Waldenstrom’sMacroglobulinemia and Amyloidosis...Waldenstrom’sMacroglobulinemia and Amyloidosis Steve Treon MD, PhD, FRCP, FACP Professor of Medicine, Harvard Medical School Dana

Waldenstrom’s Macroglobulinemia and Amyloidosis

Steve Treon MD, PhD, FRCP, FACPProfessor of Medicine, Harvard Medical School

Dana Farber Cancer Institute

Manifestations of WM Disease

≤20% at diagnosis;50-60% at relapse.

↓Hb>>> ↓PLT> ↓WBC

Hyperviscosity Syndrome:Epistaxis, Headaches

Impaired vision>6,000 mg/dL or >4.0 CP

Treon S., Hematol Oncol. 2013; 31:76-80.

Cold Agglutinemia (5%)Cryoglobulinemia (10%)IgM Neuropathy (22%)Amyloidosis (10-15%)

Hepcidin ↓Fe Anemia

Bone Marrow

Bing NeelSyndrome

Primary Therapy of WM with RituximabRegimen ORR CR TTP (mo)

Rituximab x 4 25-30% 0-5% 13 Rituximab x 8 40-45% 0-5% 16-22Rituximab/thalidomide 70% 5% 30Rituximab/cyclophosphamidei.e. CHOP-R, CVP-R, CPR, CDR

70-80% 5-15% 30-36

Rituximab/nucleoside analoguesi.e. FR, FCR, CDA-R

70-90% 5-15% 36-62

Rituximab/Proteasome Inhibitori.e. BDR, VR, CaRD

70-90% 5-15% 42-66

Rituximab/bendamustine 90% 15-20% 69

Reviewed in Dimopoulos et al, Blood 2014; 124(9):1404-11; Treon et al, Blood 2015; How I Treat WM

Agent WM Toxicities

Rituximab • IgM flare (40-60%)-> Hyperviscosity crisis, Aggravation of IgM related PN, CAGG, Cryos.

• Hypogammaglobulinemia-> infections, IVIG • Intolerance (10-15%)

Fludarabine • Hypogammaglobulinemia-> infections, IVIG• Transformation, AML/MDS (15%)

Bendamustine • Prolonged neutropenia, thrombocytopenia(especially after fludarabine)

• AML/MDS (5-8%)

Bortezomib • Grade 2+3 Peripheral neuropathy (60-70%); High discontinuation (20-60%)

WM–centric toxicities with commonly used therapies

Mutated MYD88 Pro-Survival Signaling in WMMYD88 mutated in 93-97% of WM patients

Treon et al, NEJM 2012Yang et al, Blood 2013Yang et al, Blood 2016

Degradation

TLRs IL-6

IL-6

IL-6

IL-6R

gp-130

growth survival

IL-6

mTOR

ERK1/2

HCK

NFKB

MYD88

BTKIRAK1/4

AKT

ibrutinib

Drug resistance

Bone Marrow Stroma

CXCR4 mutations permit ongoing pro-survival signaling by CXCL12, the ligand for CXCR4 receptor

CXCR4 is mutated in 30-40% of WM patients

CXCR4

WM Cell

CXCL12

Hunter et al, Blood 2013; Cao et al, Leukemia 2014; Roccaro et al, Blood 2014.

CXCR4 receptor remainsup with mutation

Multicenter study of Ibrutinib in Relapsed/Refractory WM (>1 prior therapy)

✔ MYD88, CXCR4 Mutation Status

Treon et al, NEJM 2015NCT01614821

R Advani L PalombaS. Treon PI

ALL MYD88Mut

CXCR4WTMYD88Mut

CXCR4MutMYD88WT

CXCR4WTP-value

N= 63 36 21 5*

ORR 90% 100% 86% 50% <0.001

Major (>PR) 78% 97% 64% 0% <0.001

VGPR 29% 44% 9% 0% <0.001

Time to Minor Response (mos.)

1.0 1.0 1.0 1.0 0.10

Time to Major response (mos.)

