Myeloproliferative Neoplasms

Myeloproliferative NeoplasmsDepartment of Internal Medicne Prince of Songkla University
WHO CLASSIFICATION OF MYELOPROLIFERATIVE NEOPLASMS
Myeloid neoplasms Lymphoid neoplasms
Author: Ayalew Tefferi, MD
Polycythemia Vera Essential Thrombocythemia Primary Myelofibrosis
Chronic Neutrophilic Leukemia Chronic Eosinophilic Leukemia, NOS MPN, unclassifiable
Chronic Myelomonocytic Leukemia Atypical Chronic Myeloid Leukemia Juvenile Myelomonocytic Leukemia MDS/MPN-RS-T MDS/MPN, unclassifiable
Chronic Myelogenous Leukemia
abnormalities of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2
Mastocytosis
MECHANISM REGARDING THE GENOMIC MUTATION OF CELL LINEAGE
Polycythemia Vera
• All carry the Jak-2 V617F mutation.
• Absent Jak-2 V617F in secondary causes
• Jak-2 mutation: the major criteria in WHO
• The criteria are shown in the following table:
Tefferi A, et al. Blood. 2007: 110(4): 1092-7.
Thiele J, et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 4th ed. Lyon, USA: International Agency for Research on Cancer Press; 2008.
Arber D et al, Blood, 2016
Polycythemia Vera
• Median age : 60 years • Male:female = 1.2:1 • 7% of patients are diagnosed before the age of 40
years • Asymptomatic or
• Complaints of a prior or current thrombotic event are common.
Tefferi A. Mayo Clin Proc. 2003; 78(2): 174-94.
Polycythemia Vera
Berlin N. Hematol Oncol Clin North Am. 2003; 17(5): 1191-210.
Polycythemia Vera
• Elevated red cell mass
• Hct and Hb might be normal or low in the presence of iron deficiency.
• Increased Platelet count – 60%
• May have basophlia and eosinophilia
Tefferi A, et al. Blood. 2007: 110(4): 1092-7 Berlin N. Hematol Oncol Clin North Am. 2003; 17(5): 1191-210.
Absolute polycythemia is characterized by an increase in
red blood cell (RBC) mass
Five common causes include:
5) erythropoietin-secreting tumors
Relative polycythemia is characterized by a decrease in plasma
volume.
1. Dehydration (e.g., from vomiting, diarrhea, excessive sweating, or diuretics) can deplete plasma volume, leading to a relative polycythemia.
2. Stress erythrocytosis (Gaisböck’s polycythemia) actually results from contraction of the plasma volume and is therefore a misnomer. This benign disorder is seen most often in hypertensive, obese men.
Red Blood Cell Mass Assay:
used to distinguish an absolute versus a relative polycythemia
does not subclassify absolute polycythemias
Polycythemia Vera
Treatment strategy of PV
1. Modification of cardiovascular risk factors
2. Antiplatelet therapy
Correction of
subjects:
Risk Stratification of PV
1) hyperviscosity and associated ischemic sequela
2) thromboses independent of hyperviscosity
3) transformation to myelofibrosis or acute myeloid
leukemia (~3%-10%)
Therapeutic Options in PV:
1) Low Risk: phlebotomy (to an Hct of <45 in and <42 in )2 +
low
2) High Risk: phlebotomy + ASA + hydroxyurea
High Risk for Thrombosis:
4. Marchioli R., J Clin Oncol.2005;23:1-9.
Polycythemia Vera
Risk Categories Treatment
Low risk without extreme thrombocytosis (age <60 years and no thrombotic history)
Low dose aspirin + Phlebotomy
Low dose aspirin + Phlebotomy + Hydroxyurea
High risk which are refractory or intolerant to hydroxyureas
Low dose aspirin + Phlebotomy + ? Ruxolitinib
Marchioli R, et al., N Engl J Med 2013; 368: 22-33
Landolfi R, et al., N Engl J Med 2004; 350: 114-24. Barbui T, et al., J Clin Oncol 2011; 29: 761-70.
Polycythemia Vera
• Indication for cytoreduction in PV: 1. Thrombotic risk: Age >60 y, and histoy of
thrombosis.
3. Platelet > 1,000,000 /uL
4. Turning to thrombotic risk group
5. Disease progression: increased spleen size, Increased number of WBC and Platelet
6. Intolerance to phlebotomy or frequent phlebotomy
Marchioli R, et al., N Engl J Med 2013; 368: 22-33
Landolfi R, et al., N Engl J Med 2004; 350: 114-24. Barbui T, et al., J Clin Oncol 2011; 29: 761-70.
