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The main primary symptoms in 363 patients with
myeloproliferative neoplasm (MPN) patients subdivided in 123 ET, 190 PV and 50
MF patients were fatigue, night sweats, pruritis and bone pain. A considerable
number of MPN patients reported vague symptoms, such as headache with or
without visual impairments, dizziness and tinnitus. MPN diagnosis was initially
not considered in 34%. MPN diagnosis was based on symptoms in 56% (n=203),
detected by coincidence in 30% (n=110) and based on complications in 14%
(n=49). Mean age of diagnosis was 53 years. The MPN patients were limited in
physical mobility in 10%, 14% and 24%, limited in the ability to exercise in
15%, 29% and 38% and social activity was restricted in 9%, 11% and 11% of ET,
PV and MF patients respectively. Non-retired MPN patients experienced
self-reported fatigue as the main reason for the inability to work full-time in
31% of ET, 40% of PV and 59% of
MF patients.
The top 20 complaints at time of diagnosis in
500 MPN patients was fatigue (N=391, 81%) equally high in ET, PV and MF
patients. Forty to 60% of ET and PV patients presented with aspirin responsive
microvascular disturbances mainly featured by tingling and prickling sensations
in foot soles, hand palms, toes and fingers, cognitive concentration and visual
disturbances. ET and PV patients presented with itching (PV 58% vs. ET 30%).
Various degrees of constitutional symptoms including night sweats were related
to splenomegaly in about half of ET, PV and MF patients. About one third of MPN
(ET, PV and MF) patients suffered from bone pain. MF patients suffered more
frequently from constitutional symptoms of prominent fatigue and night sweats
related to pronounced splenomegaly. Before the MPN diagnosis was made the
complaints were ascribed by doctors to other causes in 173 (35%) patients
including stress, burned out or overstrained in 41 (24%), to depression or
hystery in 14 (8%), migraine of unknown origin in 13 (8%) and to rheuma,
hypertension or fibromalgia in a few. Treatment in 497 MPN patients consisted
of low dose aspirin in 70% and phlebotomy in 42% (mainly PV 91%), hydroxyurea
in about 30% of ET, PV and MF and pegylated interferon-alpha-2a in 16% of ET
and PV patients.
Keywords: Myeloproliferative neoplasm, Fatigue,
Sweat, Patients,
Diagnosis
INTRODUCTION
The Dutch MPN Patients Foundation was founded in
2003 by Connie Luteijn with the support of the medical advisory committee of
Dutch Internists and MPN experts in Hematology. This foundation aims to supply
information towards MPN patients, to look after their interests, to stimulate
contact between MPN patients and to exchange information and relevant knowledge
among medical doctors and MPN patients [1-6]. The Dutch MPN Foundation is a not
for profit organization and independently supported by the Dutch Government.
Important data became available by Mesa et al. [7] on the full spectrum of complaints related to the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) and on the impact of these MPN diseases on the quality of life, social activity and work participation. We therefore conducted a similar survey in 2007 and 2009 among MPN patients being a member of the Dutch MPN Foundation. The MPN Patients Foundation has its own MPN-magazine PUR SANG to inform the MPN patients members independently from MPN doctors and specialists [8]. The Medical Advisory Board members of the MPN Foundation continuously provide the MPN Foundation patient members detailed information on signs and symptoms, diagnostic criteria and treatment recommendations by means of MPN Doctors and Patients Brochure in the Dutch and English language [9-11].
METHODS
Anno 2007, the Dutch MPN Foundation had a
total of 552 patient members. A written questionnaire was sent to 516 MPN
patients members concerning primary presenting manifestations of MPN, vascular
symptom burden and used validated instruments of fatigue, physical mobility,
social activity and work participation according to Mesa et al. [7] and Mendeza
et al. [8]. In addition information was acquired regarding the diagnosis ET, PV
and MF, the JAK2V617F mutation status, treatment and adverse reactions anno
2007 [9-11]. This survey was completed by 363 (response rate 70%) MPN patients [6].
Anno 2010, the Dutch MPN Foundation had
nearly 700 MPN patient members. A second written questionnaire was sent to 624
MPN patient members concerning symptoms, treatment, physical mobility, social
activity and labor participation [7,8]. A subgroup of respondents was selected
for an additional digital questionnaire containing two validated fatigue
measurement instruments: the Brief Fatigue Inventory (BFI) as used by Mendoza
et al. [8] and the Multidimensional Fatigue Inventory (MFI-20). This survey was
completed by 450 (response rate 72%) MPN patients.
