ash highlights 2015 - nihr · dr shankara paneesha ash highlights 2015 . ... dr shankara paneesha...

Department of Haematology & Stem cell Transplantation

Dr Shankara Paneesha

ASH Highlights 2015



Themes of ASH 2015

Novel therapies

- Myeloma

– AML

– Lymphoma

– Pd-L1 & PD-l inhibitors

Emerging concepts in biology

– HIF-1a pathway

Cautionary tales

ASH Choosing Wisely list



IFM/DFCI 2009: Phase III Study Design

Primary objective: PFS

Secondary objectives: ORR, MRD, TTP, OS, Safety

Attal M, et al. ASH 2015. Abstract 391. Slide credit: clinicaloptions.com

RVd*†

8 cycles

Pts 65 yrs of age or younger

with symptomatic, measurable NDMM

(N = 700) RVd*

3 cycles

Lenalidomide

maintenance

12 mos RVd*

2 cycles

consolidation

MEL200

ASCT†

*RVD: bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, 11 + lenalidomide 25 mg on Days 1-14 + dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12.

†Included PBSC collection with cyclophosphamide 3 g/m2 + G-CSF after cycle 3.

http://www.clinicaloptions.com/oncology



IFM/DFCI 2009 : Responses

Response, % RVd (n = 350) Transplantation (n = 350) P Value

CR 49 59

.02 VGPR 29 29

PR 20 11

< PR 2 1

≥ VGPR 78 88 .001

Negative MRD by FCM 65 80 .001

Attal M, et al. ASH 2015. Abstract 391.

Slide credit: clinicaloptions.com

Treatment Phase ≥ VGPR Rate, %

P value RVd (n = 350) Transplantation (n = 350)

After induction 47 50 NS

After transplant or

cycle 4 of consolidation 55 73 < .0001

After consolidation completed 71 81 < .006

At end of maintenance phase 78 88 < .001




IFM/DFCI 2009 : PFS (Primary Endpoint)

Parameter RVd

(n = 350)

Transplantation

(n = 350) P Value

Median follow-up, mos 41 41

Progression or death, n 204 158

Median PFS, mos 34 43

4-yr PFS, % 35 47

HR (95% CI) 1 0.69 (0.56-0.84) < .001

Attal M, et al. ASH 2015. Abstract 391.


At second interim analysis in June 2015 with median follow-up of 39 mos, the data and safety monitoring board for this trial recommended that the trial be stopped




IFM 2009: Overall Conclusions

ASCT vs RVD in pts with NDMM is associated with:

– 31% reduced risk of progression or death (P < .001)

– Improved TTP and rate of MRD negativity

– Similar, low rate of mortality

Longer follow-up required to make any conclusions about

OS

Authors concluded that ASCT should remain a standard of

care for eligible pts with myeloma

Similar, confirmatory trial ongoing in US

Attal M, et al. ASH 2015. Abstract 391. Slide credit: clinicaloptions.com




Blinatumomab in MRD-Positive BCP ALL:

Study Design International, multicenter, open-label phase II study from 2010-2013

– 46 centers

– 11 countries

Primary endpoint: achieving MRD < 10-4 in cycle 1

Secondary endpoints: OS, RFS, DoR, MRD < 10-4, safety

CD19+ BCP ALL pts

18 yrs of age or older with < 5% BM blasts,

MRD ≥ 10-3 after ≥ 3 chemotherapies,

and no prior allo-SCT, CNS/extramedullary involvement, or Ph+ ALL eligible for TKIs

(N = 116)

•Blinatumomab

•15 µg/m2 QD IVCI


•Cycle 1*

Gökbuget N, et al. ASH 2015. Abstract 680.

Followed for 2-yr efficacy,

survival

*28 days on tx, 14 days off.

Pts with MRD response received

≤ 3 additional cycles and/or allo-SCT (eligible pts); tx

discontinuation upon hematologic relapse





Efficacy

Median follow-up: 30 mos

Complete MRD response: 80%

Transplant realization rate: 72%

•Slide credit: clinicaloptions.com •Gökbuget N, et al. ASH 2015. Abstract 680.

