CLL what do I need to know as an Internist in Taimur Sher MD Associate Professor of Medicine Mayo Clinic

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1 CLL what do I need to know as an Internist in 218 Taimur Sher MD Associate Professor of Medicine Mayo Clinic

2 Case 1 7 y/o white male for yearly medical evaluation Doing well and healthy Past medical history Hypertension Dyslipidemia Coronary artery disease Normal exam CBC: Hb 12.5 WBC 12.6 Platelet count 156/ ul Absolute lymphocyte count: 7.1 Absolute neutrophil count 3.5

3 Case 2 48 y/o female with 6 months of weight loss, elbow and knee swelling and itchy rash Exam: Chronically ill appearing female, inflamed elbow and knee. 1 year ago rheumatoid arthritis. On Mtx. CBC: Hb 7.8; WC 15. platelet 15. ALC 1.5 Mother died of non-hodgkin lymphoma. CRP-15; Beta-2 microglobulin 14 Flow: CD 5+, CD 23+ kappa restricted B-cells.

4 Chronic Lymphocytic Leukemia (CLL) Most prevalent adult B-cell leukemia in west (~15, cases / year) Blood Bone marrow Median age at diagnosis is 72yrs Presentation: Incidental Disease related tumor burden Autoimmune phenomenon Infections Lymph Nodes CD23+ Ries LAG et al. based on November 26 SEER data submission. Accessed September 17, 27; Stilgenbauer S. Hematology. 24;1:

5 CLL Diagnosis ALC: >5,/µL matureappearing lymphocytes Immunophenotype CD5+ / CD19+ / CD23+ / surface Ig light-chain restricted ( or ) BM biopsy: not required for diagnosis >3% lymphocytes on aspirate What do I order for work up? CBC with diff Flow cytometry peripheral blood Liver and renal function LDH, beta-2 microglobulin Quantitative Igs FISH in peripheral blood Somatic hypermutation

6 Prognostic Versus Predictive Factors Prognostic factor Situation, condition, or characteristic used to estimate overall outcome of disease, independent of treatment Predictive factor Situation, condition, or characteristic that predicts the efficacy of a therapy Prognostic factor that provides information on effect of a treatment

7 Prognostic Factors Associated With Inferior Survival in CLL FISH cytogenetic abnormalities 17p deletion 11q deletion Complex cytogenetic abnormalities Unmutated (<2% homology to germline) IgHV Expression of ZAP-7 ( 2% positive) Expression of CD38 ( 3% positive)

8 Clinical Stage Rai staging Stage Lymphocytosis Stage I Lys+adenopathy Stage II Lys+ Splenomegaly Stage III Anemia Stage IV Thrombocytopenia

9 Patients Surviving, % FISH: Cytogenetics are important p deletion 11q deletion 12q trisomy Normal 13q deletion as sole abnormality Dohner et al. N Engl J Med. 2;343: Months Months

10 Surviving, % Surviving, % Survival of CLL Patients With Mutated Versus Unmutated IgHV Gene 1 All Patients (N = 84) Stage-A CLL Patients (n = 62) Mutated 8 6 Mutated 4 4 P =.8 2 Unmutated 2 Unmutated P = Months Months 1. Hamblin TJ et al. Blood. 1999;94:

11 CLL-International Prognostic Index (CLL-IPI) Variable Adverse Factor Grading TP53 / 17p Mutated/deleted 4 IgHV status Unmutated 2 B2M >3.5 mg/l 2 Clinical stage Binet B/C or Rai II-IV 1 Age > 65 y 1 Prognostic score -1 Risk Group Score Low -1 Intermediate The International CLL-IPI Working Group. Lancet Oncol High 4-6 Very high 7-1

12 OS, % OS, % 1 CLL-IPI: OS Outcomes Training Dataset 1 Internal-Validation Dataset Low risk Intermediate risk High Risk Very high risk 12 P < Time From Study Entry, mo Number at risk Low risk Intermediate risk High risk Very high risk MAYO Cohort 12 P < Time From Study Entry, mo Number at risk Low risk Intermediate risk High risk Very high risk SCAN Cohort 2 2 Number at risk Low risk Intermediate risk High risk Very high risk 12 P < Time From Study Entry, mo The International CLL-IPI Working Group. Lancet Oncol. 216;17: P < Time From Study Entry, mo Number at risk Low risk Intermediate risk High risk Very high risk

13 Multivariable Model for Time-to-First CLL Treatment (N = 687; 193 treated) Characteristic HR P IgHV mutation status (UM vs M) 1.68 <.1 Diameter of largest cervical LN (cm) 1.32 <.1 FISH category (11q del vs others) FISH category (17p del vs others) Number of involved LN sites (3 vs <3) LDH (IU/L/1) for IgHV mutated Wierda WG et al. J Clin Oncol. 211;29:

14 Time to First Treatment, % Time to First Treatment, % CLL-IPI: Time-to-First CLL Treatment Outcomes 1 Watch-and-Wait Patients MAYO Cohort SCAN Cohort Low risk 1 1 Intermediate risk High risk Very high risk P <.1 1 P <.1 1 P < Time From Diagnosis, mo Time From Diagnosis, mo Time From Diagnosis, mo Number at risk Low risk Intermediate risk High risk Very high risk The International CLL-IPI Working Group. Lancet Oncol. 216;17:

15 IWCLL-NCI: Indications to Initiate Treatment for CLL 1 Constitutional symptoms referable to CLL Progressive marrow failure Autoimmune anemia +/- thrombocytopenia poorly responsive to steroids or other treatment Massive (>6 cm) or progressive splenomegaly Massive (>1 cm) or progressive lymphadenopathy Progressive lymphocytosis, >5% increase over 2 months or LDT <6 months NO EARLY TREATMENT, EVEN FOR HIGH-RISK PATIENTS 1. Hallek M et al. Blood. 28;111:

16 Treatment

17 The cancer cell does not live in isolation

18 CD79B CD79A TIRAP T-cells CAR T-cells PD-1 PD-L1 CD38 B-cell receptor CD19 Toll-like receptor(s) p85 PI3K Centrosome AKT Aurora kinase p53 MYC IkBa? RAS RAF Blnk BTK AKT Lyn Syk PLCγ2 Fyn IP 3 Ca ++ DAG PKC mtor PIP 3 IkBa p5 p6 BTK TRAF6 MYD88 L265P IRAK4 IRAK1 MYD88 L265P Proteasome Deactivated/degraded FOXO3a p53 IkB ERK / MAPK MEK NFAT XPO1 p53 FOXO3a IkB MYC SK6 4E-BP1 BIM NFkB Bcl-2 BAX Cell proliferation survival, and migration

19 Evolution of Therapy for CLL 196s / 197s 198s 199s 2s 21s Alkylating agents Chlorambucil Cyclophosphamide Purine nucleosides Fludarabine Pentostatin Cladribine Combination chemotherapy Small molecule inhibitors BCR pathway Bcl-2 Chemoimmunotherapy (FCR) Alemtuzumab CD2 mabs Bendamustine

20 Factors affecting treatment choice Age Patient related Medical comorbidities Disease related Cytogenetic risk: FISH TP 53/ 17p deletion 11q deletion Concurrent medications Drug interactions IgVH mutation status Logistics

21 1. Eichhorst B et al. ASH 214. CLL1: PFS Outcomes With FCR Versus BR 1

22 Choice of initial CIT in younger patients: BR vs. FCR FCR superior to BR with respect response rate and progression free survival No OS benefit, though survival analysis not mature Severe neutropenia and infections more frequently observed with FCR (84% and 39%) vs BR (59% and 25%, respectively) Increased frequency of infectious complications and cytopenias with FCR was more pronounced in patients aged >65 y No PFS benefit for FCR in patients aged >65 y 1. Eichhorst B et al. ASH 214.

23 PFS, % Predictive factor: PFS by IgHV Mutation Status P< Time, y 1. Thompson PA et al. Blood. 216;127:33-39.

24 PFS, % Minimal Residual Disease and IgHV Mutation Status P = IgHV M, MRD neg IgHV UM, MRD neg IgHV M, MRD pos IgHV UM, MRD pos Months Thompson PA. MDACC unpublished.

25 Phase 3 CLL11 Trial: Obinutuzumab Plus Chlorambucil in Newly Diagnosed CLL 1 Patients with newly diagnosed CLL and significant comorbidities CIRS score >6 and/or estimated CrCl <7 ml/min N = 781 1:2:2 Chlorambucil.5 mg/kg PO, d 1 and 15, x 6 cycles Rituximab 375 mg/m 2 IV, cycle 1 on d 1; 5 mg/m 2 cycles 2-6, d 1 plus chlorambucil Obinutuzumab 1, mg IV cycle 1, d 1, 8, 15; cycles 2-6 d 1 plus chlorambucil 1. Goede V et al. N Engl J Med. 214;37:

26 CLL11: PFS Outcomes 1 Obin/Chl vs Obin/Chl vs Ritux/Chl Chl Obinutuzumab/chlorambucil was associated with prolonged PFS vs chlorambucil (left) and rituximab/chlorambucil (right) 1. Goede V et al. N Engl J Med.. 214;37:

27 Updated CLL11 Results: OS 1 Obinutuzumab/chlorambu cil was associated with significant OS benefit vs chlorambucil a No statistically significant difference in OS is noted vs rituximab/chlorambucil a Time to next treatment for obin/chl is about 48 mo

28 Ibrutinib vs Chlorambucil All patients All d(11q) 88% reduction in risk of progression or death in for patients randomized to ibrutinib Ibrutinib led to 99% reduction in risk of progression or death in high-risk del(11q) subgroup (82% reduction in those without del(11q) compared with chemotherapy 1. Barr PM et al. ASH 216.

29 Venetoclax in Relapsed CLL: Progression-Free Survival and Duration of Response 1 1. Roberts AW et al. N Engl J Med. 216;374:

30 Current Standards of Care for the CLL Patient Untreated, high-risk: watch and wait First-line therapy Del(17p): ibrutinib Elderly : chlorambucil + CD2 mab Fit CIT-eligible: FCR / BR Salvage treatments for active disease, including del(17p) BTK inhibitor (ibrutinib) PI3K inhibitor (idelalisib) + rituximab Rel / Ref del(17p): venetoclax Richter s transformation: intensive CIT, then allo-sct

31 Novel agents what to look for Ibrutinib: Oral agent; targets Bruton s tyrosine kinase Effective for 17p deletion Atrial fibrillation Bleeding Infections Venetoclax: Oral agent; targets Bcl2 Tumor lysis syndrome Drug interactions Cytopenias

32 Summary CLL is the most common adult leukemia Diagnosis is made by flowcytometry evaluation of the blood FISH studies and IgVH somatic hypermutation are most important prognostic/predictive markers: 17 p deletion, 11q deletion and unmutated are bad Not everybody needs treatment at diagnosis Chemo-immunotherapy is the frontline of treatment- Age is important Ibrutinib is effective in 17p- watch for Afib and bleeding Venetoclax is highly effective watch for infections, drug interactions, tumor lysis syndrome

33 Thank You!