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Tailoring Treatment:�The Role of Precision Medicine in Hematology

Christopher A. Fausel, Pharm.D. MHA BCOP

Director of Pharmacy, Precision Genomics

Indiana University Simon Comprehensive Cancer Center

Indianapolis, IN

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Learning Objectives

  • Understand the origins of targeted therapy in hematologic malignancies
  • Identify targeted agents in hematologic malignancies with activity not predicated on the presence of a biomarker
  • Describe genomically tailored therapy in hematologic malignancies

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Arsenic Trioxide/Tretinoin Acute Promyelocytic Leukemia Phase 3 Trial

Lo-Coco F et al. N Engl J Med. 2013;369:111-21.

R

A

N

D

O

M

I

Z

E

Patients with newly diagnosed acute promyelocytic leukemia aged 18–71 years; detection of PML-RARA/t(15;17)

�(n=156)

Primary Endpoint: Event-Free Survival (EFS) – non-inferiority design

Tretinoin (all-trans retinoic acid) (45 mg/m2/day PO)

​

Arsenic trioxide (0.15mg/kg)/day 5 days per week

Tretinoin (all-trans retinoic acid) (45 mg/m2/day PO)

​

Idarubicin (12 mg/m2 IV on days 2, 4, 6, 8)

​

Arsenic trioxide 0.15mg/kg/day 5 days per week on weeks 0 through 4 then 8 through 12 then 16 through 20 then 24 through 28

Tretinoin (45 mg/m2) PO daily for 15 days �x 7 cycles

If CR achieved

Idarubicin (12 mg/m2) IV on days 1 - 4 consolidation 1

​

Mitoxantrone (10 mg/m2) IV on days 1 – 5 consolidation 2

​

Idarubicin (12 mg/m2) IV on days 1 consolidation 3

​

​

Tretinoin (45 mg/m2) PO daily for 15 days �x 3 cycles

Post-consolidation maintenance for 2 years with

tretinoin/methotrexate (PO)/6-mercaptopurine

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Tretinoin/Arsenic Trioxide Efficacy Results

Parameter

Tretinoin/Arsenic Trioxide (n=77)

Tretinoin/Idarubicin (n=79)

Hematologic CR

100%

95%

Median time to Hematologic CR

32 days

35 days

EFS at 24 months

97%

86%

2-year OS

99%

91%

Disease-free survival at 24 months

97%

90%

Differentation syndrome

19%

16%

Deaths during induction

0

4

Deaths during consolidation

1

3

Lo-Coco F et al. N Engl J Med. 2013;369:111-21.

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The Philadelphia (Ph) Chromosome/The bcr-abl Oncoprotein�

bcr-abl

abl

FUSION PROTEIN�WITH TYROSINE�KINASE ACTIVITY

22

bcr

Ph (or 22q-)

9

9 q+

t(9;22) translocation

1

p210bcr-abl

p190bcr-abl

2-11

2-11

Chromosome 9

c-bcr

Chromosome 22

c-abl

2-11

Exons

Introns

CML Breakpoints

ALL Breakpoints

bcr-abl gene structure

p230bcr-abl

2-11

Pasternak G, et al. J Cancer Res Clin Oncol. 1998;124:643-660.

Melo JV. Blood. 1996;88:2375-2384.

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Imatinib: Phase III IRIS Trial

Hochhaus A et al. Leukemia 2009; 23:1054-61; O’Brien S et al. N Engl J Med 2003; 348:994-1004.

Patients with chronic-phase CML

(N = 1106)

Imatinib

400 mg/day*

(n = 553)

Interferon alfa

5 million Units/m2 daily +

Cytarabine

20 mg/m2 10 days/mo

(n = 553)

Imatinib

(n = 364)

Crossover to Imatinib†

(n = 359)

Crossover to Interferon†

(n = 14)

Interferon alfa/ Cytarabine

(n = 13)

*Increased stepwise to 400 mg BID allowed if no complete hematologic response (CHR)

at 3 months or > 65% Ph+ cells at 12 months.

†Permitted for no CHR at 6 months, no major cytogenetic response (MCyR) at 12 months, loss of

response, or treatment intolerance. IRIS – International Randomized Study of Interferon vs STI571.

