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Waldenstrm Macroglobulinemia Debates and Didactics in Hematology and Oncology Sea Island, GA August 6 10, 2014 Leonard T. Heffner, Jr., M.D. Disclosures Consulting fees: Spectrum Pharmaceuticals Contracted Research: Onyx,

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Waldenström Macroglobulinemia

Leonard T. Heffner, Jr., M.D.

Debates and Didactics in Hematology and Oncology Sea Island, GA August 6‐10, 2014

Disclosures

  • Consulting fees:

– Spectrum Pharmaceuticals

  • Contracted Research:

– Onyx, Idera, Amgen, Pfizer, Biotest, Dana‐Farber CI, Gilead, Pharmacyclics, Janssen, Genentech, Talon Therapeutics

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1944: Jan Waldenström described 2 pts with lymphadenopathy, but also oronasal bleeding, anemia, thrombocytopenia, increased viscosity, elevated ESR, normal bone survey, and bone marrow showing predominantly lymphoid cells.

Waldenström, J: Incipient myelomatosis or essential hyperglobulinemia with fibrinogenopenia--A new syndrome? Acta Medica Scand 117:216-247, 1944.

WHO 2008: The Mature B‐cell Neoplasms

  • Lymphoplasmacytic lymphoma
  • a. Bone marrow infiltration by small lymphocytes,

plasmacytoid cells, and plasma cells

  • b. diffuse, interstitial or nodular pattern of bone

marrow infiltration

  • c. Immunophenotype: CD5‐,CD10‐, usually CD23‐,

CD19+,CD20+,sIg+

  • 1. Waldenström macroglobulinemia

IgM monoclonal gammopathy of any concentration

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Demographics

Incidence Age-adjusted : 3.8/million persons/yr.(1500/yr) Amyloidosis: 8/mil persons/yr Myeloma: 40/mil persons/yr Gender: Males: 5.4/mil Females: 2.7/mil Race: Caucasian- 4.1/mil African-American- 1.8/mil Age: 65-73 yo (median at Dx)

Wang H, et al. Cancer 2011;doi:10.1002/cncr.26627

Clinicopathological Manifestations of WM

Adenopathy, splenomegaly ≤15%

HCT, PLT, WBC

Hyperviscosity Syndrome: Epistaxis, HA, Impaired vision >4.0 CP IgM Neuropathy (~20%) Cryoglobulinemia (<5%) Cold Agglutinemia (<10%) Fatigue, Constitutional Sxs Cytokinemia?

Cancer Treat Res. 2008;142:211-242.

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Indications for treatment of WM

Bone Marrow/Node Related

  • 1. Hgb <10
  • 2. Plts <100k
  • 3. Bulky lymphadenopathy
  • 4. Organomegaly
  • 5. “B” symptoms

Indications for treatment of WM

IgM-related

  • 1. Hyperviscosity - HAs, epistaxis, blurred vision, retinal bleed, ICH, leg cramps, AMS
  • 2. Cyroglobulinemia, type 1: Raynaud’s, acrocyanosis, ulcers, purpura, cold urticaria
  • 3. Peripheral neuropathy: sensorimotor, painful PNx, ataxic gait, bilat. Footdrop
  • 4. Cryoglobulinemia, type II: purpura, arthralgias, renal failure
  • 5. Cold agglutinins: hemolytic anemia, Raynaud’s, acrocyanosis
  • 6. Organ dysfunction

a) tissue deposition as amorphous aggregates

  • skin(bullae, Schnitzler’s) GI(diarrhea, malabsorption) Kidney(proteinuria, ARF)

b) tissue deposition as amyloid fibrils

  • fatigue, wt. loss, edema, hepatomegaly, macroglossia, specific organ involved

kidney, heart, liver, peripheral nerve

Adapted from : Treon , SP Blood;2009:2375

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International prognostic scoring system for Waldenström

Variables Age >65 Hgb <11.5 Plts <100k B2M >3 IgM >7.0 Score Med surv 5-yr surv Low 0-1

age<65

142.5 mos. 87% Int 2

  • r age>65

98.6 mos. 68% High >3 43.5 mos. 36 %

For pts. needing therapy

Morel P, et al. Blood 2009;113:4163

nl LDH = 94 mos Inc LDH = 36 mos

Kastritis E, et al Leu Res 2010;doi:10;1016

Making the decision to treat WM

  • There is NO one standard of care regimen.
  • Does the patient meet the criteria for symptomatic

disease?

