Ideal induction therapy for newly diagnosed AML. Do we have a consensus? Prof Vikram Mathews. CMC, Vellore

1. VIKRAM MATHEWS, MD
CMC, Vellore, India
 Professor & Chair, Department of Hematology,
Christian Medical College, Vellore, India
 Dr. Matthews is leading hematologist in India. His
interests include: Acute myeloid leukemia, Acute
Promyelocytic leukemia, Evaluation of mechanisms of
resistance to arsenic trioxide and impact of novel
agents in the management of acute promyelocytic
leukemia, Allogeneic stem cell transplant. Improving
clinical outcomes by studying risk stratification,
modifying conditioning regimens and graft
manipulation. Study of inhibitors in hemophilia.

2. Ideal induction therapy for newly
diagnosed AML. Do we have a
consensus?
BTG Beijing Jan 2015
Vikram Mathews
Department of Haematology
Christian Medical College
Vellore

3. Overview:
 Limit data and presentation to young adults
 Overview of risk stratification
 Bench mark clinical outcomes: which any
additional interventions should attempt to
improve on.
 Variations in induction:
 - Dose of anthracycline
 - Variations in anthracycline
 - Dose of Cytosine arabinoside
 - Addition of a third drug
 - Novel agents
 Perspective from our data (developing
country challenges)

4. Risk Stratification
ELN 2010
Based on initial German AML 6 study
Validated CALGB data (N=1550). Mrozek et al. JCO 2012
Updated ELN 2012. Patel et al. NEJM 2012
included additional mutations: IDH1/2, TET2, ASXLI, PHF6+
Separate analysis of ELN
Rollig et al. JCO 2011
<60 years: RFS Int1 7.9mths
Vs. Int2 39.1mths
>60 years no significant
difference
Medan OS not as significantly
different

5. Risk Stratification
Last 5 years recognition of subset ‘Monosomal Karyotypes’ defined as
≥ 2 autosomal monosomies – Very poor prognosis
SWOG studies of n=1344 ; 13% MK: 4 year OS 3% (Medieros et al. Blood 2010)

6. Bench mark of clinical outcome:
CALGB data: Mayers et al. NEJM 1994
< 60 years
Conventional 7/3 followed by 3-4 HiDAC (3gm/m2)
4 year DFS 44%
TRM 5%
Severe neurological toxicity 12%
Subsequent analysis of 5yr RFS (CCR) CTG groups:
Favorable 50%
Intermediate (NK-AML) 32%
Others 15%

7. Dose of anthracycline:

8. Phase III study (ECOG):
n = 657
Age 17 – 60 years
Randomized:
1. 45mg/m2 x 3 days
2. 90mg/m2 x 3 days
Induction:
Std dose 63.9% CR P<0.001
High dose 70.6% CR
Toxicity profile comparable
Exception of LV function (4 cases Vs. 0)
Prior SWOG study with 60mg/m2 better data?

10. ASH 2014
A Randomised Comparison of Daunorubicin 90mg/m2
Vs 60mg/m2 in AML Induction: Results from the UK
NCRI AML17 Trial in 1206 Patients. Burnett et al.

11. Idarubicin: Randomized studies
__________________________________________________
Group Drugs n CR% Ref%
MSKCC Ida / AraC 60 80 13
DNR / AraC 60 58 35
GIMEMMA Ida / AraC 124 40 14
DNR / AraC 125 39 31
GOELAM Ida / AraC 111 78 14
Rubidazone/ AraC 112 81 14
SECSG Ida / AraC 105 71 10
DNR / AraC 113 58 18
Intergroup Ida / AraC 97 70 -
DNR / AraC 111 59 -
Long term FU
Benefit +
No difference
No difference
Alternative anthracyclines:
Recent reported meta-analysis : No difference between Ida and high dose DNR
Teuffel et al. BJH 2013

12. JCO 2009
Dnr:Mito:Ida = 50:12:10 mg/m2

13. ALSG:
Bishop et al. Blood 1996
SWOG
Appelbaum et al.Blood 1996
Note: OS not significantly
different from CALGB data
with standard approach
Benefit<50 years
Similar experience in German AML Co-operative trial. No difference in CR, DFS or OS
Subset with - poor risk karyotype ]
- > 50% blasts on BM on day 16 ] beneficial
- high LDH ]
Buchner et al. Blood 1999
High dose cytosine in induction

