 1 Rituximab: Overall response
42
MZL, Gastric MALT 1 Rituximab (375 mg/m2 , 4 infusions weekly, then 1 every 3 months over a
year): Overall response
MZL + Prostate Cancer + 1 “Chemotherapy”:
Cryoglobulinemia12
No response
50
MZL, Nodal 1 “Multidrug therapy”: Overall response

(Continues)
NICOL ET AL . 7

TA B L E 2 (Continued)

LRD with AWS and possible/confirmed

other treatment criterion Patient(s)
53
MCL 1 R-CHOP (3 cycles) then R-Cytarabine (2 cycles): Overall response
56
Hairy cell leukaemia 1 Splenectomy: Overall response, despite persistent hairy cell in blood tests
“Lymphoma”72 1 Chemotherapy: Overall response then relapse of both AWS and lymphoma
73
“Lymphoproliferative diseases” 3 Chemotherapy: Overall response for one patient.
No response for two patients
Second line of treatment
WM51 2 1) VMP (25 cycles – 4 years): Overall response then maintenance with
Idelalisib (3 years): persistence of Overall response
2) VMP (17 cycles): Overall response then maintenance with Idelalisib (8
months): relapse of WM and AWS two months after discontinuation of
idelalisib (toxicity)
CLL44 1 Rituximab + Fludarabine + Cyclophosphamide: Overall response
CLL47 1 R-Idelalisib: No response
Richter’s transformation of CLL44 1 R-HyperCVAD: Overall response
46
CLL then Richter’s transformation of CLL 1 R-Bendamustine (8 cycles): No response
Splenic MZL9 1 CHOP (5 cycles): Overall response
Third Line of treatment
Richter’s transformation of CLL44 1 R-OFAR : Overall response
46
CLL then Richter’s transformation of CLL 1 R-Lenalidomide: No response
47
CLL 1 Venetoclax: Overall response
Fourth line of treatment
Richter’s transformation of CLL44 1 R-Bendamustine: Overall response
CLL then Richter’s transformation of CLL46 1 Ibrutinib No response
Fifth line of treatment
Richter’s transformation of CLL44 1 R-Lenalidomide: Overall response
CLL then Richter’s transformation of CLL46 1 R-CHOP (suspected Richter’s transformation): No response
Six line of treatment
Richter’s transformation of CLL44 1 Ofatumumab: Overall response
46
CLL then Richter’s transformation of CLL 1 Allogeneic SCT: Overall response
Disease type
Waldenstrom Macroglobulinemia 14 (32.6%)
Chronic lymphocytic leukaemia/ 10 (23.3%)
lymphocytic lymphoma
“B cell lymphoproliferative disease/ 8 (18.6%)
lymphoma” without specific details
Marginal zone lymphoma (any subtype) 7 (16.3%)
Monoclonal B cell lymphocytosis 1
Mantle cell lymphoma 1
Hairy cell leukaemia 1
IgM MGUS 1
CLL including Richter syndrome 2
Total patients 43

Abbreviations: AWS, acquired von Willebrand syndrome; CHOP, cyclophosphamide-adriamycin-vincristine-prednisone; CLL/SLL, chronic lymphocytic
leukaemia/small lymphocytic lymphoma; CVP, cyclophosphamide-vincristine-prednisone; HyperCVAD, hyper-fractionated cyclophosphamide-vincristine-
cytarabine; LRD, lymphocyte related disorders ; MALT, mucosa associated lymphoid tissues; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma;
Nb, number; OFAR, rituximab-oxaliplatine-fludarabine-cytarabine; R, rituximab; VMP, bortezomib-melphalan-prednisone; WM, Waldenström Macroglobu-
linemia. Cases coloured in grey (full) means there was an overall response of AWS to indicated therapy.
8 NICOL ET AL .

