associate professor, department of medicine...

Rena Buckstein MD Head, Haematology Site GroupAssociate Professor, Department of MedicineOdette Cancer Centre, Sunnybrook Health Sciences Centre

Research funding and honoraria: Celgene Advisory Boards: Celgene, Novartis and Abbvie

Novel insights into MDS and AML diagnosis, pathophysiology and prognosisNew therapies for AML and ALLNew therapies for relapsed Hodgkin’s Improved survival Multiple Myeloma B cell receptor signaling inhibitors

A group of hematopoietic neoplasms characterized by1

Bone marrow failure with resultant cytopenia(s) and related complications High frequency of clonal cytogenetic alterations Dysplastic cytologic morphology Instability and tendency to progress to AML

Overall incidence >3.7-4.8/100,0002

>10,000/yr in US (claims data true estimates ≈37,000-48,000)

AML = acute myeloid leukemia.1. Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, eds. Clinical Oncology. New York, NY: Churchill Livingstone; 2004:2849-2881. 2. SEER data. 2000-2009. 3. SEER 18 data. 2000-2009.

Median age at diagnosis: 72

Age at Diagnosis (Yrs)*P for trend < .05Rollison DE, et al. Blood. 2008;112:45-52.

0

10

20

30

40

50

< 40 40-49 50-59 60-69 70-79 ≥ 80

0.1 0.7 2.07.5

20.9

36.4*

FemalesMalesOverall

Prerequisite criteria Constant cytopenia in ≥1 of the

following cell lineages Erythroid (hemoglobin [Hgb]

<11 g/dL) Neutrophilic (ANC <1500/μL) Megakaryocytic (platelets

<100,000/μL) Exclusion of all other hematopoietic

or nonhematopoietic disorders as primary reason for cytopenia/dysplasia

MDS-related (decisive) criteria Dysplasia in ≥10% of

all cells in 1 of the following lineages in the bone marrow smear: erythroid, neutrophilic, or megakaryocytic or >15% ring sideroblasts (iron stain) 5%-19% blast cells in bone marrow smears Typical chromosomal abnormality

(by conventional karyotyping or FISH) only in 50% de novo

Haferlach et al., Leukemia (2014) 28, 241–247; doi:10.1038/leu.2013.336.

~89% of patients had a mutation by NGS

9

Kennedy & Ebert, JCO 2017, PMID: 28297619

Y e a r s

Ove

rall

Surv

ival

(%)

0 2 4 6 8 1 0 1 2 1 40

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

0 (n = 3 7 7 )1 (n = 5 9 5 )2 (n = 4 6 0 )3 (n = 2 1 0 )4 (n = 1 2 5 )5 /6 /7 (n = 2 2 )

S F 3 B 1 o n ly (n = 2 0 7 )

N u m b e r o f M u ta te d G e n e s

Overall Survival by Mutation Number

17 genes sequenced in 1996 patients with OS dataASXL1CBLDNMT3AETV6EZH2IDH1IDH2JAK2KRASNPM1NRASRUNX1SRSF2TET2TP53U2AF1

SF3B1With permission, R Bejar

Genovese, G. et al. NEJM 2014 Jaiswal S. et al. NEJM 2014

N=12000N=17000

Genovese, G. et al. NEJM 2014 Jaiswal, S. et al. NEJM 2017

HR 12.9

HR 1.4

CHD: HR 2.0 (4 x MI)Ischemic stroke: HR 2.6

Non-clonal ICUSCHIP CCUS LR-MDS HR-MDS

Traditional ICUS MDS by WHO 2008

Clonality

Dysplasia

Cytopenias

Overall Risk

+ – ++ ++ ++

–/+ – – + ++

– + + + ++

Very Low Very Low Low (?) Low High

BM Blast % < 5% < 5% < 5% < 5% 5-19%

Are these two the same?Does morphologic dysplasia matter?

