Novel treatment options for Waldenstrom

Macroglobulinemia

Irene Ghobrial, MD

Associate Professor of Medicine

Harvard Medical School

Dana Farber Cancer Institute

Boston, MA

Ghobrial et al, Lancet Oncol 2004, Treon et al, Blood 2009

MYD88 in WM

Treon et al, NEJM 2012

Molecular characteristics

• 30-50% of patients: deletion 6q by FISH• BLIMP (on 6q21): a tumor-suppressor gene, is the

master gene regulator for B-lymphocytic cell proliferation.

• 70-90% of patients have MYD88 mutation.• CXCR4 somatic mutation in 24% of samples

Treon et al NEJM 2012

Consensus recommendations of the 4th International WM meeting

• First Line therapy:– Combination therapy

• (RCD or CPR; Cytoxan+nucleoside analogues+R; R-CHOP, R-CVP)

– Rituximab single agent– Nucleoside analogues– Alkylators

• Salvage therapy:– Re-use therapies– Bortezomib– Thalidomide+steroids– Alemtuzumab– AHSCT

Dimopoulos, JCO 2009, Treon et al Clin Lymph and Myeloma 2009

Primary Therapy of WM with Rituximab-Based Options

Regimen ORR CR

Rituximab x 4 25-30% 0%

Rituximab x 8 40-45% 0%

Rituximab/cyclophosphamide i.e. CHOP-R, CVP-R, CPR, RCD

70-80% 8-10%

Rituximab/nucleoside analoguesi.e. FR, FCR, CDA-R

70-90% 5-10%

Rituximab/thalidomide 70% 5%

Rituximab/bortezomib i.e. BDR, VR

70-90% 10-25%

Rituximab/bendamustine 90% NA

Courtesy of Dr. Steven Treon

Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab,

and cyclophosphamide.

• 72 patients• cyclophosphamide 100 mg/m2 orally bid on days 1 to

5 (total dose, 1,000 mg/m2). • 83% of patients achieved a response• Including 7% complete, 67% partial, and 9% minor

responses. • The median time to response was 4.1 months. • The 2-year progression-free survival rate for all

patients was 67%

Dimopoulos, JCO 2007

Bendamustine plus Rituximab versus CHOP plus Rituximab in the First-Line- Treatment of Patients with Waldenstrom

disease: Randomized Phase III Study of the Studygroup Indolent Lymphomas (StiL)

Rummel, WM-Workshop2012

•42 pts with WM, report on 40 evaluable in interim analysis, BR=23 and CHOP-R=17.

•The ORR for pts treated with B-R was similar to that associated with CHOP-R (96% vs 94%, respectively).

•The median follow-up time for both groups is 26 months.

•Progressive or relapsed disease: 2 in pts treated with B-R and 7 in the CHOP-R group.

•Less toxicity and non-inferior response.

PFS: Benda-R vs CHOP-R in Frontline WM

0 12 24 36 48 60 72

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

months

Pro

bab

ilit

y

Bendamustine-R

CHOP-R

Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.

Phase II trial of bortezomib+ rituximab in upfront or R/R WM

•A total of 6 cycles, a cycle= 28 days

•No rituximab maintenance

•No dexamethasone

•ORR 80-90%. CR 10-15%

•Minimal peripheral neuropathy

Ghobrial et al, JCO 2010

Ghobrial et al, AJH 2011

New developments

PI3K/mTOR inhibitors

Proteasome inhibitors

BTK inhibitors

HDAC inhibitors

IMIDs

The PI3K/mTOR pathway

Phase II trial of RAD001 in WM

Par

tial

res

po

nse

Par

tial

res

po

nse

Sta

ble

dis

ease

A

B

C

Phase I/II Study of Everolimus, Bortezomib and/or Rituximab in Relapsed/Refractory WM

Registration

Determine maximum tolerated dose (MTD)

Study Design

The RVR phase I study

Response N= 23 evaluable

CR 1 (5%)

PR 7 (30%)MR 9 (39%)ORR (CR+PR+MR) 17 (74%)Stable Disease 6 (26%)

MLN128• TORC1 and 2 inhibitor

• Oral agent before after 6 months

Maiso, Blood 2010

Targeting PKC in WM

Phase II study

38% ORR in 42 patients relapsed/ref

Ghobrial, CCR 2012

Phase II trial of perifosine in patients with relapsed/refractory WM

•ORR 35%, with another 54% showing stabilization of their disease

•Only 11% of patients demonstrated progression.

