Waldenström s Macroglobulinemia Biology and Management

Transcription

1 Waldenström s Macroglobulinemia Biology and Management Steven P. Treon, MD, MA, MS, PhD, FRCP, FACP Professor of Medicine, Harvard Medical School Director, Bing Center for WM Dana Farber Cancer Institute Chair, WM Clinical Trials Group

2 Waldenström s Macroglobulinemia first described by Jan Gosta Waldenström in 1944.

3 Waldenstrom s Macroglobulinemia: Genetic Predisposition Strong familial predisposition (20-25%) Ashkenazi Jews (20%) Rare in African Americans (<5%) IgM MGUS 1.8-2% annual progression rate: 40-90% progress to WM. Kyle et al, Blood 2003; 102(10): ; Treon et al, Ann Oncol 2006; 17(3): ; Hanzis et al, Clin Lymph Myeloma 2011; 11(1):88-92.

4 B-cell CD19+CD20+CD38- Plasma cell CD19-CD20-CD38+ LPC cell CD19+CD20+CD38+/- From Dr. Marvin Stone WHO Classification: IgM secreting lymphoplasmacytic lymphoma

5 80-90% sigm retained in intravascular space

6 Manifestations of WM Disease Bone Marrow Hb>>> PLT> WBC Bing Neel Syndrome Hyperviscosity Syndrome: Epistaxis, Headaches Impaired vision >6,000 mg/dl or >4.0 CP 20% at diagnosis; 50-60% at relapse. Hepcidin Fe Anemia Cold Agglutinemia (5%) Cryoglobulinemia (10%) IgM Neuropathy (22%) Amyloidosis (10-15%) Treon S., Hematol Oncol. 2013; 31:76-80.

7 Hyperviscosity Related Retinal Changes in WM Retinal vein dilatation seen IgM >3,000 mg/dl Retrograde flow and hemorrhages >6,000 mg/dl Stone, Clin Lymphoma 2005; Menke et al, Arch Opthal 2006

8 Cryoglobulinemia in a patient with Waldenstrom s macroglobulinemia Post-Pheresis Pre-Pheresis

9 Peripheral Neuropathies in WM 20-25% of WM patients Usually a sensory demyelinating neuropathy related to anti- Myelin Associated Glycoprotein (MAG) IgM antibody. MAG IgM Amyloid neuropathy is rare and associated with axonal degeneration. Treon et al, ASCO 2010; Photomicrograph Courtesy Todd Levine, MD Baldini et al, Am J Hematol 1994; 45(1):25-31; Treon et al, J Clin Oncol 2010; 28:15S (Abstract 8114). Photomicrograph courtesy of Todd Levine, M.D.

10 NCCN Guidelines for Initiation of Therapy in WM Hb 10 g/dl on basis of disease PLT <100,000 mm 3 on basis of disease Symptomatic hyperviscosity Moderate/severe peripheral neuropathy Symptomatic cryoglobulins, cold agglutinins, autoimmune-related events, amyloid. Kyle RA, et al. Semin Oncol. 2003;30(2): ; Anderson et al, JNCCN 2012; 10(10):

11 Primary Therapy of WM with Rituximab Regimen ORR VGPR/CR TTP (mo) Rituximab x % 0-5% 13 Rituximab x % 5-10% Rituximab/thalidomide 70% 10% 30 Rituximab/cyclophosphamide i.e. CHOP-R, CVP-R, CPR, CDR Rituximab/nucleoside analogues i.e. FR, FCR, CDA-R Rituximab/Proteasome Inhibitor i.e. BDR, VR, CaRD 70-80% 20-25% % 20-30% % 20-40% Rituximab/bendamustine 90% 30-40% 69 Reviewed in Dimopoulos et al, Blood 2014; 124(9): ; Treon et al, Blood 2015; How I Treat WM

12 WM centric toxicities with commonly used therapies Agent WM Toxicities Rituximab IgM flare (40-60%)-> Hyperiscosity crisis, Aggravation of IgM related PN, CAGG, Cryos. Hypogammaglobulinemia-> infections, IVIG Intolerance (10-15%) Fludarabine Hypogammaglobulinemia-> infections, IVIG Transformation, AML/MDS (15%) Bendamustine Prolonged neutropenia, thrombocytopenia (especially after fludarabine) AML/MDS (5-8%) Bortezomib Grade 2+3 Peripheral neuropathy (60-70%); High discontinuation (20-60%)