Outcome, Mos Blinatumomab

(n = 110)

MRD Complete vs

Incomplete, P Value

Median OS

MRD complete responder

MRD incomplete responder

36.5

38.9

12.5

.002

Median RFS

CR1

CR2/CR3



18.9

24.6

11.0

23.6

5.7

.003

Median DoR



NR

NR

17.2

.049





Conclusions 80% of MRD-positive BCP ALL pts achieved complete MRD response

on blinatumomab therapy

Achieving complete (vs incomplete) MRD response was associated

with improved outcomes

– OS: 38.9 vs 12.5 mos; P = .002

– RFS: 23.6 vs 5.7 mos; P = .003

– DOR: NR vs 17.2 mos; P = .049

67% of pts in CR following blinatumomab were able to receive allo-

SCT

Most neurologic AEs were grade ≤ 2

– 10% of pts required therapy interruption or discontinuation

•Slide credit: clinicaloptions.com •Gökbuget N, et al. ASH 2015. Abstract 680.




•Slide credit: clinicaloptions.com •Stone RM, et al. ASH 2015. Abstract 6.

RATIFY: Midostaurin in FLT3-Positive AML:

Study Design

Double-blind, placebo-controlled, randomized phase III study of midostaurin, an FLT3 inhibitor

– Primary endpoint: OS (not censored for SCT)

– Secondary endpoint: EFS

•18-60 yrs of age with

•FLT3-mutated

•(non-APL) AML

•(N = 717)

•Daunorubicin

•60 mg/m2 IVP D1-3 +

•Cytarabine

•200 mg/m2/d IVCI D1-7 +

•Midostaurin

•50 mg PO BID D8-21

•(n= 360) Daunorubicin

60 mg/m2 IVP D1-3 +

Cytarabine

200 mg/m2/d IVCI D1-7 +

Placebo

D8-21

(n = 357)

•Cytarabine

•3 g/m2 over 3h q12h

•D1,3,5 +

•Midostaurin


•(n = 231)

Cytarabine

3 g/m2 over 3h q12h

D1,3,5 +

Placebo

D8-21

(n = 210)

•Midostaurin


•(n = 120)

Placebo

D1-28

(n = 85)

•Stratified by ITD/TKD;

randomized

•Induction*

•(1-2 cycles)

•Consolidation

•(up to 4 cycles)

•Maintenance

•(12 cycles)

•CR

•CR

*Hydroxyurea allowed for ≤ 5 days prior to induction therapy.




RATIFY: Efficacy


Characteristic

Midostaurin +

Chemo

(n = 360)

Placebo +

Chemo

(n = 357)

P Value

Median OS, mos (range) 74.7 (31.7-NE) 25.6 (18.6-42.9)

4-yr OS, % (95% CI)

Uncensored*

Censored for SCT†

51.4 (46.0-57.0)

63.8 (56.0-71.0)

44.2 (39.0-50.0)

55.7 (47.0-63.0)

.0074

.04

SCT, n (%)

Any time

CR1 only

212 (59)

100 (28)

196 (55)

79 (22)

.28

.08

CR, n (%)

By Day 60

In induction/consolidation

212 (59)

239 (66)

191 (53)

211 (59)

.15

.045

Median EFS, mos (range)

By day 60

In induction/consolidation

8.0 (5.1-10.6)

11.3 (8.4-15.1)

3.0 (1.9-5.9)

6.1 (4.7-7.5)

.0025

.0002

DFS, mos (range) 25.9 (19.4-NE) 14.4 (11.0-22.2) .002

*HR: 0.77. †HR: 0.75.

Longer OS shown in midostaurin arm in all FLT3 cohorts.

4-yr EFS rate was 28% with midostaurin vs 20% in placebo, regardless of FLT3

status.