​

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IRIS 8-Year Annual Event Rates

  • Estimated EFS at 8 years = 81%
    • 1 progression to AP/BC and 2 non-CML related deaths occurred in year 8
  • Estimated rate of freedom from progression to AP/BC at 8 years = 92%

0

1

2

3

4

5

6

7

8

1

2

3

4

5

6

7

8

3.3

1.5

7.5

2.8

4.8

1.8

1.7

0.9

0.8

0.5

0.3

0

0

1.4

1.3

0.4

Year

Event, %

Event� Loss of CHR,� Loss of MCyR,� AP/BC,� Death during treatment

AP/BC

Deininger et al. ASH 2009;114:Abs # 1126.

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Resistance Genotypes in CML

TKI Point Mutations

Imatinib

Dasatinib

Nilotinib

WT BCR-ABL

M224V

G250E

Q252H

Y253H

Y253F

E255K

E255V

V299L

F311L

T315I

S

I

I

I

R

R

R

R

S

S

R

S

S

S

I

S

S

I

I

I

S

R

S

S

S

I

I

I

I

I

NA

S

R

S = Highly Sensitive I = Intermediate Sensitivity R = Resistance

Quintas-Cardama A. Blood 2009; 113:1619.

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The Era of Molecularly Targeted Drugs in Hematologic Malignancies

Drug

Target

Disease

Acalabrutinib/ibrutinib/ zanubrutinib

Bortezomib/carfilzomib/ixazomib

Copanlisib/duvelisib/idelalisib

Lenalidomide/pomalidomide

Selinexor

Venetoclax

Bruton’s Tyrosine Kinase

​

Proteosome

PIK3CA

Immunomodulation

XPO1

BCL-2

CLL

​

Myeloma

NHL/CLL

Myeloma/CLL

Myeloma

CLL/AML

Rosenquist R, et al. J Intern Med 2023;294;413-36.

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Midostaurin Phase 3 Trial

Stone RM, et al. N Engl J Med. 2017;377(5):454-464.

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A

N

D

O

M

I

Z

E

Patients with newly diagnosed AML with FLT3 mutations �(ITD and TKD) aged 18–59 years

�(n=717; 3277 originally screened for FLT3 mutations)

Primary Endpoint: OS

Cytarabine (200 mg/m2) continuous IV on days 1–7

Daunorubicin (60 mg/m2) IV �on days 1–3

​

Midostaurin 50 mg PO bid �on days 8–21

Cytarabine (200 mg/m2) continuous IV on days 1–7

Daunorubicin (60mg/m2) IV �on days 1–3

​

Placebo PO bid on days 8–21

Cytarabine (3000 mg/m2) IV Q12H on days 1, 3, and 5

​

Midostaurin 50 mg PO bid �on days 8–21

OR

Placebo PO bid on days 8–21

​

Repeat cycle every 28 days �x4 cycles

If CR achieved

*Maintenance: midostaurin 50 mg PO bid or placebo every 28 days x12 cycles

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Midostaurin Efficacy Results

Parameter

Midostaurin (n=355)

Placebo (n=354)

Median OS

74.7 months

25.6 months

4-year OS

51.4%

44.3%

Median EFS

8.2 months

3 months

4-year EFS

28.2%

20.6%

Median disease-free survival

26.7 months

15.5 months

SCT performed in first remission �(57% of all patients received SCT at some point)

28.1%

22.7%

Protocol-specified complete remission

59%

54%

Median time to complete remission

35 days

35 days

Stone RM, et al. N Engl J Med. 2017;377(5):454-464.

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Gilteritinib vs. Salvage Chemotherapy

R

A

N

D

O

M

I

Z

E

AML patients with confirmed FLT3 mutation refractory to induction chemotherapy or in untreated first relapse

(N=371)

Primary endpoint: OS

Median follow-up:�13.7 months

Gilteritinib 120mg PO daily x 28 day cycles

(n = 247)

Pre-randomization selected salvage chemotherapy:

Low-dose cytarabine; azacitidine; mitoxantrone/etoposide/cytarabine; fludarabine/cytarabine/idarubicin/filgrastim

(n = 124)

Cortes JE, Heidel FH, Hellmann A, et al. Leukemia. 2019;33(2):379-389.

