Hot Topic 1: WM

What's New in Waldenström MacroglobulinemiaPresentation Hot Topic

PD Dr Dominik HeimUniversitätsspital Basel

Waldentröm Macroglobulinemia

Definition

• Lymphoplasmocytic Lymphoma ( LPL)

→ mature B-Zell neoplasm

• Waldeström Macroglobulinemia ( WM)

→ LPL bone marrow infiltration (no threshold) and presence of monoclonal IgM

MYD88myeloid differentiation primary response Gene 88

o Mutated in >90% of WM: MYD88L265P

o Not diagnostic for WM:

o MYD88L265P found in IgM MGUS, othersmall B-cell lymphomas, non-GC DLBCL, other rare type DLBCL

o MYD88L265P not in Myeloma

o MYD88L265P → Gain of function mutation→ constitutive activation of BTK

CXCR4C-X-C chemokine receptor type 4

o Mutated in 30-40% of WM: CXCR4WHIM

o >30 nonsense and frameshift mutations

o Almost always occur with MYD88L265P

WHIM syndrome: warts, hypogammaglobulinemia, infections, and myelokathexis.

Congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.

Bendamustin, Rituximab (BR) Bortezomib, Dexamethason, Rituximab (BDR)Dexamethason, Cyclophosphamid, Rituximab (DCR)(R-CHOP, FCR)

*not fit for immunochemotherapy> approved

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R-maintenance or not

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Rituximab maintenance in WM

BR, BDR, CDR induction, up to 2 years maintanence with Rituximab q2-3m

Castillo et al, BJH 2018

m PFS 2.8 years 6.8 years

First line therapy, retrospective study

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B-R + watch & wait vs. B-R + 2 years Rituximab

StiL NHL 7-2008 MAINTAIN

Rummel et al, #343, ASH 2019

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Rummel et al, #343, ASH 2019

Rituximab maintenance in WM

StiL NHL 7-2008 MAINTAIN

PFS and OS

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New drugs in WM

• 2nd G BTK inhibitors

• 2nd G Proteosome inhibitors

• BCL-2 inhibitors

• CXCR4 antagonists

• Daratumumab

Treon et al, N Engl J Med 2015

Response n

VGPR 10

PR 36

MR 11

ORR 90%

Ibrutinib in Previously Treated

Waldenström’s Macroglobulinemia

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iNNOVATE

Phase 3 Trial of Ibrutinib plus Rituximab

in Waldenström’s Macroglobulinemia

75 pts in each armm-Age 70 years45% first line tx

Dimopoulos et al, NEJM 2018

PFS

Zanubrutinib Efficacy in WM

Overall(n = 73)

TN(n = 24)

RR(n = 49)

Median Follow-up

22.5 mo 10.6 mo 23.1 mo

Response CriteriaMod. 6th IWWM

(IgM and lymph node reduction)

Median Prior Lines of Therapy

0 2 (1-8)

ORR 92% 96% 90%

MRR 82% 88% 80%

VGPR 41% 25% 49%

PR/PR-L 41% 63% 31%

Tam et al. IWWM 2018.

MosSu

rviv

al (

%)

Patients at Risk, n

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

73 73 71 66 61 50 43 42 36 36 34 27 19 17 15 14 9 5 4

100

80

60

40

20

0

+ Censored

++++++++++++++++++++++++++ +++++++

++++++++

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ASPEN Ibrutinib vs Zanubrutinib

in WM

• Randomized, open-label, multicenter phase III study

▪ Patients with WM and indication for treatment

▪ no prior BTK treatment;

▪ if TN: not suitable for standard chemo

Tx until PD, unacceptable

AE, death, withdrawal of

consent

Ibrutinib 420 mg PO QD

Zanubrutinib 160 mg PO BID

▪ Primary endpoint: rate of CR or VGPR in cohort 1

▪ Secondary endpoints: response, DoR, PFS, and safety

NCT03053440.

