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RAYMONDWONG,MD
HongKong
• Consultant of the Department of Medicine & Therapeutics,
Prince of Wales Hospital
• Dr. Wong rec...
Myeloproliferative Neoplasms
Revised Classification/Prognostication
Dr. Raymond SM Wong
Department of Medicine & Therapeut...
Ph- Myeloproliferative Neoplasms (MPNs)
2008 WHO diagnostic criteria for Ph- MPNs
Diagnosis:
Both major + 1 minor
OR
1st major + 2 minor
All 4 majors All 3 major ...
Incidence of JAK2 mutations
JAK2 V617F
JAK2 ex12
?
JAK2 V617F JAK2 V617F
PV ET MF
N Cross. Hematology Am Soc Hemat Educ Pr...
Alternative mechanisms of JAK2 activations
97% JAK2 V617F
2% JAK2 ex12
1% ?
60% JAK2 V617F
3% MPL ex10
3% SH2B3 (LNK)
34% ...
Calreticulin (CALR)
• In December 2013, two groups
reported the occurrence of novel
calreticulin (CALR) mutations in
JAK2/...
Klampfl et al.
NEJM 2013
Somatic Mutations of
Calreticulin in MPNs
• Among patients with nonmutated
JAK2 or MPL, CALR mutations
were detected in
• ...
CALR, compared with JAK2 mutations:
ET
• ↓ hemoglobin level
• ↓ leukocyte count
• ↑ platelet count
• ↓ risk of thrombosis
...
Nangalia J, et al. NEJM 2013
CALR Mutations According to Diagnosis
Nangalia J, et al. NEJM 2013
Nangalia J, et al. NEJM 2013
Nangalia J, et al. NEJM 2013
Somatic CALR Mutationsin MPNs with Non-mutated JAK2
• In ET, an association between CALR mutations and
• higher platelet c...
• 168 MPN patients (PV = 36, ET = 114, PMF = 18)
Ann Lab Med 2015;35:22-27
CALR Exon 9 Mutations in MPNs
• ET patients with CALR mutation had lower leukocyte counts
and ages compared with JAK2-muta...
• 576 patients with WHO-defined ET
• In JAK2/MPL-unmutated cases, CALR mutational frequency was 49%
Blood. 2014;123(10):15...
CALR mutations in ET
• CALR-mutated and triple-
negative cases displayed superior
thrombosis-free survival
• CALR mutation...
Blood. 2014;123(10):1544-1551
JAK2 or CALR mutation in ET
• Compared with JAK2-mutated cases, CALR-mutated patients
were:
• younger
• ↓ leukocyte count
...
JAK2 or CALR mutation in ET
CALR- vs JAK2-mutated patients
• No difference in OS, risk of
leukemic or fibrotic
transformat...
CALRexon 9 frameshiftmutationsin patientswith
thrombocytosis(not confirmedET)
• In 289 patients referred for evaluation of...
CALRvs JAK2vs MPL-mutatedor triple-negativeMF
• 254 MF patients who were cytogenetically characterized and screened for
se...
CALR vs JAK2 vs MPL-mutatedor triple-negativeMF
• CALR mutations had a favorable survival
independent of DIPSS-plus risk a...
CALR-mutated patients (vs. JAK2)
Essential Thrombocythemia
• younger age
• male sex
• higher platelet count,
• lower hemog...
Frequencyof JAK2, CALR, andMPLmutationsin MPNs
96%
3%
55% 65%
4%
8%
15-24% 25-35%
Nanglia J and Green R, Hematology 2014; ...
Diagnostic algorithm for BCR-ABL1-negative MPNs
• Genotyping for CALR could be a useful diagnostic tool for JAK2-or MPL-
n...
ProposedRevised ET Diagnostic Criteria
2008 (Current) Proposed Revision
Tefferi A, et al. Leukemia 2014
All 4 major or fir...
ProposedRevised MF Diagnostic Criteria
2008 (Current) Proposed Revision
Tefferi A, et al. Leukemia 2014
All 4 major or fir...
“MaskedPV”
• JAK2-mutated patients who display PV-characteristic BM
morphology but display hemoglobin levels 16-18.5 g/dl ...
A. Thrombosis-free survival
B. Myelofibrosis / leukemia-
free survival
C. overall survival
in masked and overt PV
“MaskedP...
ProposedRevised PV Diagnostic Criteria
2008 (Current) Proposed Revision
Tefferi A, et al. Leukemia 2014
Both major + 1 min...
Summary
• The molecular diagnostic gap in JAK2/MPL-unmutated ET/PMF
is now partially addressed by the recent discovery of
...
The End
Thank you
Revised classification/ prognostication Myelofibrosis
Revised classification/ prognostication Myelofibrosis
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Revised classification/ prognostication Myelofibrosis

