Current Treatment Options for WM

Transcription

1 Current Treatment Options for WM Shuo Ma, MD, PhD Northwestern University and Robert H. Lurie Comprehensive Cancer Center

2 Waldenström s Macroglobulinemia Described by Jan Waldenström in 1944 Low grade B-cell lymphoma, 1% of NHL new cases per year in the US 3.8/million-persons/year Median age at diagnosis is 69 years More common in Caucasians Familial predisposition in up to 26% cases

3 Definition Waldenstrom s Macroglobulinemia (WM) Lymphoplasmacytic lymphoma (LPL) in the bone marrow IgM protein in the blood LPL IgM

4 Clinical Presentation Lymphoma infiltration Fever, night sweats, weight loss Bone marrow infiltration causing cytopenias Enlarged lymph nodes, liver, spleen Monoclonal IgM (M-protein) Hyperviscosity Cold agglutinin hemolytic anemia Peripheral Neuropathy Cryoglobulinemia Amyloidosis

5 IgM related syndromes (1) Hyperviscosity Syndrome 15% Blurry vision, headache, dizziness, hearing impairment, confusion, stroke, bleeding. Often viscosity is >4.0 cp, IgM>3000 mg/dl Peripheral Neuropathy - 20% Symmetric, slowly progressing numbness/tingling and weakness Distal, sensory, demyelinating Associated with auto-antibody MAG, GM1, sulfatide

6 IgM related syndromes (2) Cold-agglutinin hemolytic anemia IgM autoantibody causing clumping of RBCs causing lysis of the RBCs Cryoglobulinemia 10% of IgM precipitate in cold temperature Raynaud phenomenon, skin rash, finger tip cyanosis and necrosis

7 IgM related syndromes (3) IgM deposition Syndromes In GI tract causing malabsorption In lungs causing cough and dyspnea In skin causing skin rash and thickening Amyloidosis Deposition of fibril material to various organs Detected by Congo red staining in bone marrow biopsy or fat pad aspiration

8 Diagnostic and staging studies Serum protein studies - to identify and quantify the IgM monoclonal protein Bone marrow biopsy to study lymphoplasmacytic lymphoma (LPL) and the extent of disease in the bone marrow Immunophenotype CD19+, CD20+, CD5-, CD10- Molecular studies MYD88 L265P mutation Imaging studies CT scan, PET-CT etc. - to examine the lymph node and organ involvement Other lab studies blood counts, b2m, chemistry

9 Differential Diagnosis of WM Non-IgM lymphoplasmacytic lymphoma (LPL) Other low-grade B-cell lymphomas, especially marginal zone lymphoma (MZL) IgM myeloma

10 Treatment of WM

11 Criteria for Initiation of Treatment in WM Hemoglobin <= 10 g/dl on basis of disease Platelet < 100 k/ul on basis of disease Constitutional symptoms in setting of disease progression Symptomatic extramedullary disease (lymphadenopathy, hepatosplenomegaly, other organ involvement) Symptomatic hyperviscosity Moderate/severe peripheral neuropathy Symptomatic cold agglutinins, cryoglobulinemia, amyloidosis

12 Treatment of WM How to treat? Plasmapheresis For rapid reduction of IgM protein level Does not treat the underlying lymphoma Cytoreduction therapy To reduce the lymphoma disease burden To reduce IgM production Maintenance therapy

13 Currently Available Active Agents in WM Chemotherapy Alkylating agents Bendamustine (Treanda ) Cyclophosphamide (Cytoxan ) Chlorambucil Melphalan Purine Nucleoside Analogues Fludarabine Pentostatin Cladribine Monoclonal Antibodies Rituximab (Rituxan ) Ofatumumab (Arzerra ) Proteosome Inhibitor Bortezomib (Velcade ) Carfilzomib (Kyprolis ) Ibrutinib (Imbruvica ) IMiDs Thalidomide Lenalidomide