TA B L E 3 Response rate of AWS with the most frequent treatments used in AWS associated with PRD. Some treatments were not included in
this table: Allogenic stem cell transplant (one case), and two other cases of “aetiological treatments” without further details

Number of Response rate of

Treatment used patients AWS Note
25–27,30,31,33,34
Regimen including at least one 9 88.9% Including 3 patients with no treatment prior to
ASCT – melphalan high dose ASCT
Bortezomib-steroid ± third drug 919,22,25–27,29,30 66.7% 3 VD,19,22,29 2 VCD (one case included an ASCT),26,27
1 VMD,25 1 VTD,27 1 VRD (including an ASCT).30
Includes one case with only one cycle of VD because
of patient’s wish.19
Rituximab 717,20–22,24 14.3% Included one case with steroids, one with
melphalan-steroids (inefficient),24 and one with
IVIg17
Melphalan-steroids 532,33,35,36 40% One inefficient case not included here because of
association with Rituximab24
Thalidomide – Steroids 313,25,31 100% One case included an ASCT
28
Lenalidomide-steroids 2 100% One case included an ASCT
25,60
Daratumumab-steroids 2 100% One case included an ASCT
Steroids only 216,19 50%
Carfilzomib 130 Unclear response Including an ASCT
Cyclophosphamide-steroids 137 0
Azathioprine 114 0
18
Mycophenolate mofetil – 1 1 Response fluctuating depending on mycophenolate
steroids mofetil dosage.

Abbreviations: ASCT, autologous stem cell transplant; AWS, acquired von Willebrand syndrome; VD, bortezomib-steroids; VCD, bortezomib-
cyclophosphamide-steroids; VMD, bortezomib-melphalan-steroids; VRD, bortezomib-lenalidomide-steroids; VTD, bortezomib-thalidomide-steroids.

3.4 AWS and haematopoietic stem cell 4 DISCUSSION

transplantation (HSCT)
HSCT is part of the therapeutic arsenal used to treat lymphoprolifer-
ative diseases. The haemorrhagic risk of AWS may be increased with
HSCT because of deep thrombocytopenia and infectious complica-
tions.
Eight patients benefited from autologous HSCT in PRD, including
two patients who underwent two autologous HSCTs.25–27,30,31,33,34 No
severe bleeding was reported. Management of AWS with low VWF:Ag
levels at the time of autologous HSCT was described twice.25,31 One
case described the management of central catheter implantation, and
used IVIg prior to the procedure, followed by VWF concentrates and
tranexamic acid because of profuse bleeding at the site of catheter
insertion, but no other bleeding occurred after transplantation.31
Another report described the use of platelet transfusion (threshold
at 50 G/L) and prophylactic tranexamic acid plus VWF concentrates
during aplasia, and no severe bleeding occurred.25
Allogenic HSCT was used twice because of the progression of the
haematological malignancy responsible for AWS.27, 46 Therapeutic
plasma exchanges were used prior to allogeneic HSCT to reduce the
load of non-neutralising anti-VWF antibodies, and the patient did not
need VWF concentrates.46 No severe bleeding was reported in either
cases.
This review provides novel key information about the haematologi-
cal malignancy management of AWS-PRD and AWS-LRD. The selected
AWS-PRD and AWS-LRD articles are fairly representative of the usual
repartition of AWS secondary to lymphoproliferative disease.1,49
Notably, the most frequent AWS-LRD was alsothe most frequent
lymphoid malignancies associated with an IgM monoclonal compound
(WM, MZL and CLL), with the exception of follicular lymphoma.59
No AWS associated with follicular lymphoma was identified in this
review. No T-cell or aggressive B-cell lymphomas were reported,
except 2 Richter’s transformations of CLL.44,46 These data highlight
the important, but not exclusive, role of IgM monoclonal compounds
in the physiopathology of AWS. The rarity of AWS could bias this
interpretation.
Symptomatic treatments are extremely important in AWS, but they
are not within the scope of this review. Other recent reviews exist
on this subject.49,60 Compared to other AWS aetiologies, IVIg is an
important drug in the arsenal of haemostastic drugs to manage AWS-
LRD and AWS-PRD symptomatically. Notably, IVIg is often described
as inefficient/useless in IgM MGUS despite some reports of efficacy,
but a lower overall response rate than IgG MGUS is likely7,60,61 Higher
monoclonal compound weights reduce the efficiency of IVIg.62 IVIg
efficiency is mostly observed on Days 2–4 and lasts for at least three
NICOL ET AL . 9

TA B L E 4 Response rate of AWS with the most frequent treatments used in AWS associated with LRD