CCUS = clonal cytopenias of undetermined significance; ICUS = idiopathic cytopenias of undetermined significance; CHIP = clonal hematopoiesis of indeterminate potential; LR = lower risk, HR = higher risk

Some Somatic Mutations Matter More:

CCUS

ICUS

• n=154 patients with cytopenia of undetermined significance10-year cumulative probabilities of progression CCUS vs ICUS:

95% vs 9% P < .001

Evolution toheme neoplasm

10-20%/year MDS, <5% blasts

Survival

CCUS with:• SF3B1• ZRSR2• TET2/DNMT3A/ASXL1

+ 1 other

Malcovati L et al. Blood 2017

Somatic mutations are found in virtually all cytogenetically normal MDS patients and can be used for diagnosis and prognosis Insights into pathogenesis and therapeutic targeting

CHIP is found in 10% age > 70 in general population and is a significant risk factor for hematologic cancer (1% risk/year), all cause mortality, CHD, ischemic stroke and premature MICCUS is a risk factor for MDS and specific mutation patterns ……survival tantamount to MDS Longer follow up needed

18Sources: Cancer Facts & Figures 2013;American Cancer Society; 2013; http://seer.cancer.gov/faststats/; http://globocan.iarc.fr

0

5

10

15

20

25

30

<20years

20-49years

50-64years

65-74years

75+years

Inci

den

ce r

ate

per

100

,000

per

son

s

2005

2010

20149200

20830

6300

12730

0

5000

10000

15000

20000

25000

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

New Cases

Deaths

5 year relative survival has improved from 13% to 28%

Rising 3%/ year x 10 years

4.2/100,000Median age 68

http://seer.cancer.gov/faststats/

http://globocan.iarc.fr/

PROGNOSIS IN AML AND ROLE OF FMS-LIKE TYROSINE KINASE-3 (FLT-3)

2010

EL

N C

lass

ific

atio

n

2017 EL

N C

lassification

Potent FLT3 inhibitor but also inhibits other tyrosine kinases Modest single agent activity in relapsed AML RATIFY study evaluated its benefits in FLT3 mutated

PROTOCOL THERAPY Induction: daunorubicin 60 mg/m2 IVP days 1-3, cytarabine 200 mg/m2/d d 1-7 via IVCI, midostaurin 50 mg po bid or placebo days 8-21marrow on day 21. If residual AML, repeat above

Consolidation ( 4 cycles): cytarabine 3 gm/m2 over 3h q 12h days 1, 3, and 5midostaurin 50 mg po bid or placebo days 8-21

Maintenance: midostaurin 50 mg po bid or placebo days 1-28 x 12 cyclesTransplant not specifically mandated

RATIFY: CONSORT DIAGRAM

Stone R. et al. NEJM 2017

CR RATE HIGHER WITH MIDO

MIDO(N=360)

PBO(N=357)

Fisher’s exact p

(2-sided)Initial CR (within 60 days) 212 191Rate 59% 54% 0.15Time to CR, median (range) 35 days (20-60) 35 days (20-60)

Initial CR (at any time) 244 216Rate 68% 61% 0.04Time to CR, median (range) 37 days (20-192) 36 days (20-108)


OVERALL SURVIVAL - PRIMARY ITT ANALYSIS

• 5 year survival rate: Mido 50.9% vs. PBO 43.3%• Median follow-up time for survivors: 56.7 mo (range: 0.1, 79.2)


OVERALL SURVIVAL POST-TRANSPLANT: IMPROVED POST MIDO IN CR

All Transplants SCT in/outside of CR1

NE: not estimable


Many more under evaluation in combination with chemotherapy upfront or relapse, as maintenance post chemotherapy or post allogeneic stem cell transplantNow SOC to use for FLT3 mutated AML which comprises roughly 25% of all AMLSurvival benefit appears to be seen in those that undergo an allogeneic stem cell transplant

APL now treated with arsenic and ATRA (NO CHEMO!) Reduced intensity allogeneic stem cell transplants non-inferior to

myeloablative : age not restricted to < 70 Maintenance or vaccines post transplant

Haplo-identical transplants CPX-351 Resurgence of gemtuzumab-ozogamycin (anti-CD33 MoAb + calichymycin) RCT: 7+3 +/- Gem - EFS 9.5 mos versus 17.3 months

Enasidinib- for IDH mutated AML Venetoclax (anti-Bcl2 inhibitor) added to hypomethylating agents or LDAC

Multiple Myeloma: 6.6/100,00010% of all Heme cancers

50% survive 5 years (70% with ASCT)

REVISED ISS STAGING SYSTEM

Palumbo A, et al. J Clin Oncol. 2015;33:2863-2869.

