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Treatment of Postthrombocythemic Myelofibrosis with Myeloid Metaplasia

Case Study. 65 yr old AA male high school principalHx throbocytosis in 1986-88BM bx '88Hypercellular (90%) dry tapM:E ratio 10:1Megakaryocytes were increased and dysplastic4 diffuse reticulin fibrosisDx with chronic myeloproliferative d/o thought to be MF. Case Study. Treated with Hydroxyur

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Treatment of Postthrombocythemic Myelofibrosis with Myeloid Metaplasia

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    1. Treatment of Postthrombocythemic Myelofibrosis with Myeloid Metaplasia Maggi Coplin June 20, 2003

    2. Case Study 65 yr old AA male high school principal Hx throbocytosis in 1986-88 BM bx 88 Hypercellular (90%) dry tap M:E ratio 10:1 Megakaryocytes were increased and dysplastic 4+ diffuse reticulin fibrosis Dx with chronic myeloproliferative d/o thought to be MF

    3. Case Study Treated with Hydroxyurea and allopurinol for 1 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

    4. Case Study 2000 comes in with WBC 78K, Hb 12.9, plt 707 BM bx 70% cellular M:E 10:1 Moderately increased platelets Diffuse reticulin fibrosis Cytogenetics normal

    5. 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)(q21;p21.3) 1 year later ? HSM

    7. 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 >40) Classified as chronic myeloproliferative disorder (like PV and ET) Clonal stem cell disorder <5% of ET go to MMM after 10-20 years

    8. 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

    9. 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

    10. 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

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

    14. 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-

    15. Dupriez Scoring

    16. Dupriez Scoring

    17. 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

    18. 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)

    19. Treatment Options Halotestin 10mg bid for anemia and prednisone (0.5/kg/d) for anemia (<30% RR and transient) EPO; PRBCs Danazol 200-800mg/day improves anemia Hydroxyurea for increased WBC or Plts Busulfan Melphalan 2-chlorodeoxyadenosine

    20. Splenectomy N=223 Indications for surgery: Mechanical discomfort (39%) Portal HTN (11%) Severe hypercatabolic symptoms (5%) PRBC needed frequently (45%)

    21. 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

    22. Splenectomy Operative mortality 9% postop morbidity 31% Postop thrombocytosis, hepatomegaly in 25%

    23. 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

    24. 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 N=9 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

    25. 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

    26. 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 2:7 responders died of AML or PD 2:5 marrows had improved fibrosis

    27. 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

    28. Thalidomide Anemia improved in 3:15 pts (20% RR) Platelets increased in 12:15pts (80% RR) Hemoglobin increased to >11 in 3:15 pts Spleen size decreased in 3:12 pts (25%) Toxicities EMH in 1 pt, leukocytosis in 2pts, thrombocytosis in 3:15 pts (in both pts with MMM post ET) No effect on fibrosis

    29. 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

    30. Thalidomide 62 pts from 5 trials with >100mg/d 49 pts (79%) had >4 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

    31. Thalidomide and Prednisone 50mg/d THAL + 0.5mg/kg/d prednisone for 1 month then taper steroid over 2 months Eligibility: anemia (<10) symptomatic SM 21 pts (5 females) Median age 66 (43-78)

    32. 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 <100K 6(75%) had 50% increase 4:21 (19%) had decrease in spleen size Responses to spleen size or plts occurred only in pts who had Hb response

    33. Thalidomide and Prednisone Toxicities: Constipation 38% Leukocytosis 38% Mild neuropathy 29% Visual changes 19% Anxiety 19% 10:13 responders finished another 3 months of thalidomide 60% of them maintained response Leukocytosis in 38% pts Thrombocytosis in 19% pts

    34. 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 3:5 pt with plts <100K had 50% increase

    35. 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

    36. Gleevec N=23 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

    37. 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 12:16 pts had 200 mg/day and 9 of them had to stop this dose also

    38. 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 <100K) No responses in bone marrow

    39. 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 N=22 with MMM

    40. 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

    41. Etanercept 60% had improvement in constitutional symptoms (12:20 pts) 6:8 (75%) had improved night sweats with 5:6 had it stop completely 7:7 (100%) with weight loss had stable weight (2) or weight gain (5) 10:20 (50%) had improved fatigue Before PM asks8 doses is $888 Rx price and $1600 patient price per month

    42. 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 <45 years old 14% if >45 yrs old

    43. Allogeneic Stem Cell Transplant Reduced Intensity Conditioning Eligibility >45 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)

    44. Allogeneic Stem Cell Transplant Reduced 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 N=4 (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

    45. Allogeneic Stem Cell Transplant Reduced 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

    46. Case Study Hydrea reduced HSM and ascites/LE edema Held hydrea for plts 61 Last CBC: WBC 45 Hb 8.3 Plts 108

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