chronic lymphocytic leukemia · leukemia: advances in therapy as presented at american hematology...

CHRONIC LYMPHOCYTIC LEUKEMIA: Advances in therapy as presented at American Hematology Society (ASH) Annual meeting

Carolyn Owen, MD MDres(UK) FRCPCAssociate Professor, Division of Hematology & Hematological

Malignancies, University of Calgary Feb 24, 2020

CHRONIC LYMPHOCYTIC LEUKEMIA STUDIES PRESENTED AT ASH DECEMBER 2018 and 2019FRONTLINE STUDIES (previously untreated patients):

1. Alliance study – BR vs Ibrutinib vs Ibrutinib + rituximab – over 65 years

2. ILLUMINATE – CLB-O vs Ibrutinib + obinutuzumab – older with comorbidities

3. ECOG 1912 – FCR vs ibrutinib + rituximab – young and fit4. CLL14 – venetoclax + obinutuzumab vs CLB-O – older with

comorbidities5. ELEVATE-TN – acalabrutinib +/- obinutuzumab vs CLB-O – older with

comorbidities

RELAPSE STUDIES (patients previously treated for CLL):1. Update of MURANO – BR vs venetoclax + R – relapsed/refractory

FRONTLINE STUDIES IN CLL

Alliance study for pts ≥ 65 years comparing BR to ibrutinib in previously untreated CLL

Stratify*

Documented progression

RANDOMIZE

BENDAMUSTINE + RITUXIMAB

IBRUTINIB until disease progression

PRE-REGISTER

IBRUTINIB until disease progression + RITUXIMAB weekly for 4 weeks then monthly x 4 more doses

Untreated patients age ≥ 65 who meet IWCLL criteria for CLL treatment

Woyach et al NEJM 2018

Alliance Study Progression Free Survival (time with no relapse and no death)

Arm C (IR)Arm B (I)

Arm A (BR)

% A

live

and

Prog

ress

ion-

Free

Censor

Patients-at-Risk176 140 129 122 103 88 57 26 11 0178 165 154 147 136 120 78 45 22 0170 159 145 138 132 115 74 40 20 0

Arm N 24 Month EstimateBR 176 74% (95% CI: 66-80%)

I 178 87% (95% CI: 81-92%)IR 170 88% (95% CI: 81-92%)


Del (17p) Subgroup shows these patients should get ibrutinib not chemo

Arm C (IR)Arm B (I)

Arm A (BR)

% A

live

and

Prog

ress

ion-

Free

Censor

Patients-at-Risk14 5 3 1 09 9 8 7 6 5 5 1 1 0

11 10 9 9 8 7 6 3 2 0

Arm N 24 Month Estimate

BR 14 0%

I 9 75% (95% CI: 31-93%)

IR 11 73% (95% CI: 37-90%)


Arm C (IR)Arm B (I)

Arm A (BR)

% A

live

and

Prog

ress

ion-

Free

Censor

Patients-at-Risk52 47 42 42 38 34 22 10 7 045 41 38 36 33 31 18 13 6 045 41 38 36 35 32 18 10 7 0

IGVH Mutated

IGVH mutated Subgroup shows these patients do well with BR (standard chemo-immunotherapy)

Arm

N 24 Month Estimate

BR 52 87% (95% CI: 74-94%)

I 45 86% (95% CI: 72-94%)

IR 45 88% (95% CI: 73-95%)


Arm C (IR)Arm B (I)

Arm A (BR)

% A

live

Censor

Patients-at-Risk183 166 163 160 153 143 98 53 23 1182 175 166 161 156 146 100 62 26 1182 172 169 165 161 147 100 55 24 1

Overall Survival not different yet for any group, suggesting all are good therapies

Arm N 24 Month Estimate

BR 183 95% (95% CI: 91-98%)

I 183 90% (95% CI: 85-94%)

IR 182 94% (95% CI: 89-97%)

Median Follow-up: 38 months


More heme side effects with BRMore non-heme side effects with ibrutinib7% deaths on therapy for ibrutinib (vs 1% for BR)

Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab as First-Line Treatment in Patients

With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results From

Phase 3 iLLUMINATE

Carol Moreno, MD, PhD1; Richard Greil, MD2; Fatih Demirkan, MD3; Alessandra Tedeschi, MD4; Bertrand Anz, MD5; Loree Larratt, MD6; Martin Simkovic, MD, PhD7; Olga Samoilova, MD8; Jan Novak, MD, PhD9; Dina Ben-Yehuda, MD10; Vladimir Strugov, MD11; Devinder Gill, MD, MRCP, FRCPath12; John G. Gribben, MD, DSc, FRCP, FRCPath, FMedSci13; Emily Hsu, PhD14; Cathy Zhou, MS14; Fong Clow, ScD14;

Danelle F. James, MD, MAS14; Lori Styles, MD14; Ian W. Flinn, MD, PhD15

iLLUMINATE Study Design: ibrutinib + O vs CLB + O

ASH 2018, PCYC-1130; Moreno et al.