  • How urgent is response needed?

‐ immediate vs. non‐immediate

  • Are there any high‐risk features?

‐ no agreement in non‐urgent pts ‐ Flow cytometry can identify poor prognostic goups in both smoldering WM and symptomatic WM

  • Is the patient a potential candidate for stem cell

transplant?

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Treatment Options in WM

Alkylating agents: chlorambucil, melphalan, cyclophosphamide, (bendamustine) Purine nucleoside analogues: fludarabine, cladribine Monoclonal antibodies: rituximab,

  • fatumumab, alemtuzumab

Proteasome inhibitors: bortezomib, carfilzomib IMiDs: thalidomide, lenalidomide, pomalidomide New Agents: inhibitors of m‐TOR, Akt, BTK, TLR, HDAC Stem cell transplant: auto and allo

Single‐Agent Treatment in WM

Regimen No. Responses (%) >PR >MR CR Chlorambucil 46-128 70-75 NR 2 Cladribine 16-46 43-94 NR 2 Fludarabine 28-183 30-36 NR 0-3 Rituximab 17-69 32-48 55-69 Bortezomib 10-27 48-60 59-85 0-4 Thalidomide 20 25 25

Rourke M, et al Leuk&Lymp, 2010;51:1779-92. (modified)

NR = not reported

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Combination Treatment in WM

Regimen (No. pts 31-72) Responses (%) >PR >MR CR Flu/Ctx 55-78 NR Flu/R 82 95 5 FCR 74 79 12 Clad/Ctx 84 NR 5 Mel/Ctx/Pred 77 NR NR Mel/Ctx/CB/Pred 74 NR 26 Ctx/R/Dex 74 83 7 R-CHOP 91 NR 9

Rourke M, et al Leuk&Lymp, 2010;51:1779-92.(modified)

NR = not reported

Phase III Trials in WM

Yr. pub Regimen No. Pop. Yrs to complete Kyle 1999 Daily vs intermit CB 46 Upfront 22 Leblond 2001 Flu vs CAP 92 Rel/Ref 4 Buske 2009 CHOP vs R-CHOP 48 Upfront 3 Rummel 2009 R-CHOP vs BR 41 Upfront 6 Leblond 2013 Flu vs CB 337 Upfront 8.5

Rourke M, et al Leuk&Lymp, 2010;51:1779-92.(modified)

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Monoclonal Antibody Therapy as Single Agent in WM

  • No. Pts

>PR >MR CR Rituximab (CD20)¹ 17‐69 32‐48% 55‐69% Ofatumumab (CD20)² 37 59% Alemtuzumab (CD52)³ 28 36% 75%

1 Rourke M, et al Leuk&Lymp, 2010;51:1779‐92 2 Furman RR, et al ASH abstracts 2011; abstract 624 3 Treon, SP, et al. Blood 2011;118:276‐81

New Drugs in Waldenström

Proteasome inhibitors: bortezomib, carfilzomib m‐TOR Inhibitors: everolimus (RAD001); temsirolimus Kinase inhibitors: perifosine; enzastaurin HDAC inhibitors: panobinostat BTK inhibitors: ibrutinib; CC‐292; ONO‐4059; ACP‐196 TLR inhibitors: IMO‐8400

JBRMO1

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Slide 16 JBRMO1 Dr Heffner should IMiDs (pomalidomide ) be included here?

Janelle Bowersox, RN, MSN, OCN, 7/23/2014

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Reference Bz/CFZ (dose in mg/m2 IV)

  • No. ORR

(%) >PR (%) CR PFS OS PNX Grade Treon (untreated) 1.3 twice weekly 23 76 83 3-CR 2-nCR NYR NR >30% Gd 3 Agathocleus (rel/ref) 1.3 2x/wk or 1.6 wk-no Dex 10 90 NR NR NR NR >Gd 3 14-19 Ghobrial (rel/ref) 1.6 weekly (no Dex) 37 81 51

  • 15.6

mos NYR Gd 3- 5 Gd 4- 0 Ghobrial (untreated) 1.6 weekly (no Dex) 26 88 58 1-CR 1-nCR NYR NYR Dimopoulos (untreated) 1.6 weekly 60 85 68 2-CR <12 mos 82% 3 yr >Gd 3- 7% Treon (mixed) CFZ: 20-36 d1,2,8,9 31 81 68 1-CR 8-vgpr NYR NYR > Gd 2-0

Reported series of bortezomib (BZ)carfilzomib (CFZ), rituximab +/- dexamethasone in WM (treated and untreated)

Responses to Everolimus (RAD001)in Relapsed/Refractory and Previously Untreated WM

  • No. Med age

VGPR % PR% MR% ORR% Rel/Ref* 60 63 50 23 73 Primary~ 33 62 6 55 12 72

* Ghobrial I, et al. Am J Hem 2014;89:237‐42 ~ Treon SP, et al. ASH 2013; abstract 1822

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Figure 1. Kaplan–Meier curve of progression free‐survival (PFS) and overall survival (OS) in 60 patients with relapsed Waldenstrom’s macroglobulinemia treated with single‐agent everolimus.