13 Targeting the Entire WM Clone with Monoclonal Antibodies Rituximab Rituximab Daratumumab CD20 CD20 CD38 IgM B-cells Lymphoplasmacytic Cells Plasma Cells WM Clone

14 Phase II Study of Daratumumab in Relapsed/Refractory WM Patients Screening Informed Consent and Registration Progressive Disease or Unacceptable Toxicity Stop Daratumumab Event Monitoring Daratumumab Weekly X 4 Biweekly X 4 Monthly X 12 SD or Response Continue Event Monitoring DFCI, MSKCC, Stanford

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16 MYD88 Mutations in B-cell LPD WM ABC DLBCL 93-95% MYD88 L265P 2% Non-L265P MYD88 29% MYD88 L265P 10% Non-L265P MYD88 Treon et al, NEJM 2012; Treon et al, NEJM 2015; Jiménez et al, 2013; Varettoni et al 2013; Poulain et al, 2013, Xu et al, 2013.

17 MYD88 mutations transactivate NFKB Ngo et al, Nature 2011 Treon et al, NEJM 2012 MYD88 L265P mutated WM cells

18 Signaling Pathways Driven by Mutated MYD88 in Waldenström's Macroglobulinemia TLRs/IL-1R IL-6R IL-6 IL-6 IL-6 Ibrutinib ACP196 CC-292 BGB-3111 MYD88 BTK IRAK4 IRAK1 BTK HCK PIK3R2 PLCγ PI3K gp-130 Ibrutinib TRAF6 TAK1 PKC AKT IKKα NEMO IKKβ ERK1/2 HCK mtor Degradation NFKB growth survival IL-6 Yang et al, Blood 2013 Yang et al, Blood 2016

19 CXCR4 C-tail mutations in WM B 30-40% of WM patients; v. rare in other LPD >30 Nonsense, Frameshift Mutations Accompany MYD88 mutations High serum IgM levels/hyperviscosity Promote ibrutinib resistance through enhanced AKT/ERK signaling. Hunter et al, Blood 2013; Rocarro et al, Blood 2014: Poulain et al, Blood 2016; Cao et al, Leukemia 2014; Cao et al, BJH 2015

20 Multicenter study of Ibrutinib in Relapsed/Refractory WM (>1 prior therapy) R R. Advani L. Palomba MYD88, CXCR4 Mutation Status

21 Responses to ibrutinib are impacted by MYD88 (L265P and non-l265p) and CXCR4 mutations. ALL MYD88 Mut CXCR4 WT MYD88 Mut CXCR4 Mut MYD88 WT CXCR4 WT N= P-value ORR 90.4% 100% 85.7% 60% Major (>PR) 77.7% 97.2% 66.6% 0% <0.001 VGPR 27.0% 44.4% 9.5% 0% Time to Minor Response (mos.) Time to Major response (mos.) N/A 0.05 Treon et al, ASH 2017

22 O Ibrutinib in Previously Treated WM: PFS Treon et al, ASH 2017

23 Ibrutinib Related Adverse Events in previously treated WM patients Toxicities >1 patient; N=63 Number of Subjects with Toxicity # of patients with toxicity No impact on IGA and IGG immunoglobulins 10% incidence with larger WM Experience; earlier presentation for those patients with prior Afib history. Treon et al, NEJM 2015; Gustine et al, AJH 2016

24 July 8, 2015 September, 2015 April 5, 2016

25 Ibrutinib in Rituximab-Refractory WM Patients: Multicenter, Open-Label Phase 3 Substudy (innovate ) Median Prior Therapies: 4 (range 1-7) Median follow-up: 18.1 (range months) ORR: 90% Major RR (> PR): 71% (N=) (%) VGPR 4 13 PR MR 6 19 Median time to > MR: 4 weeks Median time to best response: 8 weeks 18 mo PFS: 86% 18 mo OS: 97% Dimopoulos et al, IWWM9 2016; Lancet Oncol 2017.

