management of all in the elderly alvaro alencar · 2018-03-14 · asparaginase in elderly all eur j...
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Management of ALL in the ElderlyAlvaro Alencar
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ALL in the elderlyseer.cancer.gov
36.2%11.7%
ALL in the elderlyJ Clin Oncol 17:2758, 2009
Biology of elderly ALL
▪ More frequent Ph(+) – 36%
▪ More complex karyotype
▪ Decline in PS
▪ Comorbidites
▪ Geriatric assesment
Br J Haematol 97:596, 1997;
Blood 115:206, 2010
Biology of elderly ALL
▪ Baseline organ function
▪ GI – vincristine
▪ CV – anthracyclines
▪ Liver – MTX, asparaginase, purine analogs
▪ Neuro – vincristine
▪ Kidney – MTX
▪ Balance toxicity and outcomes
Asparaginase in elderly ALLEur J Haematol 78_102, 2007
▪ PETHEMA
▪ induction w vincristine, daunorubicin, prednisone, cyclophosphamide, asparaginase
▪ Induction mortality – infection
▪ No cyclophosphamide and asparaginase - early death rate 70% to 22%
▪ UKALL14
▪ Peg-asparaginase extremely toxic in Ph(+)ALL
▪ Possible interaction with imatinib
Biology of elderly ALL
▪ Infectious complications
▪ Main cause of death at induction
▪ Growth factor support
▪ Azoles
▪ Stabilize prior to start
▪ Goals of care
▪ “Palliative”
Br J Haematol 157:463, 2012;
Blood 113:28, 2009;
Blood 121:2618, 2013
Biology of elderly ALLBlood 122:1366, 2013
Approach Age No of
studies
No of
patients
CR (%) Early death
(%)
Survival in
mos
Population-based
studies
>65 4 N/R 40 N/R 6-30
Palliative treatment 60-91 4 94 43 (34-53) 24 (18-42) 7 (3-10)
Intensive
chemotherapy
designed for adult ALL
without focus on older
patients
60-92 12 519 56 (40-81) 23 (6-42) 14 (3-29)
Prospective studies for
older ALL patient
55-81 9 447 71 (43-90) 15 (0-36) 33 (16-71)
2-yr OS 20-25% for >65, 10% for >75
EWALL protocolHaematologica 98:abstr S1124, 2013
▪ Induction
▪ Phase 1 (4 wks) - dexamethasone, vincristine, and idarubicin
▪ Phase 2 (4 wks) - cyclophosphamide and cytarabine
▪ Consolidation
▪ Alternating ID-MTX + asparaginase and HD-Cyt x 6
▪ Maintenance
EWALL protocolHaematologica 98:abstr S1124, 2013
▪ n=59, median age 66 yrs (56-73)
▪ 22% older than 70 yrs
▪ Gr 3-4 cytopenias 90%
▪ Infection – 16% phase I, ,25% phase II of induction
▪ CR 85% (49% maintained after 1 yr)
▪ 1 yr OS 61%
EWALL-PH-01 protocolBlood 128:774, 2016
▪ n=71, median age 69 (59-83)
▪ 77% CIRS-G>4
▪ CR 96%
▪ 54% relapse – 75% T315i mut
▪ 28% CR2
▪ Death 69%
▪ 29% non-relapse mortality
▪ 12% TRM
▪ 5 yr OS 36%
▪ 7 allo-HSCT
▪ Median age 60.3
▪ 3 died p HSCT
▪ 4 alive 53-65 mos
EWALL-PH-01 protocolBlood 128:774, 2016
Less intense protocol Ph(+) ALL
Blood 109:3676, 2007;
Blood 118:6521, 2011