Definition

I

ISS stage I AND Normal LDH No t(4;14), t(14;16), or del(17p)

II Not stage I or III

III

ISS stage IIIAND Serum LDH > ULNOR With t(4;14), t(14;16), or

del(17p)

100

80

60

40

20

00 12 24 36 48 60 72

R-ISS I NRR-ISS II 83R-ISS III 43

Median OS, Mos

MosO

S (%

)

R-ISS Stage

MYELOMA TREATMENT PARADIGM

Induction

Induction followed by continuous therapy

Consolidation MaintenanceSCT

Elig

ible

SCT

Inel

igib

le

Dia

gnos

is a

nd R

isk

Stra

tific

atio

n

Tumor Burden

IFM prospective, randomized trial comparing conventional chemotherapy vs high-dose therapy and ASCT (N = 200)

Attal M, et al. N Engl J Med. 1996;335:91-97.

HIGH-DOSE THERAPY AS CONSOLIDATION IMPROVES OVERALL SURVIVAL BY 1 YEAR

Slide credit: clinicaloptions.com

15 30 45 60

25

50

75

100

OS

(%)

00

High doseConventional dose

Mos15 30 45 60

25

50

75

100

Even

t-Fre

e Su

rviv

al (%

)

00

High doseConventional dose

Mos

http://www.clinicaloptions.com/oncology

META-ANALYSIS OF 3 PHASE III TRIALS: OS IS IMPROVED WITH LENALIDOMIDEMAINT AFTER HIGH-DOSE MELPHALAN AND ASCT

26% reduction in risk of death; estimated 2.5-yr increase in median OS

Attal M, et al. ASCO 2016. Abstract 8001.

Median follow-up: 80 mos

100

80

60

40

20

0

OS

(%)

0 10 20 30 40 50 60 70 80 90 100 110 120Mos

N = 1209

Median OS, mos (95% CI)HR (95% CI)P value

Lenalidomide

NE(NE-NE)

Control

86.0(79.8-96.0)

0.74 (0.62-0.89).001

7-yr OS62%

50%

NON-TRANSPLANT ELIGIBLE: FIRST TRIAL: PFS WITH CONTINUOUS RD BEST, BUT NOT OS

HR:Continuous Rd vs MPT: 0.72 (P < .001)Continuous Rd vs Rd18: 0.70 (P < .001)

PFS OS

Benboubker L, et al. N Engl J Med. 2014;371:906-917.

Pts

(%)

100

80

60

40

20

0

Continuous Rd (n = 535) Rd18 (n = 541)MPT (n = 547)

Median PFS, Mos

25.520.721.2

0 6 12 18 24 30 36 42 48 54 60Mos

Pts

(%)

100

80

60

40

20

0

Continuous Rd (n = 535) Rd18 (n = 541)MPT (n = 547)

4-Yr OS, %595651

0 6 12 18 24 30 36 42 48 54 60

Mos

Survival has increased from 3-6 years…….still incurable Better prognostication guides different therapiesHDT/ASCT offers a 10-15% improvement in overall survival (roughly 1-

1.5 years)Maintenance after stem cell transplant with lenalidomide low dose

improves OS by 2.5 years but at expense of increased rate of secondary primary malignancies, neuropathy, myelosuppression, thrombosisNew oral proteosome inhibitors, monoclonal antibodies, PD-1 inhibitors

are showing promise in the relapsed/refractory patients – toxicities Achieving a deep response to therapy (CR or VGPR) associated with

improved overall survival- doublet versus triplet therapy

The decision followed the FDA’s Oncologic Drugs Advisory Committee’s unanimous vote to

recommend the immunotherapy for approval; in remarks, one panel member called it the “most

exciting thing I’ve seen in my lifetime.”