14. High dose cytosine in induction
High-Dose Cytarabine in Induction Treatment Improves the Outcome of
Adult Patients Younger Than Age 46 Years With Acute Myeloid Leukemia:
Results of the EORTC-GIMEMA AML-12 Trial Roelof Willemze,
Willemze et al. JCO 2014
N = 1942: CR rates were 72.0% and 78.7%, respectively (P < .001)
At a median follow-up of 6 years
OS 38.7% for patients randomly assigned to SD cytarabine
42.5% for those randomly assigned to HD cytarabine
(log-rank test P = .06; multivariable analysis P = .009).
For patients younger than age 46 years:
OS 43.3% and 51.9%, respectively
(P = .009; multivariable analysis P = .003)
For patients age 46 to 60 years
OS 33.9% and 32.9%, respectively (P = .91).
Patients of all ages with very-bad-risk cytogenetic abnormalities and/or
FLT3-ITD , or with secondary AML benefitted from HD cytarabine.
Category 1 recommendation
In NCCN 2015 for patients
<45 years
Note: Only one consolidation and then SCT

15. ALSG (Bishop et al. 1990) suggested that addition of etoposide
beneficial to younger patients
There is little evidence to suggest that addition of third drug
confers any benefit (excluding high dose induction
protocols)
UK MRC AML 10 trial no difference if third drug was thioguanine
or etoposide
Similarly in more recent UK MRC AML 15 trial no benefit of addition
of etoposide in induction (Burnett et al. JCO 2015)
Addition of third drug to induction regimen:

16. CR rate: no difference ~85%
FLAG-Ida: reducing relapse (38% v 55%; P=.001)
relapse-free survival (45% v 34%; P=.01)
MACE/MidAc was superior for high-risk patients.
Cytarabine at 1.5 g/m2 is equivalent to a 3 g/m2 dose
A fifth course provided no benefit.
Patients receiving FLAG-Ida
+Cytosine consolidation

17. N=632
DAC benefitted > 50 years
High risk karyotype
WBC >50,000/mm3
Toxicity profile comparable

18. Novel agents
 Gemtuzumab
 Sorafenib
 Lestaurtinib (CEP701) – negative data at
ASH 2014 (UK; N=500 RCT)
 Dasatinib for Kit mutated CBF leukemia
(CALGB10801). Small numbers : n=59, 10
ckit mutated
 Aurora kinase inhibitors – Phase I study
Alisertib (n=14)

19. ASH
2014

23. Sorafenib:
 Multi-kinase inhibitor
 Promise in FLT3 mutated AML
 Negative data in elderly RCT and
increased toxicity (Serve et al. JCO
2013)
 ASH 2014: RCT in young adults (SAL-
Soraml Trial, Germany) n = 276
Improvement in EFS
No significant benefit on OS
Significant increase risk of infection,
bleeding and hand foot syndrome

24. Presentation in India (?developing world)
“DIFFERENT”
 Younger age
 Delay in presentation / diagnosis
 More advanced disease and
co morbidities
 Partially treated
 Difficult to quantify adverse variables
 Treatment expensive
 Predominantly self pay
 39 million people / year go below the poverty
line due to medical related expenses

25. Results:
Diagnosed AML: 427
Newly diagnosed 380
≤ 15 years 47 (12.3%)
>15 - <60 years 271 (71.3%)
≥ 60 years 62 (16.3%)
Median age 40 (1 – 79)
Males 244 (64.2%)
5
14.7
15.8
15
18.4
15.5
12.1
3.4
0
2
4
6
8
10
12
14
16
18
20
0--10 11--20 21--30 31--40 41--50 51--60 61--70 71--80
Percentage
Age(years)
A
BJH 2015 In Pres

26. Results:
 Median duration of symptoms 4 weeks (1 – 52)
 Median distance from hospital 580 km (6 –
3200); 29 from another country
 ECOG score ≥ 2 23%
6.5
16.8
6.5
26.1
9.6
7.9
6.8
9.2
6.1
2.6 1.8
0
10
20
30Percentage
Duration of symptoms
BJH 2015 In Pres

