Treatment of Postthrombocythemic Myelofibrosis with Myeloid Metaplasia

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Treatment ofPostthrombocythemicMyelofibrosis
with Myeloid Metaplasia

• Maggi Coplin
• June 20, 2003

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Case Study

• 65 yr old AA male high school principal
• Hx throbocytosis in 1986-88
• BM bx 88
• Hypercellular (90) dry tap
• ME ratio 101
• Megakaryocytes were increased and dysplastic
• 4 diffuse reticulin fibrosis
• Dx with chronic myeloproliferative d/o thought to
  be MF

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Case Study

• Treated with Hydroxyurea and allopurinol for 1 ½
  yrs then stopped on his own
• Seen at BJC 1998 (12 years later)
• (Plts 639K, WBC 11, Hb 13.1, LDH 551)
• Bone marrow biopsy similar to 1988
• Dx with ET - stable for 2 years

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Case Study

• 2000 comes in with WBC 78K, Hb 12.9, plt 707
• BM bx 70 cellular
• ME 101
• Moderately increased platelets
• Diffuse reticulin fibrosis
• Cytogenetics normal

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Case Study

• Repeat CBC WBC 10, Hb 12, plt 616
• 15 months later..flu-like symptoms
• peripheral blasts on routine CBC
• WBC 35, 17 blasts Hgb 11.5, plts 108
• BM bx RAEB with MF
• Cytogenetics 46,XY, der(6)t(1,6)(q21p21.3)
• 1 year later ? HSM

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Myelofibrosis with Myeloid Metaplasia

• First described in 1879
• Aka agnogenic myeloid metaplasia or
  postthrombocythemic myeloid metaplasia
• 1.3/100,00 people
• Median age 60 (90 are gt40)
• Classified as chronic myeloproliferative disorder
  (like PV and ET)
• Clonal stem cell disorder
• lt5 of ET go to MMM after 10-20 years

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Clinical features

• Chronic, idiopathic progressive anemia
• Extramedullary hematopoiesis
• HSM (SM is the hallmark)
• Bone marrow fibrosis
• Hypercatabolic syndromes (Fatigue, fevers, weight
  loss, night sweats)
• Evolution to acute leukemia

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Diagnosis

• suggested by peripheral blood smear
• normocytic anemia
• increased or decreased number of granulocytes and
  platelets.
• myelophthisis
• teardrop-shaped RBCs (dacryocytes)
• leukoerythroblastosis (nucleated RBCs and
  granulocyte precursors)
• confirmed by bone marrow biopsy
• Usually dry tap

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Bone Marrow Features

• Ineffective erythropoiesis
• Dysplastic-megakaryocyte hyperplasia (secrete
  PDGF, TGF-b, 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

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From   Tefferi N Engl J Med, Volume
342(17).April 27, 2000.1255-1265
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Cytogenetics

• In 30-50 of patients
• 13q-, 20q-, Trisomy 8,9 chromosome 1, 12 abn
• Chromo 5 and 7 unusual and suggest MDS

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Prognosis

• Median survival 3-5 yrs
• Adverse prognostic factors
• Anemia
• Age gt64
• Hypercatabolic sx (wt loss, fatigue, NS, fever)
• WBCgt30 or lt4
• Blastsgt1
• Cytogenetics 8, 12p-

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Dupriez Scoring
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Dupriez Scoring
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Myelofibrosis with myeloid metaplasia following
Essential Thrombocythemia

• 195 patients with ET
• Median age 60 (11-90)
• 7.3 years median F/U
• 31 had elevated LDH (moderate)
• 74 asymptomatic
• 74 had some treatment
• 13 got MMM (6.6) at a median of 8 yrs (3-20)
• Actuarial probability
• 2.7 at 5 years, 8.3 at 10 years, 15 at 15 years

Cervantes et al. BJH 2002118786-790
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MMM following Essential Thrombocythemia

• Features preceding diagnosis of MMM
• Myeloid precursors in peripheral blood
• Increased LDH
• Plt count decrease
• Leukocytosis
• Palpable spleen
• No constitutional symptoms (unlike de novo MMM)

Cervantes et al. BJH 2002118786-790
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Treatment Options

• Halotestin 10mg bid for anemia and prednisone
  (0.5/kg/d) for anemia (lt30 RR and transient)
• EPO PRBCs
• Danazol 200-800mg/day improves anemia
• Hydroxyurea for increased WBC or Plts
• Busulfan
• Melphalan
• 2-chlorodeoxyadenosine

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Splenectomy

• N223
• Indications for surgery
• Mechanical discomfort (39)
• Portal HTN (11)
• Severe hypercatabolic symptoms (5)
• PRBC needed frequently (45)