Patients (N=229)• Previously untreated CLL/SLL • Requiring treatment per

iwCLL criteria • Age ≥65 years or <65 years

old with ≥1 coexisting condition: CIRS >6 CrCl <70 mL/min del(17p) or TP53

mutation

RANDOMIZE

1:1

Ibrutinib-obinutuzumab

Chlorambucil-obinutuzumabIf progression, single-agent

ibrutiniba

Superior Progression-Free Survival with Ibrutinib-Obinutuzumab

Moreno et al. Lancet Oncol 2019 • Median PFS with CLB-O in CLL11 = 29.7 months• This study used CT scans regularly to look for recurrence (not just clinical exams)

Overall Survival with Median 31 Months of Follow-Up

9% patients on ibrutinib+ obinutuzumab arm died of adverse event –mostly heart-related

Moreno et al. Lancet Oncol 2019

Ibrutinib & Rituximab Improves Progression Free and Overall Survival Relative to FCR in Younger Patients

with Previously Untreated Chronic Lymphocytic Leukemia (CLL)

Tait Shanafelt1, Xin Victoria Wang2, Neil E. Kay3, Susan O’Brien5, Jacqueline Barrientos6, Curt Hanson4, Harry Erba7, Rich Stone8, Mark Litzow3, Marty Tallman9

E1912 Study for young and fit CLL patients

Shanafelt, T. et al. Abstract LBA-4. ASH 2018

Ibrutinib + Rituximab

FCR

Ibrutinib until progression

E1912Eligibility:-Previously untreated CLL -Requires treatment (IWCLL 2008)-Age < 70-ECOG 0-2-CrCL>40 -Able to tolerate FCR-No deletion 17p by FISH

Ran

dom

izat

ion

Dis

ease

Pro

gres

sion

Progression Free Survival shows patients with unmutatedIGHV have the biggest gain from ibrutinib over FCR


Overall Survival also slightly favoured the ibrutinib (+R) arm


Only 1% deaths on ibrutinib treatment for these young and fit patients


Update From the E1912 Trial ComparingIbrutinib & Rituximab to FCR in Younger Patients with

Previously Untreated Chronic Lymphocytic Leukemia (CLL)

Tait Shanafelt, Xin Victoria Wang, Neil E. Kay, Susan O’Brien, Jacqueline Barrientos , Curt Hanson, Harry Erba, Rich Stone, Mark Litzow, Marty Tallman

Reasons for Ibrutinib Discontinuation

18

Reason for Discontinuation All Patients Who Started IRN=352

Progression or death 23 (7%)

Adverse event 48 (14%)

Other reason* 24 (7%)

*Other health conditions, patient preference, lost to follow-up

Shanafelt T, et al. Abst 33, ASH 2019

• 257 (73%) of 354 patients randomized to IR remain on ibrutinib (median time on treatment 43 months)

• Among the 95 patients who discontinued ibrutinib, the median time on treatment was 20.3 months

Progression Free Survival Post Discontinuation of Ibrutinibshows many patients can have no therapy for a long time before their CLL progresses

19

N=72

Median time of therapy 15.1 months


Overall Survival continues to favour Ibrutinib (+R)

20


CLL14 Study Design of venetoclax + obinutuzumabin 1L older CLL

chlorambucil x 12 cycles, PO QD RAN

DO

MIZ

E 1:

1venetoclax† x 12 cycles, PO QD

1L CLL unfitTotal CIRS >6 or CrCl <70 ml/minAge ≥18 years

(N=432)

obinutuzumab, IV x 6 cycles

obinutuzumab, IV x 6 cycles

VenG safety run-in(N=12)

Fischer K, et al. N Engl J Med 2019;

CLL14 shows an improvement in PFS for venetoclax +O compared to CLB-O but no difference in Overall Survival

Fischer K, et al. N Engl J Med 2019

Previously Untreated CLLKey inclusion criteria includes:• Age ≥65 y or 18-65 y and ≥1 of the following criteria:o CrCl = 30-69 mL/mino CIRS-G score >6

• ECOG PS ≤2• Adequate hematologic, hepatic, and renal functionKey exclusion criteria includes:• Significant cardiovascular disease• Concomitant treatment with warfarin or equivalent

vitamin K antagonistsN=535

Acalabrutinib (until progression)

