CLL: from past to present from present to future

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1 CLL: from past to present from present to future Ann Janssens MD, PhD Hematology UZ Leuven BHS course, 8 th february

2 2 Part1 Diagnosis Prognostic factors Part 2 Complications Treatment

3 B-cell neoplasms Precursor B-cell neoplasm B-ALL, B-lymfoblastenlymfoom Mature B-cell neoplasms >85% CLL/SLL B-cell prolymphocytic leukemia Follicular lymphoma Hairy cell leukemia Lymphoplasmacytic lymphoma Marginal zone B-cell lymphoma Extranodal MZL (gastric and non-gastric MALT) Splenic MZL Nodal MZL Plasma cell myeloma/plasmacytoma/mgus Mantle cell lymphoma Diffuse large B-cell lymphoma Burkitt lymphoma/burkitt cell leukemia

4 CLL is a Non Hodgkin lymphoma B cell lymphoma Mainly leukemic: B-ALL, CLL, MCL, B-PLL, SLVL, HCL Mainly nodal: FL, nodal MZL Nodal/extranodal: DLBCL, Burkitt, MALT Mainly bone marrow:waldenström, Multiple Myeloma T cell lymphoma Mainly leukemic: Mainly nodal: Nodal/extranodal: Mainly extranodal: T-ALL, LGL, T-PLL, ATLL, AITL, ALCL, peripheral T cell lymphoma NOS cutaneous lymphomas (mycosis fungoides), NK/T cell lymphoma, EATL, hepatosplenic lymphoma WHO classification of tumours of Haematopoietic and Lymphoid tissues, 4th ed., 2008

5 Hematological malignancies CLL is the most common form of adult leukemia in Western countries CML 4% CLL 11% NHL 50% AML 9% ALL 4% SEER Ho 7% MM 15%

Epidemiology of CLL US 4.2/100000 person-years median age 72y The Netherlands 3.

6 Epidemiology of CLL US 4.2/ person-years median age 72y The Netherlands 3.8/ person-years 2/3 >65y at diagnosis M/F: 2/1 Van den Broek et al. Eur J Cancer 2012

7 How to diagnose and stage a lymphoma/cll? Clinical data Personal history Clinical examination Blood examination Histopathology Bone marrow/threphine Imaging

8 How to diagnose and stage CLL? Clinical data Personal history: most asymptomatic, only 5% reveal B-symptoms Clinical examination: 25% lymphadenopathies, 15% organomegaly Blood examination: leukocytosis due to a lymphocytosis Histopathology Bone marrow/threphine Imaging: X-ray thorax, echo abdomen, CT-scan neck, thorax, abdomen & pelvis, PET-CT?

9 Clinical examination

10 How to diagnose and stage CLL? Clinical data Personal history: most asympthomatic, only 5% reveal B-symptoms Clinical examination: 25% lymphadenopathies, 15% organomegaly Blood examination: leukocytosis due to a lymphocytosis Histopathology Bone marrow/threphine Imaging: X-ray thorax, echo abdomen, CT-scan neck, thorax, abdomen & pelvis, PET-CT?

DIAGNOSIS OF CLL: 1:MORPHOLOGY BLOOD SMEAR CLL cell

dense nucleus with partially aggregated chromatin no

cells Microscopy blood smear: easy, rapid and

11 DIAGNOSIS OF CLL: 1:MORPHOLOGY BLOOD SMEAR CLL cell characterictics: small mature narrow border of cytoplasm dense nucleus with partially aggregated chromatin no discernible nucleoli Gumprecht nuclear shadows or smudge cells Microscopy blood smear: easy, rapid and inexpensive Hallek et al., Blood 2008, guidelines CLL, updating NCI-WG 1996

12 MORPHOLOGY CLL: GUMPRECHT NUCLEAR SHADOWS

13 DIAGNOSIS CLL 2: IMMUNOPHENOTYPE CLL score 3/5 CD5 positive CD19, CD23 positive CD20, CD79b low expression sig, k of l low expression FMC7 negative CLL 3 à 5/5 B-PLL 0 à 1/5 HC 0 à 1/5 FL, SLVL, MCL 0 à 2/5 Moreau, Am J Pathol 1997

14 How to diagnose and stage CLL? Clinical data Personal history: most asympthomatic, only 5% reveal B-symptoms Clinical examination: 25% lymphadenopathies, 15% organomegaly Blood examination: leukocytosis due to a lymphocytosis, morphology and immunophenotyping Bone marrow/ threphine Imaging: X-ray thorax, echo abdomen, CT-scan neck, thorax, abdomen & pelvis, PET-CT? Histopathology

15 DIAGNOSIS CLL: 3: MARROW EXAMINATION Bone marrow aspirate + biopsy + immunophenotyping + genetics For diagnosis or staging CLL? No Unexplained cytopenia (disease related, auto-immune, drug related) Yes Confirming complete remission after treatment in clinical trials: Yes

