3. • History of Present illness:
• Insidious onset, gradually progressive exertional
breathlessness and fatigability for 2 months
• Pedal edema and puffiness of face +
• Excessive menstrual bleeding for last 7 days with
passage of clots
• H/o joint pain involving both elbows+
• H/o head ache +
4. • No rash, bleeding gums, swelling of joints, bone
pain, fever, night sweats, cough with expectoration,
hemoptysis, chest pain, orthopnoea, PND
• No h/o jaundice, abdominal distension,
hematemesis, melena
• No h/o easy bruisability or uncontrolled bleeding
after trivial trauma
5. • Past medical history:
Admitted at GRH in Feb ’09
• Similar complaints with bleeding gums and arthralgia (Δ:
Iron def anemia), received blood transfusion
• Discharged after complete evaluation with advice for
follow up.
Admitted at RSRM in May ’10
• Excessive bleeding, severe than previous episode, received
blood transfusion, was reevaluated.
• No diabetes, hypertension, RHD, tuberculosis or recurrent
jaundice
6. • Personal History:
• Menarche at 12 yrs,
• Regular cycles 3-4/30days
• Menorrhagia(10/30) with clots for last 6 months
• Family history:
• Born of non consanguinous marriage,
• No bleeding disorders
7. • On Examination:
• Patient was conscious, oriented
• Afebrile, moderately built, poorly nourished
• Dyspnoeic and Tachypnoeic
• Pallor++, facial puffiness +
• No J/Cy/Cl/LNE
• No rash, no petechiae, ecchymosis, hemarthroses
• Mild bilateral Pedal edema +
• No bone tenderness
8. • Vitals
• PR: 90/min, regular
• BP: 110/70 mm Hg
• RR: 24/min
• CVS: S1S2 heard, systolic murmer +
• RS: NVBS b/l, no added sounds
• Abdomen: soft, normal in shape
• No dilated veins, liver palpable 2 cm, firm, non tender
• Splenomegaly(8cm), firm, smooth, non tender
• CNS: No FND, no meningeal signs, fundus N
11. Peripheral Smear
• RBCs:
Microcytic, hypochromic RBCs
No nucleated RBCs seen. No sickle cells.
No target cells. No inclusion bodies
• WBCs:
Leukopenia observed
Distribution and morphology normal
No immature cells seen
• Platelets: Thrombocytopenia
• Parasites: No blood parasites
24. • Based on this report a bone marrow biopsy was
done on 17th
:
• Cellular marrow showing preponderance of
granulocyte precursors including eosinophil
precursors, plasma cells, megakaryocytes, large
histiocyte like cells with abundant eosinophilic
cytoplasm and vesicular nucleus and foci of
fibrosis
• Imp: Early cellular phase of myelofibrosis
28. Primary Myelofibrosis
(Myelofibrosis with Myeloid Metaplasia)
• First described in 1879
• Later classified in 1951 as a myeloproliferative disorder
• Agnogenic myeloid metaplasia/Idiopathic myelofibrosis
• Myeloproliferative disorders include
1. Chronic myeloid Leukemia(Ph)
2. Polycythemia Vera
3. Essential Thrombocytosis
4. Primary Myelofibrosis
In 1960 -Philadelphia chromosome, Ph(t9:22) (BCR-ABL)
In 2005- JAK2V617F- a novel GOF mutation of JAK2 tyrosine
kinase- in PV(100%), ET & PMF (50%)
29. Primary Myelofibrosis
• It is a rare disease
• 1.3/100,00 people
• Median age 57yrs (90% are >40)
• Ashkenazy Jews
• Clonal stem cell disorder
• Classified as chronic myeloproliferative disorder
• WHO system- CIMF( chronic idiopathic myelofibrosis )
• Myeloid metaplasia refers to earlier proliferative
phase where extramedullary hematopoiesis
predominates
• <5% of ET go to MMM after 10-20 years
32. Clinical features
• Chronic, idiopathic progressive
anemia/thrombocytopenia
• Extramedullary hematopoiesis - HSM
• Splenomegaly is the hallmark
• Constitutional hypercatabolic syndromes (Fatigue,
fevers, weight loss, night sweats)- ultimately go for
cachexia.
• As spleen enlarges, pts may have left upper quadrant
discomfort, abdominal pain & early satiety
33. • Pruritus, easy bruising, lymphadenopathy
• Peripheral edema, ascites
• Bleeding/thrombosis
• Splenic infarcts
• EMH—LN, pleura, peritoneum, lung, paraspinal &
epidural spaces
• Secondary gout
• All myeloproliferative disorders can result in a
spent phase which can be difficult to distinguish
from primary MF
34. Diagnosis
• Peripheral blood smear
• normocytic anemia
• granulocytes and platelets.
