Elderly AML by Mohamad Mohty


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  • This progress in the outcome of young and middle age adults with AML is in part due to a better selection of the treatment option availables, based on classic and new prognostic indicators. The current status of both, prognostic parameters and risk adapted therapy for adults with non APL will be summarized in this lecture. This slide reflects the usual approach for AML patients including the different decission steps and the possible treatment choices. At diagnosis the first decission is whether the patient is candidate for no therapy, low dose treatment or intensive chemotherapy. If the latter is administered and a CR is achieved practically all the patients receive one consolidation course and further treatment that may be postremission intermediate or high dose chemotherapy or hematopoietic transplantation. Subsequently, in contrast to ALL, only a minority of the patients receive further low or moderate dose maintenance, usually in the setting of clinical trials. If the patient unfortunately relapses, the options are no further treatment or low or high dose rescue therapy. What aspects may guide us to take between all these options the most appropriate choice in particular patients?
  • However, despite the higher frequency of impaired PS in the elderly population, early death occuring in the first month after diagnosis was significanlty more frequent with palliative measures than with intensive treatment, across all age groups and WHO grades, in exception of very old patients with good PS. Although these findings would favor intensive treatment in all cases, these data have some limitations: first, we have now comorbidity scores developed for transplantation that may be more precise than PS, second, cytogenetic categories were not considered and it is well know the poor chemosensitivity of AML with poor risk cytogenetics, particularly in the elderly. In contrast, encouraging results have been communicated in patients with abnormalities in chromosome 7, 5 and complex karyotype with demethylating and antiangiogenic agents. Also, investigational targeted therapy deserves to be investigated in the old and fragile patients.
  • Adult AML Slide Deck Master 08/22/13 03:53 A major area of progress and one of the most promising classes of therapeutic agents relate epigenetic or differentiation therapy. In addition to the impact of chromosomal abnormalities, gene expression in cancer cells in general, and to a high degree especially in myeloid malignancies, may be silenced by epigenetic alterations of DNA, which happens through two broad mechanisms: Global hypermethylation of DNA and promotors and changes in chromatin structure by modification of histone structures. Epigenetic alterations have been associated with disease progression and worse outcome for patients with myeloid leukemias and MDS and hence efforts to reverse these processes take an increasingly prominent role in current AML and MDS therapy.
  • Clofarabine is a second generation purine nucleoside analogue with significant single agent activity in patients with AML and ALL
  • Elderly AML by Mohamad Mohty

    1. 1. "Challenges in Treatment of"Challenges in Treatment of Elderly AML"Elderly AML" Pr. Mohamad MOHTY Head, Clinical Hematology and Cellular Therapy Dpt. Université Pierre & Marie Curie Hôpital Saint-Antoine Paris, France
    2. 2. AML: Change in overall survival with time (A) Age 15 to 59 years (B) 60 or more years