14 Response Criteria for WM Complete response (CR) Abscence of M-protein, no BM involvement, resolution of extramedullary disease (adenopathy/organomegaly) and bone marrow disease Very good partial response (VGPR) 90% reduction of M-protein, resolution of adenopathy/organomegaly and Partial response (PR) 50% reduction of M-protein and adenopathy/organomegaly symptoms Minor response (MR) 25%-49% reduction of IgM, no new symptoms/signs Stable disease (SD) <25% reduction and <25% increase in IgM, no progression Progressive disease (PD) 25% increase in IgM or progression of clinically significant findings due to disease (cytopenia, adenopathy, organomegaly, symptoms) VI International Workshop on WM

15 Understanding Treatment Efficacy in WM Overall Response Rate (ORR) At least a minor response (CR+VGPR+PR+MR) Major Response Rate At least a partial response (CR+VGPR+PR) Progression-Free Survival (PFS) Duration of Response (DoR)

16 Anti-CD20 monoclonal antibodies (mab) Rituximab (Rituxan) Ofatumumab (Arzerra)

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18 Rituximab-based Treatments Rituximab alone Previously untreated patients (4/8 weekly): ORR 35%/60% Relapsed disease (4/8 weekly): ORR 25%/45% DOR months Rituximab combinations (ORR >80-90%) R + Bendamustine R + Cyclophosphamide + steroids R + Purine analogue R + Bortezomib + steroids Leblond et al 2016_Blood_8th International workshop

19 Rituximab Common Adverse Effects Infusion-related reaction (IRR) 7% rituximab intolerant in WM Infections due to low immunoglobulin levels Screen for hepatitis B and C Antiviral prophylaxis Consider IVIG for recurrent infections IgM flare Transient increase of IgM level during initial treatment

20 Plasma pheresis should be considered for patients with IgM>5gm/dL or serum viscosity >3.5cp prior to Rituxan treatment

21 Cyclophosphamide (Cytoxan) based regimens

22 Cyclophosphamide-Based Regimens CHOP-R Cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab. CVP-R Cyclophosphamide, vincristine, prednisone, rituximab. CP-R Cyclophosphamide, prednisone, rituximab CD-R Cyclophosphamide, dexamethasone, rituximab Iokimidis et al, Clin Lymph Myeloma 2009; Dimopoulos at al. JCO 2007

23 * CHOP-R group has more patients with IgM>5 g/dl, whose RR and TTP is inferior

24 Toxicity in CP-R, CVP-R and CHOP-R Iokimidis et al, Clin Lymph Myeloma 2009

25 DRC (dex, rituximab, cyclophosphamide) as 1 st line treatment for WM multicenter phase 2 trial of 72 pts in Greece. 3 years follow up. Treatment Dex 20mg IV followed by Rituximab 375 mg/m 2 on day 1, oral Cyclophosphamide 100 mg/m 2 BID on day 1-5 (total dose of 1000 mg/m 2 ), q21 days for 6 cycles Results ORR 80-90% Median PFS 35 months Median time to next treatment - 51 months 5-year OS 59%, cause-specific survival (CSS) 74% No MDS or secondary AML Dimopoulos et al., ASH 2009, abstract 2887

26 Bendamustine-Rituximab (BR)

27 B-R vs. CHOP-R Rummel rd International Patient Physician Summits on WM

28 B-R Rummel vs CHOP-R 3 rd International Patient Physician Summits on WM

29 Rummel rd International Patient Physician Summits on WM

30 Progression-Free Survival in 41 WM Patients: B-R vs. CHOP-R Mathias J Rummel, Norbert Niederle, Georg Maschmeyer, G Andre Banat, Ulrich von Grünhagen, Christoph Losem,... Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial The Lancet, Volume 381, Issue 9873, 2013,

