HSCT for Myeloproliferative Disorders Jane Apperley
Myeloproliferative disorders CML Polycythemia vera Essential thrombocythemia Primary myelofibrosis bcr-abl + bcr-abl - JAK2 (valine to phenylalanin an position 617) PV 65-95% ET 25-57% IMF ca. 50%
Myelofibrosis Incidence: 0.5-1.5 per 100.000 Primary (idiopathic): 90%; secondary (prior PV or ET): 10% Inappropriate release of fibrogenic cytokines or growth factors, resulting in myelofibrosis Splenomegaly Absence of Ph+ chromosome Leuko-erythroplastic blood picture
Variable clinical course of MF The Lille Scoring System Low: Hb > 10 g/dl and WBC 4-30 x 10 9 /l (median OS 93 months) Intermediate: Hb < 10 g/dl or WBC > 30 x 10 9 /l (median OS 26 months) High: HB < 10 g/dl and WBC < 4 or > 30 x 10 9 /l (median OS 13 months)
1. Hb < 10 g/dl Variable clinical course of MF Cervantes Scoring System 2. Presence of constitutional symptoms (fever, night sweats, weight loss) 3. Circulating blasts 1% Low: up to 1 adverse prognostic factor (median OS 176 months) High: 2 or 3 adverse prognostic factors (median OS 33 months)
Prognosis of MF
Inhibitors of JAK2 LS104 Atiprimod Degrasyn Erlotinib TG101209 AZ-01 In Vitro Murine ITF2357 MK-4567 AZ1480 AT9483 TG101348 XL019 CEP-701 INCB018424 Phase I 0 1 2 Phase II
INCB18424 Results in Rapid and Profound Reduction in Spleen Size 22.5 20.0 17.5 25 mg BID 24 Patients with Palpable Spleen or Liver 10 mg BID 12 Patients with Palpable Spleen or Liver Spleen Size, cm 15.0 12.5 10.0 7.5 N=11 N=19 N=8 5.0 2.5 N=17 N=9 N=2 0.0 0 28 56 84 112 140 168 196 224 252 Days on Therapy NOTE: Data is censored after a dose change or dose interruption
Improvement in constitutional symptoms 25 mg BID 10 mg BID 7 6 5 4 3 2 1 N=14 N=10 N=7 N=11 N=8 N=8 Fatigue Night Sweats Pruritis MFSAF Score (Maximum = 10) 0 Baseline 1 Mo 3 Mo Baseline 1 Mo 3 Mo Baseline 1 Mo 3 Mo Baseline 1 Mo Baseline 1 Mo Baseline 1 Mo Includes only patients with assessment for all time points
Effect of INCB018424 treatment on the percentage of V617F JAK2 Ratio of V617F to WT JAK2 assessed by quantitative genotypic analysis Peripheral Blood V617F Bone Marrow V617F V617F (% of baseline) 100 90 80 N=21 P=0.001 N=19 P=0.013 N=18 P=0.020 N=7 P=0.054 N=3 P=0.094 70 0 28 56 84 112 140 168 196 224 252 Day V617F (% of baseline) 100 90 80 70 N=6 P=0.005 N=2 0 28 56 84 112 140 168 Day Statistically significant but minor reduction of V617F:WT JAK2 ratio was noted in both peripheral blood and bone marrow
INCB018424 treatment (25 mg BID): other aspects of myelofibrosis Bone Marrow No significant changes in fibrosis score or cellularity No significant change in blasts Peripheral Blood No significant change in LDH No significant change in CD34+ cells
Allogeneic SCT for myelofibrosis n=55 (EBMT, GITMO,FHCRC) Overall survival Years after transplantation
Allogeneic SCT for myelofibrosis Myeloablative Pts Med. Age OS TRM Guardiola (1999) 55 42 47% (5y) 27% Deeg (2003) 56 43 58% (3y) 32% ----------------------------------------------------------------------------- Dose-reduced Rondelli (2005) 21 54 85% (2.5 y) 10% Kröger (2005) 21 53 84% (3y) 16%
High dose conditioning regimens and survival (related & unrelated, HLA identical)
EBMT Allo (RIC) Myelofibrosis Aim of the study To evaluate a dose-reduced conditioning regimen in patients with myelofibrosis with myeloid metaplasia (MMM)
Reduced intensity conditioning and allogeneic SCT for myelofibrosis PBSCT Fludarabine 30mg/m 2 Busulfan10mg/kg p.o. or Busilvex 8mg/kg i.v. ATG* ATG ATG Day -6-5 -4-3 -2-1 0 GvHD prophylaxis: CSA day 1 to 180 MTX 10 mg/m² day 1,3+6 *3x 10-20mg/kg