Ghobrial et al, CCR 2010

CAL-101PI3K delta (p110)OralWell toleratedSignificant Lymph node response but

increase in peripheral blood lymphocytes in CLL

60% ORR in indolent lymphomas, 86% in MCL, 95% ORR in CLL in lymph nodes

Roccaro et al, Blood 2011

New Proteasome inhibitors

Upfront therapy with Carfilzomib/dex/rituxan (CARD study)

Onyx 0912 in relapsed WM

Roccaro et al, Blood 2010Sacco et al, CCR 2011

IMIDs in WM• Thalidomide and rituximab:

– Thalidomide 200-400 mg, rituximab weeks 2-5, 13-16– 25 pts (20 untreated)– 70% ORR– TTP ≥38 months observed among responders. – 44% >G2 PN

• Lenalidomide and rituximab: – 25 mg lenalidomide 21 days, and rituximab weeks 2-5, 13-16– 16 pts (12 untreated)– 50% response rate, TTP of 18.9 months– 88% discontinuation of therapy– Most due to anemia that occurred early with therapy– Median decrease in Hct from 32 to 27%, 4 pts required hospitalization

• Phase I trials of lenalidomide ongoing, phase I pomalidomide/rituximab ongoing.

Treon et al, Blood 2008, CCR 2008

Phase II Study of Panobinostat in WM

Ghobrial I, et al. Blood. 2010;116:3952.[Oral Presentation].

Best overall response

N %

CR 0 0

VGPR 1 3

PR 10 27

MR 9 25

SD 14 39

PD 1 3

Unevaluable 1 3

Total 36  

PR or better11

30(90%CI:18, 46)

MR or better20

55 (90%CI:41,70)

IgM response to Panobinostat

Bruton’s Tyrosine Kinase (BTK)

Nat Rev Imm 2:945

• B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation

• Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway

• Inhibitors of Btk block BCR signaling and induces apoptosis

IgM

Ibrutinib

• Breakthrough designation by the FDA for WM.

• Over 80% response rate.

• Very well tolerated.

• Currently, no trials available. Awaiting approval and more trials or expanded access in the next few months.

New Proteasome inhibitors

Oprozomib in relapsed WM

Roccaro et al, Blood 2010Sacco et al, CCR 2011

Oprozomib

• Oral agent.• Proteasome inhibitor without neuropathy.• Over 80% response rate so far in WM• Considering breakthrough designation in

WM.• Study open in multiple sites and accruing

now.

Future developments

• MYD88 targeting (IRAK4)

• CXCR4 targeting

• miRNA155 targeting (MiRNA LNA)

miRNA expression in bone marrow CD19+ WM cells vs CD19+ normal counterpart

Roccaro et al. Blood 2009

P = .009

P = .001

P = .004

Association between microRNAs and clinical prognostic features

Roccaro et al. Blood 2009

Summary Significant advances in WM specifically MYD88

miRNA155 as a prognostic maker and therapeutic target

New agents including mTOR inhibitors, BTK inhibitors, PI3K inhibitors, HDAC inhibitors, new proteasome inhibitors

Can we personalize therapy in WM?

Should we treat earlier to prevent complications/clonal heterogeneity and resistance

FDA approval for agents in WM

Acknowledgement

• Ken Anderson, MD, Steven Treon, MD, Paul Richardson, MD, Nikhil Munshi, MD, Jacob Laubach, MD, Claudia Paba-Prada, MD

• Supported by the NIH, FDA, IWMF, LLS, Kirsch Lab for WM, Heje Fellowship, All our patients.