▪ GIMEMA
▪ Imatinib 800 mg + prednisone
▪ ORR 100%, 1yr OS 74%, 1 yr DFS 48%
▪ Dasatinib 140 mg + prednisone
▪ CR 92%, 20-mo OS 69%
HSCT in elderly ALL
Oncotarget 8:112972, 2017;
Am J Hematol 92:42, 2017
▪ Survey from EBMT
▪ n=142, median age 62 (60-76)
▪ 3 yr OS 42%, leuk-free survival 35%
▪ RIC - CIBMTR data
▪ n=273, median age 61 (55-72), 50% Ph(+)
▪ 3 yr NRM 25%, 3yr relapse 47%, 3 yr OS 38%
▪ RR death (66+ vs. 55-60): 1.51 (95% CI: 1.00-2.29, p = 0.05)
▪ 3 yr OS in CR1 45% (95% CI: 38-52%), no relapse p 2 yrs
HSCT in elderly ALL
Cancer 122:2379, 2016;
Am J Hematol 91:793, 2016
▪ Ph 2 study
▪ n=30, median age 58 (51-72), Ph(+) 40%
▪ CR 67%
▪ 2 yr OS 52%, HSCT p CR – no improvement in OS
▪ Retrospective review pts >40
▪ N=80 (50% chemo only, 50% HSCT)
▪ 3 yr OS 46% vs. 40%, p= 0.35; 3 yr DFS, 31% vs. 40%, p = 0.98
▪ 3-yr CIR 61% vs 28%, p = 0.011; 3 yr NRM 9% and 32%, p = 0.014
Blinatumomab in R/R ALL
N Engl J Med 376:836, 2017
Blinatumomab in R/R ALL
N Engl J Med 376:836, 2017
Blinatumomab in elderly R/R ALL
Cancer 122:2178, 2016
Blinatumomab in elderly R/R ALL
Cancer 122:2178, 2016
Blinatumomab in elderly R/R ALL
Cancer 122:2178, 2016
Blinatumomab in R/R Ph(+) ALL
J Clin Oncol 35:1795, 2017
Blinatumomab in R/R Ph(+) ALL
J Clin Oncol 35:1795, 2017
Inotuzumab in R/R ALL
N Engl J Med 375:740, 2016
Inotuzumab in R/R ALL
N Engl J Med 375:740, 2016
Inotuzumab in R/R ALL
N Engl J Med 375:740, 2016
Inotuzumab in elderly R/R ALL
Cancer epub ahead of print Jan 30 2018
Inotuzumab in elderly R/R ALL
Cancer epub ahead of print Jan 30 2018
Inotuzumab + mini-HCVAD in R/R ALL
Cancer epub ahead of print Jan 30 2018
▪ Ph 2 study
▪ cyclophosphamide and dexamethasone 50% dose red
▪ no anthracycline
▪ methotrexate 75% dose reduction
▪ cytarabine 0.5 g/m2 × 4 doses
▪ Inotuzumab 1.3 mg/m2 C1 D3, 1.0 mg/m2 C2-4 D3 (ursodiol)
▪ IT x 8
▪ Maint POMP x 3 yrs
Inotuzumab + mini-HCVAD in R/R ALL
Cancer epub ahead of print Jan 30 2018
▪ N=59, 59% CR, ORR 78%, 1 yr OS 46%, median OS 11 mos
▪ MRD(-) 52% at morphological response, 82% up to C3
Inotuzumab + mini-HCVAD in 1L ALL
Lancet Oncol 19:240, 2018
▪ ORR 98%
▪ 85% CR, 10% CRi, 2% CRh
▪ 79% CR p C1
▪ 78% MRD(-) at morphological response
▪ 96% MRD(-) up to C3
Inotuzumab + mini-HCVAD in 1L ALL
Lancet Oncol 19:240, 2018
Inotuzumab + mini-HCVAD in 1L ALL
Lancet Oncol 19:240, 2018
Conclusion
▪ Strongly considered for therapy
▪ Comorbidities and goals taken into consideration
▪ Large proportion Ph(+) – TKI
▪ Selected patients could be considered for allo HSCT
▪ Newer agents changing landscape of disease
Thank you
aalencar@med.miami.edu
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