31 Bendamustine-based regimen in WM Efficacy High response rate (ORR 95% in frontline, ORR 83% in relapsed WM) Long-lasting effect (BR as frontline - median PFS 69.5 months) Better tolerated (when compared to R-CHOP) Adverse effects Cytopenias, infection risk Rummel et al. Lancet Treon et al. Clin Lymphoma Myeloma Leuk Tedeschi et al. Leuk Lymphoma. 2015

32 Purine Analogue-based regimens Fludarabine

33 Purine Analogue Based Regimens Single agent Previously untreated: Cladribine 38-85% RR; Fludarabine % Relapsed: Cladribine 38-43% RR; Fludarabine 30-41% FC: Fludarabine/cyclophosphamide: ORR 55-89% FR: Fludarabine/Rituxan WMCTG reported long term outcomes. Treon et al. Blood 2009 ORR 96%, CR 5%, VGPR 32%, PR 49%, minor R 9% ) Median time to progression 51.2 months Toxicity: myelosuppression and immunosuppression; transformation FCR: Fludarabine/cytoxan/Rituxan: ORR 56-90% Tedeschi ASH 2008 Increased toxicity;? Improved efficacy Delayed response

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35 Proteosome Inhibitor Bortezomib (Velcade ) Carfilzomib (Kyprolis )

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37 Bortezomib-based Regimens Bortezomib Monotherapy ORR 60-85% in 3 trials Grade >=3 sensory neuropathy in 20-30%, most reversible BDR (bortezomib/ dexamethasone/rituxan) in untreated WM ORR 96%, MRR 83%, CR 22% Rapid response, median 1.4 months 80% PFS at 2 years Most common toxicity neuropathy 69%; grade 3 or above 30%. Neutropenia 30%; thrombocytopenia 9%. Herpes Zoster infection. Treon et al Clin Cancer Res; Treon et al JCO; Rohatiner et al. 2009

38 Weekly Bortezomib, Dex and Rituximab (BDR) in untreated WM A Phase 2 study from Europe Treatment regimen Cycle 1 (21 days): bortezomib 1.3mg/m 2 on day 1,4,8,11 Cycle 2-5 (35 days): Bortezomib 1.6mg/m 2 on day 1, 8, 15 and 22 per cycle For cycle 2 and 5, add dex 40mg IV and rituximab 375 mg/m 2 following each dose of bortezomib. Total of 8 doses. Results (n=59) ORR 85% (3% CR, 7% VGPR, 58% PR); Median time to best response 4.8 months IgM flare (increase >25%) in 11% patients median progression-free survival was 42 months (32 f/u time) Peripheral neuropathy in 46% (grade 3/4 in 7%); Dimopoulos et al. Blood. 2013;122(19):

39 Bortezomib-based regimens in WM Efficacy High response rate ORR 85-96% Rapid onset of response PFS 42 months Adverse effects Peripheral neuropathy Cytopenias Infection Peripheral neuropathy may be mitigated by once weekly and subcutaneous dosing of bortezomib Consider carfilzomib as an alternative

40 Alternative proteasome inhibitor Carfilzomib CaRD (Carfilzomib+Rituximab+Dexamethasone) Phase 2 study, 31 patients with WM (previously 28 untreated) ORR 87% (VGPR 36%) Lower rate of neuropathy (All grade 19%, grade 2 at 3%) Other adverse effects: cytopenias, infection, elevated lipid, bilirubin and pancreatic enzymes, cardiomyopathy Treon et al. Blood 2014

41 Maintenance Therapy with Rituximab

42 Maintenance Rituximab is Associated with Improved PFS and OS in WM Retrospective analysis of 248 WM pts treated at DFCI PFS (56 3 vs months; P = ) OS (Not reached vs. 116 months; P = ) British Journal of Haematology Volume 154, Issue 3, pages , 25 MAY 2011 DOI: /j x