• myelophthisis (most characteristic finding)
• leukoerythroblastosis (nucleated RBCs and granulocyte
precursors)
• teardrop-shaped RBCs (dacryocytes)
• Bone Marrow:
cellular phase(↑granulocytic and MKcytic,
↓erythrocytic )
hypocellular phase
fibrosis/osteosclerosis- usually dry tap
• Confirmed by bone marrow biopsy( reticulin stain)
35. Bone Marrow Features
• Ineffective erythropoiesis
• Dysplastic-megakaryocyte hyperplasia (secrete
PDGF, TGF-β, VEGF, bFGF, TNF)
• Increase in ratio of immature to total granulocytes
• Reactive bone marrow fibrosis (polyclonal
fibroblasts)
• Thickening and distortion of the bony trabeculae
(osteosclerosis)
• Bcr-abl negative
39. Tear Drop Cells
1. Myelofibosis
2. Infiltration of BM
3. Tumours of BM
4. Thalassemia
40. Proposed Modifications in Diagnostic Criteria
MAJOR
1. Atypical megakaryocytic
hyperplasia with
reticulin/collagen fibrosis
2. Exclusion of WHO criteria
for PV, CML, MDS, Other
MPDs
3. JAK2V617F or other clonal
marker, if not rule out
seconadary fibrosis
MINOR (2 out of 4)
1. Leukoerythroblastosis
2. Elevated serum LDH
3. Anemia
4. Palpable splenomegaly
41. Diagnostic Problems
• Neither myelophthisis nor marrow fibrosis is diagnostic
• Myeloid / Lymphoid / Non hematological disorders
• Close mimickers are
CML
MDS
Atypical MPD
AML
Specific tests include
• JAK2V617F screening
• cytogenetics
• FISH for BCR-ABL
43. Disease Course
• As disease progresses majority of patients become
transfusion dependent ( 2U in 7-14 d)
• Thrombocytopenia/neutropenia
• Spenomegaly and discomforts
• Symptomatic portal hypertension
• Bone pain
• Non thrombotic pulmonary hypertension
• Blastic transformation ~ 10% (2.6 month)
• Death: infection, bleeding, heart failure, liver failure,
portal htn, respiratory failure
44. Prognosis
• Median survival 3-5 yrs
• Adverse prognostic factors:
Anemia, Age >64
Hypercatabolic sx (wt loss, fatigue, NS, fever)
WBC>30 or <4, Blasts>1%
Cytogenetics +8, 12p-
• Most recent PSS (Mayo clinic)
Plt < 100 x10⁹/L
Hb <10 g%
TLC <4 or >30 x10⁹/L
Ab. Monocyte >1 x10⁹/L
Median survival in pts <60 yrs 14.4/5/2.2 yrs
45. Treatment
• There is no definitive therapy –
“WATCHFUL WAITING”
• Rx is supportive, with PRBC transfusions
• Drug therapy
• Splenectomy
• Radiation therapy
• Allogenic SCT
47. Splenectomy
Indications for surgery:
1. Symptomatic portal hypertension
2. Drug refractory splenomegaly with machanical
& hypercatabolic symptoms
3. Frequent transfusion requirement
48. Radiation Therapy
• Useful mainly for non hepatosplenic extra
medullary hemopoiesis in PMF
• Thoracic vertebral column- most frequent
site
• Other sites: LN, lung, pleura, small bowel,
peritoneum, urogenital tract and heart
• Idiopathic Pulm htn (due to occult pulmonary
EMH)- single fraction whole lung irradiation
49. Allogenic Stem Cell Transplantation
• Risk benefit ratio is not favorable
• But young patients have survival upto 60% at 5 yrs
( comp. to 14% in >44 yrs)
50. Back to our patient
• 32 yr, unmarried, menorrhagia, chronic anemia….of
late we have diagnosed a disease with poor PSS where
the treatment to date is ineffective
• Pending investigations are bone marrow iron staining
cytogenetic analysis
• Patient is now on
1. Danazol 200mg TDS
2. Prednisolone 10 mg OD
3. Folic Acid 5 mg OD
4. FST/Multivitamins
5. PRBC transfusions
51. Future
• Current treatment is inadequate…
• Each patient is different, response to therapy
also different.
• Eagerly looking for “small-molecule drug
therapy” targeting JAK2 or its downstream
effector molecules (STAT3, STAT5)
• Imatinib did wonders…. Future looks
promising
