L’Ipertensione Polmonare nelle Malattie Ematologiche

Corso di aggiornamento sull’ipertensione polmonare. Pavia 21 maggio 2011

Giovanni Barosi Laboratorio di Epidemiologia Clinica/Centro per lo

Studio della Mielofibrosi. IRCCS Policlinico S. Matteo Foundation, Pavia, Italy

Malattie ematologiche con ipertensione polmonare

Hemolytic anemias• Thalassemia intermedia

• Sickle cell anemia

• Hereditary spherocytosis

• PK deficiency

• Unstable hemoglobin

• Paroxysmal nocturnal hemoglobinuria

• Microangiopathic hemolytic anemia

Myeloproliferative neoplasms• Essential thrombocythemia

• Polycythemia vera

• Primary myelofibrosis

• Eosinophilic leukemia

Lymphoproliferative disorders• Castelman disease

• POEMS

Pathogenesis of PH in hemolytic anemias

Perspectives

• Primary myelofibrosis –associated PH

• PH-associated myelofibrosis

Myelofibrosis and Pulmonary Arterial Hypertension (PH)

WHO Classification of tumours of hematopoietic and lymphoid tissues (2008)

MYELOPROLIFERATIVE NEOPLASMS

• Chronic myelogenous leukemia, BCR-ABL1 positive

• Chronic neutrophilic leukemia

• Polycythemia vera

• Primary myelofibrosis

• Essential thrombocythemia

• Chronic eosinophilic leukemia, NOS

• Mastocytosis

• Myeloproliferative neoplasm, unclassifiable

Classical Ph1-neg MPNsClassical Ph1-neg MPNs

Myeloproliferative Neoplasms (MPNs)

CML CNL/MCD

PV ET

PMF

1. Clonal proliferation of hematopoietic stem cell (mutational events like JAK2V617F)

Current Biological Pradigm of MMM

2. Clonal cells (CD34+, megakaryocytes, monocytes) excessively produce hematopoietic, fibrogenic and angiogenic growth factors

Current Biological Pradigm of MMM

MO

fibroblast

endothelium

M-CSF

SCF

IL-6

TGF-

MYELOPROLIFERATION MYELOFIBROSIS NEOANGIOGENESIS

TGF- PDGF

MKCD34+

TGF-VEGF

Castro-Malaspina, 1984; Le Bousse Kardiles et al, 2001; Rameshwar et al, 2000

Primary myelofibrosis

Barosi et al. Blood 2001

Barosi et al, BJH 2003

0

50

100

150

200

250

300

350

MMM PV ET Controls

3. CD34+ hemopoietic stem cells constitutionally migrate from bone marrow to blood and to extramedullary organs

Current Biological Paradigm of MMM

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

4,5

5,0

MMM Normal

CD34 + in PB CD34 + in Spleen

PERIPHERAL BLOOD

HEMATOPOIESIS FIBROSIS BONE

MARROW

A Biological Model of MMM

CD34+ CELLS

HEMATOPOIESIS

Anemia, thrombocytopenia

SPLEEN

Splenomegaly

Blast transformation

ANGIOGENESIS

ANGIOGENESIS?

•Relief of fatigue and constitutional symptoms•Relief of pruritus•Relief of severe anemia•Relief of transfusion dependent anemia•Treatment of transfusional iron overload•Relief of symptomatic splenomegaly•Relentless of spleen enlargement in progressive splenomegaly•Reversion of accelerated phase or blast transformation of the

disease•Treatment of extramedullary non-hepatosplenic hematopoiesis•Treatment of pulmonary hypertension•Treatment of portal hypertension•Treatment of splanchnic vein thrombosis•Treatment of thrombotic or hemorrhagic complication

Common clinical needs in PMF

PH in PMF (and MPNs)

Author Disorders Diagnosis of PH Incidence

Garypidou et al. (Haematologica 2004)

PV =2ET=14PMF=6CML=2

Transthoracic Echo (TTE)

41.7%

Altintas et al. (Leukemia & Lymphoma, 2007)

ET=46Reactive thrombocytosis=40

TTE ET= 47.8%Reactive thrombocytosis=0%

Gupta et al. (J Natl Med Ass 2006)

ET=9PV=15CML=3

TTE 48%

Cortelezzi et al. (Leukemia, 2008)

PMF or post ET/Post PV MF =36

TTE 36%

Limitations of epidemiological studies in MPNs

• Diagnosis of PH was not established as recommended by guidelines (Overestimation of the incidence)

• No distinction between post-embolic PH and primary PH

Clinical forms of PH in MPNs

• Chronic thromboembolic PH (CTEPH)

• Precapillary PH, mimicking Primary PH

Mechanisms for the development of PAH–like disease in primary myelofibrosis

• Thrombocythosis

• Non-hepatosplenic extramedullary hematopoiesis

• Enhanced angiogenesis

• Portal hypertension

Thrombocytosis

Secretion of vasoactive cytokines

Circulating TPO levels

PDGF secretion

Smooth muscle cells hyperplasia

Pulmonary hypertension

Non-hepatosplenic extramedullary hematopoiesis

Pulmonary myeloid infiltration

Growth factors and cytokine secretion

Pulmonary hypertension

Circulating megakaryocytes

Megakaryocyte embolism

Pulmonary capillary obstruction

Pulmonary hypertension

Enhanced angiogenesisHigh serum VEGF levels, low number of

circulating EPCs

Pulmonary hypertension

The current recommendations for how to manage PH in PMF

Tefferi, Mayo Clinic, 2011

• MF-associated PH is suspected in the presence of dyspnea/hypoxia on exertion and peripheral edema.

• It is important to rule out thromboembolic, infectious or inflammatory lung processes (high resolution CT scanning)

• Increased systolic pulmonary artery pressure on echography and an abnormal pulmonary uptake during technetium 99m sulphur colloid scintigraphy should be documented

• In the absence of an alternative explanation for pulmonary hypertension, treatment with single-fraction (100cGy) whole-lung irradiation is reasonable even if technetium scan was negative

PH-associated myelofibrosis

•Myelofibrosis is present in patients with PH. It is not a primary neoplastic hematopoietic disorder. Its mechanism remains to be elucidated (Popat U et al. Ann Intern Med, 2005

•Increased bone marrow hemangioblast number, alterations in erythroid/myeloid lineages, increased reticulin, and greater mobilization of bone marrow progenitor cells are integral part of PH disease (subclinical myeloproliferative process?) (Farha S et al. Blood 2011)

• Elevation of bone marrow progenitors and reticulin was revealed in non affected family members of patients with familial PH.

Pulmonary vascular disease and myeloid abnormalities in PAH.

Farha S et al. Blood 2011;117:3485-3493