Zanubrutinib 160 mg PO BID

Cohort 1: MYD88

mutationN=201

(164 R/R)

Cohort 2: MYD88

wildtype

Tam et al: ASCO 2020

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ASPEN Ibrutinib vs Zanubrutinib in WM

Efficacy – Response by IRC (Data Cutoff: 31 August 2019)

M.Dimopoulos; EHA25-2020

Superiority in CR and VGPR rate compared with Ibrutinib in R/R population(primary study hypothesis) was not significant

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ASPEN Ibrutinib vs Zanubrutinib in WM

PFS and OS in ITT population

M.Dimopoulos; EHA25-2020

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AE categories of interest (BTKi class AEs) withadditional 5-mo follow-up (Data Cutoff: 31 January 2020)

An additional 5 patients in the ibrutinib arm discontinued treatmentbecause of AEs vs 0 in the zanubrutinib arm (14.3% vs 4%)

ASPEN Ibrutinib vs Zanubrutinib in WM

Higher AE rate in bold blue with >10% difference in any grade or >5% in grade 3 or above*defined as any grade >3 hemorrhage or any-grade central nervous system hemorrhage+Descriptive 2-sided P

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Acalabrutinib monotherapy in patients withWaldenström macroglobulinemia: a single-arm, multicentre, phase 2 study

Owen et al: Lancet Hematology 2019

Response6th IWWM Criteria

TN (n = 14) R/R (n = 92)

ORR (≥ MR), % (95% CI) 93 (66-100) 93 (86-98)

MRR (≥ PR), % (95% CI) 79 (49-95) 80 (71-88)

Best response, n (%)▪ CR▪ VGPR▪ PR▪ MR▪ SD

00

11 (79)2 (14)1 (7)

08 (9)

66 (72)12 (13)

6 (7)

Median time to best response, mos (range) 4.9 (1.8-16.6) 1.9 (0.9-23.2)

▪ ORR similar (> 90%) across strata by age, baseline PS, baseline IgM, and prior number of regimens, and slightly lower for baseline Hb < 110 g/L (89%) vs ≥ 110 g/L (100%)

Acalabrutinib 100 mg BID or 200 mg QD* PO in 28-day cycles

PD or unacceptable

toxicity

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Proteasome Inhibitors

Castillo JJ et al; Clin Cancer Res 2018

Ixazomib Rituximab Dexamethason

• 26 pts, first line treament• All MYD88MUT, 60% CXCR4WHIM

• ORR 96%, VGPR 15%, PR 62%• Better responses in CXCRWT

• M follow up 22 m

Carfilzomib Rituximab Dexamethason

Treon et al, Blood 2014

Bortezomib Rituximab Dexamethason

Dimopoulos et al, Blood 2013

C1 Bort 1,4,8,11C2-5 Bort weeklyPN grade >1: 24%

PN grade >1: 1 of 31 pts

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IXAZOMIB, RITUXIMAB, DEXAMETHASONE (IRD)

IN R/R WALDENSTROM’S MACROBLOBULINEMIA:

PHASE I/II HOVON 124/ECWM-R2 TRIAl

Kersten + Amaador: EHA25-2020

8 cycles induction IRD (R sc), 2 years maintenance R sc q 3m

Response during induction

ORR PR VGPR

85% 46% 15%

PFS and OS at 24 months

PFS 56%

OS 88%

New onset PN grade >1: 3%

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Venetoclax

Castillo JJ et al, EHA 2018, updated at IMW 2019

PROSPECTIVE PHASE II STUDY OF VENETOCLAX IN PATIENTS WITH PREVIOUSLY TREATED WM

Venetoclax 800mg for max 2 years31 patients, m-followup 18 months, previous lines of therapy was 2 (range 1-10)52% previously exposed to IbrutinibMYD88 L265P in all patients, CXCR4 mutations in 17 (55%)

2-year PFS rate is 76%Grade 4 neutropenia in 5 patients. Grade 3 adverse events: neutropenia (n=15), anemia (n=4), diarrhea (n=4).No IgM flare or clinical TLS

Response

VGPR 19%

PR 61%

Minor 6%

ORR 87%

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Ulocuplumab + IbrutinibCXCR4 moAb NCT03225716

Daratumumab + Ibrutinib

NCT03679624

Mavorixafor + Ibrutiniboral CXCR4 antagonist NCT04274738

Clinical Trials

CAR-T cell Therapy for WM

Clinical trials with anti-CD19 CAR-T and anti-CD20 CAR-T cellsincluding patients with WM are ongoing

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Thank you foryour attention

Jan Gösta Waldenström 1906-1996