management of all in the elderly alvaro alencar · 2018-03-14 · asparaginase in elderly all eur j...

Management of ALL in the ElderlyAlvaro Alencar

1

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


▪ 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


▪ 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 elderly R/R ALL

Cancer 122:2178, 2016

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 elderly R/R ALL

Cancer epub ahead of print Jan 30 2018

Inotuzumab + mini-HCVAD in R/R ALL


▪ 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


▪ 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

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

[email protected]

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management of all in the elderly alvaro alencar · 2018-03-14 · asparaginase in elderly all eur j...

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