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Current Treatment Options for WM

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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
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