Revised classification/ prognostication Myelofibrosis. Prof. Raymond Wong

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Revised classification/ prognostication Myelofibrosis

  1. 1. RAYMONDWONG,MD HongKong • Consultant of the Department of Medicine & Therapeutics, Prince of Wales Hospital • Dr. Wong received his medical degree from the Chinese University of Hong Kong and received his training in Haematology, Internal Medicine as well as Clinical Pharmacology and Therapeutics at the Prince of Wales Hospital, Hong Kong. He also obtained his Doctor of Medicine from the Chinese University of Hong Kong. He joined the Prince of Wales Hospital Poison Treatment Centre since its establishment in 2005 which is a tertiary referral centre for the management of patients with poisoning. Dr. Wong has published over 70 articles in peer-reviewed journals including Blood, Circulation, JAMA and the New England Journal of Medicine in various areas of haematology and therapeutics.
  2. 2. Myeloproliferative Neoplasms Revised Classification/Prognostication Dr. Raymond SM Wong Department of Medicine & Therapeutics The Chinese University of Hong Kong BTG 2015
  3. 3. Ph- Myeloproliferative Neoplasms (MPNs)
  4. 4. 2008 WHO diagnostic criteria for Ph- MPNs Diagnosis: Both major + 1 minor OR 1st major + 2 minor All 4 majors All 3 major + 2 minor
  5. 5. Incidence of JAK2 mutations JAK2 V617F JAK2 ex12 ? JAK2 V617F JAK2 V617F PV ET MF N Cross. Hematology Am Soc Hemat Educ Program 2011: 208-14
  6. 6. Alternative mechanisms of JAK2 activations 97% JAK2 V617F 2% JAK2 ex12 1% ? 60% JAK2 V617F 3% MPL ex10 3% SH2B3 (LNK) 34% ? 60% JAK2 V617F 5% MPL ex10 3% SH2B3 (LNK) 5% CBL 27% ? PV ET MF N Cross. Hematology Am Soc Hemat Educ Program 2011: 208-14
  7. 7. Calreticulin (CALR) • In December 2013, two groups reported the occurrence of novel calreticulin (CALR) mutations in JAK2/MPL-unmutated PMF or ET • CALR is a multi-functional Ca2+-binding protein chaperone mostly localized in the endoplasmic reticulum (ER) • CALR is located on chromosome 19p13.2, contains 9 exons and its protein three domains Ellgaard, L. & Helenius, A. Nature Reviews Molecular Cell Biology 4, 181–191 (2003)
  8. 8. Klampfl et al. NEJM 2013
  9. 9. Somatic Mutations of Calreticulin in MPNs • Among patients with nonmutated JAK2 or MPL, CALR mutations were detected in • 67% of those with ET • 88% of those with PMF • A total of 36 types of insertions or deletions were identified: all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin Klampfl et al. NEJM 2013
  10. 10. CALR, compared with JAK2 mutations: ET • ↓ hemoglobin level • ↓ leukocyte count • ↑ platelet count • ↓ risk of thrombosis • Better survival (P = 0.04) MF • ↓ leukocyte count (P = 0.03) • ↑ platelet count (P<0.001) • Better survival (P<0.001) P<0.001 Klampfl et al. NEJM 2013 The clinical course in patients with CALR mutation was more indolent than that in patients with the JAK2 V617F mutation
  11. 11. Nangalia J, et al. NEJM 2013
  12. 12. CALR Mutations According to Diagnosis Nangalia J, et al. NEJM 2013
  13. 13. Nangalia J, et al. NEJM 2013
  14. 14. Nangalia J, et al. NEJM 2013
  15. 15. Somatic CALR Mutationsin MPNs with Non-mutated JAK2 • In ET, an association between CALR mutations and • higher platelet count • lower hemoglobin level • In addition, the study also suggested an increased incidence of fibrotic transformation in CALR-mutated ET without apparent survival difference Nangalia J, et al. NEJM 2013
  16. 16. • 168 MPN patients (PV = 36, ET = 114, PMF = 18) Ann Lab Med 2015;35:22-27
  17. 17. CALR Exon 9 Mutations in MPNs • ET patients with CALR mutation had lower leukocyte counts and ages compared with JAK2-mutated ET patients Ann Lab Med 2015;35:22-27
  18. 18. • 576 patients with WHO-defined ET • In JAK2/MPL-unmutated cases, CALR mutational frequency was 49% Blood. 2014;123(10):1552-1555 CALR+ JAK2 V617F+ MPL W515+ CALR, JAK2, MPL wt % of patients 15.5% 64.1% 4.3% 16.1% CALR+ vs JAK2 V617F+ CALR+ vs MPL W515+ CALR+ vs. triple negative • Male • Younger age • Lower leukocyte count • Lower hemoglobin level • Higher platelet count • Male • Male