This approval “marks an important shift in the blood cancer treatment paradigm,” commented Kenneth Anderson, MD, president of the American Society of Hematology (ASH), in a press release. “We now

have proof that it is possible to eradicate cancer by harnessing the power of a patient’s own immune

system.”

AG recognition domain from MoAB

Intracellular T cell signalling and costimulatory domains

Multicenter, open-label, single-arm phase II study

Primary endpoint: ORR (CR + CRi) within 3 mos, assessed by IRC 4-wk maintenance of remission required

Secondary endpoints: MRD status, DoR, OS, cellular kinetics, safety

Pts aged 3-21 yrs* with B-cell ALL; ≥ 5% BM lymphoblasts; no isolated extramedullary disease

relapse, prior CD19-directed therapy, or prior gene therapy

(N = 81)

Single-Dose CTL0192.0-5.0 x 106/kg IV if ≤ 50 kg

1.0-2.5 x 108 IV if > 50 kg(n = 62†)

Grupp SA, et al. ASH 2016. Abstract 221.

Fludarabine30 mg/m² IV QD for 4 doses

Cyclophosphamide500 mg/m² IV QD for 2 doses

*From 3 yrs at screening to 21 yrs at initial diagnosis.

†14 pts discontinued before infusion: deaths (n = 6), manufacturing failures (n = 5), AEs (n = 3).

Grupp SA, et al. ASH 2016. Abstract 221.

*Interim analysis set: first 50 pts infused with CTL019 with 3-mo follow-up. †P < .0001. ‡Full analysis set: all pts infused with CTL019.

Outcome CTL019 (n = 50*)ORR (CR + CRi) within 3 mos (with MRD < 0.01% in BM), % (95% CI) 82 (69-91)†

Best overall response, %CRCRi

6814

OS6 mos, % (95% CI)Median, mos (95% CI)

89 (76-95)‡

NE (8.6-NE)‡

Duration of remission6 mos, % (95% CI)Median, mos (95% CI)

62 (36-78)NE (4.8-NE)

Advantages:Offers cellular immunotherapy in heavily pre-treated hematologic cancers

(ALL, DLBCL……….CLL, HL, MM, solid tumours) High rate and durable CRs ……Cure? Replace allogeneic stem cell transplants?

DisadvantagesOnly specialized centersCost- ½ million dollarsNot off the shelf Cytokine release syndrome- 59% ICU x 8 daysNeuropsychiatric events- serious in 18% Prolonged hypogammaglobulinemiaDurability unknown



25% will be refractory/relapse Younger patients (39) Salvage chemotherapy + ASCT

curable in 50% Brentuximab-Vedotin if relapse

Older patients: Brentuximab-Vedotin or palliative chemotherapy Brentuximab-Vedotin: monoclonal

antibody-antitubulin agent 75% ORR (CR 34%) 2 year OS 65%

Study Drug N ORR Miscell

Checkmate 2051

Phase 2Nivolumab 3 mg/kg IV q 2 weeks

80 66%CR: 7%

Failed both ASCT and Brentuximab

Keynote-0872

Ongoing Phase 2Pembrolizumab 200 mg IV q 3 weeks x 2 years

210(Results for 60 cohorts 1-2)

