Guidelines for diagnosis and
management of adult
myeloproliferative neoplasms
(PV, ET, PMF and HES)
Author:
Dr N Butt, Consultant Haematologist
On behalf of the Haematology CNG
Written:
Reviewed:
Re-issued:
Review:
July 2010
September 2012, Jan 2013, April 2015
May 2015
No later than April 2017
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
Page 1 of 9
Polycythaemia Vera (PV)
Diagnostic Criteria1
JAK2-positive PV
A1
A2
High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above
predicted)*
Mutation in JAK2
Diagnosis requires both criteria to be present
JAK2-negative PV
A1
A2
A3
A4
A5
B1
B2
B3
B4
Raised red cell mass (>25% above predicted)
OR haematocrit >0.60 in men, >0.56 in women.
Absence of mutation in JAK2
No cause of secondary erythrocytosis
Palpable splenomegaly
Presence of an acquired genetic abnormality (excluding BCR-ABL)
in the haematopoietic cells
Thrombocytosis (platelet count >450 × 109/l)
Neutrophil leucocytosis
(neutrophil count > 10 × 109/l in non-smokers; >12.5 × 109/l in smokers)
Radiological evidence of splenomegaly
Endogenous erythroid colonies or low serum erythropoietin
Diagnosis requires A1 + A2 + A3 + either another A or two B criteria
--------------------------------------------------------------------------------
*Dual pathology (co-existent secondary erythrocytosis or relative erythrocytosis) may rarely be
present in patients with a JAK2-positive myeloproliferative neoplasm. In this situation, it would be
prudent to reduce the haematocrit to the same target as for polycythaemia vera.
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
Page 2 of 9
Algorithm for the management of PV
• Advise primary care to address conventional risk factors for
atherosclerosis (hypertension, hyperlipidaemia, diabetes, smoking)
• Aspirin 75 mg per day unless contraindicated; clopidogrel if aspirin
intolerant
• Commence venesection to maintain the Hct to <0·45
Cytoreduction should be considered if:
• thrombocytosis.
• symptomatic splenomegaly
• poor tolerance of venesection
• significant constitutional symptoms
Age 40-75 yrs
Age <40yrs
1st line – interferon
2nd line – hydroxycarbamide or
anagrelide**
3rd line – consider MAJIC trial *
Age >75yrs
1st line – hydroxycarbamide
2nd line - consider MAJIC trial*
- else interferon or anagrelide**
MAJIC trial* - ruxolitinib in high risk PV (or ET) intolerant
or refractory to hydroxycarbamide
(Open at RLUH / APH)
Special Considerations: Thrombosis; Bleeding; Pregnancy
Please refer to BCSH guidelines2.
**Funding may need to be
sought. Check with local
haematology pharmacist.
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
1st line – hydroxycarbamide
2nd line - consider MAJIC trial*; P32 or low dose
busulphan
Page 3 of 9
Essential Thrombocythaemia (ET)
Diagnostic Criteria3
A1
Sustained platelet count >450 × 109/l
A2
Presence of an acquired pathogenetic mutation (e.g. in the JAK2 or MPL genes) [+CALR∆]
A3
No other myeloid malignancy, especially PV*, PMF†, CML‡ or MDS§
A4
No reactive cause for thrombocytosis and normal iron stores
A5
Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers
displaying a spectrum of morphology with predominant large megakaryocytes with
hyperlobated nuclei and abundant cytoplasm. Reticulin is generally not increased (grades 0–
2/4 or grade 0/3)
Diagnosis requires:
A1–A3 OR A1 + A3–A5
-------------------------------------------------------------------------------*Excluded by a normal haematocrit in an iron-replete patient; PV,polycythaemia vera.
†Indicated by presence of significant marrow bone marrow fibrosis (greater or equal to 2/3 or 3/4
reticulin) AND palpable splenomegaly, blood film abnormalities (circulating progenitors and tear-drop
cells) or unexplained anaemia; PMF, primary myelofibrosis.
‡Excluded by absence of BCR-ABL1 fusion from bone marrow or peripheral blood; CML, chronic
myeloid leukaemia.
§Excluded by absence of dysplasia on examination of blood film and bone marrow aspirate; MDS,
myelodysplastic syndrome.