Number of Response rate

Treatment used patients Most frequent LRD of AWS Note
44–49
Rituximab-bendamustine 6 1 WM, 1 CLL, no MZL. 66.7%
Rituximab 539–43 3 MZL, no WM or CLL 60%
CHOP-based 59,44,46,52,53 1 WM, 1 MZL and no 80% Including one case without
CLL rituximab (unavailable at that
time)9
Idelalisib ± rituximab 447,51 3 WM, 1 CLL 75% One case of idelalisib-rituximab,
without response of AWS in
CLL47
Lenalidomide ± rituximab 444–46 1 CLL, 2 Richter’s 50% Only one case without rituximab
transformation of CLL in IgM MGUS, with an overall
response of AWS45
R-CVP 350,51 3 WM 66.7%
Chlorambucil 414,54,55 2 WM, 1 SLL 50%
51
Bortezomib-melphalan- 2 2 WM 100%
steroids
Bortezomib-Thalidomide- 170 WM 100%
steroids
Carfilzomib – Rituximab - 115 WM 100%
Dexamethasone
Rituximab-Fludarabine- 144 CLL 100%
Cyclophosphamide
Fludarabine ± Rituximab 246,58 2 CLL 50%
Cyclophosphamide- 171 CLL 100%
Dexamethasone
Lenalidomide 145 IgM MGUS 100%
Obinutuzumab-chlorambucil 157 CLL 100%
47
Venetoclax 1 CLL 100%
Ibrutinib 146 CLL 0%

Abbreviations: AWS, acquired von Willebrand syndrome; CHOP, cyclophosphamide, adriamycin, vincristine, steroids; CLL, chronic lymphocytic leukaemia;
CVP, cyclophosphamide, vincristine, steroids; MGUS, monoclonal gammopathy of undetermined significance; MZL, marginal zone lymphoma; SLL, small
lymphocytic lymphoma; WM, Waldenström macroglobulinemia.

