David Steensma, MD FACP -...
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4/23/2012 1 Will Advances in Genomics and Proteomics Lead to Therapeutic Advances in Higher‐Risk MDS i th N Ft ? [Y ] “Great Debates and Updates in Hematological Malignancies” New York, New York – April 2012 MDS in the Near Future? [Y es] David Steensma, MD FACP Associate Professor of Medicine, Harvard Medical School Adult Leukemia Program, Dana‐Farber Cancer Institute ACCME Disclosures David Steensma, MD I have the following financial relationships to disclose: • Member of an independent study data monitoring committee: Amgen • Scientific advisory board / consulting: Celgene, Novartis, Janssen‐Cilag I will discuss the following investigational or off‐label uses: • Only azacitidine , decitabine , and lenalidomide are FDA approved for MDS therapy; lenalidomide’s approval is limited to lower‐risk patients with del(5q). • The iron chelators deferasirox and deferoxamine are FDA approved for • The iron chelators deferasirox and deferoxamine are FDA approved for treatment of iron overload related to repeated RBC transfusion. • All other compounds discussed or specific uses should be considered unapproved, investigational, or off‐label in MDS.
Transcript of David Steensma, MD FACP -...
4/23/2012
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Will Advances in Genomics and Proteomics Lead to Therapeutic Advances in Higher‐Risk
MDS i th N F t ? [Y ]
“Great Debates and Updates in Hematological Malignancies”New York, New York – April 2012
MDS in the Near Future? [Yes]
David Steensma, MD FACPAssociate Professor of Medicine, Harvard Medical School
Adult Leukemia Program, Dana‐Farber Cancer Institute
ACCME DisclosuresDavid Steensma, MD
I have the following financial relationships to disclose:
• Member of an independent study data monitoring committee: Amgenp y g g
• Scientific advisory board / consulting: Celgene, Novartis, Janssen‐Cilag
I will discuss the following investigational or off‐label uses:
• Only azacitidine, decitabine, and lenalidomide are FDA approved for MDS therapy; lenalidomide’s approval is limited to lower‐risk patients with del(5q).
• The iron chelators deferasirox and deferoxamine are FDA approved for• The iron chelators deferasirox and deferoxamine are FDA approved for treatment of iron overload related to repeated RBC transfusion.
• All other compounds discussed or specific uses should be considered unapproved, investigational, or off‐label in MDS.
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Not a cop‐out; I do not mean “near” in geological time.
In truth I am somewhat skeptical about progress in the current political, regulatory
and economic climate.
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Courtesy Dr Matthew Walter, Washington University in St Louis
Targetable mutation
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Most of this is in the last 8 years (admittedly, aza and dac were synthesized during the Johnson Administration, and EPO under Reagan)
Hypomethylating agents / DNA methyltransferase inhibitors /
“epigenetic drugs”
A itidi
FDA approved for MDS‐related indications Approved for other indications
Blood cell (hematopoietic)growth factors
lf
Red blood cell growth factorsAzacitidine
Approved May 2004
Decitabine Approved May 2006
LenalidomideApproved December 2005
Immunomodulatory agent (iMiD)
Epoetin alfa
Darbepoetin alfa
Filgrastim, G‐CSF
Pegfilgrastim
White cell / myeloid growth factors
Megakaryocyte/platelet growth factors
Sargramostim, GM‐CSF
Iron chelators
Approved December 2005
DeferasiroxApproved November 2005
Romiplostim
Eltrombopag
Megakaryocyte/platelet growth factors
Immunosuppressive drugs (ATG, CsA)
Chemotherapy & stem cell transplant
Thalidomide, androgens, other biologicsDeferoxamineApproved 1968Deferiprone/L1
Approved October 2011
S1117 (US/Canada Intergroup) study
Azacitidinemonotherapyn 80
Power:81% probability of detecting a 20% difference in ORR
Eligible:Higher‐risk MDS or
CMML(5‐19% blasts or IPSS Int‐2/High)
py(7 days x 75 mg/m2/day)
Azacitidine + lenalidomide(10 mg/d for 21/28 days)
n=80
n=80
difference in ORR (with alpha 0.05)
Azacitidine + vorinostat(600 mg/day)
Principal investigator: Mikkael Sekeres, Cleveland Clinic
n=80
