Update in Myeloproliferative Neoplasms January 20, 2012
Feb 23, 2016
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