1. Integration of Novel Therapies in WM and CLL : When and How to Use Them
Neil E Kay, M.D.
October 2014

2. Mayo Team Deb Bowen Tim Call Michael Conte Wei Ding Tait Shanafelt
Steve Ansell

3. Learning Objectives Review “standard therapies” of WM and CLL
Can we still consider standard therapies in WM and CLL?
What novel therapies are available for us in clinical practice?

4. Waldenström’s Macroglobulinemia “A disease with two problems”
Lymphoplasmacytic infiltrate
Monoclonal IgM protein
Gertz et al. The Oncologist 2000;5:63-67

5. Patient
67 year old man
Severe fatigue, nausea, visual difficulties, increasing confusion and sleepiness, gums bleed easily.
Anemic (Hgb 8.8g/dl). Platelets decreased to 96,000.
Ulcers have developed on his ankles
Monoclonal IgM – 6.6 g/dl. Viscosity – 5.8
Bone marrow biopsy – 85% involvement by lymphoplasmacytic lymphoma
CT scan – enlarged liver and spleen and multiple bulky lymph nodes in the abdomen

6. What Clinical Findings Suggest That Treatment Should Be Started?
Fever, night sweats, or weight loss.
Lymphadenopathy or splenomegaly.
Hemoglobin ≤ 10 g/dL or a platelet count < 100 x 10(9)/L due to marrow infiltration.
Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia.
Kyle et al. Semin Oncol Apr;30(2):116-20
Dimopoulos et al, Blood prepublished online,July 15,2014

7. Indications For Initiation of Therapy in WM
Clinical indications for initiation of therapy:
Recurrent fever, night sweats, weight loss, fatigue
• Lymphadenopathy which is either symptomatic or bulky (≥5cm in maximum diameter)
• Symptomatic hepatomegaly and/or splenomegaly
• Symptomatic organomegaly and/or organ or tissue infiltration
Nephropathy related to WM
Amyloidosis related to WM
Dimopoulos Blood Aug 28;124(9):

8. Indications For Initiation of Therapy in WM
Laboratory indications for initiation of therapy:
Hyperviscosity
Symptomatic cryoglobulinemia
Cold agglutinin anemia
Immune hemolytic anemia and/or thrombocytopenia
Hemoglobin ≤10g/dL or Platelet count <100x109/L
Dimopoulos Blood Aug 28;124(9):

9. IPSS For WM Five adverse covariates were identified: Three risk groups
advanced age (>65 years),
hemoglobin less than or equal to 11.5 g/dL
platelet count less than or equal to 100 x 10(9)/L,
beta2-microglobulin more than 3 mg/L
serum monoclonal protein concentration more than 7.0 g/dl
Three risk groups
Low, Intermediate, high risk
5 year survival rates of 87, 68 and 36 %
Morel,Blood Apr 30;113(18):

10. Many Treatment Options
Watch and wait
Single agent rituximab
Chemoimmunotherapy combinations
Plasmapheresis
Clinical trials with new agents
Stem cell transplantation
Which approach is best?

11. Common Treatments used For Initial Therapy
Purine analogue based combinations:
FCR/FR
Alkylating agent based combinations :
R-CHOP
DRC
R-Bendamustine
Bortezomib based combinations
BDR
Rituximab alone
BDR =bortezomib/dexamethasone
(DRC)-Rituximab combinations with cyclophosphamide/dexamethasone

12. Mayo Clinic (mSMART) Consensus for Management of Newly Diagnosed WM
#Bendamustine + rituximab is an alternative
Ansell et al. Mayo Clin Proc. 2010;85:

13. Mayo Clinic (mSMART) Consensus for Management of Newly Diagnosed WM
#Bendamustine + rituximab is an alternative
Ansell et al. Mayo Clin Proc. 2010;85:

14. Mayo Clinic (mSMART) Consensus for Management of Newly Diagnosed WM#
#Bendamustine + rituximab is an alternative
Ansell et al. Mayo Clin Proc. 2010;85:

15. Mayo Clinic (mSMART) Consensus for Management of Relapsed Waldenström Macroglobulinemia.
Ansell et al. Mayo Clin Proc. 2010;85:

16. New Drugs with Promise BTK inhibitors - ibrutinib Bendamustine
mTOR inhibitors - RAD001 (Everolimus)
New anti-CD20 antibodies
Anti-bcl2 agents - Obatoclax
New HDAC inhibitors - LBH589
New proteosome inhibitors – MLN9708
New Imids - Pomalidomide (CC-4047)
Other agents – Enzastaurin, perifosine, imatinib, Simvastatin, sildenafil citrate

17. Phase II Study of Ibrutinib in Relapsed/Refractory WM
Screening
Informed Consent and Registration
Ibrutinib
420 mg po daily
Progressive Disease or Unacceptable Toxicity
SD or Response
Continue x 26 cycles
Stop Ibrutinib
Event Monitoring
Opened May 2012
DFCI, MSKCC, STANFORD
N=35; expanded to 63
Treon et al, Blood 2013; 122(21): Abstract 251

18. Extramedullary Disease following Ibrutinib
For patients with baseline and Cycle 6 CT scans
Adenopathy > 1.5 cm N=
Improved
Stable
Increased 31
21 (67.7%)
8 (25.8%)
2 (6.5%)
Splenomegaly > 15 cm N=
Improved
Stable
Increased 5
1 (20.0%)
4 (80.0%)
0 (0.0%)
Data Lock November 8, 2013
(based on local review)
Treon et al, Blood 2013; 122(21): Abstract 251

19. Summary of Other Results
The BTK inhibitor ibrutinib is associated with rapid reduction of serum IgM and improved HCT
ORR of 83%,
major RR of 65% in relapsed/refractory patients.
Responses are durable with 87% of patients continuing on treatment at a median of 9 cycles.
Ibrutinib is well tolerated, with good safety profile.
Treon et al, Blood 2013; 122(21): Abstract 251

20. Take Home Message
“Traditional therapies” are still valuable in the management of WM
Novel therapies such as BTK inhibitors can be considered for at least relapsed/refractory WM and are the subject of clinical trial evaluation

21. Novel Therapy Integration in CLL
Review where we have been
New options
Application to separate cohorts of CLL
Early stage (high risk)
Upfront
Young vs. “Elderly”
Relapsed/refractory
Transplant

22. Chemoimmunotherapy (CIT) 2014
Now over a decade of testing CIT in various forms:
FCR (Fludarabine) FR
PCR (Pentostatin)
BR (Bendamustine)
Current Data suggest that high OR with approximately 45-50% CRs in upfront setting but:
High RISK FISH and IGVH unmutated do not do well
Can see significant cytopenias
A subset of patient can have very durable remissions

23. Long term Remissions After FCR
CLL 8 Design
Patients with untreated active CLL & good physical fitness*
Randomization
Fludarabine
Cyclophosphamide
Fludarabine
Cyclophosphamide
Rituximab
Six courses of therapy
Follow-up phase
*CIRS ≤ 6, Creatinine Clearance ≥ 70 ml/min

24. Long Term Remissions After FCR
Overall survival (OS)
Median observation time
5.9 years
FCR 69.4% alive
Median not reached
FC 62.3% alive
Median 86 months
HR 0.68,
95% CI
p=0.001
Fischer K et al. iwCLL 2013

25. Long Term Remissions After FCR
Overall survival (OS) in IGHV mutated / unmutated patients
IGVH Mutated
Median observation time
5.9 years
Median OS FCR IGHV mutated
Not reached
FC IGHV mutated
FCR IGHV unmutated
86 months
FC IGHV unmutated
75 months
FC vs. FCR
HR 1.63,
95% CI
Fischer K et al. iwCLL 2013

26. Long Term Remissions After FCR
Progression free survival (PFS) in IGHV mutated / unmutated patients
Median observation time
5.9 years
IGVH Mutated
Median PFS FCR IGHV mutated
Not reached
FC IGHV mutated
42 months
FCR IGHV unmutated
FC IGHV unmutated
29 months
FC vs. FCR
HR 2.12,
95% CI
Fischer K et al. iwCLL 2013