Tefferi et al 2000952226
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Splenectomy

• Improvement in symptoms in majority
• 16 had increase in hepatomegaly
• 22 had increase in thrombocytosis
• 16 had blast transformation
• Median survival 2 years
• Low plts and BM without hypercellularity assoc
  with poor prognosis

Tefferi et al 2000952226
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Splenectomy

• Operative mortality 9
• postop morbidity 31
• Postop thrombocytosis, hepatomegaly in 25

Tefferi et al 2000952226
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Splenic Radiation

• Radiation in 23 pts
• 100-500cGy to spleen
• Transient benefit (6 months) from pain, spleen
  size
• 10 mortality from prolonged cytopenias
• Median survival 2 years

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2-CdA after splenectomy

• Pts post splenectomy with HM or increased plts
• 2-CdA 0.05-0.1 mg/kg/d civi for 7d q28d
• N9
• 6 male, 3 female
• median age 54 (43-72)
• 7 with MMM median of 8 years
• 1 with MMM post PV for 2 years
• 1 with MMM post ET for 3 years
• Median of 16 mo (2-47) post splenectomy

Tefferi et al BJH 199799352
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2-CdA after splenectomy

• Marked fibrosis in 7 pts
• Mild/moderate fibrosis in 2 pts
• 7pts had abnormal cytogenetics
• 8 had HM, 1 had increased plts
• All had palpable HM
• 3 pts were transfusion dependent
• 2 had mild anemia

Tefferi et al BJH 199799352
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2-CdA after splenectomy

• At median F/U of 15 months
• 4 were dead (PD in 2, AML in 1, GIB in 1)
• 78 pts had reduction in liver size of 50 and
  improvement in fatigue and plts
• 50 of responders had durable remission
  (4-28months)
• No improvement in anemia
• 27 responders died of AML or PD
• 25 marrows had improved fibrosis

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Thalidomide

• Single-agent thalidomide at 200 mg/d has been
  evaluated in MMM
• 15 pts accrued at a 200mg/d dose
• Dose escalation of 200mg/d q month planned
• Primary endpoint improved anemia or SM
• Median age 65 (42-79)
• 13 with de novo dz 2 with post ET dz
• Dupriez score 2- 4pts, 1 8pts, 0-3pts

Elliott et al BJH 2002117288
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Thalidomide

• Anemia improved in 315 pts (20 RR)
• Platelets increased in 1215pts (80 RR)
• Hemoglobin increased to gt11 in 315 pts
• Spleen size decreased in 312 pts (25)
• Toxicities EMH in 1 pt, leukocytosis in 2pts,
  thrombocytosis in 315 pts (in both pts with MMM
  post ET)
• No effect on fibrosis

Elliott et al BJH 2002117288
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Thalidomide

• Dose escalation was only allowed in 2 pts
• SE constipation, fatigue, parasthesia,
  somnolence, anxiety,depression, decreased
  hearing, visual changes, tremor
• 50mg/d gave same efficacy
• Concluded Myeloproliferative reactions are
  possible and serious and that 50mg was safe

Elliott et al BJH 2002117288
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Thalidomide

• 62 pts from 5 trials with gt100mg/d
• 49 pts (79) had gt4 weeks of trt
• 29 had increase in Hgb
• 38 had increase in plts
• 41 had decreased spleen size
• 45 had a decrease in symptom score
• 18 had myeloproliferative reaction
• 66 had SE and stopped before 6 monhts

Barosi et al ASH 2002 Abstract 3157
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Thalidomide and Prednisone

• 50mg/d THAL 0.5mg/kg/d prednisone for 1 month
  then taper steroid over 2 months
• Eligibility
• anemia (lt10)
• symptomatic SM
• 21 pts (5 females)
• Median age 66 (43-78)

Mesa et al. Blood 2003 101(7) 2534-41
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Thalidomide and Prednisone

• 95 completed three months
• 13(62) had clinical response (improved Hgb)
• 10 transfusion-dependent pts 70 responded and
  40 were independent
• 8pts with plts lt100K 6(75) had 50 increase
• 421 (19) had decrease in spleen size
• Responses to spleen size or plts occurred only in
  pts who had Hb response

Mesa et al. Blood 2003 101(7) 2534-41
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Thalidomide and Prednisone

• Toxicities
• Constipation 38
• Leukocytosis 38
• Mild neuropathy 29
• Visual changes 19
• Anxiety 19
• 1013 responders finished another 3 months of
  thalidomide 60 of them maintained response
• Leukocytosis in 38 pts
• Thrombocytosis in 19 pts

Mesa et al. Blood 2003 101(7) 2534-41
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Gleevec