Polycythemia Vera
• Criteria for hydroxyurea resistance or intolerance:
1. No Hct response even having hydroxyurea ≥2 g/day for more than 3 months, or
2. WBC >10,000/uL and platelet count >400,000/uL even having hydroxyurea ≥2 g/day for more than 3 months, or
3. Splenic size reduction not more than 50% by palpation or still having abdominal discomfort from splenomegaly even hydroxyurea ≥2 g/day for more than 3 months, or
4. Absolute neutrophil count <1000/uL or platelet count <100,000/uL or Hb <10g/dL even having least dose of hydroxyurea to maintain CR or PR, or
5. Chronic leg ulcer or other serious adverse complication of hydroxyurea i.e. mucositis, GI side effect or pneuminitis.
Barosi G, et al., Br J Haematol 2010; 148: 961-3.
ESSENTIAL THROMBOCYTHEMIA (ET)
Etiology of Thrombocytosis Primary - if the thrombocytosis is caused by a myeloproliferative neoplasm, the platelets are frequently abnormal and the patient may be prone to both bleeding and clotting events.
Secondary - if thrombocytosis is secondary to another disorder (reactive), even patients with extremely high platelet counts (e.g., > 1,000,000 cells/μl) are usually asymptomatic.
Differential Diagnosis of secondary thrombocytosis: 1.Malignancies 2.Infections and inflammatory disorders (e.g., Crohn’s
disease) 3.Post surgical status 4.Connective tissue disorders 5.Iron deficiency anemia 6.Splenectomy 7.Recovery of the bone marrow from a stress
(chemotherapy or alcohol) 8.Essential Thrombocythemia
Thrombocytosis
2016 WHO Diagnostic Criteria for ET vs prePMF
Clinical Presentation of Essential Thrombocythemia (ET)
Asymptomatic (~ 30-50%)
Vasomotor symptoms including headache, syncope, atypical chest pain, acral paresthesia, livedo reticularis, and erythromelalgia
Thrombosis and hemorrhage occur to various degrees in 5%-25% of patients
Early satiety and abdominal bloating due to splenomegaly
JAK 2+ (V617F) in approximately 50% of patients
Risk Stratefication in ET
Most patients with ET enjoy a normal life expectancy
Like PV, the major risks are secondary to thrombosis and disease transformation:
15-year cumulative risks:
thrombosis - 17% risk
High risk for thrombosis:
(a plt count of > 600,000 not increase risk of thrombosis)
Risk Adapted Therapy for PV and ET
Treatment of ET Low Risk: Age <60 years
No previous history of thrombosis
Platelet count <1 million/μl
→ aspirin (81 mg daily) if vasomotor Sx or other medical need for ASA
→ if otherwise low risk and plt >1,500 X 109/L, screen for an acquired
von Willebrand disease before instituting ASA
High Risk: Age ≥60 years
A previous history of thrombosis
→ hydroxyurea + aspirin (81 mg daily)
→ if plt >1,500 X 109/L, screen for an acquired von Willebrand disease
before instituting ASA
→ anagrelide is an option, but when c/w hydroxyurea, it was ass with
an increased risk of arterial thrombosis, venous thrombosis, serious
hemorrhage, or death from vascular causes
Blood 2012
– Very low: no risk factors
– Low: JAK2 V617F only
– Intermediate: age > 60 only
– Very low: no risk factors – no ASA?
– Low: JAK2 V617F only
– High: h/o thrombosis OR age > 60 + JAK2 V617F
Essential Thrombocythemia
• Criteria for hydroxyurea resistance or intolerance:
1. No platelet response (Platelet >600 x 109/L) even having hydroxyurea ≥2 g/day for more than 3 months, or
2. WBC <2.5 x 109/L and platelet count >400 x 109/L at any dose of hydroxyurea, or
3. Platelet >400 x 109/L, Hb <10g/dL at any dose of hydroxyurea or
4. Chronic leg ulcer or other serious adverse complication of hydroxyurea i.e. mucositis, GI side effect or pneumonitis at any dose of hydroxuurea
5. Fever from the usage of hydroxyurea
Barbui T, et al., J Clin Oncol 2011; 29: 761-70.