27. Long Term Remissions After FCR Take Home Message
Results on progression-free survival, overall survival, confirm superiority of the FCR regimen
FCR induced long term remissions in IGHV mutated patients
Historical comparison supports the observed benefit of FCR in IGHV mutated patients

28. So Where Do We Go From Here?
Ideally need regimens that are effective in:
Early stage (high risk)
Progressive CLL (upfront)
Including the elderly
Relapsed / Refractory
Non toxic in terms of
Immune suppression
Bone marrow suppression

29. Selected “New” and Emerging Therapies
Agent
MOA
Status
Alemtuzumab
Anti-CD52 MoAb
Approved 2007*
Bendamustine
Alkylating agent
Approved 2008
Ofatumumab
Anti-CD20 MoAb
Approved 2009, 2014
Obinutuzumab**
Approved 2014
Ibrutinib
BTK inhibitor
Idelalisib***
PI3K inhibitor
Approval Q4 2014
ABT-199****
BCL-2 inhibitor
Phase 3
CAR
Chimeric Antigen Receptor therapy
Phase 2
*Withdrawn from commercial sale in 2012; only available by special program
** Also known as Gazyva
***Also known as Zydelig
****Also known as GDC-0199

30. Response Levels for Novel Agents (Relapsed/Refractory/Naïve )
ORR CR PR
PFS
(median) OS
Ibrutinib:
R/R 1
71 %
2/51
34/51
75 % **
83% **
Naïve 2
87%
13%
65%
96.3% ***
96.6%***
Idelalisib 3,4
R/R
72%
39% *
15.8 months NR
* Note that 81.5% achieved a nodal response
** Estimated at 26 months
*** Estimated at 30 months
Byrd J, N Engl J Med Jul 4;369(1):32-42.
O’Brien , ASCO, 2014.
Brown J, Blood May 29;123(22):
Furman, N Engl J Med 2014; 370:

31. More Information Alemtuzumab no longer routinely available
Ibrutinib as compared with ofatumumab, significantly improved PFS, OS and RR in previously treated CLL 1
Responses improve over time !
Prolonged use may be needed 2
Median time to first response-1.9 months
Best response seen at 7.3 months
1. Byrd, N Engl J Med 2014; 371:
2. O’Brien , ASCO, 2014

32. Some Information Good news - Bad news
Responses are seen in all risk categories
IGVH unmutated ,del 17p, p53 mutated
BUT
Earliest relapses are seen in the high risk categories as well
Byrd J, N Engl J Med Jul 4;369(1):32-42.
O’Brien , ASCO, 2014.
Brown J, Blood May 29;123(22):

33. High Risk FISH in Novel Trials
O’Brien , ASCO, 2014.

34. FDA expands approved use of ibrutinib for CLL
More Good News!
FDA expands approved use of ibrutinib for CLL
July 2014
FDA approved Ibrutinib as first-line therapy for the subset of CLL patients with deletion 17p. 
If you do not have an alternative trial specifically for 17p- patients that could be an option.

35. At What Price New Agents ?
Two considerations
New toxicity profiles
Cost of these agents
Average Whole Sale cost1 (current pricing)
Chlorambucil-~$3,500 for 6 cycles of treatment
CIT- ~$60,000 for standard treatment course
Ofatumumab-$120,000/treatment course
Ibrutinib~$118,000/year.
1. Shanafelt et al, manuscript submitted

36. Signal Inhibitor Toxicity Profile
Side effects associated with Signal Inhibitors
Quoted in most articles as “modest with the most frequent”
nausea (24%), diarrhea (19%), vomiting (12%) and liver function abnormalities (35%)., rash, arthralgia , pneumonitis, bruising and infections
CYP3A inhibitors/inducers (Cytochrome P450 3A4 )
Avoid co-administration with strong or moderate CYP3A inhibitors or CYP3A inducers
Issue of difficulties in using anticoagulants with novel agents
BTK experience (20% grade 1 ecchymoses)
Association with bleeding events and defective platelet aggregation in response to collagen 1-2
Hold drug for surgical/dental procedure ?
1.Levade Blood Oct 10
2.Kamel, S, Leukemia. 2014