Primary endpoint: overall response rate [ORR] (IWG 2006)Secondary endpoints: overall and progression‐free survival, safety
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AZA‐PLUS (GFM) randomized phase II study
Azacitidinemonotherapyn 80
Eligible:Higher‐risk MDS or
CMML with WBC<13K(IPSS Int‐2/High)
py(75 mg/m2/d x 7 days) x 6 cycles
Azacitidine + lenalidomide(10 mg/d for 14/28 days) x 6 cycles
n=80
n=80
Azacitidine + valproic acid(50 mg/kg/d x 7 days, reduced to 35 mg/kg/d if >60 years) x 6 cycles
Principal investigator: Pierre Fenaux, Avicenne Hospital, Bobigny, France
n=80
Primary endpoint: overall response rate [ORR, CR + mCR + PR] (IWG 2006)Secondary endpoints: SD/HI, OS and PFS, response duration, safety
Throw enough darts, one will stick
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Novel therapies being tested in MDS (1)
Compound name (former) Route of administration; feature
Clofarabine IV; approved for pediatric ALL in 2004, oral in development; purine analogue resistant
Nucleoside analogs
to deamination/disruption of glycosidic link
Sapacitabine (CYC682) Oral; single‐strand DNA breaks and G2 arrest
Compound name (former) Kinase(s) inhibited
Rigosertib/ON 01910 Na PI3Ka ?Plk‐1
Kinase inhibitors
Rigosertib/ON 01910.Na PI3Ka, ?Plk‐1
ARRY‐614 p38 MAPK, Abl, Tie2 and VEGFR2
Midostaurin (PKC412) FLT3, PKC
MLN4924 Nedd8 activating enzyme
KB004 antibody EphA3 oncofetoprotein
CYT387 JAK1/JAK2
*374 interventional studies open/unresulted on clinicaltrials.gov as of March 12, 2012
Novel therapies being tested in MDS (2)
Compound name (former) Comments
Oral azacitidine DNMT1 inhibitor
SGI‐110PDE‐linked dinucleotide of decitabine and deoxyguanosine, resistant to deamination
Epigenetic modifiers
deoxyguanosine, resistant to deamination
5‐Fluoro‐2'‐DeoxycytidineWith tetrahydrouridine
THU is a cytidine deaminase inhibitor; preventsFdCyd from being deaminated
Panobinostat (LBH589) DACi
Vorinostat (SAHA) DACi
Belinostat (PXD101) No activity as monotherapy
Entinostat (MS‐275) May be “dead” in MDS after E1905
Monoclonal antibodies
Compound name (former) Target
Siltuximab (CNTO‐328) IL‐6 antibody
Etanercept TNFα chimeric antibody
Alemtuzumab Anti‐CD52 monoclonal
Lintuzumab (SGN‐33) Anti‐CD33
Monoclonal antibodies
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Compound name (former)
Tosedostat (CHR‐2797) Aminopeptidase inhibitor
Proteasome/Amino Acid recycling inhibitors
Novel therapies being tested in MDS (3)
Bortezomib Proteasome inhibition
Immunomodulation / Disruption of immune tolerance
Compound names
Vaccine‐based approaches (WT1, dendritic cells/PD‐1, Disruption of immunotoleranceetc)
Umbilical cord/placental‐derived mesenchymal stem cells
Disruption of immunotolerance
AS‐101 Tellurium(IV)‐based immunomodulator / redox
Maitake mushroom extractImmunomodulatory (beta‐D‐glucan induces T/NK cells and IL‐1/2)
Novel therapies being tested in MDS (4)
Compound name (former) Mechanism
Ezatiostat (TLK199) Glutathione analog; augments JNK signaling
Miscellaneous
Ezatiostat (TLK199) Glutathione analog; augments JNK signaling
BP100‐1.01GRB2 inhibitor, liposomally delivered antisense nucleotide
PM01183 IV; DNA minor groove covalent binder
PF‐04449913 Hedgehog pathway inhibitor
OXi4503 (combretastatin A1 diphosphate, CA1P)
Vascular disrupting agent
Ganetespib (STA‐9090) Hsp90 inhibitor
Pharmaceutical‐grade angiotensin; increasesTXA127
Pharmaceutical grade angiotensin; increases hematopoiesis
Sodium stibogluconate Antimony derivative; inhibits PTPase1, SHP‐1, PTP1B
CPI‐613Lipoic acid analog; inhibits mitochondrial energy metabolism
Omacetaxine / homoharringtonineMarine‐derived alkaloid; apoptosis induction by inhibition of Mcl‐1 etc.
Plerixafor (AMD3100) CXCR4 signaling blockade; ?chemosensitizing
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Acknowledgments
DF/HCC Research Collaborators:Rafael Bejar MD PhD
R. Coleman Lindsley MD PhD Benjamin Ebert MD PhDMark Fleming MD DPhil
Boston Harbor skyline at dusk
Harvard Medical School quadrangle
DFCI Adult Leukemia Clinical Program:Director: Richard Stone MD
Clinical Director: Daniel Deangelo MD PhDMartha Wadleigh MD
Gabriela Motyckova MD PhDGregory (Goyo) Abel MD MPH
gNancy Berliner MDRobert Soiffer MD
Yawkey Center (2011)Dana‐Farber Cancer Institute