PRIMARY MYELOFIBROSIS (PMF)
Primary Myelofibrosis
Signs and Symptoms: asymptomatic (15% - 30%) severe fatigue splenomegaly hepatomegaly fever and night sweats signs or symptoms of anemia or thrombocytopenia foci of extramedullary hematopoiesis may occur in
almost any organ bone or joint involvement
Myeloid Neoplasms
AML
• Median age of diagnosis 65
• Main causes of death are due to infection and bleeding from progressive BM failure, thrombosis, and AML
• About 10 – 20% of patients will develop acute leukemia
PMF has the worst prognosis
WHO 2016 Criteria WHO 2008
Criteria WHO 2016 Criteria
atypia accompanied by either reticulin and/or collagen fibrosis; or in absence of reticulin fibrosis, megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis (ie pre-fibrotic PMF)
• Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm
• Demonstration of JAK2V617F or other clonal marker; in absence of clonal markers, no evidence of secondary bone marrow fibrosis
Minor Criteria • Leukoerythroblastosis • Increased serum LDH • Anemia • Palpable splenomegaly
Major Criteria • Megakaryocytic proliferation and
atypia, without reticulin fibrosis > grade 1, accompanied by increased age-adjusted bone marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis
• Not meeting WHO criteria for BCR- ABL1+ CML, PV, ET, MDS, or other myeloid neoplasm
• Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker or absence of minor reactive bone marrow reticulin fibrosis
Minor Criteria • Anemia not attributed to a comorbid
condition • Palpable splenomegaly • Leukocytosis >= 11 x 109/L • Elevated LDH
Major Criteria • Megakaryocyte proliferation and
atypia accompanied by either reticulin and/or collagen fibrosis (grade 2 or 3)
• Not meeting WHO criteria for BCR- ABL1+CML, PV, ET, MDS, or other myeloid neoplasm
• Presence of JAK2, CALR, or MPL mutation or in the absence, the presence of another clonal marker or absence of evidence for reactive bone marrow fibrosis
Minor Criteria • Anemia not attributed to a comorbid
condition • Palpable splenomegaly • Leukocytosis >= 11 x 109/L • Elevated LDH • Leukoerythroblastosis
Pre-PMF as a distinct subgroup in MPN
Increased Risk of Bleeding Complications in Pre-PMF
International cohort of 1104 patients with ET
180 had pre-PMF
Incidence of major bleeding was 1.39% pts/year in early PF MF versus 0.79% pts/year in ET
Prognostic Scoring Systems in PMF
• IPSS – At time of diagnosis
• DIPSS – Anytime during the disease course
• DIPSS Plus – Anytime during the disease course
• MIPSS/MIPSS Plus – Anytime during the disease course
IPSS
• Blood Blasts ≥1%
Only applicable at time of diagnosis Low 0, Intermediate-1 1, Intermediate-2
2, High ≥ 3
• Can be applied at anytime during disease course
• Same factors as IPSS, but greater weight given to anemia (2 points)
Low 0, Intermediate-1 (1 – 2), Intermediate-2 (3 – 4), High ≥ 5
Not reached
14.2 years
4 years
1.5 years
DIPSS Plus
Risk Factors DIPSS int-1 1 point DIPSS int-2 2 points High risk 3 points
1 point for: Unfavorable karyotype Platelets < 100 x 109/L RBC transfusion dependent
Unfavorable karyotype = complex karyotype, +8, -7/7q, i(17q), -5/5q, 12p-, inv(3), 11q23 rearrangement
IPSS, DIPSS, and DIPSS plus for post PV/ET MF
Prognostic Model for post-ET/PV MF
MYSEC-PM:
• Hb < 11 g/dL (2 points) • Platelet count < 150 x109/L (1
point) • Circulating blasts >= 3% (2 points) • Constitutional symptoms (1 point) • CALR-unmutated (2 points)
Not reached
9.3 years
JAK2 V617F Mutation
Located on chromosome 9p24
MPL Exon 10 Mutations
MPL W515 mutations lead to cytokine- independent activation of the receptor
First described in 2006
Mutations in CALR
CALR Mutations (19p13.3) CALR is a molecular chaperone for glycoproteins and resides in the endoplasmic reticulum
C-terminal domain is responsible for calcium homeostasis
All mutations are indels
Both Type 1 and Type 2 lead to the same frameshift and more positively charged C- terminus
CALR Mutations
Mutations affect Exon 9 and lead to loss of ER retention signal (KDEL) and generation of a novel C-terminus
Nangalia J, Green TR. The evolving genomic landscape of myeloproliferative neoplasms. Hematology 2014.
