Integration of Novel Therapies in WM and CLL : When and How to Use

Them

Neil E Kay, M.D.

October 2014

Mayo Team

• Deb Bowen• Tim Call• Michael Conte• Wei Ding• Tait Shanafelt• Steve Ansell

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?

Waldenström’s Macroglobulinemia“A disease with two problems”

Gertz et al. The Oncologist 2000;5:63-67

Lymphoplasmacytic infiltrate Monoclonal IgM protein

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

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. 2003 Apr;30(2):116-20

Dimopoulos et al, Blood prepublished online,July 15,2014

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. 2014 Aug 28;124(9):1404-1411

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. 2014 Aug 28;124(9):1404-1411

IPSS For WM

• Five adverse covariates were identified: – 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. 2009 Apr 30;113(18):4163-70.

Many Treatment Options

• Watch and wait• Single agent rituximab• Chemoimmunotherapy combinations• Plasmapheresis• Clinical trials with new agents• Stem cell transplantation

• Which approach is best?

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

Mayo Clinic (mSMART) Consensus for Management of Newly Diagnosed WM

Ansell et al. Mayo Clin Proc. 2010;85:824-833#Bendamustine + rituximab is an alternative

Mayo Clinic (mSMART) Consensus for Management of Newly Diagnosed WM

Ansell et al. Mayo Clin Proc. 2010;85:824-833#Bendamustine + rituximab is an alternative

Mayo Clinic (mSMART) Consensus for Management of Newly Diagnosed WM

Ansell et al. Mayo Clin Proc. 2010;85:824-833#Bendamustine + rituximab is an alternative

#

Mayo Clinic (mSMART) Consensus for Management of Relapsed Waldenström Macroglobulinemia.

Ansell et al. Mayo Clin Proc. 2010;85:824-833

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

Screening

Informed Consent and Registration

Ibrutinib420 mg po daily

Progressive Disease or Unacceptable Toxicity

SD or ResponseContinue x 26 cycles

Stop Ibrutinib

Event Monitoring

Event Monitoring

Opened May 2012DFCI, MSKCC, STANFORD

N=35; expanded to 63

17

Phase II Study of Ibrutinib in Relapsed/Refractory WM

Treon et al, Blood 2013; 122(21): Abstract 251

Extramedullary Disease following Ibrutinib

N= Improved Stable Increased

31 21 (67.7%)

8 (25.8%)

2 (6.5%)

Adenopathy > 1.5 cmFor patients with baseline and Cycle 6 CT scans

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

Splenomegaly > 15 cm

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

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

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

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

Long term Remissions After FCR

Patients with untreated active CLL & good physical fitness*

Randomization

FludarabineCyclophosphamide

FludarabineCyclophosphamide

Rituximab

Follow-up phase

Six courses of therapy

*CIRS ≤ 6, Creatinine Clearance ≥ 70 ml/min

• CLL 8 Design

Long Term Remissions After FCR

• Overall survival (OS)

Median observation time 5.9 years

FCR 69.4% aliveMedian not reached

FC 62.3% alive Median 86 months

HR 0.68, 95% CI 0.535 - 0.858

p=0.001

Fischer K et al. iwCLL 2013

Long Term Remissions After FCR

• Overall survival (OS) in IGHV mutated / unmutated patients

Median observation time 5.9 years

Median OS FCR IGHV mutated

Not reachedFC IGHV mutated

Not reachedFCR IGHV unmutated

86 monthsFC IGHV unmutated

75 months

Fischer K et al. iwCLL 2013

FC vs. FCRHR 1.63,

95% CI 0.908 - 2.916

IGVH Mutated

Long Term Remissions After FCR• Progression free survival (PFS) in IGHV mutated / unmutated

patients

Median observation time 5.9 years

Median PFS FCR IGHV mutated

Not reachedFC IGHV mutated

42 monthsFCR IGHV unmutated

42 monthsFC IGHV unmutated

29 months

FC vs. FCRHR 2.12,

95% CI 1.464 - 3.063

IGVH Mutated

Fischer K et al. iwCLL 2013

• 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

Long Term Remissions After FCRTake Home Message

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

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** Anti-CD20 MoAb Approved 2014

