Waldenström 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, Idera, Amgen, Pfizer, Biotest, Dana ‐ Farber CI, Gilead, Pharmacyclics, Janssen, Genentech, Talon Therapeutics 1
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 2
Demographics Incidence Age-adjusted : 3.8/million persons/yr.(1500/yr) Amyloidosis: 8/mil persons/yr Myeloma: 40/mil persons/yr Age: 65-73 yo (median at Dx) Gender : Males: 5.4/mil Females: 2.7/mil Race : Caucasian- 4.1/mil African-American- 1.8/mil Wang H, et al. Cancer 2011;doi:10.1002/cncr.26627 Clinicopathological Manifestations of WM HCT, PLT, WBC Hyperviscosity Syndrome: Epistaxis, HA, Impaired vision >4.0 CP Adenopathy, splenomegaly ≤ 15% IgM Neuropathy (~20%) Cryoglobulinemia (<5%) Fatigue, Constitutional Sxs Cold Agglutinemia (<10%) Cytokinemia? Cancer Treat Res. 2008;142:211-242. 3
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 4
International prognostic scoring system for Waldenström Variables For pts. needing therapy Age >65 Score Med surv 5-yr surv Hgb <11.5 Low 0-1 142.5 mos. 87% age<65 Plts <100k Int 2 98.6 mos. 68% B2M >3 or age>65 High >3 43.5 mos. 36 % IgM >7.0 nl LDH = 94 mos Inc LDH = 36 mos Morel P, et al. Blood 2009;113:4163 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? 5
Treatment Options in WM Alkylating agents : chlorambucil, melphalan, cyclophosphamide, (bendamustine) Purine nucleoside analogues : fludarabine, cladribine Monoclonal antibodies : rituximab, ofatumumab, 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 0 Bortezomib 10-27 48-60 59-85 0-4 Thalidomide 20 25 25 0 NR = not reported Rourke M, et al Leuk&Lymp, 2010;51:1779-92. (modified) 6
Combination Treatment in WM Regimen Responses (%) (No. pts 31-72) >PR >MR CR Flu/Ctx 55-78 NR 0 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 NR = not reported Rourke M, et al Leuk&Lymp, 2010;51:1779-92.(modified) Phase III Trials in WM Yr. Regimen No. Pop. Yrs to pub 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) 7
Monoclonal Antibody Therapy as Single Agent in WM No. Pts >PR >MR CR Rituximab (CD20)¹ 17 ‐ 69 32 ‐ 48% 55 ‐ 69% 0 Ofatumumab (CD20)² 37 59% 0 Alemtuzumab 28 36% 75% 0 (CD52)³ 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 JBRMO1 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 8
Slide 16 JBRMO1 Dr Heffner should IMiDs (pomalidomide ) be included here? Janelle Bowersox, RN, MSN, OCN, 7/23/2014
Reported series of bortezomib (BZ)carfilzomib (CFZ), rituximab +/- dexamethasone in WM (treated and untreated) Reference Bz/CFZ No. ORR >PR CR PFS OS PNX (dose in (%) (%) Grade mg/m2 IV) Treon 1.3 twice 23 76 83 3-CR NYR NR >30% weekly Gd 3 (untreated) 2-nCR Agathocleus 1.3 2x/wk or 10 90 NR NR NR NR >Gd 3 1.6 wk-no 14-19 (rel/ref) Dex Ghobrial 1.6 weekly 37 81 51 - 15.6 NYR Gd 3- 5 mos (rel/ref) (no Dex) Gd 4- 0 Ghobrial 1.6 weekly 26 88 58 1-CR NYR NYR 0 (untreated) (no Dex) 1-nCR Dimopoulos 1.6 weekly 60 85 68 2-CR <12 82% >Gd 3- mos 3 yr 7% (untreated) Treon CFZ: 20-36 31 81 68 1-CR NYR NYR > Gd 2-0 d1,2,8,9 (mixed) 8-vgpr 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 9
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. = not reached =21 mos Ghobrial I, et al. Am. J. Hematol. 89:237–242, 2014. 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 Q 28d x6 R Dexamethasone 20mg PO d1,8,15 A N D O M I Bortezomib 1.6mg/m2 IV/SQ d1,8,15,22 Z Rituximab* 375mg/m2 IV d1,8,15,22 Q 28d x6 E Dexamethasone 20mg PO d1,8,15 Temsirolimus at MTD IV d1,8,15,22 Accrual goal = 144 pts *Rituximab cycles 1 & 4 only 10
Phase I and II Trials of New Agents in Relapsed/Refractory WM Agent No. PR% MR% ORR% SD% CR PFS (mos) Perifosine ⁴ 37 11 24 35 54 0 12.6 Enzasturin ⁵ 42 5 33 38 33 0 10.6 (TTP) Panobinostat ⁶ 36 22 25 47 50 0 6.6 Pomalidomide ⁷ 8* 0 25 25 38 0 NA * MTD 1mg/day; 3 pts had prog disease 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) 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 11
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 ‐κ B Signaling. Treon SP et al. N Engl J Med 2012;367:826-833. 12
Recommend
More recommend