2.0 2.0 6.0 N/A 0.05

Responses to ibrutinib are impacted by MYD88 (L265P and non-L265P) and CXCR4 mutations.

One patient had MYD88 mutation, but no CXCR4 determination and had SD.

Treon et al, ICML 2019Median follow-up: 47.1 months

OIbrutinib in Previously Treated WM: Updated PFS

5 year PFS: 54%5 year OS: 87%

All patients MYD88 and CXCR4 Status

MYD88 MUTATED ONLY

MYD88 AND CXCR4 MUTATED

NO MYD88 OR CXCR4 MUTATIONS

Treon et al, ICML 2019

5 yr 34%

5 yr 71%

★

Adverse Events related to ibrutinib monotherapy

Number of Subjects with Toxicity

• No impact on IGA and IGG immunoglobulins

Update on Adverse Events (Grade >2) in >5% of patients: Neutropenia (22%);Thrombocytopenia (14%), Pneumonia (9%); GERD (8%); Hypertension (8%); anemia (6%); andskin infection (5%). Seven patients (11%) had atrial arrhythmia [Grade 1 (n=1); Grade 2 (n=5);Grade 3 (n=1)], and 6 continued ibrutinib following medical management.

5% to 11% with longer follow-up

22% (No change)

14% (No change)

2% to 8% with longer follow-up

Minimal changes in serum IGG, IGA during course of treatment.

R

Ibrutinib Monotherapy in Symptomatic Treatment Naive WM

✔ MYD88, CXCR4 Mutation Status

Treon et al, JCO 2018NCT02604511

Time to and depth of response to ibrutinib are impacted by CXCR4 mutations.

All Patients MYD88MUT

CXCR4WTMYD88MUT

CXCR4MUT P-value

N= 30 16 14 N/AOverall Response Rate-no. (%)

30 (100%) 16 (100%) 14 (100%) 1.00Major Response Rate-no. (%)

25 (83%) 15 (94%) 10 (71%) 0.16

Categorical responsesMinor responses-no. (%)

5 (17%) 1 (6%) 4 (29%) 0.16Partial responses-no. (%)

19 (63%) 10 (63%) 9 (64%) 1.00Very good partial responses-no. (%)

6 (20%) 5 (31%) 1 (7%) 0.18

Median time to response (months)Minor response (≥Minor response)

1.0 0.9 1.7 0.07Major response (≥Partial response)

1.9 1.8 7.3 0.01

Median f/u: 14.6 months 18 mo. PFS: 92% Treon et al, JCO 2018

Frontline Ibrutinib: Adverse Events (>5%)

Event or Abnormality Grade 2 Grade 3 Grade 4 Total

Grades 2-4Arthralgia 2 (7%) 0 (0%) 0 (0%) 2 (7%)

Atrial fibrillation 3 (10%) 0 (0%) 0 (0%) 3 (10%)

Bruising 2 (7%) 0 (0%) 0 (0%) 2 (7%)

Hypertension 2 (7%) 2 (7%) 0 (0%) 4 (13%)

Neutropenia 2 (7%) 0 (0%) 0 (0%) 2 (7%)

Upper respiratory infection

2 (7%) 0 (0%) 0 (0%) 2 (7%)

Urinary tract infection

2 (7%) 0 (0%) 0 (0%) 2 (7%)

• Minimal hematological toxicity• Median serum IgA levels decreased from 62 to 39 mg/dL; p=0.04• Median serum IgG levels declined from 563 to 462; p=0.003• Afib medically managed in 2 patients who continue on treatment; cardiac

ablation for one patient with left atrial enlargement off treatment.