∆Somatic
CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. Nangalia et al. N
Engl J Med 2013; 369:2391-2405
Risk Stratification3
Patients should be stratified according to their risk of thrombotic complications. The most widely
accepted risk stratification is as follows:
High risk:
Patients who are either >60 years of age OR have had an ETrelated thrombotic or haemorrhagic event OR who have a platelet count of >1500 ×
109/l.
Intermediate risk : Patients aged 40–60 years with no high risk features
Low risk:
Patients <40 years of age with no high risk features
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
Page 4 of 9
Algorithm for the management of ET
•Determine risk group stratification
•Advise primary care to address conventional risk factors for
atherosclerosis (hypertension, hyperlipidaemia, diabetes, smoking)
•Aspirin 75 mg per day unless contraindicated; clopidogrel if aspirin
intolerant
There are currently no clinical trials open across the
MCCN for 1st line therapy in ET
Management by Risk Group
Intermediate Risk / Low risk
High risk ET
Cytoreductive therapy:
- aim : bring platelet count to <400 x
10 9/
•No
proven
benefit
cytoreductive therapy
l
•Observe for high risk features
1st line - <40 years old interferon
>40 years old hydroxycarbamide
2nd line – failed 1st line therapy
- consider entry MAJIC trial (RLUH / APH)
- otherwise – consider • relax platelet target to 400 – 600 x 109/ l
• consider alternative cytoreductive agents
(including anagrelide, interferon alpha, P32,
busulphan, pipobroman) as either
monotherapy or in combination.
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
in
Page 5 of 9
Primary Myelofibrosis (PMF)
Diagnostic Criteria 4
A1 Bone marrow fibrosis >3 (on 0-4 scale)
A2 Pathogenetic mutation (e.g. JAK2 or MPL), or absence of both BCR-ABL1 and reactive causes of
bone marrow fibrosis
B1 Palpable splenomegaly
B2 Unexplained anaemia
B3 Leuco-erythroblastosis
B4 Tear-drop red cells
B5 Constitutional symptoms**
B6 Histological evidence of extramedullary haematopoiesis
Diagnosis requires A1 + A2 and any two B criteria
**Drenching night sweats, weight loss >10% over 6 months, unexplained fever (>37.5 oC) or diffuse
bone pains.
Prognosis
There are many prognostic scoring systems for myelofibrosis the current BCSH guidelines
recommend the DIPSS-Plus5 prognostic scoring system for treatment decisions.
DIPSS-Plus – Variables :
•Age >65
•Constitutional symptoms
•Hb<10g/l**
•WCC >25x109/l**
•PB blast ≥1%
•Plt <100 x109/l
•RBC transfusion needed
•Poor risk BM cytogenetics (+8,-7/7q-, i(17q), inv(3),-5/5q, 12p-, or 11q23 rearrangements).
One point is scored for each variable:
-
0 adverse points
1 adverse point
2-3 adverse points
4-6 adverse points
-
Low-risk disease
Intermediate-1 disease
Intermediate-2 disease
High-risk disease
- median survival 185 months
- median survival 78 months
- median survival 35 months
- median survival 16 months
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
Page 6 of 9
Algorithm for the management of PMF
No role
PMF : Calculate DIPSS-Plus score
Autograft
Transplant
Eligible
Transplant
Ineligible
Transplant candidate
†Contact Katy
Knight – Research
Nurse RLUH
Intermediate / High risk MF
Allograft donor available
<40yrs, ≥INT2
>40yrs, ≥INT2,
(must meet all
criteria)
>2 HSCT-CI
No donor available
Consider PERSIST 2 Trial (RLUH†)
Consider ruxolitinib (as per CDF)
Low risk MF or declines / ineligible for
ruxolitinib or PERSIST 2
(must meet all criteria)
For supportive care
Myeloablative SCT
Non-myeloablative SCT
Surgical
management –
splenectomy
Ruxolitinib CDF criteria (March 2015)
1.
2.
Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant
specialist specifically trained and accredited in the use
of systemic anti-cancer therapy
a) Intermediate / high risk primary myelofibrosis, OR b)
Post polycythaemia myelofibrosis, OR c) Post
essential thrombocytosis myelofibrosis
3.
a) 1st line indication, OR b) 2nd line indication
4.
Symptomatic splenomegaly and/or constitutional
symptoms
5.