27. Objective 2: Compare the frequency of these markers in our population with
previously published data.
The trend suggests that for the majority of markers evaluated the
incidence of of these mutations in our population is similar to that
reported in the literature.
Gene N Mutation n(%) Reported (%)
NPM1 337 96 (28.5) 35
FLT3-ITD 336 64 (19) 20
FLT3-TKD 335 13 (3.88) 5
WT1 (exon7/9) 316 11 (3.5) 12
JAK2 270 1 (0.3) NA
c-KIT (exon 8/17) 272 6 (2.2) 7
CEBPα - single 248 61 (21.5) 25
CEBPα - double 284 10 (3.52) 5-7
N-RAS 276 25 (9) 18
AML1-ETO 337 30 (8.9) 5-10
MYH-CBFβ 337 19 (5.6) 5-10
MLL-PTD 297 8 (2.7) 5
Final report DBT COE June 2014

28. Results: Proportion that opted
for treatment
Of the 109 who received treatment:
Pediatric (≤15 years) : 23 (21%)
Young adults (>15 - <60 years) : 75 (69%)
Elderly (≥60 years): 11(10%)
0
2
0--10 11--20 21--30 31--40 41
Age (years
Treated
(n=109)
29%
Nottreated
(n=271)
71%
E
B C
D
N
No Isolate
(n=38)
35% Non CRE*
(n=31)
69%
Gram
Negative
No
(
BJH 2015 In Pres

29. Results: Microbiologic isolates
in Induction
Mixed
(n=8)
7%
Gram
positive
cocci
(n=18)
16%
No Isolate
(n=38)
35% Non CRE*
(n=31)
69%
CRE*
(n=14)
31%
Gram
Negative
Bacilli
(n=45)
42%
Carbapenem resistant enterobacteriaceae (CRE) infections were
identified based on the CDC, USA interim surveillance definitions
as enterobacteriaceae with non-susceptibility to carbapenem and
resistance to third generation cephalosporins. Euro Surveill. 2012;17(26)
Following induction chemotherapy:
 Febrile neutropenia: 100%
 Blood culture +ve 71 (65%)
(on at least one occasion)
 GNB 45 (42%)
 GPC 18 (16%)
 Mixed 8 (7%)
BJH 2015 In Pres

30. Results: Early deaths
Following induction chemotherapy:
 Febrile neutropenia 100%
 Early post induction deaths 27 (24%)
 Majority related to sepsis and fungal
infection
 An additional 17 died in period of study of which 9 due to
disease recurrence
Mixed
(n=3)
11%
Gram positive
cocci (n=2) 7%
No isolate
(n=4)
15%
CRE
(n=7)
39%
Non CRE
(n=11)
61%
Gram
negative
bacilli
(n=18)
67%
Of non-CRE Carbepenem
Resistant Pseudomonas in 5
MDR organism 12 (45%)
Invasive fungal infection 12 (44%)
BJH 2015 In Pres

31. Results: Survival
 Numbers small
 Follow up short
Median FU 7 mths
 22 alloSCT CR1
 18 young adults
 4 pediatric
 One year KM values
BJH 2015 In Pres

32. Results: Patients not receiving
treatment
The patients who opted not to have treatment at our
center were significantly:
 Older,
 Lived further away from the hospital
 Longer duration of symptoms
Variable* Patients (n = 271)
n (%)
Lack of financial resources to proceed with treatment 219 (81)
Alternative medicine (Ayurveda / Homeopathy / Traditional / Native) 5 (1.9)
Lack of social support 45 (16.6)
Concerned about toxicity of chemotherapy 26 (9.5)
Apathy and fatalistic attitude 17 (6.2)
Preferred to seek treatment elsewhere 4 (1.4)
Data not available 10 (3.7)
Summary of reasons
for not proceeding
with treatment :
More than one reason
allowed / patient

33. Conclusion :
 Major challenge is financial burden and absence of a
health security net to treat all newly diagnosed
patients with AML
 Fungal infections remain a problem
 MDR bacterial infections is major challenge. Likely to
increase world wide. Limits ability to intensify
therapy to improve clinical outcomes
 Cost of therapy directly related to recurrent cycles of
cytopenia, duration of neutropenia and need for
intensive support in ICU
 Novel combinations and targeted therapy without
recurrent cytopenia are needed

34. Thankyoufor yourattention