Mason et al. Br J Haematol 2016

Ibrutinib penetrates the CNS and produces response in Bing Neel Syndrome

Phase III Study of Zanubrutinib vs. Ibrutinib in WM

Strategies to Enhance BTK Inhibitors in WM

ARM B: Placebo+ Rituximab 375mg/m2 x 8 infusions (weeks 1,2,3,4,17,18,19, and 20)

ARM A: ibrutinib 420mg+ Rituximab 375mg/m2 x 8 infusions (weeks 1,2,3,4,17,18,19, and 20)

1:1 Randomization

N = 150

ARM C: ibrutinib 420mgSubjects considered

refractory to prior rituximab

N=31

iNNOVATE Study in WMTreatment Naïve + Previously Treated

45 centers in 9 countries

ABC patients genotyped for MYD88 and CXCR4

Dimopoulos et al, Lancet Oncol 2017; NEJM 2018

16 15 6 17 239

27 22

5329 56

23

58

44

3633

25

3

38

6

1527

14

0102030405060708090

100

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Ibrutinib-RTX

Placebo-RTX

Innovate: Impact of CXCR4 on WM responseB

est

Res

pons

e (%

) ORR 95%

ORR 48%

aFollowing modified 6th IWWM Response Criteria (NCCN 2014); required two consecutive assessments.

MYD88L265P/CXCR4WT MYD88L265P/CXCR4WHIM MYD88WT/CXCR4WT

ORR 100%

ORR 46%

ORR 96%

ORR 57%

ORR 91%

ORR 56%

CRVGPRPRMR

Median time to ≥PR, months (range) 2

(1–28)6

(2–26)2

(1–28)5

(2–17)3

(1–19)11

(4–18)6

(1–17)6

(5–26)

Median time to ≥MR, months (range) 1

(1–18)3

(1–24)1

(1–18)3

(1–24)1

(1–11)3

(1–8)2

(1-17)3

(2–17)

Overall

Major33%

Major79%

Major29%

Major94%

Major48%

Major73%

Major33%

Major64%

??

Dimopoulos et al, NEJM 2018; Updated by Buske et al, ASH 2018

Importance of CXCR4 in PFS

• Improved PFS with ibrutinib

• 36-month PFS rates MYD88L265P/CXCR4WT: 84%

vs 29%

MYD88L265P/CXCR4WHIM: 64% vs 26%

MYD88WT/CXCR4WT: 82% vs 44%

MYD88L265P/CXCR4WT

Prog

ress

ion-

Free

Sur

viva

l (%

)

Months

MYD88WT/CXCR4WT

MYD88L265P/CXCR4WHIM

MYD88L265P/CXCR4WHIM

MYD88WT/CXCR4WT

MYD88L265P/CXCR4WT

Ibrutinib-RTX

RTX

Dimopoulos et al, NEJM 2018; Updated by Buske et al, ASH 2018

Phase I/II Trial of Ulocuplumab and Ibrutinib in CXCR4 mutated patients with symptomatic WM

Ibrutinib Until PD or Intolerance

Weekly Ulo

4 weeks

Biweekly Ulo

20 weeks

ClinicalTrials.gov Identifier: NCT03225716

STOP

Dose Level Ibrutinib Ulocuplumab Cycle 1 Ulocuplumab Cycles 2-6

Level 1 –Starting dose 420mg PO DQ 400 mg weekly 800 mg every other week

Level 2 420mg PO DQ 800 mg weekly 1200 mg every other week

Level 3 420mg PO DQ 800 mg weekly 1600 mg every other week

Schema

Phase II Study of Venetoclaxin Previously Treated WM

ResponseNo prior ibrutinib

(n=15)Prior ibrutinib

(n=15)

Overall 14 (93%) 12 (80%)

Major 13 (87%) 9 (60%)

Very good 4 (27%) 1 (7%)

Partial 9 (60%) 8 (53%)

Minor 1 (7%) 3 (20%)

Stable 1 (7%) 3 (20%)

CXCR4 WT(n=14)

CXCR4 MUT(n=16)

12 (86%) 14 (87%)

9 (86%) 13 (63%)

4 (29%) 1 (7%)

8 (57%) 9 (56%)

0 (0%) 4 (25%)

2 (14%) 2 (13%)

1 patient had progressive disease at 9 months (MYD88, CXCR4, TP53)

