Integration of Novel Therapies into WM and CLL : When and How ...

Integration of Novel Therapies into WM and CLL : When and How ...

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? Waldenstrms Macroglobulinemia A disease with two problems Lymphoplasmacytic infiltrate Monoclonal IgM protein Gertz et al. The Oncologist 2000;5:63-67

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 #Bendamustine + rituximab is an alternative Ansell et al. Mayo Clin Proc. 2010;85:824-833 Mayo Clinic (mSMART) Consensus for Management of Newly Diagnosed WM #Bendamustine + rituximab is an

alternative Ansell et al. Mayo Clin Proc. 2010;85:824-833 Mayo Clinic (mSMART) Consensus for Management of Newly Diagnosed WM # #Bendamustine + rituximab is an alternative Ansell et al. Mayo Clin Proc. 2010;85:824-833 Mayo Clinic (mSMART) Consensus for Management of Relapsed Waldenstrm 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 Phase II Study of Ibrutinib in Relapsed/Refractory WM Screening Informed Consent and Registration Ibrutinib 420 mg po daily Progressive Disease or Unacceptable Toxicity Stop Ibrutinib Event Monitoring SD or Response Continue x 26 cycles Event Monitoring

Opened May 2012 DFCI, MSKCC, STANFORD N=35; expanded to 63 Treon et al, Blood 2013; 122(21): Abstract 251 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 Treon et al, Blood 2013; 122(21): Abstract 251 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 CLL 8 Design Patients with untreated active CLL & good physical fitness* Randomization Fludarabine Cyclophosphamide Rituximab Fludarabine Cyclophosphamide Six courses of therapy Follow-up phase *CIRS 6, Creatinine Clearance 70 ml/min Long Term Remissions After FCR Overall survival (OS)

Median observation observation time time 5.9 5.9 years FCR 69.4% alive Median Median not reached FC 62.3% alive Median 86 months HR 0.68, 95% 95% CI 0.535 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 IGVH Mutated Median observation observation time time 5.9 5.9 years Median OS mutated FCR FCR IGHV mutated Not reached mutated FC IGHV mutated Not reached

unmutated FCR IGHV unmutated 86 months unmutated FC IGHV unmutated 75 months FC vs. FCR HR 1.63, 95% 95% CI 0.908 0.908 - 2.916 Fischer K et al. iwCLL 2013 Long Term Remissions After FCR Progression free survival (PFS) in IGHV mutated / unmutated patients Median observation observation time

time 5.9 5.9 years IGVH Mutated Median PFS mutated FCR FCR IGHV mutated Not reached mutated FC IGHV mutated 42 months unmutated FCR IGHV unmutated 42 months unmutated FC IGHV unmutated

29 months FC vs. FCR HR 2.12, 95% 95% CI 1.464 1.464 - 3.063 Fischer K et al. iwCLL 2013 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 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 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 Response Levels for Novel Agents (Relapsed/Refractory/Nave

) Agent ORR CR PR PFS OS (median) Ibrutinib: R/R 1 71 % 2/51 34/51 75 % **

83% ** Ibrutinib: Nave 2 87% 13% 65% 96.3% *** 96.6%*** 39% * 15.8 months

NR Idelalisib 3,4 R/R 72% * Note that 81.5% achieved a nodal response ** Estimated at 26 months *** Estimated at 30 months 1. 2. 3. 4. Byrd J, N Engl J Med. 2013 Jul 4;369(1):32-42. OBrien , ASCO, 2014.

Brown J, Blood. 2014 May 29;123(22):3390-7. Furman, N Engl J Med 2014; 370:997-1007 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; 371:213-223 2. OBrien , 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. 2. 3. Byrd J, N Engl J Med. 2013 Jul 4;369(1):32-42. OBrien , ASCO, 2014. Brown J, Blood. 2014 May 29;123(22):3390-7. High Risk FISH in Novel Trials OBrien , ASCO, 2014. 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. 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 10 2.Kamel, S, Leukemia. 2014

Mayo Approach Early stage (high risk) Early Stage Asymptomatic Non-high risk Observe Clinical Trial low toxicity agents Vitamin D/ EGCG Autoimmune cytopenias

High risk 17p-/p53 mutated IGHV UM Observe increased frequency FU Clinical Trial (Novel Agents) ITP AIHA Steroids/IVIG Rituximab ChlorambucilObinituzumab R-CP Splenectomy

* Purine nucleoside analogues (e.g. fludarabine, pentostatin) are contra-indicated in patients with active autoimmune hemolytic anemia or ITP 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. Integrating Multiple Markers: CLLintegrating Prognostic Index

Challenge multiple molecular biomarkers Pooled analysis 3 trials ~1950 patients (1223 all markers) MV analysis: 8 factors independently associated survival stage not independent predictor OS Male Age (>60) Del 11q23 PS (ECOG>0) IGHV B2M sTK del 17p13 HR

1.3 1.3 1.4 1.7 1.9 2.3 2.8 6.0 points 1 1 1 1 1 2 2 6

Integrating Multiple Markers: CLL Prognostic Index Created weighted model: Points Low risk 0-2 HR death - Intermediate risk 3-5 5 87%

High risk 6-10 13 68% Very high risk 11-14 58 19% Phlug, Blood. 2014 Jul 3;124(1):49-62.

5 yr Survival 95% Integrating Multiple Markers: CLL Prognostic Index All patients Binet A --- Low Risk (N = 249) Low Risk (N=300) Intermediate risk (N=460) --- Intermediate Risk (N = 196) High risk (N=410) Very high risk (N=53)

--- High Risk (N = 76) --- Very High Risk (N = 9) ) Phlug, Blood. 2014 Jul 3;124(1):49-62 CLL12 Trial CLL 12:GCLLSG trial Primary Objectives To demonstrate superiority of ibrutinib over placebo in prolonging EFS for subjects with treatment-nave 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

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; 371:213-223 2. Castro, Leukemia. Oct 2009; 23(10): 17791789. 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):1101-10 2. Hillmen, JCO Sep 20, 2014:3039-3047 3. Castro, Leukemia. Oct 2009; 23(10): 17791789. 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; 371:213-223 2. Furman,N Engl J Med 2014; 370:997-1007 3. Wierda , J CO 28: 1749-1755,2010 4. Castro, Leukemia. Oct 2009; 23(10): 17791789.

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; 371:213-223 2. Furman,N Engl J Med 2014; 370:997-1007 3. Castro, Leukemia.23: 17791789.2009 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; 371:213-223 2. Furman,N Engl J Med 2014; 370:997-1007 3. Goede, V, N Engl J Med. 2014 20:1101-10 4. Castro, Leukemia.23: 17791789.2009 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 !

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