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Belangenverklaring In overeenstemming met de regels van de Inspectie van de Gezondheidszorg (IGZ) Naam: Organisatie: E. Meijer VU medisch centrum Ik heb geen 'potentiële' belangenverstrengeling Type van verstrengeling / financieel belang Ontvangst van subsidie(s)/research ondersteuning: Ontvangst van honoraria of adviseursfee: Lid van een commercieel gesponsord speakersbureau : Financiële belangen in een bedrijf (aandelen of opties): Andere ondersteuning (gelieve te specificeren): Wetenschappelijke adviesraad: Naam van commercieel bedrijf Geen Geen Geen Geen Geen Geen 2
Controverses in de postremissie behandeling bij AML patiënten in 1 ste complete remissie Ellen Meijer 8DHC 3
Postremissie therapie Chemotherapie Autologe SCT Allogene SCT 4
OS and RFS of patients with AML in CR1 randomized to ASCT or consolidation chemotherapy Vellenga E et al. Blood 2011;118:6037-6042 5 2011 by American Society of Hematology
From: Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission: Systematic Review and Meta-analysis of Prospective Clinical Trials JAMA. 2009;301(22):2349-2361. doi:10.1001/jama.2009.813 RFS benefit by cytogenetic risk Risk group Donor No-Donor No of trials HR (95% CI) Good risk 188 359 10 1.06 (0.80-1.42) Intermediate risk 864 1635 14 0.76 (0.68-0.85) Poor risk 226 366 14 0.69 (0.57-0.84) Figure Legend: Black rectangles indicate summary effects estimates (hazard ratios [HRs]) for individual study reports. Sizes of data markers are proportional to the study weights. Error bars indicate 95% confidence intervals (CIs). AML indicates acute myeloid leukemia; 6 RFS, relapse-free survival. a Studies only reporting RFS end points.
From: Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission: Systematic Review and Meta-analysis of Prospective Clinical Trials JAMA. 2009;301(22):2349-2361. doi:10.1001/jama.2009.813 OS benefit by cytogenetic risk Risk group Donor No-Donor No of trials HR (95% CI) Good risk 188 359 10 1.07 (0.83-1.38) Intermediate risk 864 1635 14 0.83 (0.74-0.93) Poor risk 226 366 14 0.73 (0.59-0.90) Figure Legend: Black rectangles indicate summary effects estimates (hazard ratios [HRs]) for individual study reports. Sizes of data markers are proportional to the study weights. Error bars indicate 95% confidence intervals (CIs). AML indicates acute myeloid leukemia. 7
Donor-No donor analysis HOVON 4/29/42 Donor No donor P HR (95% CI) n Relapse rate % @ 4 y (±SE) n Relapse rate % @ 4 y (±SE) All patients 326 32 ± 3 599 59 ± 2 <.001 Good risk 32 22 ± 7 73 32 ± 6.17 0.46 (0.37 0.57) 0.57 (0.24 1.31) Intermediate risk 178 28 ± 3 333 55 ± 3 <.001 0.47 (0.34 0.64) Poor risk 116 39 ± 5 193 77 ± 3 <.001 0.43 (0.31 0.60) Cornelissen Blood 2007 8
Monosomal karyotype vs other cytogenetic risk categories HOVON 4/29/42 Cytogenetic Subgroup No. of Patients Outcome (% at 5 years) OS RFS Relapse NRM AlloHSCT CN 306 60 57 23 20 CA 87 58 53 26 20 CA-unfavorable 117 46 40 43 17 MK 45 19 17 68 15 AutoHSCT/CT CN 688 46 37 59 4 CA 168 36 31 67 2 CA-unfavorable 115 26 14 83 3 MK 62 8 7 91 2 Cornelissen JCO 2012 9
Nonrelapse mortality Reductie relapse risico 10
HOVON 116 Cyclofosfamide 14.5 mg/kg iv dag -6 en -5 Fludarabine 1dd 30 mg/m2 iv dag -6 t/m -2 TBI 2 Gy dag -1 SC infusie dag 0 CsAdag +5 tot +30 DLI Dag +90 Cy 50 mg/kg dag +3 en +4 2 cycli Panabinostat/decitabine dag +30 tot +90 Panabinostat 20 mg po dag 1,4,8,11 Decitabine 20 (10) mg/m2 iv dag 1 t/m 3(5) 11
Figure 2 The metabolic pathway of cyclophosphamide Emadi, A. et al.(2009) Cyclophosphamide and cancer: golden anniversary Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2009.146