70-80%CR 20-27%

1. Failed SCT + BV2. Chemo resistant + Failed BV3. Failed ASCT

Nivolumab: Accelerated approval by FDA May 2016 for relapsed post ASCT + BV

1. Younes, A. Lancet Oncol 20162. Chen R. et al, JCO 2016 34:15_suppl, 7555-7555

Fig 1. Response to treatment. (A) Maximum percentage change from baseline in target lesions. (B) Change from baseline in target lesions. (C) Treatment exposure and response duration. Three patients had a formal response assessment before the protocol-required time point of 12 weeks. One patient only received one dose of pembrolizumab, discontinued treatment because of toxicity at 4 weeks, and had nonprotocol scans to assess response, which showed CR. The other two patients had nonprotocol scans to confirm the clinical impression of progressive disease before the 12-week time point. Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Published in: Philippe Armand; Margaret A. Shipp; Vincent Ribrag; Jean-Marie Michot; Pier Luigi Zinzani; John Kuruvilla; Ellen S. Snyder; Alejandro D. Ricart; Arun Balakumaran; Shelonitda Rose; Craig H. Moskowitz; JCO 2016, 34, 3733-3739.DOI: 10.1200/JCO.2016.67.3467Copyright © 2016 American Society of Clinical Oncology

Keynote 013- phase 1, n=31, 4+ lines of therapy, 71% post ASCT

Ongoing trials in aggressive and indolent B cell lymphomas, MM, MDS, AML, CLLWell tolerated but immune related adverse events GI, derm, hepatic, endocrine

Duration of treatment unknownDurability of response unknownHD: Being moved up earlier in combination with chemotherapy or other

immune checkpoint inhibitors Expensive

BCR signaling is required for tumor expansion and proliferation BTK is an essential element of the

BCR signaling pathway[28]

Inhibitors of BTK block BCR signaling, diminish proliferation, impair adhesion and migration and induce apoptosis[29]

Targeted inhibition of BTK is a novel approach for the treatment of B-cell malignancies

LYN

SYK

BCR

BTK

PLCγ2

PKC

PI3KDelta

AKT

mTOR

p70s6k elf4E

GSK-3 NF-kβPathway

Herman SEM, et al. Blood. 2011;117:6287-6296. 30. Davis RE, et al. Nature. 2010;463:88-92.

Forms a specific bond with cysteine-481 in BTKHighly potent BTK inhibition[30]

Orally administered with once-daily dosing resulting in 24-hr target inhibition[31]

No cytotoxic effect on T cells or NK cells[32]

In CLL cells, promotes apoptosis and inhibits CLL cell migration and adhesion[33,34]

31. Honigberg LA, et al. Proc Natl Acad Sci U S A. 2010;107:13075-13080. 32. Advani R, et al. J Clin Oncol. 2013;31:88-94. 33. Herman SE, et al, Blood. 2011;117:6287-6296. 34. Ponader S, et al. Blood. 2012;119:1182-21189. 35. de Rooij MF, et al. Blood. 2012;119:2590-2594.

N

N NN

N

O

NH2

O

Treatment Naive ≥ 65 yrsIbrutinib

420 mg/day or 840 mg/day (n = 31)

Relapsed/Refractory Ibrutinib

420 mg/day or 840 mg/day (n = 61)

Patients with CLL/SLL treated with ibrutinib

monotherapy* and ECOG PS ≤ 2

(N = 116)

Enrolled May 2010 - July 2011

36. Byrd JC, et al. ASH 2012. Abstract 189.

A multicohort phase Ib/II trial

High-risk† Relapsed/RefractoryIbrutinib

420 mg/day (n = 24)

20.3 mosmedian follow-up



*Patients with SLL not included in current analysis†Defined as progression of disease < 24 mos after initiation of a chemoimmunotherapy regimen or failure to respond.

Single-agent ibrutinib active across CLL patient populations

38. Byrd JC, et al. ASH 2012. Abstract 189.

Response or Survival Outcome, %

Treatment-Naive Patients ≥ 65 Yrs of Age

(n = 31)

Relapsed/Refractory and High-Risk

Relapsed/Refractory Patients (n = 85)

ORRCRPR

681058

712

68PR with lymphocytosis 13 18SD 13 4PD 0 2

Ibrutinib monotherapy superior to chlorambucil for ORR, EFS, PFS, and OS Risk of death reduced by 84% with favorable AE profile

Burger JA, et al. N Engl J Med. 2015;373:2425-2437. Slide credit: clinicaloptions.com

100

80

60

40

20

00 6 12 18 273 9 15 21 24

PFS According to Investigator Assessment

Mos

Pts

With

PFS

(%)

