update in myeloproliferative neoplasms

Update in Myeloproliferative Neoplasms

January 20, 2012

November 16, 2011

FDA Indications for Ruxolitinib (Jakafi)

Intermediate or high-risk Myelofibrosis=80-90% of MF patients

JAK2V617F NOT required

Diagnostic Criteria for myelofibrosis

PMF Post PV or ET MF

Must meet all 3 major and ≥2 minor criteria

Must meet both major and ≥2 minor criteria

JAK2V617F mutation:Not just for MPN anymore

95-97% PV>50% ET50-60% MF

3-13% CMML3-5% MDS (RARS & thrombocytosis)<5% AML

DIPSS

1-2 = Intermediate-1

3-4 = Intermediate-2

5-6 = High

0 = Low

Passamonti et al, Blood 2010

Dynamic International Prognostic Scoring System in MF

Obtained at any time during follow-up

DIPSS-plus3 additional factors

Tefferi, Blood 2011

**Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding diagnosis, unexplained fever, or excessive sweats persisting for > 1 month ***Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q− 12p−, or 11q23 rearrangement

COMFORT-I

Primary endpoint • Proportion of subjects achieving >35% reduction in spleen volume from baseline to Week 24 as measured by MRI (or CT scan in applicable subjects)

Secondary endpoints • Duration of maintenance of a >35% reduction from baseline in spleen volume among subjects initially randomized to receive INCB018424 • Proportion of subjects with >50% reduction in total symptom score from baseline to Week 24 as measured by the modified MFSAF v2.0 diary

* Patients randomized to placebo will be eligible to cross over to ruxolitinib

Percent Change From Baseline in Spleen Volume in Individual Patients at Week 24

Verstovsek, S. Presented at ASCO 2011

Primary Endpoint: % of Patients with ≥35% Decrease in Spleen Volume at

Week 24 (ITT)

Verstovsek, S. Presented at ASCO 2011

insomniaInactivity

Fatigue

ItchingBone Pain

CoughAbdominal Discomfort

Early Satiety

FeverWeight Loss

Night Sweats

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

74%

76%

99%

54%

55%

55%

72%

75%

29%

48%

62%

Symptomatic Burden in MF

Percentage of patients reporting symptoms

Scherber et al, Blood 2011

Splenomegaly

ConstitutionalSymptoms

Myeloproliferation

Functioning

Percent of Patients with ≥50% Decrease in

Total Symptom Score at Week 24 (ITT)

Verstovsek, S. Presented at ASCO 2011

Proportion of Patients with ≥50% Reduction in Total Symptom Score Over Time

Verstovsek, S. Presented at ASCO 2011

Percent Change From Baseline in Total Symptom Score in Individual Patients at Week 24

Verstovsek, S. Presented at ASCO 2011

Mean Percent Change in Individual Symptoms

Verstovsek, S. Presented at ASCO 2011

Symptoms Return without drug

IFN-γLower in MPN

(Tyner et al, 2010) (Verstovsek et al, 2010 Slezak et al, 2009, Boissinot et al, 2010, Tefferi et al 2011)

KC

CD40

IL-2

IL-7

IL-9

IL-6

VEGFTNF

MIP-1β

MIP-1α

TIMP-1 G-CSF

IL-1α,ß

IL-18

IL-16

ICAM-1

MMP-10

MMP-2VCAM-1

IFN-αIL-11

IL-8

Mouse Model MPN patients

Increased serum cytokines in MPN

IL-10

IL-12

IL-2R

IL-13 IL-15

TNF is elevated in MPN and correlates with JAK2V617F allele burden

Fleischman et al, Blood 2011

Elevated IL-8 and IL-2R associated with decreased survival in PMF

All patients

Intermediate-1

Intermediate-2

Tefferi et al, JCO 2011

Consequences of Increased Inflammation

Stress hematopoiesis

HSCexhaustion

Constitutional Symptoms-weight loss-fatigue-fever

Impact of Ruxolitinib on inflammatory cytokines

Verstovsek et al, NEJM 2010

Ruxolitinib decreases inflammatory cytokines

Verstovsek et al, NEJM 2010

JAK inhibitors: not just for MPN

Hematology Laboratory Values

*Patients are included at their worst on study grade regardless of whether this represents a change from their baseline