    3. 3. Simplified Classification of AML • AML sensitive to conventional chemotherapy • CBF leukemias (without c-KIT mutation) • Diploid AML with NPM1 and CEBPα mutation (without FLT3 mutation) • Dose intensification of chemotherapy may be helpful • Chemo-resistant and high risk AML • AML with adverse cytogenetics • AML with FLT3-ITD • Others (older patients, younger patients with t-AML and/or AHD) • New agents are needed • Allo-SCT in the mainstay of therapy
    4. 4. Therapy for AML (non-APL): Decision checkpointsTherapy for AML (non-APL): Decision checkpoints and Factors influencing therapeutic decisionsand Factors influencing therapeutic decisions Diagnosis Intensive CT Postremission therapy Rescue treatment Relapse Performance status Age Comorbidities Cytogenetics Molecular profile MRD persistencePharmacogenetics
    5. 5. Early death seems to be increased if palliative-low dose treatment is administered WHO/ECOG PS 0-II WHO/ECOG PS III-IV Intensive Palliative Intensive Palliative N.Pts % ED N.Pts % ED N.Pts % ED N.Pts % ED 491 4 12 25 38 26 4 50 344 6 22 27 43 28 19 63 435 8 131 21 62 34 92 54 211 14 397 17 56 36 271 52 Age group (yrs) 16-55 56-65 66-75 76-89 Juliusson G, et al. Blood 2009;113:4179-87 Although, • Comorbidity scores may be more discriminant • Cytogenetics should be taken into account • Is this true with targeted treatment? Intensive CT is the first option, regardless of age. Consider alternative agents if poor cytogenetics
    6. 6. Targeting molecular abnormalities Target Class of Agents FLT3 FLT3-inhibitors - Non specific - Specific KIT (CD117) TKI (imatinib, dasatinib) Epigenetic changes - Hypomethylating agents - HDAC inhibitors RAS FT inhibitors CD33 Anti-CD33 MoAbs
    7. 7. Me O O NH S H HO O OCH3 NH O O OCH3 N CH 3 CH2 O OH OCH3 HO CH3 O CH3 HN HO O O OH CH3 S CH3 OCH3 OCH3 I O O O O S O NHN Me Me O CH3 hP67.6 hP67.6 conjugated to NAc-calicheamicin Gemtuzumab Ozogamicin (GO)
    8. 8. Arm A Arm B 2nd course if BM blasts >10% at D15 DNR 60 mg/m2 D1, D2 AraC 1g/m2 /12h D1 to D3 INDUCTION 1st CONSOLIDATION 2nd CONSOLIDATION Fractionated Doses of Gemtuzumab Ozogamicin Combined to Standard ChemotherapyIn Newly-Diagnosed de novo AML Patients Aged 50-70 Yrs Randomization CR or CRp DNR 60 mg/m2 D1 to D3 AraC 200 mg/m2 D1 to D7 DNR 60 mg/m2 D1 AraC 1g/m2 /12h D1 to D4 DNR 60mg/m2 D1,D2 AraC 1g/m2 /12h D1 to D4 DNR 60 mg/m2 D1 to D3 AraC 200 mg/m2 D1 to D7 GO 3 mg/m2 D1, D4, D7 DNR 60 mg/m2 D1 AraC 1g/m2 /12h D1 to D4 GO 3 mg/m2 D1 DNR 60 mg/m2 D1,D2 AraC 1g/m2/ 12h D1 to D4 GO 3mg/m2 D1 Castaigne et al., Lancet 2012
    9. 9. Event-free survival EFS A (control) (n=139) B (GO) (n=139) Events 104 76 Median 11,9 mo 19.6 mo 2-year 16.5% 41.1% HR (95% CI) 1 0.57 (0.42-0.77) P= 0.00018 by the log-rank test GO arm Control arm Castaigne et al., Lancet 2012
    10. 10. Overall survival OS A (control) (n=139) B (GO) (n=139) Deaths 71 59 Median 19.2 mo 34 mo 2-year 43.5% 53.1% HR (95% CI) 1 0.70 (0.50-0.99) P= 0.046 by the log-rank test GO arm Control arm Castaigne et al., Lancet 2012
    11. 11. Epigenetic Therapy M M M M DNA Methylation Histone Modification Phosphorylation Methylation Acetylation 5-Azacytidine Decitabine SAHA Valproic acid Belinostat •
    12. 12. Azacitidine in AML • 358 pts AZA-001; 113 ≥20% blasts (WHO AML) • 55 randomized to AZA, 58 to CCR • Median age 70 y.; poor cytogen 24% • Median FU 20 m.; median cycles 8 (1-39) • Parameter AZA CCR P - Median OS (m) 24 16 .004 - % 2-yr survival 50 16 .004 - % CR 18 16 NS • Survival better in int cytogen., not in unfavourable cytogenetics. Fenaux et al. J Clin Oncol 2010