43 Rummel rd International Patient Physician Summits on WM

44 Imbruvica (Ibrutinib) A novel oral inhibitor for Bruton s tyrosine kinase (BTK)

45 Mechanism of Action of Ibrutinib in WM

46 Treon et al. NEJM 2015

47 Lancet Oncology 2016

48 Ibrutinib in Relapsed/Refractory WM Treon et al. NEJM 2015 N=63, median age 63, median prior therapies 2 ORR 91%, MR 73% 2 year PFS 69% Dimopoulos et al. Lancet Oncology 2016 Rituxan-refractory WM N=31, ORR 90%, MR 71% 18 month PFS 86% Major responses was impacted by mutations in CXCR4 and MYD88 L265P. The major response rate was 77% for patients with wt CXCR4 vs. 30% in those with WHIM-like CXCR4 mutations (p=0.018). Decreases in serum IgM (p=0.047) and improvements in hemoglobin (p=0.058) were greater in patients with wild-type CXCR4. Patients with wild-type CXCR4 also had increased peripheral lymphocytosis following ibrutinib treatment versus those with WHIM-like CXCR4 mutations (p=0.001).

49 Genomic Mutations in WM Activating MYD88 as well as nonsense and frameshift WHIMlike CXCR4 somatic mutations are common in WM MYD88 L265P mutation was found in 90-95% of WM patients An activating mutation that triggers IRAK and BTK that in turn activate NFkB signaling and malignant cell growth CXCR4 mutations (CXCR4 WHIM/NS and CXCR4 WHIM/FS ) were found in 30% of WM patients Regulate signaling of CXCR4 by its only known ligand SDF-1a (CXCL12), leading to persistent activation of CXCR4, enhanced AKT and BTK signaling, as well increased cell migration, adhesion, growth, and survival of WM cells. CXCR4 NS mutations are present in aggressive cases including hyperviscosity syndrome, and MYD88 status is a determinant of survival. Steven P. Treon et al. Blood 2014;123:

50 Long-term Follow-up on Ibrutinib study in Relapsed WM (Median follow up 47 months) IgM reduction mg/dl Hemoglobin Bone marrow 60% 20% Steven P Treon et al. Blood 2017;130: by American Society of Hematology

51 IgM Changes

52 Hgb Changes

53 Long-term Follow-up on Ibrutinib study in Relapsed WM (Median follow up 47 months) Steven P Treon et al. Blood 2017;130: by American Society of Hematology

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56 Ibrutinib Adverse Effects Gastrointestinal side effects: diarrhea, nausea, indigestion, heartburn. Fatigue, joint or muscle ache. Increased risk of bleeding Infection. Low blood counts Hypertension Cardiac: atrial fibrillation

57 Common Treatment Regimens Immunotherapy (Rituximab alone) Immunochemotherapy combination Cyclophosphamide-based therapy (RCD, RCP) Bendamustine-based therapy (BR) Velcade-based therapy (VRD) Fludarabine-based therapy (FR) Novel targeted therapy Ibrutinib +/- Rituxan

58 Current Treatment Options Induction Rituximab Bendamustine-based (BR) Cyclophosphamide-based (RCP, RCD) Bortezomib-based (BDR) Maintenance Rituximab Ofatumumab Ibrutinib Dimopoulos et al. Blood. 2013;122(19):

59 Novel agents under investigation for WM Novel oral targeted therapies BTK inhibitors (acalabrutinib, BGB3111) PI3K inhibitor (idelalisib, Umbralisib) Bcl2 inhibitor (Venetoclax) PI3K/mTOR inhibitor (Everolimus) Novel monoclonal antibodies Obinutuzumab (anti-cd20) Ulocuplumab (anti-cxcr4) Daratumumab (anti-cd38) Novel Proteosome inhibitors Carfilzomib, Ixazomib, Oprozomib Nove Immunomodulatory agents (IMiDs) Pomalidomide

60 Valuable Resources on WM American Cancer Society (ACS) National Cancer Institute (NCI) ClinicalTrials.gov International Waldenstrom s Macroglobulinemia Foundation (IWMF) Lymphoma Research Foundation (LRF)

61 Q & A Questions?