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Efficacy – Gilteritinib in Relapsed/Refractory FLT3 Mutated AML: Phase III Trial

Parameter

Gilteritinib �(n=247)

Salvage Chemotherapy �(n=124)

Median OS

9.3 months

5.6 months

(HR=0.64, P<0.001)

OS at 1 Year

37.1%

16.7%

CR with Full or Partial Hematologic Recovery

34%

15.3%

(risk difference 18.6 [9.8-27.4])

CR

21%

11%

PR

13.4%

4%

Median EFS

2.8 months

0.7 months

Median Leukemia-free Survival

4.4 months

6.7 months

Perl AE, et al. N Engl J Med. 2019;381(18):1728-1740.

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Enasidenib: Phase I/II – IDH2 AML

Stein EM, et al. Blood. 2017;130(6):722-731.

E

N

R

O

L

L

Patients with relapsed/refractory AML with mutant IDH2

�(n=239; 109 for �Phase 2 dose)

Primary Endpoint Phase 1: �Maximum Tolerated Dose (MTD)

Phase 2: �Response Rate

Phase 2 Portion:

Enasidenib 100 mg PO daily

​

Dose Escalation for Phase 1:

Once Daily:

50 mg PO daily

75 mg PO daily

100 mg PO daily

150 mg PO daily

200 mg PO daily

300 mg PO daily

450 mg PO daily

650 mg PO daily

​

Twice Daily:

30 mg PO bid

50 mg PO bid

75 mg PO bid

100 mg PO bid

150 mg PO bid

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Efficacy in Relapsed/Refractory IDH2 Mutant AML: Enasidenib Phase I/II

Parameter

Enasidenib 100 mg PO Daily

(n=214)

Enasidenib (All Doses) �(n=280)

ORR

38%

40%

CR

20%

19%

CRi

9%

9%

PR

5%

6%

SD

46%

44%

PD

9%

9%

Median OS

8.8 months

8.8 months

Median Time to First Response

1.9 months

1.9 months

Median Duration of Response

5.6 months

5.6 months

ORR = overall response rate; PR = partial remission; SD = stable disease; PD = progressive disease.�Stein EM, et al. Blood. 2017;130(6):722-731. Stein EM, et al. Blood. 2019;133(7):676-687.

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Ivosidenib (AG-120) Phase I and Dose Expansion – IDH1 AML

  • Dinardo CD, Stein EM, De botton S, et al. N Engl J Med. 2018;378(25):2386-2398.

E

N

R

O

L

L

​

Dose escalation for phase 1

Once daily

100 PO BID, 300 mg, 500 mg, 800 mg, or 1200 mg PO daily

​

Dose expansion cohort

Ivosidenib 500 mg PO daily

​

​

Patients with R/R AML with mutant IDH1

�(n=258; 180 for �dose expansion)

Primary endpoints: Phase 1�Maximum-tolerated dose

Dose expansion �Pharmacokinetics/

Clinical response

Median follow-up

14.8 months

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Efficacy in Relapsed/Refractory IDH1 Mutant AML: Ivosidenib Phase I/Dose Expansion

Parameter

Primary Efficacy Population (n=125)

Relapsed or Refractory AML (n=179)

CR or CRh

30%

30%

Overall RR

42%

39%

Median Duration of Response

6.5 months

NR

Median Time to Response

1.9 months

NR

Median Overall Survival

8.8 months

NR

18-month Survival

50%

NR

Transfusion Independence*

35% for 56 days or more

NR

*Based on 84 patients who required transfusions.�CRh = complete remission with partial hematologic recovery; NR = not reported.�DiNardo CD, et al. N Engl J Med. 2018;378(25):2386-2398.

​

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Azacitidine +/- Ivosidenib Phase 3 Trial

Montesinos P, et al. N Engl J Med. 2022;386:1519-31.

R

A

N

D

O

M

I

Z

E

Patients with newly diagnosed AML with IDH1 mutation�Ineligible for intensive induction therapy

�(n=146)

Primary Endpoint: EFS

​

Azacitidine (75 mg/m2) IV or Sub-Q on days 1–7

Every 28 days

Ivosidenib 500 mg PO daily

Azacitidine (75 mg/m2) IV or Sub-Q on days 1–7

Every 28 days

​

With Matching Placebo

Progression

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Efficacy Results

Parameter

Ivosidenib/Azacitidine (n=72)

Azacitidine/Placebo (n=74)

Event-Free Survival at 12 months

Median overall survival

CR

CR with incomplete hematologic/platelet recovery

SD

Progression

Median duration of CR

37%

24 months

47%

7%

​

10%

3%

Not yet reached

12%

7.9 months

15%

1%

​

36%

5%

11.2 months

Montesinos P, et al. New Engl J Med 2022;386:1519-

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Revumetinib: Phase I/II (AUGMENT-101)

CRh – Complete Response with partial hematologic recovery

Issa GC et al. J Clin Oncol. 2025;43:75-84..

