what's new in waldenström macroglobulinemia · 2020. 8. 31. · in r/r waldenstrom’s...
TRANSCRIPT
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Hot Topic 1: WM
What's New in Waldenström MacroglobulinemiaPresentation Hot Topic
PD Dr Dominik HeimUniversitätsspital Basel
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Waldentröm Macroglobulinemia
Definition
• Lymphoplasmocytic Lymphoma ( LPL)
→ mature B-Zell neoplasm
• Waldeström Macroglobulinemia ( WM)
→ LPL bone marrow infiltration (no threshold) and presence of monoclonal IgM
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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.
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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
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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
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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