RATIFY: Conclusions

Midostaurin added to standard chemo in pts with newly

diagnosed FLT3-mutated AML

– Improved OS and EFS, regardless of ITD/TKD stratification

group and despite high SCT rate (57%), vs placebo

– Reduced risk of death by 23% vs placebo

Safety/tolerability similar in midostaurin and placebo arms

Study investigators suggest midostaurin addition to current

standard chemo with 1-yr subsequent maintenance as a

new standard of care for these pts





Ibrutinib vs Chlorambucil in Tx-Naive

Elderly Pts With CLL (RESONATE-2) Open-label, randomized phase III trial

Primary endpoint: IRC-evaluated PFS

Secondary endpoints: OS, ORR, hematologic improvement, safety

•Treatment-naive CLL pts 65 yrs of age or older; for pts 65-69

yrs, comorbidity that precludes FCR;

• no warfarin use;

•no del(17p)

•(N = 269)

Ibrutinib 420 mg QD

until PD or unacceptable toxicity

(n = 136)

Chlorambucil 0.5 mg/kg*

Days 1 and 15 of 28-d cycle

up to 12 cycles

(n = 133)

PCYC-1116 extension study after IRC-

confirmed progression

Stratified by

ECOG PS 0-1 vs 2

Rai stage III-IV vs ≤ II

Tedeschi A, et al. ASH 2015. Abstract 495. Burger JA, et al. N Engl J Med. 2015:373;2425-2437. Slide credit: clinicaloptions.com

Crossover upon PD (n = 43)

•*Up to 0.8 mg/kg maximum.




•20

RESONATE-2: PFS (Primary Endpoint)

PFS results not dependent on age, Rai stage, ECOG PS, or bulky disease

1 Richter’s transformation in chlorambucil arm; none on ibrutinib arm


IRC Assessment Investigator Assessment

•100

•80

•60

•40

•20

•0

•PF

S (

%)

•Mos

•27 •0 •3 •6 •9 •12 •15 •18 •21 •24

•Pts at Risk, n Ibrutinib

Chlorambucil •136 133

•133 121

•130 95

•126 85

•122 74

•98 49

•66 34

•21 10

•2 0

•0 0

Ibrutinib

Chlorambucil

Median, mos

HR: 0.16 (95% CI: 0.09-0.28; P < .001)

Chlorambucil 18.9

Ibrutinib NR

•100

•80

•60

•40

•0

•PF

S (

%)

•Mos

•27 •0 •3 •6 •9 •12 •15 •18 •21 •24


Chlorambucil •136 133

•133 121

•129 88

•125 88

•123 69

•104 46

•69 31

•22 10

•2 0

•0 0

Ibrutinib

Chlorambucil

Median, mos

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

Chlorambucil 15.0

Ibrutinib NR




RESONATE-2: OS

84% reduction in risk of death with ibrutinib


•100

•80

•60

•40

•20

•0

•OS

(%

)

•Mos •0 •27 •3 •6 •9 •12 •15 •18 •21 •24


Chlorambucil

•136 133

•134 127

•131 125

•131 121

•131 118

•129 113

•74 62

•32 24

•4 1

•0 0

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

Ibrutinib

Chlorambucil




Ibrutinib vs Temsirolimus in Previously Treated

MCL: MCL3001 (RAY) Randomized, open-label phase III trial

Primary endpoint: PFS

Secondary endpoints: ORR, OS, DoR, time to next

treatment, and safety •Slide credit: clinicaloptions.com

•Rule S, et al. ASH 2015. Abstract 469. Dreyling M, et al. Lancet. 2015;[Epub ahead of print].

•Ibrutinib 560 mg QD PO

•(n = 139) •Previously treated

pts with MCL

•(N = 280)

•Temsirolimus IV

•Cycle 1: 175 mg Days 1, 8, 15

•Subsequent cycles: 75 mg Days 1, 8, 15

•(n = 141)

•Crossover to ibrutinib arm if

progressive disease

•(n = 32)

Stratified by sMIPI and prior lines of therapy

•Median drug exposure: 14 mos of ibrutinib vs 3 mos of temsirolimus.




Median DoR:

– Not reached (95% CI: 16.2-NE) with ibrutinib vs 7.0 mos (95% CI: 4.2-9.9)

for temsirolimus

MCL3001 (RAY): Response

•Slide credit: clinicaloptions.com •Rule S, et al. ASH 2015. Abstract 469.

Dreyling M, et al. Lancet. 2015;[Epub ahead of print].