E

N

R

O

L

L

​

Revumetinib

163mg PO Q12H (if strong CYP3A4 inhibitor) or 276mg PO Q12H

​

​

Patients with R/R AML with mutant KMT2A rearrangement

�(n=94)

Primary endpoints:

Phase I�Maximum-tolerated dose

Phase II

CR/ or CRh

Median follow-up

14.8 months

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Efficacy in Relapsed/Refractory KMT2A Mutant AML: Revumenib

Parameter

Primary Efficacy Population (n=57)

CR + CRh

23%

Overall RR

63%

Median Duration of Response

4.3 months

Median Time to Response

1.9 months

Median Overall Survival

8 months

MRD negative rate within CR/ + CRh

70%

Remaining in CR +CRh

6.4 months

MRD = Measureable residual disease�CRh = complete remission with partial hematologic recovery; NR = not reported.�Issa GC, et al. J Clin Oncol 2025;43:75-84.

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Hairy Cell Leukemia: Vemurafenib/rituximab in Relapsed/Refractory Disease

Tiacci E, et al. N Engl J Med 2021;384:1810-23.

E

N

R

O

L

L

​

Vemurafenib

960mg PO Q12H with rituximab (375mg/m2) IV x 8 doses over 18 weeks

​

Patients with R/R Hairy Cell Leukemia with BRAF V600E

�(n=30)

Primary endpoints:

CR

Median follow-up

34 months

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Vemurafenib/Rituximab Efficacy Results

Parameter

(n = 30)

CR (overall)

CR (in purine refractory patients n = 10)

MRD (PCR testing for BRAF V600E) in CR patients

Progression-free survival at 37 months

Relapse-free survival at 34 months

MRD-free survival at 28.5 months (n = 17)

87%

100%

65%

78%

85%

100%

Tiacci E, et al. N Engl J Med 2021;384:1810-23.

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Follicular Non-Hodgkin Lymphoma: Tazemetostat in Relapsed/Refractory Disease

Morschauser F, et al. Lancet Oncol 2020;21:1433-42.

E

N

R

O

L

L

​

Tazemetostat

800mg PO Q12H

Patients with R/R follicular NHL with 2 prior lines of therapy

�(n=99 – 45 patients EZH2 mutant)

Primary endpoints:

Objective RR

Median follow-up

22 months

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Tazemetostat Efficacy Results

Parameter

EZH2 mutant (n=45)

EZH2 – Wild Type (n = 54)

Overall RR

CR

PR

SD

Progression

Median Duration of Response

Median Progression-Free Survival

Overall Survival

​

69%

13%

56%

29%

2%

10.9 months

13.8 months

Not reached

35%

4%

31%

33%

22%

13 months

11.1 months

Not reached

Morschauser F, et al. Lancet Oncol 2020;21:1433-42.

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Future Targets for Hematologic Malignancies

Genomic Abberation

Disease Implication

ALK fusion

CBFB-MYH11 fusion

CEBPA

CRLF2 fusions

DEK-NUP214 fusion

EPOR fusions

IGH-IL3 fusion

JAK-2 fusion/PCMI-JAK-2 fusion

KMT2A fusions

MYC fusions

PDGFRA/PDGFRB fusions

RUNX1/ETV-RUNX1/RUNX1T1 fusions

Anaplastic large cell lymphoma

AML (inv16/ t16;16)

AML

B-ALL/B-NHL

AML (t6;9)(p2323;q34.1)

B-ALL/B-NHL

B-ALL/B-NHL

B-ALL/B-NHL

B-ALL/B-NHL/AML

NHL

B-ALL/B-NHL/AML

B-ALL/B-NHL/AML

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https://www.oncokb.org/actionable-genes#sections=Tx. Accessed 1/13/25.

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Resources

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Questions?