Ghobrial I, et al. Am. J. Hematol. 89:237–242, 2014.

=21 mos = not reached

E1A10: Treatment for Primary or Relapsed WM and Rel/Ref MZL, MCL, FL, and SLL. Bortezomib 1.6mg/m2 IV/SQ d1,8,15,22 Rituximab* 375mg/m2 IV d1,8,15,22 Dexamethasone 20mg PO d1,8,15 Bortezomib 1.6mg/m2 IV/SQ d1,8,15,22 Rituximab* 375mg/m2 IV d1,8,15,22 Dexamethasone 20mg PO d1,8,15 Temsirolimus at MTD IV d1,8,15,22

Q 28d x6 Q 28d x6 R A N D O M I Z E Accrual goal = 144 pts *Rituximab cycles 1 & 4 only

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Phase I and II Trials of New Agents in Relapsed/Refractory WM

Agent No. PR% MR% ORR% SD% CR PFS (mos) Perifosine⁴ 37 11 24 35 54 12.6 Enzasturin⁵ 42 5 33 38 33 10.6 (TTP) Panobinostat⁶ 36 22 25 47 50 6.6 Pomalidomide⁷ 8* 25 25 38 NA

  • 4. Ghobrial IM, et al. Clin Ca Res 2010;16:1033‐41.
  • 5. Ghobrial, IM, et al. Clin Ca Res 2012;18:5043‐50.
  • 6. Ghobrial, IM, et al. Blood 2013;121:1296‐303.
  • 7. Sheeba KT, et al. JCO 32:5s, 2014, abstract 8536(Phase I)

* MTD 1mg/day; 3 pts had prog disease

Somatic Gene Mutation in WM

  • 30 pts: whole genome sequencing

26/30 had variant at 3p22.2 ‐single nucleotide T C in MYD88 ‐switch of leucine to proline at position 265 (L265P)

  • Familial cases = 9/9 (100%)
  • Sporadic cases = 18/21 (86%)
  • IgM MGUS = 2/21 (9.5%)

Treon SP, et al NEJM 2012;367:826

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What is MYD88?

  • An adaptor molecule in toll-like receptor (TLR) and interleukin-

1 receptor signaling (IL-1R)

  • Recruited to an activated receptor complex leading to

activation of several intermediate proteins resulting ultimately in activation of NF-kB

  • NF-kB: transcription factor
  • regulates survival of normal and malignant B-cells
  • targets genes that enhance survival, inhibit

apoptosis and limit activity of pro-apoptotic BCL-2 family

  • necessary for growth and survival of WM cells
  • Knockdown model of MYD88 interrupts NF-kB signaling with

apoptosis of 2 different WM cell lines

MYD88‐Directed NF‐κB Signaling.

Treon SP et al. N Engl J Med 2012;367:826-833.

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Bruton Tyrosine Kinase (BTK)

  • Ogden Bruton, U.S. Navy pediatrician described in 1952 a

rare X-linked immunodeficiency in children characterized by virtual absence of B cells and circulating immunoglobulin

  • The gene mutated, BTK, was cloned and characterized in

1993

  • Member of the TEC family of non-receptor tyrosine kinases
  • Essential for transmission of mitogenic signals from the B-

cell receptor, which is responsible for the generation and maintenance of B lymphocytes

IBRUTINIB: Small Molecule Inhibitor of BTK

  • Inactivates BTK through covalent

binding to cysteine-481 near the ATP binding domain of BTK.

  • Orally

bioavailable with daily dosing resulting in 24-hr target inhibition.

  • Blocks IkBa and NFKB p65

signaling in WM cells.

  • Induces apoptosis of MYD88

L265P expressing WM cells in preclinical studies.

Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010 Herman SEM et al: : Blood. 2011 Mar 21. [Epub] Ponader, et al., Proc ASH, 2010; Yang et al. Proc. ASH 2012. N N N N NH 2 O N O

IBRUTINIB

Slide permission of SP Treon, MD

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SCHEMA FOR MULTICENTER PHASE II STUDY OF IBRUTINIB IN RELAPSED REFRACTORY WM

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Screening Informed Consent and Registration Ibrutinib 420 mg po daily Progressive Disease or Unacceptable Toxicity Stable Disease or Response Continue x 26 four week cycles (maximum) Stop Ibrutinib Event Monitoring Event Monitoring

N=35, expanded to 63.

OPENED MAY 2012 DFCI, MSKCC, STANFORD

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Schema for Multi‐center Study of Ibrutinib in Relapsed/Refractory Waldenstrom CHARDPACTERISTICS AT BASELINE (N=35)

Median Range

Age (yrs) 63 44‐86 Prior therapies 2 1‐6 Refractory 12 (34%) NA Hematocrit (%) 30.8 26.7‐39.2 Serum IgM (mg/dL) 3190 735‐8390 M‐protein (g/dL) 2.08 0.5‐5.4 B2M (mg/dL) 4.4 1.3‐14.2 BM Involvement (%) 70 5‐95 Adenopathy or Splenomegaly 29 (83%) NA

Treon et al, ICML-12, Lugano 2013

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Patient Characteristics at Baseline

Treon SP, et al ASH abstract 251, 2013.

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Best Clinical Response to Ibrutinib* >6 cycles: N=63(rel/ref)

No. Percent VGPR 4 6 PR 32 51 MR 15 24 SD 11 17 No Resp 1 1 ORR = 81% Major RR (>PR) = 57.1%

Treon SP, et al ASH abstract 251, 2013.

* Dose 420 mg daily for intent of 2 years

Ibrutinib in Rel/Ref WM: Toxicities grade >2 in 63 pts.

Event No. Percent Thrombocytopenia 9 14.3 Neutropenia 12 19.1 Stomatitis 1 1.6 Atrial fib 1 1.6 Diarrhea 1 1.6 Herpes zoster 1 1.6 Hematoma 1 1.6 Hypertension 1 1.6 Epistaxis 1 1.6

Treon, SP, et al. ASH abstract 251;2013

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BTK Inhibitors in preclinical and clinical development

BTK Inhibitor Stage of development Disease(s) Ibrutinib Phase II/III CLL/SLL, MCL, WM,ABC‐ DLBL, MM GDC‐0834 Phase I Rheumatoid arthritis RN‐486 Preclinical RA, SLE CGI‐560 Preclincal Not reported CGI‐1746 Preclincal RA HM‐71224 Phase I RA CC‐292 Phase I CLL/B‐NHL ONO‐4059 Phase I CLL CNX‐774 Preclinical Autoimmune and B‐NHL LFM‐A13 Preclinical B‐NHL ACP‐196 Phase I CLL/SLL

Akinleye,A, et al. J Hem&Onc 2013;6:59 (modified)

Toll‐like Receptors (TLRs)

TLRs consist of a family of 10 members that are part of the normal human innate immunity against bacteria, viruses and fungi and will activate the host immune defenses, specifically generating NF‐kB. All but TLR3 require MYD88 as an adaptor molecule. Of this family, TLRs 7,8 and 9 are located in the endosome rather than on the cell surface and in humans are expressed on dendritic cells and B‐cells Over activation of the TLR signaling pathway represents an autonomous activation resulting in a malignant phenotype and

  • ccurs in cells expressing the MYD88 L265P mutation. Blocking of

this pathway results in decreased cell survival as demonstrated in mutated WM cell lines and WM patient cell lines vs wild‐type control lines and in pre‐clinical models.

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Toll‐like Receptors (TLRs)

MYD88 signaling for NF‐kB can occur through dual mechanisms:

  • a. TLR signaling
  • b. BCR pathway through BTK (antigen mediated)

Both mechanisms are dysregulated by the MYD88 L265P mutation IMO‐8400 is an oral, small molecule that is an antagonist for the receptor that mediates activation of TLR7, 8 and 9

The TLR signaling pathway and downstream effector molecules

Zhu J and Mohan C. Media Inflamm. 2010;781235

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BCR signaling

Young RM and Staudt LM. Nature Rev. Drug Discov 2013;12:229

Phase I/II study of IMO‐8400 in Rel/Ref Waldenström Macroglobulinemia

Registered at Clinicaltrials.gov