Pathogenesis of CALR-mutant MPNs
MPL coupled with mutant CALR is exported to cell surface
Resultant constitutive activation of JAK/STAT in megakaryocytes harboring CALR mutation
Prognosis according to mutational status in patients with PMF
Additional Mutations
Mutations in ASXL1 and EZH2 are associated with worse prognosis
SRSF2 and IDH mutations also associated with worse prognosis
ASXL1 and SRSF2 Mutations
Tefferi et al. BJH (2017) doi: 10.1111/bjh.15010
676 PMF patients from multiple Italian institutions (AGIMM) 413 PMF patients from Mayo Clinic
MIPSS 70
Hb < 10 g/dL 1 WBC > 25 x 109/L 2
Blasts ≥ 2% 1 Plt count < 100 x 109/L 2
Fibrosis grade ≥ 2 1 ≥ 2 HMR mutations 2
Constitutional sx 1
1
Guglielmelli et al. JCO Feb 1 2018 36(4): 310 - 317
Italian cohort Mayo cohort
Guglielmelli et al. JCO Feb 1 2018 36(4): 310 - 317
Mayo Cohort Italian Cohort
Guglielmelli et al. JCO Feb 1 2018 36(4): 310 - 317
Risk Factor Point Risk Factor Point
Hb < 10 g/dL 1 Absence of CALR type 1 mutation 2
Blasts ≥ 2% 1 ≥ 2 HMR mutations 2
Constitutional sx 1 Unfavorable karyotype 3
HMR Category 1
Risk Category Points
Guglielmelli et al. JCO Feb 1 2018 36(4): 310 - 317
Mayo Cohort Italian Cohort
MIPSS 70 vs IPSS
Guglielmelli et al. JCO Feb 1 2018 36(4): 310 - 317
MIPSS Plus vs DIPSS Plus
Guglielmelli et al. JCO Feb 1 2018 36(4): 310 - 317
Treatment Options Before JAK2 Inhibitors
Allogeneic HSCT remains the only curative therapy
Barriers to HSCT in Myelofibrosis
• Older age of patients and comorbidities
• Graft failure
• Hepatotoxicity after transplantation
CIBMTR Study on HSCT in MF
• Included 289 patients with MF who received allo HSCT from 1989 to 2002
• Median age of patients 45 – 49
• Majority received myeloablative conditioning and bone marrow as source of stem cells
CIBMTR Study on HSCT in MF
Relapse Rate at 5 years post transplant: 32% for MSD vs 23% for MUD
Graft failure was 9% of MSD and 20% for MUD
Transplant related mortality at one year: 27% for MSD vs 43% for MUD
aGVHD 43% for MSD, 40% for MUD and cGVHD: 40% for MSD, 32% MUD
5 year OS for MSD was 37% versus 30% for MUD
CIBMTR: Reduced Intensity Conditioning
233 patients with MF underwent allo HSCT with RIC from 1997 to 2010
Median age 55 yo
Majority received PBSC (88%)
Probability at 5 years of: OS 47% PFS 27% NRM 24% Relapse/disease progression 48%
CIBMTR Study: RIC
MSD 56% MUD 48% Partially/mis-matched URD 34%
Rate of grade II-IV aGVHD 37% and 51% for cGVHD at 5 years
MPD-RC 101 Study
OS EFS
OS EFS
Prospective study of 66 MF patients who received RIC with mel/Flu
2 year OS: 75% in MSD 32% MUD
NRM was 22% for MSD versus 59% for MUD
MPD-RC Study
A retrospective analysis performed on data from 188 patients with PMF who underwent transplant and 255 patients with PMF treated with conventional non-HCT modalities at several European centers and Fred Hutch
Excluded post ET/PV patients, patients > age 65, and none of the patients in the non-HCT group received JAK inhibitors
Transplant vs Non-Transplant
FDA approved for intermediate and high risk MF
Effective in JAK2 mutated AND JAK2 WT MF patients
The COMFORT Trials
COMFORT 1: Ruxolitinib improved symptoms compared to placebo
COMFORT-2 Trial
Improvements in spleen response and constitutional symptoms compared to BAT
Overall Survival COMFORT 1
HR 0.44 (CI 0.18 – 1.04)
Long term follow up showed modest OS benefit with ruxolitinib compared to placebo and BAT
Durability of Spleen Response
COMFORT-1
COMFORT-2
Probability of maintaining response: 0.51 at 3 years 0.48 at 5 years
Myelosuppression with Ruxolitinib
Infectious complications such as shingles, PML, PCP pneumonia, and disseminated TB have been reported
“Ruxolitinib withdrawal syndrome”: accelerated splenomegaly, worsening cytopenias, hemodynamic decompensation, septic shock-like syndrome
Limitations of Ruxolitinib
• Does not decrease risk of leukemic transformation
• Does not lead to hematologic response
• Dose-limiting myelosuppression
• Does not improve bone marrow fibrosis in most patients
Take Home Message
• To approach MPN needs following the 2016 WHI criteria, classifying risk stratification and treatment according to risk stratification.
• For PV still using PV risk score (age > 60 and h/o thrombosis), for ET using IPSET plus thrombosis, for PMF, the most flexible is Thailand still IPSS score.
• Thrombocytosis is the risk for thrombosis in ET.
• For PMF, the treatment will be started with ruxolitinib if the the patients have IPSS >/=2.
• The BM transplantation for PMF wil have benefit when the patients have IPSS >/= 2.
THANKS FOR YOUR ATTENTION