  19. 19. CALR mutations in ET • CALR-mutated and triple- negative cases displayed superior thrombosis-free survival • CALR mutation had no impact on survival or transformation to post-ET myelofibrosis Blood. 2014;123(10):1552-1555
  20. 20. Blood. 2014;123(10):1544-1551
  21. 21. JAK2 or CALR mutation in ET • Compared with JAK2-mutated cases, CALR-mutated patients were: • younger • ↓ leukocyte count • ↓ hemoglobin • ↑ platelet count Blood. 2014;123(10):1544-1551
  22. 22. JAK2 or CALR mutation in ET CALR- vs JAK2-mutated patients • No difference in OS, risk of leukemic or fibrotic transformation • Better thrombosis-free survival
  23. 23. CALRexon 9 frameshiftmutationsin patientswith thrombocytosis(not confirmedET) • In 289 patients referred for evaluation of persistent thrombocytosis Chi J, et al. Leukemia 2014
  24. 24. CALRvs JAK2vs MPL-mutatedor triple-negativeMF • 254 MF patients who were cytogenetically characterized and screened for several MPN-characteristic mutations including ASXL1, EZH2, IDH and spliceosome mutations (SF3B1, SRSF2 and U2AF1) • In JAK2/MPL-unmutated cases, CALR mutational frequency was 74% • Patients with CALR mutations: • younger • higher platelet count • lower DIPSS-plus score • less likely to be anemic, require transfusions or display leukocytosis Tefferi A, et al. Leukemia (2014) 28, 1472–1477 CALR+ JAK2 V617F+ MPL W515+ CALR, JAK2, MPL wt % of patients 25% 58% 8% 9%
  25. 25. CALR vs JAK2 vs MPL-mutatedor triple-negativeMF • CALR mutations had a favorable survival independent of DIPSS-plus risk and ASXL1 mutation status • Triple-negative patients displayed inferior leukemia-free survival • “CALR–ASXL1+” and “triple-negative” mutation profiles are prognostically detrimental Tefferi A, et al. Leukemia (2014) 28, 1472–1477
  26. 26. CALR-mutated patients (vs. JAK2) Essential Thrombocythemia • younger age • male sex • higher platelet count, • lower hemoglobin level • lower leukocyte count • lower incidence of thrombotic events Primary Myelofibrosis • younger • higher platelet count • better risk profile • higher hemoglobin • lower leukocyte count • less spliceosome mutations Tefferi A, et al. AJH 2015
  27. 27. Frequencyof JAK2, CALR, andMPLmutationsin MPNs 96% 3% 55% 65% 4% 8% 15-24% 25-35% Nanglia J and Green R, Hematology 2014; Tefferi A and Barbui T, AJH 2015
  28. 28. Diagnostic algorithm for BCR-ABL1-negative MPNs • Genotyping for CALR could be a useful diagnostic tool for JAK2-or MPL- negative ET or PMF patients in conjunction with BM morphology Tefferi A, et al. AJH 2015
  29. 29. ProposedRevised ET Diagnostic Criteria 2008 (Current) Proposed Revision Tefferi A, et al. Leukemia 2014 All 4 major or first 3 major + 1 minorAll 4 major criteria
  30. 30. ProposedRevised MF Diagnostic Criteria 2008 (Current) Proposed Revision Tefferi A, et al. Leukemia 2014 All 4 major or first 2 major + all minorAll 3 major criteria + 2 minor criteria
  31. 31. “MaskedPV” • JAK2-mutated patients who display PV-characteristic BM morphology but display hemoglobin levels 16-18.5 g/dl for men and 15-16.5 g/dl for women Barbui T, et al. AJH 2013
  32. 32. A. Thrombosis-free survival B. Myelofibrosis / leukemia- free survival C. overall survival in masked and overt PV “MaskedPV”
  33. 33. ProposedRevised PV Diagnostic Criteria 2008 (Current) Proposed Revision Tefferi A, et al. Leukemia 2014 Both major + 1 minor 1st major + 2 minor All 3 major OR first 2 major + minor
  34. 34. Summary • The molecular diagnostic gap in JAK2/MPL-unmutated ET/PMF is now partially addressed by the recent discovery of calreticulin (CALR) mutations in the majority of such cases • Genotyping for CALR could be a useful diagnostic tool for JAK2- or MPL-negative ET or PMF patients. BM marrow morphology remains the central diagnostic platform • CALR mutation may be a distinct disease group, with different clinical and hematological characteristics than that of JAK2- mutated patients • Inclusion of CALR mutations in the WHO classification system for ET/PMF has been proposed
  35. 35. The End Thank you

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    Aug. 29, 2018

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