Acalabrutinib (until progression) + Obinutuzumab

Chlorambucil + ObinutuzumabRANDOMIZATION

1:1:1

ELEVATE TN Study of Acalabrutinib + O in older CLL patients

Crossover was allowed upon IRC confirmed PD from Arm A to Arm C

Sharman JP et al ASH 2019

PFS shows that acalabrutinib patients have longer remissions than CLB-O patients

End PointObinutuzumab+ Chlorambucil

(n=177)

Acalabrutinib + Obinutuzumab

(n=179)

Acalabrutinib(n=179)

Median follow-up (mo)

28.3a 28.5 28.4

Events, n (%) 93 (52.5) 14 (7.8) 26(14.5)


Overall survival not yet different

End Point

Obinutuzumab + Chlorambucil

(n=177)

Acalabrutinib + Obinutuzumab

(n=179)

Acalabrutinib(n=179)

Eventsa, n (%) 17 (9.6) 9 (5) 11 (6.1)

Censoredb, n (%) 160 (90.4) 170 (95) 168 (93.9)

OS at 30 mo, % (95% CI)

90.1(84.3, 93.9)

94.9(90.5, 97.3)

93.5(88.6, 96.4)


Subgroup data shows patients with unmut IGHV benefit the most

Chlorambucil + ObinutuzumabAcalabrutinib + ObinutuzumabAcalabrutinib

Legend

• To date, rates of AFIB and high blood pressure have low and there have been no cardiac deaths clearly attributed to acalabrutinib


Older patients (either ≥ 65 yrs or with comorbidities)• Indefinite ibrutinib leads to longer remissions than 6 months of BR• So far, no difference in overall survival (getting ibrutinib firstline or after a

remission with BR)• Rituximab did not add benefit to ibrutinib• Venetoclax + obinutuzumab leads to longer remissions than CLB-O but no

difference in overall survival yet• Acalabrutinib (+/- obinutuzumab) leads to longer remissions than CLB-O but no

difference in overall survival yet• Unsure how much extra benefit obinutuzumab adds to acalabrutinib or ibrutinib

Younger patients (young with no medical problems)• Indefinite ibrutinib (+R) leads to longer remissions than FCR but also better

overall survival (in this one small study

SUMMARY – FRONTLINE CLL STUDIES

RELAPSED OR REFRACTORY CLL

Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax–rituximab (VenR) in relapsed/refractory (R/R)

chronic lymphocytic leukemia (CLL)

John F Seymour,1 Thomas J Kipps,2 Barbara F Eichhorst,3 Peter Hillmen,4 James D'Rozario,5 Sarit Assouline,6 Carolyn Owen,7 Tadeusz Robak,8 Javier de la Serna,9 Ulrich Jaeger,10 Guillaume

Cartron,11 Marco Montillo,12Nicole Lamanna,13 Su Young Kim,14 Jenny Wu,15 Yanwen Jiang,15 JueWang,15 Marcus Lefebure,16 Michelle Boyer,16 Kathryn Humphrey,17 and Arnon P Kater18

MURANO study of venetoclax + R vs BR

D1C1

R/R CLL (N=389)

R1:1

VENETOCLAX + RITUXIMAB(6 monthly cycles)

BENDAMUSTINE + RITUXIMAB(6 monthly cycles)

VENETOCLAX(total duration 2 years)

EOCT EOT

Ven5-week ramp-up

20–400mg

Seymour et al NEJM 2018; ASH 2019

PFS benefit with VenR vs BR sustained 2 years after stopping treatment

Treatment4-yr PFS, %

(95% CI)

VenR(n=194)

57.3 (49.4–65.3)

BR (n=195)

4.6 (0.1–9.2)

PFS

(%)

Time (months)

100

80

60

20

0

40

5718126 602115930 5451484542393633302724

HR, 0.19 (95% CI, 0.14–0.25); p<0.0001EOCT EOT

Median follow up: 48 months


Time (months)

Treatment 4-yr OS, %

VenR (n=194) 85.3

BR (n=195) 66.8

OS

(%)

100

80

60

20

0

40

5718126 602115930 5451484542393633302724

HR, 0.41 (95% CI, 0.26–0.65); p<0.0001

EOCT EOT

OS benefit maintained with VenR vs BR 2 years post-end of treatment


Efficacy of Therapies Following VenetoclaxDiscontinuation in CLL: Focus on B-cell Receptor

Signal Transduction Inhibitors and Cellular Therapies

Anthony R. Mato1,2, Lindsey E. Roeker3, Toby A. Eyre4*, Ryan Jacobs5, Brian T. Hill6,7, Nicole Lamanna8, Danielle M. Brander9, Mazyar Shadman10, Chaitra Ujjani11*, Maryam Yazdy12, Guilherme Fleury