Discussie tav waarde van een allosct bij: -Intermediaire risicogroep Prognostische waarde van MRD bepalingen -Ouderen Veranderingen in risicoclassificatie Analyse naar de uitkomst van allogeen transplanteren in 2 de CR 13
Discussie tav waarde van een allosct bij: -Intermediaire risicogroep Prognostische waarde van MRD bepalingen -Ouderen Veranderingen in risicoclassificatie Analyse naar de uitkomst van allogeen transplanteren in 2 de CR 14
Association between pre-hct MRD, as determined by multiparameter flow cytometry, and post-hct outcome for AML patients in CR1 and CR2 2013 by American Society of Hematology Walter R B et al. Blood 2013;122:1813-1821
Discussie tav waarde van een allosct bij: -Intermediaire risicogroep Prognostische waarde van MRD bepalingen -Ouderen Veranderingen in risicoclassificatie Analyse naar de uitkomst van allogeen transplanteren in 2 de CR 16
Risicoclassificatie bij AML in HOVON verband HOVON 4/29/42 Group Good Intermediate Poor Risicogroep Verdeling Definition t(8;21) and WBC count 20 10 9 /L and no additional Good risk 11% unfavorable cytogenetic abnormalities inv/del(16) and no additional unfavorable cytogenetic abnormalities Intermediate risk 55% Poor risk 33% Patients not assigned to good or poor-risk groups Unfavorable cytogenetics: complex karyotypes ( 3); del(5q)/ 5; del(7q)/ 7; abn(3q); t(6;9)/t(9;22); abn(11q23); and late CR 17
HOVON 92/102 Risk Good GR1 GR2 GR3 GR4 Risicogroep Definition t(8;21) or AML1-ETO, WBC 20 inv16/t(16;16) or CBFB-MYH11 MI-, CEBPA+ MI-, FLT3ITD-/NMP1+, CRe Verdeling Intermediate IR1 t(8;21) or AML1-ETO, WBC>20 Good risk 11% IR2 CN X Y, WBC 100, CRe Poor Very Poor Intermediate risk 31% PR1 PR2 PR3 VPR1 VPR2 VPR3 CN X Y, WBC 100, not CRe CN X Y, WBC>100 CA, non CBF, MI-, no abn3q26, EVI1- Poor risk 47% Very poor 11% Non CBF, MI+ Non CBF, abn3q26 Non CBF, EVI1+ 18
HOVON 132 Risicogroep Criteria bij diagnose plus vroege/late CR MRD status na cyclus II Postremissie behandeling Gunstig t(8;21) of AML1-ETO, WBC 20 inv16/t(16;16) of CBFB-MYH11 MK-, biallelic CEBPA+ MK-, FLT3ITD-/NMP1+ MRD- of MRD+ MRD- of MRD+ MRD- of MRD+ MRD- of MRD+ AutoSCT Intermediair CN X Y, WBC 100, CRe t(8;21) of AML1-ETO, WBC>20 MRD- MRD- AutoSCT CN X Y, WBC 100, CRe t(8;21) of AML1-ETO, WBC>20 MRD+ MRD+ Ongunstig CN X Y, WBC 100, not CRe CN X Y, WBC>100, CA, geen CBF, MK-, geen abn3q26, EVI1-neg MRD- or MRD+ MRD- MRD- AlloSCT CN X Y, WBC>100 CA, geen CBF, MK-, geen abn3q26, EVI1-neg MRD+ MRD+ Zeer ongunstig MK+ abn3q26 Geen CBF, EVI1+ Geen CBF, mutant p53, mutant RUNX1, mutant ASXL1 Biallelic FLT3-ITD+ MRD- of MRD+ MRD- of MRD+ MRD- of MRD+ MRD- of MRD+ MRD- of MRD+ AlloSCT 19
Discussie tav waarde van een allosct bij: -Intermediaire risicogroep Prognostische waarde van MRD bepalingen -Ouderen Veranderingen in risicoclassificatie Analyse naar de uitkomst van allogeen transplanteren in 2 de CR 20
Curability of Patients With Acute Myeloid Leukemia Who Did Not Undergo Transplantation in First Remission Alan K. Burnett, Anthony Goldstone, Robert K. Hills, Donald Milligan, Archie Prentice, John Yin, Keith Wheatley, Ann Hunter, and Nigel Russell Conclusion Successful salvage treatment of patients who do not undergo transplantation in CR1 and relapse can be achieved in 19% of patients, which is improved by a transplant except in favorable risk disease. This result suggests that, for intermediate-risk patients in particular, equivalent overall survival can be achieved by delaying transplantation until after relapse, which would require many fewer transplants. 21
Discussie tav waarde van een allosct bij: -Intermediaire risicogroep -Ouderen 22