-Grade 3 and 4 anemia and thrombocytopenia were more common in those with higher baseline grade

-Discontinuation of treatment because of anemia and thrombocytopenia was rare (1 patient in each treatment group for each event

Verstovsek, S. Presented at ASCO 2011

Non-hematologic Adverse Events Observed in at Least 10% of Ruxolitinib-Treated Patients

Verstovsek, S. Presented at ASCO 2011

Mean hemoglobin and Red Blood Cell Products Over Time

Verstovsek, S. Presented at ASCO 2011

Red Blood Cell Transfusions

Verstovsek, S. Presented at ASCO 2011

JAK2V617F allele burden

Percentage of JAK2V617F mutant allele can be quantitatively measured (available at OHSU), but clinical relevance is unknown

Low JAK2V617F allele burden in PMF has negative impact

Low V617Fallele burden associated with shorter survival in PMF

Guglielmelli et al, Blood 2009

Other

Secondary Neoplasm

Portal Hypertension

Bleeding

Infection

Thrombosis

Progression without leukemia

Leukemia

0% 5% 10% 15% 20% 25% 30% 35%

13%

4%

4%

5%

10%

14%

19%

31%

Causes of Death in PMF

Cervantes et al, Blood 2009.

* COMFORT-I was not designed nor powered to demonstrate a statistically significant difference in overall survival within the timeframe of the study endpoint. Patients who remain in COMFORT-I continue to be followed.

Incyte, JP Morgan Healthcare conference Jan 9,2012

COMFORT-I Overall Survival*

Ruxolitinib Dosing

For plts 50-100 X 109/L: OHSU currently enrolling for clinical trial of ruxolitinib in thrombocytopenic patients with MF

Jakafi prescribing information packet

Dose adjustment for thrombocytopeniaHold Drug for platelets <50 X 109/L

Jakafi prescribing information packet

Drug Interactions:

Strong CYP3A4 inhibitors will increase levels of ruxolitinib, with strong CYP3A4 inhibitors dose reduction is recommended. Patients should be closely monitored and dose titrated based on safety and efficacy.

Jakafi prescribing insert

No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy

http://www.jakafi.com/Files/RUX1066.pdf

How to prescribe Ruxolitinib

Comparing various JAK inhibitors

Drug Target Phase Disease Efficacy Toxicity

INCB18424 JAK2, JAK1 ApprovedIII

MFPV/ET

Splenomegaly, symptoms Anemia, thrombocytopenia

TG101348, (SAR302503) JAK2, FLT3 II MF Splenomegaly,

symptomsAnemia, thrombocytopenia, gastrointestinal

SB1518 JAK2, FLT3 II MF Splenomegaly, symptoms Gastrointestinal

CEP701 JAK2, FLT3 II MF, PV/ET Splenomegaly, symptoms

Gastrointestinal, anemia, thrombocytopenia

CYT387 JAK1, JAK2 I MF Splenomegaly, symptoms, anemia First dose effect, cytopenias

LY2784544 JAK2 I MF, ET/PV NPR NPR

AZD1480 JAK2, JAK3 I/II MF NPR NPR

NS018 JAK2 I MF NPR NPR

Drug Target Phase Disease Efficacy Toxicity

RAD001 mTOR II MFSplenomegaly, symptoms Minimal

Pomalidomide IMiD III MF Anemia Minimal

PEG-IFNa-2a Biological III PV/ET

Erythrocytosis, thrombocytosis, symptoms

Myelosuppression, depression

LBH589 HDAC II MFSplenomegaly, anemia

Anemia, thrombocytopenia, gastrointestinal

Clinical trials of non-JAK2 targeted therapies for MPN

Lenalidomide for MF• Mayo Clinic - Blood. 2006 Aug 15;108(4):1158-64.

– 68 patients; lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia.

• MD Anderson - J Clin Oncol. 2009 Oct 1;27(28):4760-6. – 40 patients; lenalidomide 10 mg/d (5 mg/d if baseline platelet count <

100 x 10(9)/L) on days 1 through 21 of a 28-day cycle for six cycles with prednisone taper. ORR 30% for anemia and 42% splenomegaly by IWG-MRT criteria.