26 Impact of CXCR4 Mutation Status on IgM and HgB Response Dimopoulos et al, IWWM9; Lancet Oncology, 2017

27 Primary Therapy of WM with Ibrutinib Median Time on Therapy: 32.4 weeks Overall Response Rate: 97% sigm: 4,380 1,780 mg/dl Hb: g/dl No CRs Treon et al, ASH 2017

28 Strategies to Enhance Ibrutinib Activity in WM

29 Phase II Study of Ibrutinib plus Ulucuplomab in CXCR4 WHIM WM Patients Screening Informed Consent and Registration Progressive Disease or Unacceptable Toxicity Stop Ibrutinib/Ulucuplomab Event Monitoring Ibrutinib 420 mg po daily + Ulucuplomab weekly x 4 then biweekly X 20 weeks SD or Response Continue Event Monitoring

30 BCL-2 is overexpressed in primary WM patient cells by transciptome analysis in MYD88 mutated patients regardless of CXCR4 mutation status. Healthy Donor CD19 + CD27 - Healthy Donor CD19 + CD27 + WM CD19 + MYD88 L265P CXCR4 WT WM CD19 + MYD88 L265P CXCR4 WHIM WM CD19 + MYD88 WT CXCR4 WT p<0.001 for healthy donor samples versus any MYD88 L265P CXCR4WT or WHIM Hunter et al, BLOOD 2016

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32 Venetoclax (ABT-199) enhances Ibrutinib killing in MYD88 mutated WM Cells. Untreated DMSO IB ABT ABT+IB 10 0 * * WM1 WM2 WM3 WM4 Ibrutinib >6 mo. Cao et al, BJH * * WM5 WM6 WM7 DMSO IB ABT ABT+IB *CXCR WHIM

33 Activity of the anti-bcl2 agent Venetoclax (ABT-199) in previously treated NHL Patients Davids et al, JCO 2017

34 Phase I/II Study of Venetoclax (ABT-199) in Previously Treated WM Screening Informed Consent and Registration Progressive Disease or Unacceptable Toxicity Stop ABT-199 Event Monitoring ABT mg a Day SD or Response Continue Event Monitoring

35 Approach to Frontline Therapy of Symptomatic WM Hyperviscosity, Severe Cryos, CAGG, PN Plasmapheresis MYD88 Mutated/No CXCR4 mutation No bulky disease, no contraindications Ibrutinib (if available) Bulky disease Benda-R Amyloidosis Bortezomib/Dex/Rituximab (BDR) IgM Peripheral Neuropathy Rituximab + Alkylator MYD88 Mutated/CXCR4 mutation Same caveats as above If immediate response needed, either BDR or Benda-R MYD88 Wild-Type non-l265p MYD88 mutations BDR or Benda-R Hunter et al, JCO 2017 Hold Rituximab until IgM <4000 mg/dl or empiric pheresis is performed. Consider Maintenance Rituximab Consider Ofatumumab if R intolerant.

36 Salvage Therapy of Symptomatic WM Consider repeat primary therapy if response >2 years MYD88 Mutated/No CXCR4 mutation Same caveats as primary therapy MYD88 Mutated/CXCR4 mutation Same caveats as primary therapy If immediate response needed, either BDR or Benda-R MYD88 Wild-Type Same caveats as primary therapy non-l265p MYD88 mutations Hunter et al, JCO 2017 Everolimus >2 prior therapies Nucleoside analogues (non-asct candidates) ASCT in multiple relapses, chemosensitive disease

37 Ibrutinib (560 mg/day) induced response in a WM patient with Bing Neel Syndrome Mason et al, BJH 2016

38 Bing Center for WM

39 UCLA Summit on WM, Los Angeles 2003

40 Dedication of Bing Center for WM at DFCI-2005

41 Chris Patterson, MAcc Kirsten Meid, MPH

42 10th International Workshop on Waldenstrom s Macroglobulinemia New York City, NY October 10-13, 2018 Patient Symposium October 13-14,

43 CASE STUDIES IN WALDENSTROM S MACROGLOBULINEMIA

44 WM Case 1 66 year old female swimmer was experiencing progressive fatigue, as well as shortness of breath while swimming her normal laps. She went to urgent care clinic, and had a hemoglobin of 5 g/dl with normal platelet and leukocyte counts. The reticulocyte count was elevated at 10.4%, and haptoglobin low consistent with autoimmune hemolysis. Cold-agglutinins were negative. She was started on steroids with modest improvement. There was no further benefit with IVIG. Her total protein was elevated, and further workup revealed an IgM kappa monoclonal protein, and total serum IgM level of 2525 mg/dl. Bone marrow biopsy showed 25% involvement with lymphoplasmacytic lymphoma. Molecular diagnostic studies showed MYD88 L265P mutation, but no CXCR4 mutation. CT scans showed prominent mesenteric, retroperitoneal and inguinal adenopathy but no splenomegaly. Viral studies are unremarkable (HCV, HBV, HIV). She is requiring supportive transfusions with packed red blood cells.