DIAGNOSIS: 2000-2002
ECP CRITERIA OF ET, PRODROMAL PV, PV, ET ASSOCIATED WITH CMGM/PMGM
Since 2000, diagnosis of the MPDs followed the European Clinical and Pathological (ECP) criteria for ET, PV and MF (Figures 1 and 2) [1-3]. The 2000 European Clinical and Pathological (ECP) criteria distinguish at least five stages of myeloproliferative neoplasm (MPN): primary MPN stage 0, essential thrombocythemia with features of latent polycythemia vera (=PV, with increased LAP score and increased erythrocythemic megakaryocytic myeloproliferation), masked PV, erythrocythemia PV and classical PV (Figure 1) [12-15]. Since 1980 we have used erythrocyte count above the upper limit of normal to replace red cell mass as a major criterion to distinguish classical PV from ET with features of PV (prodromal PV) (http://www.mpn-stichting.nl/doctors_brochure_2004.pdf) [3]. The bone marrow histology of “true” ET is featured by large to giant megakaryocytes with hyper lobulated stag-horn like nuclei, normal LAP score and no features of PV at diagnosis and during follow-up (Figure 2) [2,14]. Chronic or primary megakaryocytic granulocytic myeloproliferations (CMGM/PMGM, Figure 2) is the third distinct MPN of hypercellular ET due dual megakaryocytic/granuloctic myeloprliferation and relative reduction of erythropoiesis in the bone marrow featured by immature megakaryocytes with clumsy cloud-like mega karyocytes, which are not seen in ET and PV [2,14].
RESULTS
The first survey was completed in 2008 by 363
MPN patients (mean age 59 years, women 56% (n=204): ET patients 34% (n=123), PV
patients 52% (n=190) and MF patients 14% (n=50) [ 9]. The JAK2V617F
mutation status anno 2007 was assessed in 43% (n=157) of MPN patients (n=34 ET,
n=66 PV, n=8 MF). The JAK2V617F PCR test was positive in 59% of ET,
94% of PV and 44% of MF patients. Interestingly, a considerable number of
patients reported vague symptoms, such as headache with or without visual
impairments, dizziness and tinnitus (Figure
3A), which may have led to a delay in diagnosis of MPN. The main primary
symptoms were fatigue, night sweats, pruritis and bone pain (Figure 3B). The numbers are in
accordance with those reported by Mesa et al. [7] (Table 1 and Figures 3B and 4). In 34% of patients MPN diagnosis
was initially not considered. MPN diagnosis was based on symptoms in 56%
(n=203), detected by coincidence in 30% (n=110) and based on complications in
14% (n=49) [9]. Mean age of diagnosis was 53 years.
Treatment modalities of the three MPNs ET, PV
and MF were recorded as graphed in Figure
3C. Remarkably, pruritis reported by 53% (n=193) of MPN patients was only
treated in 31% (n=60) of these patients, being efficient in only half of them.
Most applied anti-pruritic agents included alpha-interferon (14%), hydroxyurea
(11%) and light therapy (PUVA) (11%). Adverse drug reactions occurred in
patients using hydroxyurea (n=53) and interferon-alpha (n=42). These adverse
reactions mainly included cutaneous and mucosal complaints, nausea and fatigue
for hydroxyurea and flu-like symptoms, fatigue and depression for
interferon-alpha [9]. Physical mobility, ability to exercise and social
activity was limited in many MPN patients as compared to the patient’s
situation before the diagnosis of MPN (Figure
3D). Importantly, 37% (n=86) of non-retired MPN patients was incapable to
work full-time due to their MPN disease.
Brief Fatigue Inventory (BFI) and Multidimensional
Fatigue Index (MFI-20) fatigue values were obtained
for a subgroup of 257 MPN patients randomly selected from the MPN population (Figure 5) [10]. This
subgroup contained of 36% ET (n=98), 45% PV, n=107 and 15% MF (n=36) patients.
Importantly to mention is that 94%, 99% and 67% of those ET, PV and MF patients
were under treatment at the time of completing the additional fatigue survey.
The MPN patients were limited in physical mobility in 10%, 14% and 24% of ET,
PV and MF patients respectively. As compared to the situation of patient’s
situation before the diagnosis of MPN, the ability to exercise was limited in
15%, 29% and 38% of ET, PV and MF patients, respectively. Social activity was
retricted on 9%, 11% and 11% of ET, PV and MF patients respectively.