Castillo et al. EHA 2018

Median follow-up: 11 months

The role of BCL2 in WM

Cao et al, BJH 2015

Higher BCL2 levels in MYD88 mutated WM

Ibrutinib and Venetoclax in Treatment Naïve WM

Ibrutinib 420 mg/day

x 4 weeks


Add Venetoclax100 mg/day week 5 200 mg/day week 6

400 mg/day weeks 7,8


And

Venetoclax400 mg/day

Observation

4 weeks 4 weeks 22 months Follow to PDor off study

24 months

Jorge Castillo, PI (DFCI)

BTK Cys481 Mutations accompany CXCR4 in WM Patients on Ibrutinib.

Patient*

L265P positive cells

with BTK C481RT>C


with BTK C481ST>A


with BTK C481SG>C


with BTK C481YG>A

L265P positive cells with PLCG2

Y495HT>C


with CARD11 L878FC>T

P1 None None None None None None

P2 32.4% 6.6% 5.8% 1.0% None None

P3 0.3% 34.4% 6.5% 0.3% None 0.2%



P6 None None 10.3% None 11.9% None

Targeted next-generation sequencing for MYD88, CXCR4, BTK, PLCG2, CARD11, LYN.All patients are MYD88 Mutated.

P2, P3, P6 are CXCR4 WHIM Mutated. Xu et al, BLOOD 2017

BTK C481S cells show uniform ERK 1/2 activation in the presence of ibrutinib.

Chen et al, Blood 2018

Ibrutinib

+ ERK-inhibitor

DFCI/ELI LILLY COLLABORATIONPhase I/II Clinical Trial of the oral ERK inhibitor LY3214996 in

BTK Cys 481 and PLCG2 mutated CLL, WM, MZL, MCL

Frontline Therapy of Symptomatic WM

Hyperviscosity, Severe Cryos, CAGG, PN Plasmapheresis

MYD88 Mutated/No CXCR4 mutationNo bulky disease, no contraindications IbrutinibBulky disease Benda-RAmyloidosis Bortezomib/Dex/Rituximab (BDR)IgM Peripheral Neuropathy Rituximab + Alkylator or Ibrutinib

MYD88 Mutated/CXCR4 mutationSame caveats as aboveIf immediate response needed, either BDR or Benda-R

MYD88 Wild-Type✓non-L265P MYD88 mutations BDR > Benda-R

• Hold Rituximab until IgM <4000 mg/dLor empiric pheresis is performed.

• Consider Maintenance Rituximab• Consider Ofatumumab if R intolerant.

Hunter et al, JCO 2017; LeBlond IWWM10

+Ibrutinib and Rituximab

Salvage Therapy of Symptomatic WMConsider repeat primary therapy if response >2 years

MYD88 Mutated/No CXCR4 mutationSame caveats as primary therapy

MYD88 Mutated/CXCR4 mutationSame caveats as primary therapyIf immediate response needed, either BDR or Benda-R

MYD88 Wild-TypeSame caveats as primary therapy ✓non-L265P MYD88 mutations

• Everolimus >2 prior therapies• Nucleoside analogues (non-ASCT candidates)• ASCT in multiple relapses,

chemosensitive disease

Hunter et al, JCO 2017

+Venetoclax for ptspreviously exposed to IB

Merlini et al, Nat Rev Dis Primers. 2018

Amyloidosis

Courtesy of G. Merlini

Diagnostic approach to systemic amyloidosis

2. Muchtar et al, Ann Med. 2017 – 3. Fernandez de Larrea et al, Blood 2015 – 4. Quarta et al, Eur Heart J 2017 – 5. Vrana et al, Blood 2009; 6. Lavatelli et al, Mol Cell Proteom. 2008; 7. Arbustini et al, Amyloid 2002; 8. Schonland et al, Blood 2012

Abdominal fat aspirate: (underutilised):2 sensitivity 81-84%3,4

Possible lip/minor salivary gland biopsy for Congo red

PositiveNegative

Cardiac MRI

Organ biopsy

Type amyloid deposits- Proteomics-MS5,6

- Immuno-EM7

- Immunohistochemistry8

CR

FSBCR


Patients with organ response (%)CR, VGPR, and PR data from 1065 patients at Pavia ARTC

