Current Treatment Options for WM
Current Treatment Options for WM
Shuo Ma, MD, PhD
Northwestern University and Robert H. Lurie Comprehensive Cancer Center
Waldenström’s Macroglobulinemia
• Described by Jan Waldenström in 1944 • Low grade B-cell lymphoma, 1% of NHL • 1000-1500 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 Definition
• Waldenstrom’s Macroglobulinemia (WM) – Lymphoplasmacytic lymphoma (LPL) in the bone marrow – IgM protein in the blood
LPL IgM 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 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
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
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
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
Differential Diagnosis of WM
• Non-IgM lymphoplasmacytic lymphoma (LPL)
• Other low-grade B-cell lymphomas, especially marginal zone lymphoma (MZL)
• IgM myeloma
Treatment of WM 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
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
Currently Available Active Agents in WM • Chemotherapy • Monoclonal Antibodies – Alkylating agents – Rituximab (Rituxan®) • Bendamustine (Treanda ®) – Ofatumumab (Arzerra®) • Cyclophosphamide (Cytoxan ® ) • Proteosome Inhibitor • Chlorambucil • Melphalan – Bortezomib (Velcade®) – Carfilzomib (Kyprolis®) – Purine Nucleoside Analogues • Ibrutinib (Imbruvica®) • Fludarabine • IMiDs • Pentostatin • Cladribine – Thalidomide – Lenalidomide
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 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)
Anti-CD20 monoclonal antibodies (mAb)
Rituximab (Rituxan) Ofatumumab (Arzerra)
Rituximab-based Treatments • Rituximab alone – Previously untreated patients (4/8 weekly): ORR 35%/60% – Relapsed disease (4/8 weekly): ORR 25%/45% – DOR 16-29 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 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 Plasma pheresis should be considered for patients with IgM>5gm/dL or serum viscosity >3.5cp prior to Rituxan treatment Cyclophosphamide (Cytoxan) – based regimens 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 * CHOP-R group has more patients with IgM>5 g/dL, whose RR and TTP is inferior Toxicity in CP-R, CVP-R and CHOP-R
Iokimidis et al, Clin Lymph Myeloma 2009 DRC (dex, rituximab, cyclophosphamide) as 1st line treatment for WM
• 2002-2006 multicenter phase 2 trial of 72 pts in Greece. 3 years follow up. • Treatment – Dex 20mg IV followed by Rituximab 375 mg/m2 on day 1, oral Cyclophosphamide 100 mg/m2 BID on day 1-5 (total dose of 1000 mg/m2), 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 Bendamustine-Rituximab (BR) B-R vs. CHOP-R
Rummel 2009 3rd International Patient Physician Summits on WM B-RummelR vs. 2009 CHOP 3rd International-R Patient Physician Summits on WM Rummel 2009 3rd International Patient Physician Summits on WM 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, 1203 - 1210 http://dx.doi.org/10.1016/S0140-6736(12)61763-2 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 2013. Treon et al. Clin Lymphoma Myeloma Leuk. 2011 Tedeschi et al. Leuk Lymphoma. 2015
Purine Analogue-based regimens
Fludarabine Purine Analogue –Based Regimens
• Single agent – Previously untreated: Cladribine 38-85% RR; Fludarabine 38-100% – 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
Proteosome Inhibitor
Bortezomib (Velcade®) Carfilzomib (Kyprolis®)
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. 2007 Clin Cancer Res; Treon et al. 2009. JCO; Rohatiner et al. 2009 Weekly Bortezomib, Dex and Rituximab (BDR) in untreated WM – A Phase 2 study from Europe • Treatment regimen – Cycle 1 (21 days): bortezomib 1.3mg/m2 on day 1,4,8,11 – Cycle 2-5 (35 days): • Bortezomib 1.6mg/m2 on day 1, 8, 15 and 22 per cycle • For cycle 2 and 5, add dex 40mg IV and rituximab 375 mg/m2 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):3276-3282 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
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
Maintenance Therapy with Rituximab Maintenance Rituximab is Associated with Improved PFS and OS in WM • Retrospective analysis of 248 WM pts treated at DFCI
PFS OS (56·3 vs. 28·6 months; P = 0·0001) (Not reached vs. 116 months; P = 0·0095)
British Journal of Haematology Volume 154, Issue 3, pages 357-362, 25 MAY 2011 DOI: 10.1111/j.1365-2141.2011.08750.x http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08750.x/full#f1 Rummel 2009 3rd International Patient Physician Summits on WM Imbruvica (Ibrutinib)
A novel oral inhibitor for Bruton’s tyrosine kinase (BTK) Mechanism of Action of Ibrutinib in WM Treon et al. NEJM 2015 Lancet Oncology 2016 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). Genomic Mutations in WM
• Activating MYD88 as well as nonsense and frameshift WHIM- like CXCR4 somatic mutations are common in WM – MYD88L265P 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 (CXCR4WHIM/NS and CXCR4WHIM/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;123:2791-2796 Long-term Follow-up on Ibrutinib study in Relapsed WM (Median follow up 47 months)
IgM reduction 3520 821 mg/dl Hemoglobin 10.5 14.2 Steven P Treon et al. Blood 2017;130:2766 Bone marrow 60% 20%
©2017 by American Society of Hematology IgM Changes Hgb Changes Long-term Follow-up on Ibrutinib study in Relapsed WM (Median follow up 47 months)
Steven P Treon et al. Blood 2017;130:2766
©2017 by American Society of Hematology
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
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
Current Treatment Options
Induction Maintenance
• Rituximab • Bendamustine-based (BR) • Rituximab • Cyclophosphamide-based (RCP, RCD) • Ofatumumab • Bortezomib-based (BDR)
Ibrutinib
Dimopoulos et al. Blood. 2013;122(19):3276-3282 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
Valuable Resources on WM
• American Cancer Society (ACS) – www.cancer.org • National Cancer Institute (NCI) – www.cancer.gov • ClinicalTrials.gov – www.ClinicalTrials.gov • International Waldenstrom’s Macroglobulinemia Foundation (IWMF) – www.iwmf.com • Lymphoma Research Foundation (LRF) – www.lymphoma.org
Q & A
Questions?