Importantly, 37% of non-retired MPN patients experienced self-reported fatigue
as the main reason for the inability to work full-time (ET 31%, PV 40%, MF
59%).
The mean BFI score in Figure 5 for MPN patients under treatment was 4.81. Disease
adjusted BFI score for ET, PV and MF patients under treatment were 4.5, 5.0 and
5.5, respectively. These results are in line with previous research my Mesa et
al. [7]. In that study the BFI score for MF patients was 5.4. The mean MFI-20
score for MPN patients under treatment was 14.8 (Figure 5). Interestingly, all relevant fatigue values appeared to
peak during treatment, compared to the period before treatment or without
treatment (Figure 5).
Interpretation: The mean BFI score for MPN
patients during treatment was 4.81. Disease specific BFI scores for ET, PV and
MF under treatment were 4.5, 5.0 and 5.5, respectively. These results are in
line with previous research by Mesa et al. [7] in which MF patients score 5.4.
The mean MFI-20 General Fatigue Index score for MPN patients ET, PV and MF was
14.8, which is higher compared to 13.69 in the period before or without
treatment in 214 MPN patients. All relevant fatigue values appeared to peak
during treatment, compared to the period before treatment or without treatment
indicating that fatigue alone is not an indication to treat MPN. The lower
table shows the BFI and MFI-20 scores in perspective of other hematological
diseases and healthy controls [10].
CLINICAL SYMPTOMS, DIAGNOSIS AND
TREATMENT OF ET, PV AND MF IN 497 MPN PATIENTS ANNO 2010
Since 2003, diagnosis of the MPNs followed
the European Clinical and Pathological (ECP) criteria for ET, PV and MF [1-6,12-15].
The second survey was completed in 2010 by 450 MPN patients (women 56%),
resulting in a 72% response rate: ET 39% (n=157), PV 47% (n=213), MF 14% (n=62)
[11]. The results of the MPN Questionaries’ published in PUR SANG anno
2010 were based on 497 filled forms by 271 females (54%) and 212 males (43%),
mean age at diagnosis 57 years (range 20 to 84 years) [11]. The 497 MPN
patients were diagnosed according to Dutch recommendations [12-15] as ET in 181
(36%), PV in 244 (50% of whom 18 as ET/PV), MF in 67 (13%), and MPN
unclassifiable in 5 (1%). The primary diagnosis in 115 Dutch and Belgian
hospitals was based on specific MPN related complaints in 55%, coincidental (e.g.
routine laboratory investigation for other reasons) in 30% and after disease
specific complications had occurred in 15%. Diagnosis of MPN was confirmed by
bone marrow aspiration from the sternum in 235 and bone marrow biopsy from the
iliac crest in 475 (96%). Red Cell Mass (RCM) measurement to diagnose PV and to
distinguish ET from PV was performed in 31%. PCR test for the JAK2V617F
mutation was performed in 230 (46%) MPN patients and found positive in 74% (ET
n=52, PV n=103, MF n=14) and negative in 26%. Sixty percent of ET, 91% of PV
and 52% of MF patients were JAK2V617F positive, thereby confirming the data in
the literature [14]. After primary diagnosis 144 (25%) MPN patients (ET n=38,
PV n=49, MF n=27) were referred for a second opinion. The second expert
evaluation led to a change in diagnosis in 8% and a change in treatment in 28%
(n=29). The second treatment option in 29 (28%) proved to be superior to the
initial treatment. A change of diagnosis during follow-up occurred in 60 MPN
patients, from ET into PV in 16 (9% of PV), from PV into MF in 15 (6% of PV)
and from ET into MF in 10 (6% of ET).
MPN RELATED SIGNS AND SYMPTOMS
Based on the Dutch MPN questionnaire
including 36 questions to answer the top 20 complaints at time of diagnosis in
399 out of 497 (81%) MPN patients are shown in Table 2. The most frequent complaint is fatigue (81%) equally high
in ET, PV and MF patients. Apart from variable severity of fatigue a specific
pattern of signs and symptoms could be retrieved by the Dutch MPN
questionnaire. The signs and symptoms in ET are mainly featured by tingling and
prickling sensations in foot soles, hand palms, toes and fingers [16-20],
cognitive concentration and visual disturbances [19,20]. Itching in PV (58%)
and ET (30%) and fatigue were much more prominent in PV. Various degrees of
night sweats related to splenomegaly occurred in about half of the MPN patients
(Table 2). About one third of MPN
patients suffered from bone pain (Table
2). MF patients suffered more
frequently from constitutional symptoms of prominent fatigue and night sweats
(78%) related to pronounced splenomegaly (Table
2).
