Immunotherapy in Waldenström Macroglobulinemia

Dra Eugenia AbellaHematologia Clínica Hospital del Mar, Barcelona

Jan Gosta WaldenströmStockholm, 1906-1996

Diagnosis of Waldenström Macroglobulinemia

Diagnosis requires:

- Histological/Cytological findings

- Flow cytometry parameters

- Molecular marker

Owen RG et al. 2nd IWWM. Sem Oncol, 2003; 30Ansell SM et al. Mayo Clin Proc, 2010; 85Mazzucchelli M et al, Mediterr J Hematol Infect Dis, 2018; 10Drandi D et al, Haematologica, 2018;103

Lymphoplasmacytic lymphoma

Small B lymphocytesPlasmacytoid lymphocytesPlasma cellsBone marrow, lymph nodes, spleen

> 90% MYD88 L265P

30% CXCR4 mutOften paraprotein IgM

Swerdlow S et al, Blood, 2016; 127

Waldenström macroglobulinemia

LPL with bone marrow involvementIgM gammopathy> 90% MYD88 L265P

30% CXCR4 mut

Diagnosis WHO 2016

Owen RG et al. Sem Oncol 2003; 30: 110-115

Immunophenotyping in Waldenström Macroglobulinemia

• B lymphocyte :CD19 +d, CD22+d, Cd20++, CD79b++

CD5-, CD10-, CD23-, CD43-, CD11c-CD25+, CD27+

SmIgM +, surface light chain ++

CD5 + en 5%CD23 neg, tumor burden

• Plasmatic cellCD38++, CD138+, CD19+, CD45 +CD56-, CD117-, CD 20-, CD81+, CD27+

Clonal plasmatic cellswith normal phenotypeDifferent from plasmaticcells in multiplemyeloma

Swerdlow S et al, Blood, 2016; 127Paiva B et al, Leukemia 2014; 28Jelinek T et al, Blood Cancer J, 2017;7

It is interesting to include plasmatic cells detection in the WM diagnosis

Treon S et al, ASH 2011, NEJM 2012; 367

93-97% of WM patients

30-40% of WM patients

MYD88 and CXCR4 mutations in Waldenström Macroglobulinemia

Adapted from Castillo JJ et al, Exp Rew Hematol 2019, Exp Rew Hematol 2017

93-97% of WM patients

30-40% of WM patients

MYD88 and CXCR4 mutations in Waldenström Macroglobulinemia

Adapted from Castillo JJ et al, Exp Rew Hematol 2019, Exp Rew Hematol 2017

Could PI3K and ERK activation produce resistance to alquilating agents, proteasome-inhibitors and BTK inhibitors ?

93-97% of WM patients

ibrutinib

x

Treon SP et al, N Eng J Med 2015; 372Treon SP et al, Br J Haematol, 2018

Bustoros M et al, J Clin Oncol 2019; 37(16)

Responses to BTK inhibitors

CXCR4 mut/BTK inhibitors

- Longer time to response- Lower rates of major or VGPR- Shorter PFS

- not associated with worse or better OS

Detecting CXCR4 mutations has not been standardized.

Castillo JJ et al, Exp Rew hematol 2019

Impact of CXCR4 mutations in clinical features of patients with Waldenström Macroglobulinemia

Clinical manifestations

• Heterogeneous

• Symptoms secondary to organ infiltration

• Symptoms secondary to specific immunological andphysicochemical features of monoclonal IgM

• Bing-Neel syndrome (1%) : CNS involvement

• Schnitzler syndrome : chronic autoimmune urticaria , IgMgammopathy and other rheumatic manifestations

Minnema MC et al, Haematologica, 2017; 102Lipsker D et al , Medicine , 2001; 80

Courtesy of E.Kimby

Waldenström Macroglobulinemia treatment:

Where we are ?

Adapted from Kastritis E, 17th IMW, 2019

Waldenström Macroglobulinemia treatment

Buske ch et al. Lancet Haematol 2018; 5: e299–309Adapted from Treon S , 17th IMW, 2019Kastritis E et al, ESMO Guidelines, 2018, Annals of Oncology29.Kastritis E , 17th IMW 2019Olszewski AJ et al, Br J Haematol, 2017; 179

Treatment choices in patients with Waldenström’s macroglobulinaemia (2000-2013)

Anti-CD20-based (rituximab-based) combinations are the mainstay of first-line treatment.

Waldenström Macroglobulinemia treatment

Adapted from Kastritis E, 17th IMW, 2019Treon S et al, Br J Haematol, 2011;154Castillo JJ et al , Br J Haematol 2018; 181Zanwar S et al, ASCO 2019, abs 7559

Although maintenance treatment with rituximab couldprovide some clinical benefit according to retrospectivedata, maintenance therapy cannot be recommended in WMdue to the lack of prospective data

Waldenström Macroglobulinemia treatment

Outcomes with rituximab plus bendamustine (R-Benda), dexamethasone, rituximab, cyclophosphamide (DRC), and bortezomib, dexamethasone, rituximab (BDR) as primarytherapy in patients with Waldenstrom macroglobulinemia (WM).

MRR, TTNT and EFS in front-line with R-Benda are superior in comparison to DRC or BDR The toxicity profile across the 3 groups was comparable.