-if failed medical
management of
anaemia,
splenomegaly,
hyperproliferation,
portal hypertension
•Hypercatabolism
•Leucocytosis /thrombocytosis
•Symptomatic splenomegaly
•Blood
transfusion
Medical Management
line
• without cytopenias –
hydroxycarbamide
Radiotherapy
-
Persist 2 trial (RLUH†)
•if unsuitable for splenectomy
-
Imetelstat trial (RLUH†)
•extramedullary haemopoiesis
-
Supportive care
•severe bone pain
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
Page 7 of 9
Anaemia
•Constitutional symptoms
1st
Unsuitable for a stem cell transplant
Failiing ruxolitinib, consider:
Hyperproliferative symptoms
•EPO therapy
•Danazol
• with cytopenias – thalidomide* +
prednisolone
*Funding may need to be
2nd line
sought. Check with local
Interferon
haematology pharmacist.
Hypereosinophilic syndromes
Diagnosis
Hypereosinophilia
PB Eosinophils >1.5 x109/l
Yes
Yes
Δ Reactive hypereosinophilia - Treat
underlying cause
Obvious secondary cause
No
Proceed to bone marrow aspirate,
trephine and cytogenetics
Yes
Eosinophilia 2y to AML (M4eo),
MDS, CML, SM etc)
Treat underlying cause
No
Positive
Δ CEL with FIP1L1-PDGFRA
Request FISH on BM for FIP1L1PDGFRA
– Treatment Box A
Negative
Yes
Abnormal cytogenetics ?
No
No
Yes
Δ probable CEL with
PDGFRB rearrangements
– Treatment Box A
Yes
Δ probable CEL with
FGFR1 rearrangements
- Treatment Box B
Yes
ΔCEL (not otherwise
specified)
5q33 ?
8p11 ?
No
Request TCR rearrangement
studies
Other ?
- Treatment Box B
Δ T-cell associated
hypereosinophilia –
Treatment Box B
Yes
Evidence of T-cell clone ?
Treatment Box A
Treat with imatinib*
Final diagnosis of
exclusion ΔIdiopathic
hypereosinophilia –
Treatment Box B
Treatment Box B
Evaluate for end organ damage.
Consider conventional therapies – corticosteroids,
hydroxycarbamide; Alternatives include cyclosporin, vincristine,
etoposide; interferon; NB low dose imatinib* 100-200mg daily may
be considered in idiopathic hypereosinophilia
*Funding may need to be
sought. Check with local
haematology pharmacist.
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
Page 8 of 9
References
1. McMullin MF, Reilly JT, Campbell P, Bareford D, Green AR, Harrison CN,
Conneally E; National Cancer Research Institute, Myeloproliferative Disorder
Subgroup, Ryan K; British Committee for Standards in Haematology (2007)
Amendment to the diagnosis and investigation of polycythaemia/erythrocytosis.
British Journal of Haematology , 138 , 821-822.
2. McMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt B, Oscier D,
Polkey MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B; General
Haematology Task Force of the British Committee for Standards in Haematology
(2005). Guidelines for the Diagnosis, Investigation and Management of
Polycythaemia/Erythrocytosis. British Journal of Haematology, 130, 174-95.
3. Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, Drummond M, Erber
W, Everington T, Green AR, Hall GW, Hunt BJ, Ludlam CA, Murrin R, Nelson-Piercy
C, Radia DH, Reilly JT, Van der Walt J, Wilkins B, McMullin MF; British Committee
for Standards in Haematology. (2010) Guideline for investigation and management
of adults and children presenting with a thrombocytosis. British Journal of
Haematology, 149, 352-375.
4. Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe A, Green AR,
Michaeel NG, Gilleece MH, Hall GW, Knapper S, Mead A, Mesa RA, Sekhar M,
Wilkins B, Harrison CN; Writing group: British Committee for Standards in
Haematology. (2012). Guideline for the diagnosis and management of
myelofibrosis.British Journal of Haematology, 158, 453-71.
5. Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, Van Dyke
D, Hanson C, Wu W, Pardanani A, Cervantes F, Passamonti F, Tefferi A. (2011)
DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary
myelofibrosis that incorporates prognostic information from karyotype, platelet count,
and transfusion status.. J Clin Oncol. Feb 1;29(4):392-7
Prepared by Dr N M Butt
On behalf of the MCCN Haematology Clinical Network Group.
Revised April 2015.
MCCN guidelines - Adult Myeloproliferative Neoplasms- April 2015
For review: no later than April 2017
Page 9 of 9