Outcome, % Ibrutinib

(n = 139)

Temsirolimus

(n = 141) P Value

ORR by IRC

CR

PR

SD

71.9

18.7

53.2

10.8

40.4

1.4

39.0

30.5

< .0001

ORR by previous lines

of therapy

1

2

3

71.9

68.4

75.0

48.0

39.5

33.3




•Median, mos

•HR (95% CI) 0.43 (0.32-0.58)

• P < .0001

MCL3001 (RAY): Survival Outcomes

Consistent PFS improvement across pt subgroups

23% of pts treated with temsirolimus crossed over to ibrutinib at

progression

•Slide credit: clinicaloptions.com

•Rule S, et al. ASH 2015. Abstract 469. Dreyling M, et al. Lancet. 2015;[Epub ahead of print].

•PFS •OS

•100

•80

•60

•40

•20

•0 •30 •27 •24 •21 •18 •15 •12 •9 •6 •3 •0

•0

•0

•0

•0

•5

•1

•8

•3

•34

•11

•45

•19

•77

•33

•83

•45

•101

•69

•114

•93

•139

•141

•Ibrutinib

•Temsirolimus

•Pts at Risk, n

•Mos

•PF

S (

%)

•Ibrutinib

•14.6

•Temsirolimus

•6.2

•Ibrutinib

•Temsirolimus

•100

•80

•60

•40

•20

•0 •30 •27 •24 •21 •18 •15 •12 •9 •6 •3 •0

•Mos

•OS

(%

)

•0

•0

•2

•2

•14

•10

•35

•25

•64

•48

•84

•71

•92

•78

•103

•85

•113

•100

•125

•116

•139

•141

•Median, mos

•HR (95% CI) 0.76 (0.53-1.09)

• P < .1324

•Ibrutinib

•NR

•Temsirolimus

•21.3




Nivolumab in R/R cHL: Phase I Dose

Expansion Cohort

Primary endpoints: safety and tolerability

Secondary endpoints included: ORR, DoR, PFS

•cHL pts with

• ECOG PS 0/1, previous treatment with ≥ 1

chemotherapy, no autoimmune or previous organ allograft or

allogeneic BMT

•(N = 23)

•Nivolumab 3 mg/kg IV

•Wk 1, Wk 4, then Q2W

•for up to 2 yrs

•Ansell S, et al. N Engl J Med. 2015;372:311-319. Ansell S, et al. ASH 2015. Abstract 583. •Slide credit: clinicaloptions.com




Idelalisib Given Front-Line for the Treatment of Chronic

Lymphocytic Leukemia Results in Frequent and Severe

Immune-Mediated Toxicities

Benjamin L Lampson, et al.



PI3Kdelta Inhibitors Increase Genomic Instability By

Upregulating Aid Expression

Mara Compagno et al.



Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in

Previously Untreated Follicular Lymphoma (Alliance 051103)

Chaitra S. Ujjani, et al.



ASH Choosing Wisely list Do not transfuse more than the minimum number of red blood cell

(RBC) units necessary to relieve symptoms of anemia or to return a

patient to a safe hemoglobin range (7 to 8 g/dL in stable, non-cardiac,

in-patients).

Don't test for thrombophilia in adult patients with venous

thromboembolism (VTE) occurring in the setting of major transient

risk factors (surgery, trauma or prolonged immobility).

Don't use inferior vena cava (IVC) filters routinely in patients with

acute venous thromboembolism (VTE).

Don't administer plasma or prothrombin complex concentrates for

non-emergent reversal of vitamin K antagonists (i.e. outside of the

setting of major bleeding, intracranial hemorrhage or anticipated

emergent surgery).

Limit surveillance computed tomography (CT) scans in asymptomatic

patients following curative-intent treatment for aggressive lymphoma.



ASH Choosing Wisely list Don't treat with an anticoagulant for more than three months in a

patient with a first venous thromboembolism occurring in the setting

of a major transient risk factor.

Don't routinely transfuse patients with sickle cell disease for chronic

anemia or uncomplicated pain crisis without an appropriate clinical

indication.

Don't perform baseline or routine surveillance computed tomography

(CT) scans in patients with asymptomatic, early stage chronic

lymphocytic leukemia.

Don't test or treat for suspected heparin-induced thrombocytopenia

(HIT) in patients with a low pre-test probability of HIT.

Don't treat patients with immune thrombocytopenic purpura in the

absence of bleeding or a very low platelet count.

ash highlights 2015 - nihr · dr shankara paneesha ash highlights 2015 . ... dr shankara paneesha...

Documents