45 WM Case 1 At this time you decide to: 1.Administer rituximab 2.Administer rituximab with an alkylator drug 3.Administer rituximab with a proteasome inhibitor 4.Administer rituximab with fludarabine 5.Start ibrutinib 6.Consider plasmapheresis

46 WM Case 1 The patient was started on ibrutinib at 420 mg a day. Over the next 10 months the IgM declined to 60 mg/dl. Immunofixation studies showed a faint spike not apparent on the electropherogram. Her reticulocytosis resolved, and haptoglobin normalized. Her hemoglobin rose 14.9 g/dl, and she did not require transfusions. Repeat bone marrow biopsy showed 5% LPL involvement. CT scans show scattered subcentimeter lymph nodes that did not meet pathological criteria.

47 WM Case 2 A 42 year-old male presented with blurry vision and nosebleeds. Physical examination revealed retinal hemorrhages, adenopathy and splenomegaly. Laboratories revealed a hematocrit of 18% (normal %), platelets of 50,000/mm 3 (normal 155, ,000/mm 3 ), and leukocyte count of 1,500/mm 3 (normal 3,800-9,200/mm 3 ). Serum total protein was high prompting a workup that revealed an IgMλ monoclonal protein and serum IgM level of 12,400 mg/dl. CT scans showed bulky adenopathy, and a bone marrow biopsy revealed that 80% of the intertrabecular space was involved with lymphoplasmacytic lymphoma. Immunohistochemistry demonstrated CD20 expressing bone marrow disease, and the MYD88 L265P mutation was present.

48 WM Case 2 Case Presentation I

49 WM Case 2 Which of the following is the best next step in the care of this patient? 1. Initiate rituximab therapy 2. Initiate proteasome inhibitor based therapy 3. Initiate alkylator (bendamustine or cyclophosphamide) based therapy 4. Initiate nucleoside analogue based therapy 5. Initiate ibrutinib 6. Initiate plasmapheresis

50 WM Case 2 The patient undergoes emergent plasmapheresis, and his vision and energy improved. His retinal exam improved, and repeat serum IgM level was 3,892 mg/dl. Genotyping shows that the patient has also a CXCR4 nonsense mutation. What intervention would you now recommend? 1. Initiate rituximab therapy 2. Initiate proteasome inhibitor based therapy 3. Initiate alkylator (bendamustine or cyclophosphamide) based therapy 4. Initiate nucleoside analogue based therapy 5. Initiate ibrutinib

51 WM Case 3 A 46 year-old male was diagnosed with WM after presentation with fatigue and a hematocrit of 28.6% (normal %). A bone marrow biopsy showed 90% involvement with lymphoplasmacytic lymphoma. CT scans were unremarkable, and the serum IgM was 2,780 mg/dl. Treatment with bortezomib, dexamethasone and rituximab was started. After 3 cycles, no treatment response was observed. The patient then received 2 cycles of cyclophosphamidebased (CDR) therapy without response. Bendamustine was then initiated, and after two cycles the serum IgM and hemoglobin levels remained unchanged. A repeat bone marrow biopsy confirmed unchanged tumor burden, and molecular diagnostics showed the patient to have MYD88 L265P mutation. The patient continues to be symptomatic.

52 WM Case 3 Which of the following is the best therapeutic intervention at this time? 1. Initiate fludarabine 2. Initiate ibrutinib 3. Initiate everolimus 4.Initiate treatment with high dose chemotherapy and autologous stem cell transplantation.

53 10th International Workshop on Waldenstrom s Macroglobulinemia New York City, NY October 10-13, 2018 Patient Symposium October 13-14,

54 Chris Patterson, MAcc Kirsten Meid, MPH