Ibrutinib BTK inhibitor Approved 2014

Idelalisib*** PI3K inhibitor Approval Q4 2014

ABT-199**** BCL-2 inhibitor Phase 3

CARChimeric 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

Response Levels for Novel Agents

(Relapsed/Refractory/Naïve )Agent ORR CR PR PFS

(median)OS

Ibrutinib:R/R 1 71 % 2/51 34/51 75 % ** 83% **

Ibrutinib:Naïve 2

87% 13% 65% 96.3% *** 96.6%***

Idelalisib 3,4

R/R 72% 39% * 15.8 months NR

1. Byrd J, N Engl J Med. 2013 Jul 4;369(1):32-42.2. O’Brien , ASCO, 2014.3. Brown J, Blood. 2014 May 29;123(22):3390-7.4. Furman, N Engl J Med 2014; 370:997-1007

* Note that 81.5% achieved a nodal response** Estimated at 26 months*** Estimated at 30 months

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; 371:213-2232. O’Brien , ASCO, 2014

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

1. Byrd J, N Engl J Med. 2013 Jul 4;369(1):32-42.2. O’Brien , ASCO, 2014.3. Brown J, Blood. 2014 May 29;123(22):3390-7.

High Risk FISH in Novel Trials

O’Brien , ASCO, 2014.

FDA expands approved use of ibrutinib for CLL

July 2014

More Good News!

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.

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

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. 2014 Oct 102.Kamel, S, Leukemia. 2014

Mayo Approach

Early stage (high risk)

* Purine nucleoside analogues (e.g. fludarabine, pentostatin) are contra-indicated in patients with active autoimmune hemolytic anemia or ITP

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

Early Stage Asymptomatic

Non-high risk

Observe Clinical Trial • low toxicity

agents• Vitamin D/

EGCG

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. 2014 Jul 3;124(1):49-62.

• 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) 1.3 1

Del 11q23 1.4 1

PS (ECOG>0) 1.7 1

IGHV 1.9 1

B2M 2.3 2

sTK 2.8 2

del 17p13 6.0 6

Integrating Multiple Markers:

CLL Prognostic Index

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%

• Created weighted model:

Integrating Multiple Markers: CLL Prognostic Index

Phlug, Blood. 2014 Jul 3;124(1):49-62.

Low Risk (N=300)

Intermediate risk (N=460)

High risk (N=410)

Very high risk (N=53)

Integrating Multiple Markers: CLL Prognostic Index

All patients Binet A

--- Very High Risk (N = 9))

--- Low Risk (N = 249)

--- Intermediate Risk (N = 196)

--- High Risk (N = 76)

Phlug, Blood. 2014 Jul 3;124(1):49-62

CLL12 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

CLL 12:GCLLSG trial

Mayo Approach

• Progressive CLL (upfront)• Including the elderly

• Relapsed / Refractory• Transplant

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– Clinical trial– Ibrutinib 1

– Idelalisib (+/-Rituximab)1. Byrd, N Engl J Med 2014; 371:213-2232. Castro, Leukemia. Oct 2009; 23(10): 1779–1789.3. ASH Education Book December 10, 2011 no. 1 119-120

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):1101-102. Hillmen, JCO Sep 20, 2014:3039-30473. Castro, Leukemia. Oct 2009; 23(10): 1779–1789.4. Fischer, J Clin Oncol. 2011 Sep 10; 29(26):3559-66 * FDA approved

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; 371:213-2232. Furman,N Engl J Med 2014; 370:997-10073. Wierda , J CO 28: 1749-1755,20104. Castro, Leukemia. Oct 2009; 23(10): 1779–1789.

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 prophylaxis1.Byrd, N Engl J Med 2014; 371:213-223

2. Furman,N Engl J Med 2014; 370:997-10073. Castro, Leukemia.23: 1779–1789.2009

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; 371:213-2232. Furman,N Engl J Med 2014; 370:997-10073. Goede, V, N Engl J Med. 2014 20:1101-104. Castro, Leukemia.23: 1779–1789.2009

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):1101-10

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):1101-10

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

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

The End !