CI of (A) nonrelapse mortality (P =.66) and (B) relapse (P =.87) in patients undergoing RIC allosct for AML in first CR or for MDS McClune B L et al. JCO 2010;28:1878-1887 2010 by American Society of Clinical Oncology
Outcome after allosct in older patients: myeloablative conditioning vs reduced intensity; Retrospective EBMT registry data Lim JCO 2010 Mohty Blood 2010 * Median Disease Donor Conditioning Age NRM % RI % LFS % OS % @ yr MDS/ Sib/ MAC, n=500 > 50 44 33-30 4 saml MUD RIC, n=833 > 50 32 41-32 4 ALL Sib MAC, n=449 50* 29 31 38-2 (45-68) 56* RIC, n=127 (45-73) 21 47 32-2 Lim JCO 2010; Mohty Blood 2010 24
RIC allosct for patients with AML: long term results of a donor versus no donor Mohty Leukemia 2008 25
Comparison of RIC allosct with CT in patients age 60-70 yr with AML in first CR Farag BBMT 2011 26
AlloSCT versus chemotherapy as postremission therapy for AML: a prospective matched pairs analysis Stelljes JCO 2014 27
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HOVON 42, 92: OS by post-remission treatment in 760 patients 40-60 yr in CR1 Of Note: preliminary data, ongoing analysis 30
HOVON 42, 92: OS and RFS by post-remission treatment in 760 patients 40-60 yr in CR1 100 Overall survival - stratified risk 100 Relapse free survival - stratified risk Cumulative percentage 75 50 25 Allo Auto CT Cumulative percentage 75 50 25 Allo Auto CT 0 CT Auto Allo N 271 152 F 148 72 CT Auto Allo 337 165 Cox LR Stratified P =0.004 0 months 60 At risk: 310 155 295 181 115 215 136 96 187 111 73 163 80 47 126 0 CT Auto Allo N 271 152 F 176 84 CT Auto Allo 337 175 Cox LR Stratified P <.001 0 months 60 At risk: 310 155 295 126 101 200 94 82 176 77 65 155 59 39 117 Unpublished results HOVON 31
OS RFS Consolidation type HR 95% CI p value HR 95% CI P value Allo vs. CT 0.70 0.55-0.88.003 0.54 0.43-0.68 <.001 Auto vs. CT 0.81 0.61-1.08.15 0.72 0.55-0.94.015 RIC vs. MAB 0.80 0.55-1.17.25 0.89 0.61-1.29.53 tcd-mab vs. MAB 1.92 1.15-3.20.016 1.74 1.06-2.86.034 Relapse NRM Consolidation type HR* 95% CI p value HR* 95% CI P value Allo vs. CT 0.35 0.27-0.46 <.001 6.82 2.67-17.40 <.001 Auto vs. CT 0.70 0.53-0.92.010 2.13 0.69-6.57.18 RIC vs. MAB 1.02 0.65-1.61.92 0.63 0.33-1.20.16 tcd-mab vs. MAB 0.56 0.22-1.46.21 3.85 1.98-7.50 <.001 32
OS by allohsct conditioning type (A), OS by allohsct conditioning type (partial T-cell depletion separately) (B) 100 Overall survival - stratified risk 100 Overall survival - stratified risk Cumulative percenta age 75 50 25 0 MAB RIC N 157 F 83 MAB RIC 180 82 Cox LR Stratified P =0.11 At risk: 157 180 96 118 84 103 75 87 RIC MAB 0 months 60 62 63 Cumulative percentage 75 50 25 0 MAB tdmab RIC N 119 38 F 59 24 MAB tdmab RIC 180 82 Cox LR Stratified P =0.03 At risk: 119 38 180 75 21 118 66 18 103 59 16 87 RIC MAB tdmab 0 months 60 49 13 63 Unpublished results HOVON 33
HOVON 42, 43, 81, 92: OS by post-remission treatment in 640 patients 60 in CR1 Of Note: preliminary data, ongoing analysis 100 Overall survival All patients 100 Overall survival Unfavorable risk NoCons CT RIC N 69 37 25 F 61 35 14 Cumulative percentage e 75 50 25 NoCons CT RIC NoCons CT RIC At risk: 637 3 0 N 366 177 97 F 285 129 62 198 105 56 114 66 45 75 47 29 RIC CT NoCons 0 0 months 60 39 35 20 Cumulative percentage e 75 50 25 NoCons CT RIC At risk: 130 1 0 18 12 14 8 6 12 4 3 7 RIC CT NoCons 0 0 months 60 1 2 3 Unpublished results HOVON 34
HOVON 42, 92: OS by H92 risk classification patients 40-60 in CR1 HOVON 42, 43, 81, 92: OS by ELN risk classification patients 60 in CR1 Unpublished results HOVON 35
Ustun BMT 2013 36
MET DANK AAN: JAN CORNELISSEN, JURJEN VERSLUIS, WIM VD PUTTEN EN BOB LÖWENBERG VOOR DE VERSTREKKING VAN DE PRELIMINAIRE HOVON DATA 37