HR: 0.09 (95% CI: 0.04-0.17; P < .001)

Chlorambucil15.0

IbrutinibNR

Median, mos

100

80

60

40

20

0

Pts

Who

Sur

vive

d (%

)

0 6 12 18 273 9 15 21 24Mos

HR: 0.16 (95% CI: 0.05-0.56; P = .001 by log-rank test)

ChlorambucilIbrutinib

OS


PFS benefit in all subgroups analyzed, including bulky disease, IgVH mutation status, no. prior therapies, presence of del(11q)

OS results confounded by crossover of 90 (31%) pts in placebo arm to ibrutinib arm after PD

Chanan-Khan AAA, et al. Lancet Oncol. 2015;[Epub ahead of print].

100

80

60

40

20

0

PFS

(%)

320 4 8 16 20 24 2812Mos

Placebo + BR(median PFS: 13.3 mos)

Ibrutinib + BR(median PFS: NR)

100

80

60

40

20

0

OS

(%)

320 4 8 16 20 24 2812Mos

Placebo + BR

Ibrutinib + BR

PFS OS

HR: 0.203 (95% CI: 0.150-0.276;P < .0001)

Median OS NR in either armHR: 0.628 (95% CI: 0.385-1.024;P = .0598)



IbrutininibCLLMantle Cell LymphomaWaldenstromsMacroglobulinemiaMarginal Zone Lymphoma

IdelalisibPreviously treated CLL + RituximabFollicular and SLL who have received 2 prior therapies

Practical recommendations for the clinic

Ibrutinib• Grade 1 bruising is frequent but harmless• Antiplatelet or anticoagulation (DOAC or

LMWH) therapy appears safe• Avoid combined antiplatelet and

anticoagulation therapy• Withhold ibrutinib 3-7 days before and after

invasive procedures• Check for atrial fibrillation regularly• Hypertension may occur even later during

therapy• Check blood counts regularly during first

months

Idelalisib• PJP prophylaxis and regular CMV

monitoring are mandatory• Take diarrhea seriously and handle

according to Figure 3• Be aware of the low but potentially life

threatening risk of pneumonitis• Check liver enzymes in the first 3

months and handle elevations according to Figure 5

• Check blood counts regularly during first months

De Weerdt, I. et al. Haematologica 2017

OUTCOMES WITH SECONDARY OR THERAPY RELATED AML ARE INFERIOR

67Granfeldt-Osgard, et al. J Clin Oncol. 2015;33:3641

Time Since AML Diagnosis (years)

0

0.2

0.4

0.6

0.8

1.0

Surv

ival

(pro

babi

lity)

1 3 5 7 9 11 13

De novo AMLsAML, MDSsAML, non-MDStAML

70Lancet J et al. ASCO, 2016

71

KAPLAN-MEIER CURVE FOR OVERALL SURVIVAL LANDMARKED AT STEM CELL TRANSPLANT ITT ANALYSIS POPULATION

100

80

60

40

20

03 6 9 12 15 18 21 24 27 30 33 36

Months from Randomization

Surv

ival

(%)

Events/NCPX-351

7+318/5226/39

Not Reached10.25 (6.21, 16.69)

Median Surv. (95% CI)

4631

4027

3420

2715

207

154

91

61

30

00

00

CPX-3517+3

5239

Hazard Ratio = 0.46p-value = 0.0046

0

Lancet J et al. ASCO, 2016

EXPLORATORY ANALYSIS BY AGE

Aged 60–69 years Aged 70–75 years

Hazard ratio = 0.55 (0.36, 0.84)Hazard ratio = 0.68 (0.49, 0.95)

• Median OS was significantly longer in the VYXEOS arm versus the 7+3 arm for both stratification age subgroups

Lancet J, et al. Biol Blood Marrow Transplant . 2017;23(3):S38-S39.For internal use & distribution only. Not for promotional purposes.

• The safety profile of CPX-351 in transplanted patients was comparable between age subgroups• Grade 3-4 adverse events and events resulting in death were generally similar between the arms

associate professor, department of medicine...

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