Before the MPN diagnosis was made the complaints
were ascribed to myeloproliferative disease ET, PV or MF by doctors in 173
(35%) patients to other causes including stress, burned out or overstrained in
41 (24%), to depression or hystery in 14 (8%), migraine of unknown origin in 13
(8%) and to rheuma, hypertension or fibromalgia in a few [11].
TREATMENT AND ADVERSE REACTIONS
Treatment in 497 MPN patients was started
with low dose aspirin or calcium carbasalate (Ascal) in 70% and phlebotomy in
42% (mainly PV 91%), hydroxyurea in 29% and pegylated interferon-alpha2a in 7%,
wait and see in 8% (n=42 of whom 26 with MF) of MPN patients at time of
diagnosis [11]. The treatment changed during follow-up in 294 (60%) of MPN
patients: ET in 64% (n=115), PV in 59% (n=143) and MF in 49% (n=33). Out of 459
evaluable adverse drug reactions or side effects were recorded in one third
(35%) of MPN patients: HU in 41% (n=69), IFN in 28% (n=47) of all side effects.
Most frequent side effects of HU were skin and mucocutaneous complaints
including dry skin, skin lesions, skin ulcers, itching, skin carcinoma, brittle
nails, aphtous ulcers and hair loss [11]. Most frequent side effects of IFN
were flu-like symptoms, fatigue and mood disturbances [11]. Low dose aspirin or
Ascal induced gastritic complaints in 11% for which treatment with metronazol
was usually indicated [11].
WORK PARTICIPATION, MOBILITY AND
SOCIAL ACTIVITY [11]
Out of 497 MPN patients 168 (34%) indicated
not to be able anymore to participate in their job. Out of 318 MPN patients who
still wish to work 18% were completely and 14% partially unable to work as the
consequence of MPN disease. As the consequence of their disease, about one
fourth of MPN patients are restricted in their activities to walk in 24%
(n=117), to bicycle in 22% (n=111), or sports in 24%, (n=117). Out of 497 MPN
patients 86% could accept their MPN disease to live with it themselves (78%) by
compassion from families and friends in 41% and professional help was given in
12%. In 46 (9%) patient MPN disease was a great suffer and nearly impossible to
live with. Collection and analysis of results derived from the Dutch MPN
questionnaire 2011 (available at: http://www.mpn-stichting.nl and info@mpn-stichting.nl) by the Dutch MPN Foundation is a continuous
process.
DISCUSSION AND CONCLUSION
In the cohort of 450 MPN patients subdivided
in 157 ET, 213 PV and 62 MF patients, we found a high impact of MPN
disease-related fatigues on daily activities and labor participation,
especially during treatment. In the light of the chronic nature of treatment of
MPN patients, this justifies that prospective unmet need (PUN) studies are
warranted in which the effect of treatment with aspirin, phlebotomy/aspirin,
pegylated interferon, anagrelide, hydroxyurea and JAK2 inhibitors in ET, PV and
MF patients of various molecular etiology should be evaluated not only directed
towards clear indications and efficacy of the non-leukemogenic agents in
particular, but that the effects on fatigue, quality of life and labor
participation should be incorporated as well. The treatment efficacy should not
only be defined as the capacity to decrease thrombosis and hemorrhages, but
should also include the capacity to reduce mutation allele burden and MPN
disease burden and the effects on quality of life and work participation as
well. In the survey of 363 MPN (123 ET, 190 PV and 50 MF) patients 93% of PV,
71% of ET and 37% of MF were on aspirin mainly because of microvascular
symptoms including migraine-like headache, acral paresthesia, erythromelalgia,
transient neurological and visual disturbances. Phlebotomy became the first
line treatment in 6% of ET, 78% of PV and 9% of MF. Because of advanced or
symptomatic MPN disease 31% of ET, 29% of PV and 30% of MF were on treatment
with hydroxyurea and 16% of ET and PV and 4% of MF were on treatment with
peglyated interferon (PegasysR). In the 2007 study of Mesa et al 50
to 60% of ET and PV patients were on hydroxyurea therapy (Table 3) [7]. In the Italian study of Vannucchi et al. [21], a
total of 214 patients were treated with phlebotomy, 58% of 219 PV and 4% of 257
ET patients. Myelosuppressive chemotherapy was administered to 497 patients
(52%) including 59% of 219 PV and 48% of 257 ET patients. The 20% difference of
HU use (50% of USA and Italian ET/PV patients versus 30% of Dutch ET/PV
patients) can readily be ascribed to significant differences in the USA/Italian
versus the Dutch guidelines for MPN-T disease in ET and PV patients [13-15].