• ECOG Phase 2 (E4903) - Blood. 2010 Nov 25;116(22):4436-8.– 48 patients; lenalidomide 10mg daily + prednisone taper; anemia

improved in 19% and splenomegaly in 10% by IWG-MRT criteria.

Pomalidomide +/- prednisone in treatment of anemia in MF

Tefferi et al, JCO 2009

Phase II trial of pomalidomide alone in MF• Low dose pomalidomide alone (0.5mg/d) in 58 MF patients

with anemia

• Response limited to JAK2V617F mutated patients

• 24% of V617F+ patients responded in terms of anemia and 9/10 became transfusion independent

• Response predicted by basophilia in first month of treatment

• 58% of patients with plts ≤ 100K experienced >50% increase in plt count Begna et al, Leukemia 2011

rIFN-α may reverse fibrosis in early PMF

Silver et al, Blood 2011

Peg-IFN-alpha2a for PV/ET• Kiladjian et al Blood 2008;112:3065:

– 37 patients; 95% had hematologic CR; only 3 stopped tx at 12 months. Decreased JAK2V617F allele burden in 90%. Molecular CR in 7 patients. 90-180 mcg weekly.

• Quintas-Cardama et al JCO 2009;27:5418: – 40 PV/39 ET; one prior cytoreductive treatment; 70%/76%

hematologic CR; 14%/6% molecular CR. Only 10% of patients discontinued due to toxicity; no grade 4 toxicities; grade 3 were not frequent but included pain, fatigue, dyspnea, and pruritis. Tolerability of PEG-IFN-alpha-2a at 90 mcg weekly was excellent.

• Phase III trials comparing Hydroxyurea vs. Pegasys are underway (upfront high risk PV or ET; HU-resistant or refractory).

PEG-IFNα induces hematologic response in PV/ET

Start at 90µg/week, with goal of 135µg/week

Kiladjian et al, Blood 2008

Tolerable dosing

Quintas-Cardama et al, JCO 2009

90µg/wk PEG-IFNα-2a induces molecular response in PV/ET

Toxicities Associated with PEG-IFNα-2a

Quintas-Cardama et al, JCO 2009

-PEG-IFNα-2a 90µg/week-10% of patients discontinued due to IFN related toxicity

The curative approach: allogenic SCT

Conditioning N StudyMedian

Age DonorTRM (%) OS

Myeloablative 551 Retr 42RD=36

URD=20 27 47% (5-y)

562 Retr 43 RD=40 URD=9 58% (3-y)

Reduced-Intensity 1033

Prosp FluBu+AT

G 55RD=33

URD=70 16 67% (5-y)

66

Prosp FluMel+/-

ATG 55RD=32

URD=34RD=16

URD=33

RD=78% (2-y)

URD=44% (1y)

Obstacles: -Donor availability -High TRM -Advanced patient age -Still ill defined morbidity -Comorbidities -Impact of cGVHD

1Guardiola et al, Blood 1999. 2Deeg et al, Blood 2003. 3Alchalby et at, Blood 2010. 4Rondelli, ASH 2011 Abst 1750.

Treatment Algorithm for myelofibrosis

DIPSS/DIPSS-plus

Int-2/highLow, Int-1

asymptomatic

observation

symptomatic

*conventional drug therapy*ruxolitinib

Investigational drug therapy

Consider SCT

YesNo

MyA 45-50yRI 45-65

refractory

Treatment of Anemia: Conventional Approach

-Prednisone-Danazol/Androgens-Erythropoietin stimulating agents (ESA)

15-20% response,Short lived

-Thalidomide + Prednisone ≈ 20% response, neurotoxicity

-Lenalidomide ≈ 20% response, myelosuppression Best in pts with del(5q31)

-Splenectomy up to 50-75% responseduration ≈ 1yr

-RBC transfusions

Treatment goals

• Prevent thrombosis• Prevent hemorrhage• Alleviate constitutional symptoms• Minimize primary and iatrogenic disease

progression • Improve QOL and survival