37. Mayo Approach
Early stage (high risk)

38. Early Stage Asymptomatic
Non-high risk
Observe
Clinical Trial
low toxicity agents
Vitamin D/ EGCG
High risk
17p-/p53 mutated
IGHV UM
Autoimmune cytopenias
ITP
AIHA
Observe
increased frequency FU
Clinical Trial
(Novel Agents)
Steroids/IVIG
Rituximab
Chlorambucil-Obinituzumab
R-CP
Splenectomy
* Purine nucleoside analogues (e.g. fludarabine, pentostatin) are contra-indicated in patients with active autoimmune hemolytic anemia or ITP

39. Early Stage (High Risk)
Can be defined by Prognostic Score
PFS and OS is much worse for these patients vs. Low Risk
5-year OS ranging from 18.7% to 95.2%
Need unique approaches to deal with high risk
Phlug, Blood Jul 3;124(1):49-62.

40. Integrating Multiple Markers: CLL Prognostic Index
Challenge integrating multiple molecular biomarkers
Pooled analysis 3 trials ~1950 patients (1223 all markers)
MV analysis: 8 factors independently associated survival
stage not independent predictor OS HR
points
Male
1.3 1
Age (>60)
Del 11q23
1.4
PS (ECOG>0)
1.7
IGHV
1.9
B2M
2.3 2
sTK
2.8
del 17p13
6.0 6

41. Integrating Multiple Markers: CLL Prognostic Index
Created weighted model:
Points
HR death
5 yr Survival
Low risk
0-2 -
95%
Intermediate risk
3-5 5
87%
High risk
6-10 13
68%
Very high risk
11-14 58
19%
Phlug, Blood Jul 3;124(1):49-62.

42. Integrating Multiple Markers: CLL Prognostic Index
All patients
Binet A
Low Risk (N=300)
--- Low Risk (N = 249)
Intermediate risk (N=460)
--- Intermediate Risk (N = 196)
High risk (N=410)
--- High Risk (N = 76)
Very high risk (N=53)
--- Very High Risk (N = 9) )
Phlug, Blood Jul 3;124(1):49-62

43. CLL12 Trial

44. CLL 12:GCLLSG trial Primary Objectives
To demonstrate superiority of ibrutinib over placebo in prolonging EFS for subjects with treatment-naïve CLL stage A and intermediate or (very) high risk of disease progression.
Trial is now activated in GCLLSG but also will be done at Mayo clinic and at Ohio State University
Rai 0

45. Mayo Approach Progressive CLL (upfront) Including the elderly
Relapsed / Refractory
Transplant

46. Upfront Treatment Indicated (Patient Fit)
More traditional treatment options
Clinical trial
Chemoimmunotherapy options:
PCR (pentostatin, cyclophosphamide, rituximab)
FR (fludarabine, rituximab)
FCR (fludarabine, cyclophosphamide, rituximab)
More traditional (avoid alkylating agents)
Methylprednisolone-rituximab 2
Alemtuzumab based treatment 3
Weekly CMV monitoring by PCR
If del (17p13) and/ or P53 mutation, then treatment options include:
Referral for transplant evaluation in 1st remission
Ibrutinib 1
Idelalisib (+/-Rituximab)
1. Byrd, N Engl J Med 2014; 371:
2. Castro, Leukemia. Oct 2009; 23(10): 1779–1789.
3. ASH Education Book December 10, 2011 no. 1 