MRD data by NGF on 69 patients at Pavia ARTC

Organ response strictly depends on the quality of hematologic response


• 1,536 patients at 134 centers from1995 to 2012• HR/CR 61/33%, TRM 4% (2007-2012)• Renal response 30%

D’Souza et al, J Clin Oncol 2015

Fit patients: ～20%age < 70 years, ECOG PS≤2, BP >90 mmHg, cTnT < 0.06 ng/mL, Creatinine clear. >30 mL/min, NYHA I or II, ≤ 2 organs involved

Treatment of Fit Amyloid Patients

1. Tandon et al, BMT 2017 - 2. Sidiqi et al, JCO 2018

• CyBorD induction3,4,5

• Consolidation with BDex if < CR6

ASCT with MEL 2001,2

CRPR

VGPR

NR

NA

3. Hwa et al, Am J Hematol, 2016 - 4. Scharman et al, ASH 2017 Abstr .4552 – 5. Afrough, et al. Biol Blood Marrow Transplant 2018 - 6. Landau et al, Leukemia 2017

1,2


Choice of upfront treatment in transplant ineligible patients

• CyBorD – stem cell sparing, is preferred in patients with renal failure, in patients with t(11;14)(～50% of patients) is associated with lower response rate

• BMDex – overcomes the effects of both gain 1q21 and t(11;14)

• MDex – preferred in patients with neuropathy or fibrotic lung disease

High risk patients (stage IIIb, NYHA class III or IV) – Low dose combinationregimens or standard regimens with intensive care support

Merlini, et al. Nat Rev Dis Primers. 2018


Stage IIIb: NT-proBNP> 8500 ng/L (～20%)

Bortezomib-based regimensPalladini et al, Blood 2015 – Le Bras et al, Eur J Cancer 2017

Heart transplantation • age < 65 yrs, • no significant extra-cardiac amyloidosis • ASCT after HTx very effective1-4

• outcomes comparable to non-amyloid5

1. Lacy et al, J Heart Lung Transplant. 2008 – 2. Dey et al, Transplantation 2010 –3. Sattianayagam et al, Am J Transplant. 2010 - 4. Gray Gilstrap, et al, J Heart Lung Transpl 2014 – 5. Kristen et al, J Heart Lung Transplant. 2018

Rapid and deep responses improve outcome of patients with advanced heart involvement

Manwani et al, Haematologica 2018


Treatment of relapsing/refractory patients

HR 68%, ≥VGPR 29% Responders 36 mos

NR 19 mos

P=0.001

IMiDs are effective rescue agents (increase in NT-proBNP, Len potentialnephrotoxicity)Pomalidomide produces rapid and profound responses(Dispenzieri et al, Blood 2012, Sanchorawala et al., Blood 2016 – Palladini et al, Blood 2017)

Daratumumab in AL amyloidosis

Phase III international study of CyBorD vs CyBorD+Dara upfront (ANDROMEDA) - Safety run-in results: Merlini et al, EHA23 PS1318

Kaufman et al, Blood 2017 & Kaufman et al, EHA23 PS1305Jaccard et al, EHA23 S851

No 44Prior lines of therapy, n (range) 3 (1–8)ORR n (%) 25 (83)CR n (%) 5 (17)VGPR n (%) 19 (63)PR n (%) 1 (3)Time to 1st/ best response, 2.2 months

Abeykoon et al, Leukemia 2018Sanchorawala et al, ASH 2018See also: Lee et al, ASH 2018 - Rahman et al, ASH 2018 - Milani et al, ASH 2018 – Kastritis et al ASH 2018

Documents

Waldenstrom’sMacroglobulinemia and Amyloidosis...Waldenstrom’sMacroglobulinemia and Amyloidosis Steve Treon MD, PhD, FRCP, FACP Professor of Medicine, Harvard Medical School Dana