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

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

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

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  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. SeminOncol. 2003 Apr;30(2):116-20 Dimopouloset 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. 2014 Aug 28;124(9):1404-1411

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

  9. 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.

  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;85:824-833

  13. 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

  14. 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

  15. Mayo Clinic (mSMART) Consensus for Management of Relapsed Waldenström Macroglobulinemia. Ansell et al. Mayo Clin Proc. 2010;85:824-833

  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 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 Splenomegaly > 15 cm 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 IgMand 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 Sixcoursesoftherapy Follow-upphase *CIRS ≤ 6, Creatinine Clearance ≥ 70 ml/min

  24. Long Term Remissions After FCR • Overall survival (OS) Median observation time 5.9 years FCR69.4% alive Median 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. iwCLL2013

  25. Long Term Remissions After FCR • Overall survival (OS) in IGHVmutated / unmutated patients Median observation time 5.9 years IGVH Mutated Median OS FCR IGHV mutated Not reached FC IGHVmutated Not reached FCR IGHV unmutated 86 months FC IGHVunmutated 75 months FC vs.FCR HR 1.63, 95% CI 0.908 - 2.916 Fischer K et al. iwCLL2013

  26. Long Term Remissions After FCR • Progression freesurvival (PFS) in IGHVmutated / unmutated patients Median observation time 5.9 years IGVH Mutated Median PFS FCR IGHV mutated Not reached FC IGHVmutated 42 months FCR IGHV unmutated 42 months FC IGHVunmutated 29 months FC vs.FCR HR 2.12, 95% CI 1.464 - 3.063 Fischer K et al. iwCLL2013

  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 *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 ) * Note that 81.5% achieved a nodal response ** Estimated at 26 months *** Estimated at 30 months • Byrd J, N Engl J Med. 2013 Jul 4;369(1):32-42. • O’Brien , ASCO, 2014. • Brown J, Blood. 2014 May 29;123(22):3390-7. • Furman, N Engl J Med 2014; 370:997-1007

  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; 371:213-223 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. 2013 Jul 4;369(1):32-42. • O’Brien , ASCO, 2014. • Brown J, Blood. 2014 May 29;123(22):3390-7.

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

  34. FDA expands approved use of ibrutinib for CLL More Good News! 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. 2014 Oct 10 2.Kamel, S, Leukemia. 2014

  37. Mayo Approach • Early stage (high risk)

  38. Early Stage Asymptomatic • Autoimmune cytopenias • ITP • AIHA • High risk • 17p-/p53 mutated • IGHV UM Non-high risk • Steroids/IVIG • Rituximab • Chlorambucil-Obinituzumab • R-CP • Splenectomy • Observe • increased frequency FU Observe Clinical Trial (Novel Agents) • Clinical Trial • low toxicity agents • Vitamin D/ EGCG * 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. 2014 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

  41. Integrating Multiple Markers: CLL Prognostic Index • Created weighted model: Phlug, Blood. 2014 Jul 3;124(1):49-62.

  42. 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) --- High Risk (N = 76) Very high risk (N=53) --- Very High Risk (N = 9) ) Phlug, Blood. 2014 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 • Clinical trial • Ibrutinib 1 • Idelalisib (+/-Rituximab) 1. Byrd, N Engl J Med 2014; 371:213-223 2. Castro, Leukemia. Oct 2009; 23(10): 1779–1789. 3. ASH Education Book December 10, 2011 no. 1 119-120

  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):1101-10 2. Hillmen, JCO Sep 20, 2014:3039-3047 3. Castro, Leukemia. Oct 2009; 23(10): 1779–1789. 4. Fischer, J Clin Oncol. 2011 Sep 10; 29(26):3559-66 * 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 • Ofatumumab3 • 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,NEngl J Med 2014; 370:997-1007 3. Wierda , J CO28: 1749-1755,2010 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; 371:213-223 2. Furman,NEngl J Med 2014; 370:997-1007 3. Castro, Leukemia.23: 1779–1789.2009

  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; 371:213-223 2. Furman,NEngl J Med 2014; 370:997-1007 3. Goede, V, N Engl J Med. 2014 20:1101-10 4. Castro, Leukemia.23: 1779–1789.2009

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