• 13 pts 9men/4 females, median age 65
• Dupriez score 2 32
• 1 46
• 0 22
• Abnormal cytogenetics in 32
• 600mg/d for three months
• Response improved anemia or splenomegaly
• No objective responses
• 35 pt with plts lt100K had 50 increase

Odenike et al. ASCO 2003 Abstract 2354
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Gleevec

• 4 patients with transfusion dependence
• 600mg/day 5wks-5 months
• 1 pt transfusion independent
• 1 has 60 less transfusions
• 3 had decreased spleen size

DeLoughery et al ASH 2002 Abstract 4944
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Gleevec

• N23
• Median age 63 (37-78)
• 7 pts Dupriez Score 2 7 (30)
• 1 10 (4)
• 0 6 (26)
• 9 PRBC dependent
• 11 with constitutional symptoms
• 8 had previous chemo
• 65 had abnormal cytogenetics

Teferri et al. Blood 2002993854
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Gleevec

• Gleevec at 400mg/d (200mg/day if reduced)
• 16 pts (70) had treatment held after 1-12 weeks
  because of side effects
• neutropenia 6pts muscle pain 5 pts
• increase plts 4pts edema 3 pts
• incr bilirubin 1pts
• 1216 pts had 200 mg/day and 9 of them had to
  stop this dose also

Teferri et al. Blood 2002993854
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Gleevec

• Overall, only 48 of patients (11) could continue
  for 3 months and 5 more dropped out later
• Only 6 pts continued for 6 months
• No improvement in anemia in any pt
• 2 PR in splenomegaly
• 48 of pts had increase in plts (none in pts with
  counts lt100K)
• No responses in bone marrow

Teferri et al. Blood 2002993854
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Etanercept

• TNF inhibits hematopoiesis, stimulates
  fibroblasts, mediates fever and cachexia
• Etanercept a soluble TNF receptor
• Open label pilot study
• Dose 25mg SQ biw for 24 weeks
• N22 with MMM

Steensma et al Blood 2002992252
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Etanercept

• 20 had objective response
• 1 had Hb increase of 3g/dl and PRBC independent
• 1 had stable Hb by 1g/dl
• 1 decrease in PRBC by 50
• 1 increase plts 16-182K
• 1 spleen 10cm BCM to 2cm BCM
• No response in marrow fibrosis
• 1 pt dropped out for reversible pancytopenia

Steensma et al Blood 2002992252
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Etanercept

• 60 had improvement in constitutional symptoms
  (1220 pts)
• 68 (75) had improved night sweats with 56 had
  it stop completely
• 77 (100) with weight loss had stable weight (2)
  or weight gain (5)
• 1020 (50) had improved fatigue
• Before PM asks8 doses is 888 Rx price and 1600
  patient price per month

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Allogeneic Stem Cell Transplant

• International collaborative study on 55pts
• Median age 42 Non relapse mortality was 27
• 91 engraftment
• 70 had complete hematological response
• 40 had a decrease in fibrosis
• 47 5 yr OS
• 1 year GvH 36
• Age determined outcome
• 62 5yr if lt45 years old
• 14 if gt45 yrs old

Guardiola et al Blood 1999932838
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Allogeneic Stem Cell TransplantReduced Intensity
Conditioning

• Eligibility
• gt45 years old
• Matched sibling ( and one willing to donate)
• Diagnosed with MMM
• Dupriez score of 1-2
• Conditioning Regimen
• Flu 30mg/m2 x5d (day 6 to 2)
• Melphalan 70mg/m2 x2d (day 3, -2)

Devine et al Blood 2002992255
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Allogeneic Stem Cell TransplantReduced Intensity
Conditioning

• GvH Prophylaxis
• FK506 0.03mg/kg/d by civi beginning day-2
• MTX 5mg/m2 IV days 1, 3, 6
• GCSF 5ug/kg/d beginning day 7
• N4 (all males, de novo dz, grade 4 fibrosis,
  constitutional sx)
• Median age 56 yrs (48-58)
• Diagnosis to Transplant 9.5 months
• F/U 13mo

Devine et al Blood 2002992255
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Allogeneic Stem Cell TransplantReduced Intensity
Conditioning

• No grade 3-4 toxicities
• One had acute GvH (grade 1) 3 chronic
• 100 engraftment by day 18
• 100 decrease in spleen size (2 complete)
• 100 decrease in fibrosis (grade 4 to 1)
• 100 have normal cellularity 1 year later

Devine et al Blood 2002992255
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Case Study

• Hydrea reduced HSM and ascites/LE edema
• Held hydrea for plts 61
• Last CBC WBC 45 Hb 8.3 Plts 108