    13. 13. Randomized trial of Decitabine vs. treatment of choice in AML ≥ 65 years Kantarjian H, J Clin Oncol, 2012 CR/CRp Decitabine 17.8% TC 7.8% P=.001 Decitabine
    14. 14. N N N N OHO HO NH2 F HO Deoxyadenosine analogues N N N N OHO HO NH2 Cl N N N N NH2 OHO HO Cl F Fludarabine Cladribine Clofarabine
    15. 15. Single Agent Clofarabine in AML • Phase I 32 pts with acute leukemia: CR 6%; OR 15% MTD: 40 mg/m2 /d i.v. x 5d; DLT: hepatotox. • Phase II N Median age (yr) CR (%) OR (%) Frontline * Faderl1 16 71 (60-83) 31 31 Burnett2 36 > 70 44 56 Salvage Kantarjian3 31 54 (19-82) 42 55 Foran4 14 54 (20-78) 7 7 * CLO 30 mg/m2 /dose 1 Blood 2005; 106: 786a; 2 Haematologica 2006; 91 (s1): 45; 3 Blood 2003; 102: 2379; 4 Blood 2002; 100: 271b
    16. 16. - N=106 - Median age= 71 years (range, 60-84) - 30% adverse-risk cytogenetics - 36% WHO PS≥2 - 48% CR (32% CR, 16% CRi)
    17. 17. Clofarabine + cytarabine combination studies 1. Faderl S et al. Blood 2005;105:940 2. Powell B et al. Blood 2008;112:Abstract 1936 3. Becker PS et al. Blood 2008;112:Abstract 2964 N Age (y) Dose* Response Faderl 2005 29 63 (18–84) CLO 40 x 5 Ara-C 1 x 5 CR 24%; OR 41%; IM 3% Powell 2008 39 53 (18–79) CLO 40 x 5 Ara-C 2 x 5 CR 38%; OR 43%; IM 8% Becker 2008 16 18–70 CLO 15,20,25 x 5 Ara-C 2 x 5 G-CSF 5/8 CR O/E (HDAC, FLAG) 3.2:1 * CLO mg/m2 ; Ara-C g/m2  The next question: anthracycline combinations with clofarabine and cytarabine (at diagnosis and at relapse)…
    18. 18.  Much of the success of allo-SCT in cancer is due to the Graft-vs.-Tumor effect Confirming Barnes et al. (Br J Haematol 3: 241, 1957) Weiden et al., N. Engl. J. Med. 300:1068, 1979  Weiden et al., N. Engl. J. Med. 304:1529, 1981. Myeloablative HCT (MTX) Years after Sibling Marrow Grafts
    19. 19. The European Group for Blood and Marrow Transplantation H.B. 3.2011 EBMT Activity Survey on HSCT 1990-2009: changes in AML H S C T  Increase of allo- SCT as from 2001 due to: - Introduction of RIC - Increased use of alternative donors
    20. 20. Flu-TBI 2 Gy.
    21. 21. d-6 d-5 d-4 d-3 d-2 d-1 d0 Fludarabine 30 mg/m²/d (or Clofarabine) X X X X X I.V. Busulfan 3.2 mg/Kg/d (X) (X) (X) X Thymoglobuline 2.5 mg/Kg/d X X Cyclosporine 3 mg/Kg/d X X X X  MMF (2 g/d if MUD) X X X X  PBSC X I.V. BU-based Reduced Toxicity Conditioning (RTC) platform  towards a patient-tailored conditioning
    22. 22. RIC allo-SCT for AML: “donor” vs. “no donor” (N=95; Intention-to-treat analysis) Median FU = 60 months Overallsurvival(“intentiontotreat”) “donor” group “no donor” group Time (months) P=0.003 Overallsurvival Time (months) “donor” group “No donor” group P=0.003  In the multivariate analysis, only actual performance of RIC-allo- SCT (P=0.0005; RR=4.1; 95%CI, 1.8-9.1), was significantly predictive of an improved long term LFS Mohty et al., Leukemia, 2005 Leukemia, 2009
    23. 23. Day -6 -5 -4 -3 -2 -1 0 Bu    130 mg/m2 qd Flu      30 mg/m2 qd Thymoglobuline   2.5 mg/Kg PBSC  I.V. Bu-based “submyeloablative" conditioning (FB3): Prospective Multicentre Trial, N=80
    24. 24. I.V. Bu-based “submyeloablative" conditioning (FB3): Prospective Multicentre Trial; N=80 NRM 0 2 4 6 8 10 12 14 10% Protocol NCT 00841724; Mohty et al. ASH 2012
    25. 25. • AML therapy remains non-specific and challenging for most patients • A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1)  multi-agent approach needed • Emerging therapies are promising, and targeted therapies started addressing small subgroups, BUT allo-SCT will remain the recommended treatment for many patients ! • RTC allo-SCT appears increasingly to be a safer procedure in the “older” AML patients Conclusions