Perini13*, Javier Pinilla Ibarz14, Jacqueline C Barrientos15, Alan Skarbnik16, Pallawi Torka17, Jeffrey J Pu18, John M. Pagel19, Satyen Gohil20, Bita Fakhri21, Michael Y. Choi22, Catherine C. Coombs23, Joanna Rhodes24, Paul M. Barr25, Craig A. Portell26, Helen Parry27*, Christine Ann Garcia28, Kate J Whitaker3*,

Allison M. Winter29, Andrea Sitlinger30, Sirin Khajavian10*, Ariel F Grajales-Cruz14*, Krista Isaac26*, Pratik Shah31*, Othman S. Akhtar32,33, Rachael Pocock34*, Kentson Lam22, Timothy J Voorhees23,

Stephen J. Schuster24, Thomas David Rodgers35, Nicolas Martinez-Calle36*, Talha Munir37*, Erica B Bhavsar38*, Neil Bailey19*, Jason C. Lee8, Hanna Weissbrot8*, Chadi Nabhan39, Julie Goodfriend3*,

Amber C. King40, Andrew D. Zelenetz41, Colleen Dorsey42*, Kayla Bigelow3*, Bruce D. Cheson43, Christopher P Fox44* and John N. Allan45

• Study design: Multicenter, retrospective cohort study across 31 centers internationally, the UK CLL Forum, and the Collaborative Study of Real Word Evidence (CORE)‒ 50 % sites recruited by Twitter

• Primary objective: Overall response rates (ORR) and PFS of treatment following venetoclax discontinuation‒ Overall response was defined by iwCLL criteria‒ PFS: time from post-ven therapy to CLL PD, death, or censored at last follow up‒ PFS2: PFS from start of Ven to progression on ibrutinib, death or last follow up

• Funding source: Unfunded, all investigators volunteered their time

Patients and methods

Mato et al ASH 2019 a502

Response to subsequent therapies following venetoclax discontinuation

Post Ven Therapy BTKi BTKi BTKi PI3Ki CAR-T Anti-CD20 abs

Agents IbrutinibAcalabrutinib

IbrutinibAcalabrutinibNon-covalent BTKi

IbrutinibAcalabrutinibNon-covalent BTKi

IdelalisibDuvelisib

Anti-CD19 RituximabObinutuzumab Ofatumumab

Pre-Ven exposure BTKi-naive BTKi-exposedBTKi-resistant

BTKi-exposedBTKi-intolerant

PI3Ki-naiveBTKi-exposed

BTKi-exposed

Patient number 44 20 10 17 18 19

ORR 83,9 % 53 % 70 % 46,9 % 66,6 % 32 %

CR 9 % 6,6 % 20 % 5,9 % 33,3 % 16 %

PR 56,8 % 26,4 % 30 % 35,2 % 33,3 % 16 %

PR-L 18,1 % 20 % 20 % 5,8 % 0 % 0 %

SD 11,6 % 20 % - 23,7 % 5,7 % 32 %

PD 4,5 % 27 % 30 % 29,4 % 27,7 % 37 %

ORR BTKi (naive) vs. BTKi (exposed, resistant), p=0.001 Mato et al ASH 2019 a502

After venetoclax: response to BTKi in BTKi exposed patients depends on reason for discontinuation


After venetoclax: cellular therapies (particularly alloHSCT) appear to be effective


SUMMARY OF RELAPSE STUDIES IN CLL

1. Venetoclax + rituximab for 2 years finite duration leads to longer remissions than BR

2. Relapses happen after Ven + R but many patients can have years off therapy before needing a next treatment

3. Data so far does not suggest a best sequence between ibrutinib (or acalabrutinib or other BTKi) and venetoclax(unsure which one patients should get first or if it matters)

TAKE-AWAY conclusions – Alberta approach to CLL management1. Restrict use of FCR to truly young, fit patients (<65-70 years) with mutated

IgHV whereas young, fit patients with unmutated IgHV should receive ibrutinib

2. All del(17p) patients should continue to receive ibrutinib

3. The data in older patients suggest ibrutinib, acalabrutinib and venetoclax + obinutuzumab all work well and lead to long remissions (but without overall survival advantage and being much more expensive than chemo, these are not clearly better and chemo-immunotherapy remains a good treatment).

4. Unsure if obinutuzumab adds to novel therapies 5. Venetoclax + R for 2 years provides long remissions for relapsed CLL and

should prove cheaper (and better tolerated) than ibrutinib given indefinitely

Questions?

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