Low risk ET and PV patients at ages 18 to 80 years is defined by platelet count
<1500 × 109/L, absence of vascular risk factors like
hypertension, hypercholesterolemia, diabetes atherosclrosis and absence of
bleeding complications. First line treatment option in in ET and PV patients
followed the published Dutch guidelines since 2000 (Table 4). If asymptomatic, no micricovascular symptoms and no
major thrombosis like minor stroke of myocardial infarction low dose aspirin 40
mg a day is given in JAK2V617F mutated thrombocythemia MPN (MPN-T)
patients. Symptomatic MPN-T patients including microcrovascular circulation
disturbances including migraine atypical TIAs, minor TIAs, low back pain,
painful toes or fingers, but no major thrombosis was treated low dose aspirin. When MPN-T is associated with
leukocytosis, moderate splenomegaly or platelet count above 1000 × 109/l
low dose Pegasys 45 ug/ml will become the treatment of choice in JAK2V617F
mutated ET and PV. At age above 70 freedom to choose hydroxyurea or low dose
pegasys must prevail. Please note that these are general Dutch MPN-T treatment
guidelines, which has to be discussed with your local hematologist or internist
for approval.
At platelet count between 1000 and 1500 × 109/L when
on aspirin for microvascular manifestation’s the risk of bleeding is increased.
If bleeding is present reduction at platelet count by anagrelide or IFN from
values above to below 1000 × 109/L
is recommended. HU is indicated if case rapid reduction of high to very high
platelet count is indicated. Symptomatic ET with features of PV, splenomegaly
and leukocytosis (masked PV or post-ET MF) treatment with low dose IFN is
indicated. If non-responsive to IFN or side effects consider hydroxyurea.
The ECMP criteria clearly define and stage the JAK2V617F defined MPN entity of prodromal PV, prefibrotic PV, early fibrotic PV, PV complicated by myelofibrosis (post-PV MF), significant myeloid metaplasia of the spleen with splenomegaly and related constitutional symptoms (Table 5) [22,23]. Within the JAK2V617F MPN phenotypes, the JAK2V617F mutated hypercellular ET is associated with clustered pleomorphic megakaryopoiesis, increased granulopoiesis and relative decrease of erythropoiesis without a documented history of ET or PV. The integrated WHO-CMP criteria surely will have important implications in choosing proper targeted treatment options for the prevention of thrombotic and bleeding complications in prodromal PV and PV and for the management of serious complications of progressive MPN disease burden requiring myeloreductive treatment with peglyated interferon (PegasysR) and if non-responsive or side effects low dose hydroxyurea to correct increased blood cell counts in overt and advanced PV patients [10,13]. Venesection aiming at a hematocrit below 0.45 in males and below 0.42 in females is the first line treatment option in PV patients. Phlebotomy aiming more strictly at a hemotocrit of less than 0.40 and a MCV of less than 70 fl in males and females on top of well controlled low dose aspirin in PV patients will significantly reduce the cumulative incidence of major thrombosis, but the microvascular syndrome of associated thrombocythemia persist [13]. According to current insights, low dose interferon is the treatment of choice in intermediate stage PV patient [15,22,23]. If not responsive to IFN or side effects induced by IFN, hydroxyurea is the second line myelosupressive treatment option in JAK2V617F mutated ET and PV patients (Table 5). Hydroxyurea is not an innocent drug and should be used with caution. Proper staging of PV in terms of JAK2V617F mutation load and MPN disease burden by measuring the degree of splenomegaly and severity of constitutional symptoms including itching on top of bone marrow histology and grading of fibrosis is of huge importance since it has significant implications for a non-leukemogenic or the least potential leukemogenic treatment options in low, intermediate and high risk PV patients (Table 5). As shown in Table 5, high risk PV and MF patients with advanced MPN-T disease in terms of high JAK2V617F allele burden, progressive MPN disease with splenomegaly and constitutional symptoms are candidates for myelosuppressive (hydroxyurea) or myeloreductive (JAK2 inhibitors) treatment [24].
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Table 3
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Table 4
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Table 5
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Table 6
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