weeks,47 and it may last 45 days.63 IVIg has also been efficiently used
as maintenance therapy.64–66
AWS was often the unique reason to initiate malignancy treatment,
notably in PRD, which emphasises the difficult choice to treat the
underlying disorder because there is no test to firmly establish the link
between AWS and LRD or PRD. There is no clear correlation between
the clinical and biological severity of AWS, and severe biological AWS
may be present for years without clinical impact, which makes treat-
ment initiation of the underlying malignancy at the proper time even
more difficult.25 Strict education on these patients would be important
to alert haematologists when new bleeding symptoms appear.
The choice of treatment is also difficult. The reported AWS-ORR
with treatments targeting the underlying disease may be overesti-
mated, because clinical cases with no efficacy are less likely to be
reported. The number of published case reports of AWS with treat-
ments of the underlying disease has greatly increased in the last 10
years, which may be the consequence of the development of more
efficient drugs in LRD/PRD, and a better awareness of the existence
of AWS and the possibility of cure AWS thanks to focusing on the
underlying neoplasm.
The use of an immunosuppressive agents in PRD that is not used
and/or efficient in usual myeloma or MGUS produced only a 30%
AWS-ORR, including one case where IVIg could bias the results (eval-
uation of AWS performed 4 weeks after IVIg), and another case with
a brief response duration of two months.16–18 IVIg may have biased
the resultants of the only case with an efficient rituximab which may
be considered 0% effective (0/7). In contrast, the use of plasmocyte-
directed drugs provided an AWS-ORR of approximately 71.4%. The
bortezomib-based regimen was the most frequently described regi-
men in AWS-PRD, with a high AWS-ORR and some association with
immunomodulatory drugs. However, immunomodulatory drugs are
associated with a higher thrombosis risk and the need for throm-
boprophylaxis prevention, which could increase the bleeding risk.61
Therefore, rituximab or other immunosuppressant drugs should not be
10
used in AWS-PRD. However, daratumumab and/or bortezomib may be
used for MGUS or asymptomatic myeloma, due to low toxicity profile,
especially for daratumumab.62 As described recently, daratumumab
may be used for a fixed duration.23 Symptomatic myeloma with AWS
should be treated as recommended, including ASCT if eligible, except if
uncontrolled recurrent major bleeding persists.
The treatment of lymphoma in LRD was generally efficient for both
AWS and LRD. For the specific case of AWS being the only criterion for
the treatment of LRD, the use of rituximab as a first line may be accept-
able, especially in elderly and/or frail patients, due to its low toxicity
profile.63
Important data on the daily management of AWS and PRD/LRD
once the treatment has begun is the TTR. The median times to nor-
malisation of VWF levels in AWS-PRD and AWS-LRD were 6 and
4.75 months, respectively, but with large maximal ranges (20 and 24
months, respectively). Data are scarce, but the clinical response of AWS
generally precedes the first improvement of VWF biology, and some-
times occurs years before the normalisation of VWF biology, but the
LRD/PRD may have responded quickly.25,31,48,51 In our opinion, the
absence of biological improvement of AWS in the context of a reduction
of haemorrhagic syndrome and PRD/LRD response should not induce
a modification of the treatment.
Based on these data, some recommendations on the management of
AWS in the context of lymphoproliferative disease may be highlighted.
(1) A diagnosis of AWS should lead to search for an haematological dis-
order. (2) Complete bone marrow exploration should be performed in
apparent MGUS to help target the causative cells as plasmocytes or
lymphocytes. (3) Severe biological AWS cases are not necessarily asso-
ciated with severe clinical bleeding. (4) Some of these cases may be
managed by symptomatic treatments only. (5) Treating the underlying
PRD or LRD should be proposed in cases of major and/or frequent clini-
cally relevant bleeding. (6) The treatment of PRD and LRD with AWS as
the only criterion for treatment should target the underlying clonal cell
(plasmocyte or B lymphocyte), possibly with a monotherapy in order
to limit toxicity (the use of purely immunosuppressive agents is proba-
bly less or not efficient). (7) Treatments that induce infrequent grade
3 and 4 thrombocytopenia and/or thrombopathy should be avoided
to reduce bleeding risk when viable alternatives exist. (8) The TTR of
AWS and PRD/LRD may be dissociated, and the clinical response may
precede the biological response of AWS, sometimes by years. (9) A
response in PRD or LRD without an AWS response should promote a
collegial decision of whether to modify the actual treatment (changes
should be discussed in cases of persistent severe clinical bleedings
and/or intolerance to the drugs). (10) Screening for alternative causes
of AWS should be repeated in the context of an apparently discordant
response.
5 CONCLUSION
This comprehensive review gathered important data on the manage-
ment of AWS in the context of lymphoproliferative diseases. Most
NICOL ET AL .
AWS-PRD and AWS-LRD that need a treatment of underlying clonal
cell are indolent malignancies associated with a monoclonal compound.
The treatment of the disease associated with AWS may be performed
solely because of symptomatic AWS because it is efficient, but its ini-
tiation should be based on clinical bleeding and not because of VWF
levels. The treatment of the underlying neoplasm of AWS-PRD and
AWS-LRD should not be used due to its immunosuppressive proper-
ties but because of its ability to kill the underlying cancer cells, whether
these cells are plasmocytes or B lymphocytes. Anti-myeloma drugs
should be used for AWS-PRD, and anti-lymphoma drugs should be used
in AWS-LRD, with a good profile of toxicity, even in elderly patients. The
response of the underlying PRD/LRD is usually associated with an AWS
response, but the time to response may be different, and a new line of
treatment should probably be not initiated solely based on the absence
of AWS biological improvement.
AWS may be a life-threatening condition, and the management of
AWS secondary to lymphoproliferative disease should be planned by
specialists of both pathologies to immediately better control bleeding
with haemostatic drugs, and to aim for prolonged remissions thanks
to a remission of the underlying neoplasm, with correlated treatment.
Due to its rarity, more reports must be published and should provide
the time to response of AWS and LRD/PRD with the clinical and bio-
logical data of AWS at the time of diagnosis and throughout the entire
patient management, including recurrences. An international register
could help collate important data.
ACKNOWLEDGEMENT
C.N. performed the review and data analysis and wrote the manuscript.
J.C.I. reviewed, criticized, and wrote the manuscript. B.P.P. reviewed
and criticized the article.
DATA AVAILABILITY STATEMENT
Data openly available in a public repository that issues datasets with
DOIs.
CONFLICT OF INTEREST
The authors have no competing interests.
ORCID
Christophe Nicol https://orcid.org/0000-0002-1270-8255
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How to cite this article: Nicol C, Pan-Petesch B, Ianotto J-C.
Acquired von Willebrand syndrome and lymphoid neoplasms:
A review of malignancy management, and propositions of
practical recommendations. Haemophilia. 2022;1-12.
https://doi.org/10.1111/hae.14648