47. Upfront Treatment Indicated (Patient Unfit)
More traditional Treatment options
R-CP (rituximab*/cyclophosphamide/prednisone)
Methylprednisolone/rituximab* 3
Bendamustine * +/- rituximab* 4
Supportive care only
Treatment options
Clinical trial
Chlorambucil +/- rituximab or obinutuzumab* 1,2
* If using rituximab or Obinutuzumab, order hepatitis B and C testing prior to treatment
1, Goede, V, N Engl J Med. 2014 Mar 20;370(12):
2. Hillmen, JCO Sep 20, 2014:
3. Castro, Leukemia. Oct 2009; 23(10): 1779–1789.
4. Fischer, J Clin Oncol Sep 10; 29(26):
* FDA approved

48. Recurrent/Refractory (Patient Fit)
Asymptomatic patients (a clinical trial or observed)
Symptomatic patients managed according to performance status.
Options for Good Performance Status:
Clinical trial
Ibrutinib * 1
Idelalisib *-rituximab 2
Ofatumumab 3
More traditional
Chemoimmunotherapy (PCR, FCR, BR, CFAR)
Alemtuzumab +/- rituximab
Methylprednisolone/rituximab 4
Consider transplant
* FDA approved
1. Byrd, N Engl J Med 2014; 371:
2. Furman,N Engl J Med 2014; 370:
3. Wierda , J CO 28:  ,2010
4. Castro, Leukemia. Oct 2009; 23(10): 1779–1789.

49. Recurrent/Refractory (Patient Fit)
If del (17p13) or P53 deletion
Options include:
Clinical trial
Ibrutinib 1
Idelalisib-rituximab 2
More traditional
Methylprednisolone-rituximab 3
Alemtuzumab based treatment
Weekly CMV monitoring by PCR
Pneumocystis and herpes zoster prophylaxis
1.Byrd, N Engl J Med 2014; 371:
2. Furman,N Engl J Med 2014; 370:
3. Castro, Leukemia.23: 1779–

50. Recurrent/Refractory (Patient Unfit)
Poor Performance Options include:
Clinical trial
Ibrutinib 1
Idelalisib-rituximab 2
More traditional
Chlorambucil +/- rituximab 3
Methylprednisolone/rituximab 4
Supportive care only
1.Byrd, N Engl J Med 2014; 371:
2. Furman,N Engl J Med 2014; 370:
3. Goede, V, N Engl J Med.  :
4. Castro, Leukemia.23: 1779–

51. Elderly Therapy (Chlorambucil And Obinutuzumab)
For Fit elderly –Can still use CIT
Obinutuzumab vs. rituximab, each combined with chlorambucil
Patients with previously untreated CLL and coexisting conditions.
The primary end point was investigator-assessed progression-free survival.
N=781 patients with previously untreated CLL
score higher than 6 on the Cumulative Illness Rating Scale (CIRS) or an estimated creatinine clearance of 30 to 69 ml
Median CIRS was 8
Median age was 73
Goede, V, N Engl J Med. 2014 Mar 20;370(12):

52. Elderly Therapy (Chlorambucil And Obinutuzumab)
Results
Median PFS, 26.7 months with obinutuzumab-chlorambucil vs.16.3 months with rituximab-chlorambucil
Higher rates of complete response (20.7% vs. 7.0%)
Toxicities
Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil vs. rituximab-chlorambucil, but risk of infection was not increased.
Bottom line
Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions.
Goede, V, N Engl J Med. 2014 Mar 20;370(12):

53. Do Novel Agents Help us in High Risk CLL heading For BMT?
Some Scenarios where could use Novel inhibitors( BTK / PI3kinase):
Younger, fit patient with TP53 disruption (via mutation or loss) who is previously untreated but in need of therapy
Relapsed patient (previously treated) meeting current EBMT criteria

54. Summary (Take Home Message)
CIT can and should still be used for upfront therapy
Young patients with IGVH mutated status
Novel agents have clinical activity
Signal inhibitors are ideal agents in terms of lack of obvious marrow toxicity and induction of high OR
Even in high risk
Newer monoclonal agents show promise alone or in combination
Negative issues
Cost / coverage
Different types of adverse reactions/toxicities
Long range outcome still not clear

55. The End !