Patient characteristics Number of patients n = 103 Patients sex male 63 female 40 Donors sex male 65 female 39 Age (median) 55 yrs (range, 32 68) Myelofibrosis primary n = 62 post ET/PV n = 41 Time from diagnosis (MF) to transplantation median 18 months (range, 3 276)
Patient characteristics Lille score low 19 intermediate 58 high 17 Cervantes score low 30 high 57 Splenectomy 16
Patient characteristics Donor unrelated n = 69 related n = 34 JAK2 positive n = 51 negative n = 29 HLA-typing matched (8/8 allele) n = 86 mismatched n = 12 DRB1 n = 2 DQB1 n = 5 A n = 4 B n = 1
Results Day 100 1 year 3 years 5 years TRM (%) 5 17 17 Overall survival (%) 71 65 Event free survival (%) 59 51 Relapse risk(%) 10 22 31
Overall survival
Multivariate Analysis Non-relapse mortality: p-value Age > 50 years 7.15 (0.945-54.21) 0.01 Lille high/intermediate HLA-mismatch DFS 4.86 (1.40 16.83) 5.09 (2.05 12.65) 0.001 <0.001 OS Age > 50 years 4.7 (1.11 20.33) 0.03 Relapse Splenectomy prior SCT 3.4 (1.23 9.35) 0.03
Regression of fibrosis Grade 3 Grade 2 Grade 1 Grade 0 Prior SCT (n=24) Day 30 (n=17) Day 100 (n=12) Day 180 (n=20) Day 360 (n= 12) 49% 51% - - 18% 35% 35% 12% 0 25% 41% 34% 5% 10% (relapse) (n=1:relapse 45% 40% 0 0 33% 67%
before allo MF-3
day +30 MF-1
day +100 MF-0
Results In 15 patients, a close monitoring for the JAK2-mutation was performed after allografting. JAK2-negativity was achieved after a median of 89 days post allografting (range, 19-750).
JAK2 monitoring after DLI in a patient with residual disease after allo SCT
The role of SCT in the management of CML
Response in newly diagnosed CML at Imperial College (Hammersmith)
Outcome: 2nd generation TKI (n=113) 3 months 6 months 12 months Complete haematological remission 24% 24% 19% Minor cytogenetic response 14% 14% 12% Partial cytogenetic response 12% 8% 12% Complete cytogenetic response 35% 42% 48% Haematological failure 15% 12% 10%
Outcome of second generation TKI
Outcome of second generation TKI
Hammersmith Hospital: prognostic indicators for response to 2 nd generation TKI 80 CP-CML patients who had failed imatinib therapy at the Hammersmith Hospital between March 2005 and Jan 2008 were treated with a 2G-TKI - dasatinib n=67 nilotinib n=13 Median FU: 28.3 months (6.5-42) Milojkovic et al. ASH 2008
Pre-therapy factors that predict for complete cytogenetic responses Time from IM failure to start of 2G-TKI Sokal risk score Best CyR Additional cytogenetic abnormalities in Ph+ clones Haematological resistance to imatinib Requirement for G-CSF support % Ph+ metaphases at the start of 2G-TKI therapy Milojkovic et al. ASH 2008
Pre- 2G-TKI therapy independent predictive factors for CCyR following multivariate analysis Milojkovic et al. ASH 2008
The Hammersmith scoring system for predicting CCyR to 2G-TKI Milojkovic et al. ASH 2008
Cumulative incidence of best CCyR according to cytogenetic response at 3 months Milojkovic et al. ASH 2008
Three month landmark analysis for OS and EFS according to the CyR response at 3 months Milojkovic et al. ASH 2008
IRIS 6 yr Update: Declining Annual Event Rates Loss of CHR, Loss of MCyR, AP/BC, Death during treatment Hochhaus A. et al, Blood. 2007; 110, 11. 45 25.
Management of imatinib failure IM failure Hammersmith score Donor available Low Intermediate High EBMT score High Low 2G-TKI 2G-TKI SCT Milojkovic et al. ASH 2008
Acknowledgements Joachim Deeg David Marin Letizia Foroni Jamshid S. Khorashad Nicolaus Kroger Hugues de Lavallade Dragana Milojkovic Eduardo Olavarria Alistair Reid Richard Szydlo Alois Gratwohl John Goldman 47