Abeykoon JP et al, ASCO 2019, abs 7509

Proteasome inhibitors - based regimensin Waldenström macroglobulinemia

TTR (m) ORR(%) ≥ VGPR/MR (%)

PFS NP (%)

Borte/DR (IV) (1,2)

1,4 96 35 5,5 60

KRD (3,4) 2,1 87 36 3,8 20citopenies

IxaRD(mant) (5)

2 96 77 NR (22m) 23

Treon SP et al, JCO 2009; 27Treon SP et al, Blood 2015; 126Treon SP et al, Blood 2014; 124Meid et al, Blood 2017; 130Castillo JJ et al, Clin Canc Res 2018;24

Bortezomib is included in the American, French and European Guidelines

Treon SP et al, N Eng J Med, 2015; 372.

PFS OS

ORR: 87% Major RR (≥PR): 68%

BTK- Inhibitors in Waldenström Macroglobulinemia

Treon SP et al, ICML, 2019Treon SP et al, IMW 2019

Ibrutinib in previously treated WM . Updated PFS

5 years PFS: 54%5 years OS: 87%

Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With WaldenströmMacroglobulinemia.

Treon S et al, J Clin Oncol, 2018;36

30 pts, 100% MYD88 mut, 47% CXCR4 mut

ORR 100%Major R 83%PFS 18 m 92%

CXCR4WT CXCR4mut p

MR (%) 94 71

VGPR (%) 31 7

TTMR (m) 1,8 7,3 0.01

Dimopoulos MA et al, N Eng J Med 2018; 378

Ibrutinib-Rituximab vs Placebo -Rituximab . A multicenter open-label phase 3 study

Dimopoulos MA et al, N Eng J Med 2018; 378

Relapsed/refractory patientsAll patients

Of note, improved PFS was seen in treatment-naïve patients, relapsed patients, and independent of MYD88/CXCR4 genotype

Dimopoulos MA et al, N Eng J Med 2018; 378

30 month PFS: 82% vs 28%

Overall Survival

30 patients in the placebo-RTX arm crossed over to single-agent ibrutinib

At a median follow-up of 26.5 months,

▪ 4 deaths on ibrutinib-RTX▪ 6 deaths on placebo-RTX

0

10

20

30

40

50

60

70

80

90

100

Months

Ibrutinib-RTX

Placebo-RTX

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Pat

ien

ts W

ho

Su

rviv

ed

(%

)

▪ 30-month OS rate: 94% vs 92%

Dimopoulos MA et al, N Eng J Med 2018; 378

Waldenström Macroglobulinemia treatment:

Where we go ?

1- inh SYK

2- Inh Pi3K (δ)

3- inh de AKT

4- inh de mTOR

5- Inh de bcl-2

6- inh de XPO1

7- inh de checkpoints

Novel therapeutic targets in WM

Adapted from Paulus A et al, Best Prac Res Clin Haematol, 2016

Adapted from Advani P et al, Hematol Oncol Stem Cell Ther , 2019

Treon S et al, 17th IMW , 2019

Novel therapeutic targets in WM. BTK Inhibitors

A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenstrom macroglobulinemia

(Clinicaltrials.gov identifier NCT03053440).

Enrollment complete

Novel therapeutic targets in WM. BTK Inhibitors

Novel therapeutic targets in WM . Anti- CXCR4 Monoclonal Antibody

Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractoryWaldenstrom macroglobulinemia

6 RVR +mant46Pts (98% prior rituximab, 57% prior bortezomib) 36/46 Full doseORR 87%, 4%CR, PFS: 21 m

Ghobrial IM et al, Leukemia 2015;164Everolimus included as an acceptable treatment option

Novel therapeutic targets in WM. Mammalian Target of rapamycin (m-TOR) inhibitors

Novel therapeutic targets in WM.BCL-2 inhibitors

• Venetoclax + ibrutinib synergy ?

• Identifying the role of venetoclax in WM

Castillo JJ et al, 10th International Workshop on WM, 2018

Role of plasma cells in Waldenström Macroglobulinemia

• Plasma cell infiltration in WM: 5-10%

• Monotypic expression (kappa or lambda intracellular)

• They would present MYD88 mut in > 90% WM cases

(Treon demonstrated existence of

mutation in CD138 cells positive)

• IgM levels related to plasmatic component

Adapted from El-Ayoubi A et al, Pathology, 2017Treon SP et al, N Eng J med 2012; 367

• The aim of the treatment in WM is destroying lymphoplasmacytic compartmentbut only an 0-7% patients achieve CR

• There may be another component in the pathogenesis of the disease

• The compartment of plasma cells remains after the treatment and could be theresponsible of the IgM persistence .

Adapted from El-Ayoubi A et al, Pathology, 2017Treon SP et al, N Eng J med 2012; 367

Role of plasma cells in Waldenström Macroglobulinemia

ClinicalTrials.gov Identifier: NCT03187262

•A Phase 2 Study of Daratumumab in Patients With Relapsed or Refractory Waldenström Macroglobulinemia

Daratumumab will be administered in three phases: Induction, consolidation and maintenance

•Daratumumab+ ibrutinibPhase I/II studyWM cells lines death including ibrutinib-resistant cells

Paulus A et al, Br J Haematol, 2018

• Immunochemotherapy remains the standard of treatment inmost patients with MW

• Ibrutinib +/- Rituximab is effective in first line and also insubsequent lines

• CXCR4 mutated patients show a slower response to ibrutinib.

• New targeted therapies open new paths for refractory patients

• The role of the plasma cells and the use of daratumumab in MWtherapy is under investigation.

Conclusions