srdan (serge) verstovsek m.d., ph.d. professor of medicine

Srdan (Serge) VerstovsekM.D., Ph.D.

Professor of MedicineDepartment of Leukemia

University of TexasMD Anderson Cancer Center

Houston, Texas, USA

JAK inhibitors and low blood cell

count

JAK inhibitor Diseases and studies

CEP701 MF: phase II finished and I/II (new formulation) ongoing ET/PV: phase II completed

AZD1480 MF: phase I finished, development stopped

XL019 MF: phase I finished, development stoppedNS-018 MF: phase I ongoingBMS-911543 MF: phase I/II ongoingLY2784544 ET/PV/MF: phase I finished; MF: phase II ongoing

CYT387 MF: phase I/II QD completed; phase I/II BID completed; phase III planned

SB1518 MF: phase I/IIx2 completed, phase III ongoing

SAR302503/TG101348MF: phase I/II completed; phase II completed, phase III completed; phase II second line ongoing

ET/PV: phase II ongoing; PV: phase III planned

INCB018424/RuxolitinibMF: approved; phase II (low platelets) ongoing

ET/PV: phase II completed; PV: phase III completed

JAK2 Inhibitor Side Effects from Phase II Studies

GI Anemia Platelets

XX

XX

X

XX

Ruxolitinib

SAR302503

SB1518

CYT387

Neuropathy

X

Ruxolitinib vs. Placebo: COMFORT-I

Background• Placebo-controlled, randomized, double-blind, phase III study• Ruxolitinib starting doses:

– Baseline platelet count 100-200×109/L: 15 mg BID– Baseline platelet count >200×109/L: 20 mg BID

• Doses individually titrated based on safety and efficacy• Ruxolitinib treatment significantly reduced spleen size and improved

myelofibrosis (MF_-related symptoms and QoL and was also associated with a survival advantage relative to placebo1

Objective • To describe long-term efficacy and safety of ruxolitinib with 1 year of

additional follow-up beyond previously published data

Data cutoff for current analysis: March 1, 2012.1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807.

Verstovsek S, et al. Blood. 2012;120: Abstract 800.

Patient Disposition at Current Analysis

Patients, n (%)Ruxolitinib

(n = 155)Placebo(n = 151)

Placebo Ruxolitinib

(n=111)Still on treatment 100 (64.5) 0 73 (65.8)Discontinued 55 (35.5) 40 (26.5) 38 (34.2)Crossed over 111 (73.5)

Primary reasons for discontinuation Death 13 (8.4) 10 (6.6) 11 (9.9) Adverse event 11 (7.1) 9 (6.0) 7 (6.3) Consent withdrawn 9 (5.8) 6 (4.0) 9 (8.1) Disease progression 12 (7.7) 12 (7.9) 5 (4.5) Other 10 (6.5) 3 (2.0) 5 (4.5) Noncompliance with study medication ̶E ̶E 1 (0.9)

• All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis

• Median time to crossover: 41.1 weeksVerstovsek S, et al. Blood. 2012;120: Abstract 800.

Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time

29.0

4.1 4.8 5.3

0

11.5

3.41.9

0 00

5

10

15

20

25

30

35

40

45

50

0–<6 6–<12 12–<18 18–<24 ≥24

Perc

enta

ge o

f Pat

ient

s

Months

8.7

1.6 1.90 0

3.41.6 0.9 0 0

0

5

10

15

20

25

30

35

40

45

50

0–<6 6–<12 12–<18 18–<24 ≥24

Perc

enta

ge o

f Pat

ient

s

Months

Anemia Thrombocytopenia

• All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo is shown for 0–<6 months only

Ruxolitinib Grade 4Ruxolitinib Grade 3

Placebo Grade 3 Placebo Grade 4

9.9

2.90.7 0


Mean Daily Dose of Ruxolitinib Over Time

• Approximately 70% of patients had dose adjustments during the first

12 weeks of therapy• Patients achieved a stable dose with longer-term use

Mean Platelet Counts Over Time

• Platelet counts remain stable with longer-term therapy

Mea

n Pe

rcen

tage

Cha

nge

From

B

asel

ine

10

-10

-30

-40

-60

0

-20

BL 12 24 36 48 60 72 84 96

Weeks

-50

Ruxolitinib Placebo

Median platelet count at baseline: Ruxolitinib, 262.0×109/L; Placebo, 238.0×109/L.

Mean Hemoglobin Levels Over Time

• Mean hemoglobin nadirs after 8–12 weeks of therapy and recovers to a new steady state which remains stable with longer-term therapy

Mea

n Pe

rcen

tage

Cha

nge

From

B

asel

ine

5

-5

-15

-20

0

-10

BL 12 24 36 48 60 72 84 96

Weeks

Ruxolitinib Placebo

Median hemoglobin at baseline: Ruxolitinib, 105 g/L; Placebo, 105 g/L


Hemoglobin Levels Over Time in Patients Without Transfusions or Dose Changes

• Recovery in hemoglobin over time was seen regardless of transfusions and dose modifications

Analyses were conducted in patients who completed Week 36.

No RBC Transfusions Before Week 36

5

0

-5

-10

Mea

n Pe

rcen

tage

Cha

nge

From

Bas

elin

e

-20BL 4 24 36

Weeks28 328 12 16 20

-15

No RBC Transfusions and No Dose Changes Before Week 36

Mea

n Pe

rcen

tage

Cha

nge

From

Bas

elin

e

5

0

-5

-10

-20BL 4 24 36

Weeks28 328 12 16 20

-15

RBC Transfusions Over Time

• By Week 36, the proportion of ruxolitinib-treated patients receiving RBC transfusions decreased to the level seen with placebo and remained stable thereafter

Perc

enta

ge o

f Pat

ient

s

BL 12 24 36 48 60 72 84 108

Weeks From First Ruxolitinib Dose

50

30

20

10

0

40

96

Weighted mean rate of the placebo group = 24.37%

Ruxolitinib Placebo

Proportion of patients with RBC transfusion in prior month

Hemoglobin Levels Over Time By Ruxolitinib Titrated Dose

Titrated dose is defined as the average dose patients received between Weeks 8 and 56.Hemoglobin levels within 60 days of transfusion are not included.

• Patients titrated to 10 mg BID after nadir hemoglobin showed faster and more complete return of hemoglobin to pretreatment levels

Efficacy by Titrated Dose

Titrated dose is defined as the average dose patients received in the last 4 weeks before assessment.

n=101

n=24 n=26 n=23 n=39 n=21

Spleen Volume

n=103

n=22 n=26 n=23 n=38 n=20

Total Symptom Score

n=35

n=28 n=20 n=31 n=17n=24

Week 24

Week 48


Verstovsek S et al. NEJM 2012; 366:799-807.

Development of Anemia Does not Affect Response to Ruxolitinib Treatment

What happens if the therapy with JAK2 inhibitor is interrupted?

Days Around Dose Change

Number of patients:34 33 33 34 34 33 33 33 36 37 39 40 40 40 34 29 26 23 24 24 22 22 22 20 21 20 18 17 15

• Return of the symptoms within 7 days

Serious Adverse Events After Therapy Interruption

• no report of “withdrawal syndrome”

• Percent of patients that discontinued ruxolitinib due to side effects was 11%

• Percent of patient that discontinued placebo due to side effects was 11%

Adverse Event Ruxolitinib (n = 155)

Placebo(n = 151)

Total with interruption, n 49 54Total SAEs, n (%) 3 (6.1) 3 (5.6)

• Danazol

• Erythropoietin

• Low dose thalidomide

Consideration in everyday practice:addition of an “Anemia Drug” to a JAK2 inhibitor

Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with

Low Starting Platelet Counts (50–100×109/L)

Abstract 176

Talpaz M, Paquette R, Afrin L, Hamburg S, Jamieson K, Terebelo H, Ortega G, Lyons RM, Tiu R, Winton E, Natrajan K, Odenike O, Peng W, O’Neill P, Erickson-Viitanen S, Leopold L,

Sandor V, Levy R, Kantarjian H, Verstovsek S

0%

20%

40%

60%

80%

100%

Week 4 Week 8 Week 12 Week 16 Week 20 Week 24

15 BID

10 AM/15 PM

10 BID

5 AM/10 PM

5 BID

5 QD

0

n = 41 n = 31n = 36 n = 25n = 28 n = 17

Distribution of Ruxolitinib Dose Over Time• In patients who completed 24 weeks of treatment, most have

optimized their dose of ruxolitinib to 10 mg BID or higher

n values represent patients with available dose information at the time of data analysis.Data shown for each time point represent the dose that patients were on during the previous 4 weeks.

15 BID

10 BID

5 BID

15 BID

10 BID

5 BID

10 / 15

10 BID

5 BID

10 BID

5 BID

10 BID

5 BID

5 / 10

5 BID

10 / 15 10 / 15

5 / 10

5 / 10

5 / 10

Talpaz M, et al. Blood. 2012;120: Abstract 176.

-60

-50

-40

-30

-20

-10

0

Perc

ent C

hang

e Fr

om B

asel

ine,

Mea

n ±S

EM

n = 41

n = 39n = 32

n = 28n = 28 n = 18

n = 38n =35

n = 31n = 27

n = 24n = 18

Total Symptom Score Spleen Length

Percent change from baseline is not calculated for patients with a “0” TSS or palpable spleen size of “0 cm” at baseline. Mean and median dose shown for patients with available dosing information.TDD, total daily dose.

Weeks 4 8 12 16 20 24

TDD, mg

Mean 10.0 13.2 15.1 16.8 18.3 19.1

Median 10 15 15 20 20 20

Reductions in Total Symptom Score and Spleen Length

Weeks 4 8 12 16 20 24

TDD, mg

Mean 10.0 13.2 15.1 16.8 18.3 19.1

Median 10 15 15 20 20 20


Change From Qualifying Platelet Count to Nadir and to Week 24 of Individual Patients

Qualifying to Nadir Qualifying to Week 24

Individual Patients

160

140

120

100

80

60

40

20

0

Plat

elet

Cou

nt. ×

109 /L

Individual Patients

160

140

120

100

80

60

40

20

0

Plat

elet

Cou

nt (×

109 /L

)


THANK YOU

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srdan (serge) verstovsek m.d., ph.d. professor of medicine

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