DIAGNOSIS CLL: 3: MARROW EXAMINATION Marrow

16 DIAGNOSIS CLL: 3: MARROW EXAMINATION Marrow aspirate/ biopsy not required for the diagnosis! CLL: > 30% of nucleated cells in the aspirate are lymphoid Diffuse or non-diffuse infiltration No prognostic value anymore Hallek et al., Blood 2008, guidelines CLL, updating NCI-WG 1996

17 How to diagnose and stage CLL? Clinical data Personal history: most asympthomatic, only 5% reveal B-symptoms Clinical examination: 25% lymphadenopathies, 15% organomegaly Blood examination: leukocytosis due to a lymphocytosis Histopathology Bone marrow/threphine Imaging: X-ray thorax, echo abdomen, CT-scan neck, thorax, abdomen & pelvis, PET-CT?

18 DIAGNOSIS CLL: 4: IMAGING Outsite clinical trials: Abdominal ultrasound: popular, clinician dependent In clinical trials: CT chest, abdomen and pelvis (before start and at the end of treatment) Positron emission tomography scan Not usefull in CLL, except when Richter transformation is suspected Hallek et al., Blood 2008, guidelines CLL, updating NCI-WG 1996

19 DIAGNOSIS CLL: 4:IMAGING??? Radiological investigation not needed for staging and response evaluation Eichhorst et al., Blood 2011 Pre- and posttreatment CT should be considered for patients treated with more intensive therapies. There is no role for routine surveillance CT in asymptomatic patients posttreatment. Oscier et al, Br J Haematol, 2012 Guidelines on diagnosis, investigation and management of CLL

20 Casus: F, 66 y Rai 0, Binet A

21 How to diagnose and stage CLL? Clinical data Personal history: most asympthomatic, only 5% reveal B-symptoms Clinical examination: 25% lymphadenopathies, 15% organomegaly Blood examination: leukocytosis due to a lymphocytosis Bone marrow/threphine Imaging: X-ray thorax, echo abdomen, CT-scan neck, thorax, abdomen & pelvis, PET-CT? Histopathology lymph node

22 DIAGNOSIS CLL: 5: LYMPH NODE BIOPSY Lymph node biopsy only necessary in case of difficult diagnosis Necessary to establish the diagnosis of Richter transformation Hallek et al., Blood 2008, guidelines CLL, updating NCI-WG 1996

Monoclonal B cell lymphocytosis Small Lymphocytic Lymphoma Chronic Lymphocytic Leukemia Clonal B cells < 5000/ l Clonal B cells < 5000/ l Clonal B cells > 5000/ l MBL + Lymphadenopathies

23 Monoclonal B cell lymphocytosis Small Lymphocytic Lymphoma Chronic Lymphocytic Leukemia Clonal B cells < 5000/ l Clonal B cells < 5000/ l Clonal B cells > 5000/ l MBL + Lymphadenopathies Lymphadenopathies +/- 1%/y Organomegaly +/- Organomegaly +/- SLL/CLL Cytopenia due to marrow infiltration +/- Cytopenia due to marrow infiltration +/- Hallek et al. Blood 2008 Constitutional symptoms +/- Constitutional symptoms +/-

24 Clinical course CLL is highly variable 1/3 never requires treatment 1/3 requires treatment after an indolent phase 1/3 progressive from the onset with immediate need for treatment Dighiero et al, Am Soc Hematol Educ Program 2005

25 Can we predict clinical course? Can we predict overall survival? Can we predict treatment response? Can we predict duration of response?

26 Predictive and prognostic factors Clinical staging: Rai and Binet Lymphocyte doubling time IGVH mutational status CD38 Genomic aberrations Response to treatment 26

71-101m III-IV high risk anemia thrombocytopenia 19m A <3 areas of lymphadenopathies nl Binet B >3

27 Clinical staging systems predict outcome Staging system Clinical features Lab results Median survival 0 low risk lymphocytosis 150m Rai I-II intermediate risk lymphadenopathy splenomegaly m III-IV high risk anemia thrombocytopenia 19m A <3 areas of lymphadenopathies nl Binet B >3 areas of lymphadenopathies 7y C anemia thrombocytopenia 2y Rai et al. Blood 1975 & 1987; Binet et al. Cancer 1981

28 Clinical staging and OS today Staging system Stage Median OS Anno 1975 N= 125 Rai 8 Median OS Anno 2009 N= 2397 Mayo 11 Median OS Anno 2011 N=1300 Czech Republic mo 130 mo 362 mo I 101 mo 106 mo 125 mo Rai II 71 mo 88 mo 120 mo III 19 mo 58 mo 72 mo Rai et al. Blood 1975 & 1987 Binet et al. Cancer 1981 Apelgren et al. Leuk Lymphoma 2006 Shanafelt et al. Cancer 2010 Doubek et al. Eur J Haematol 2011 Binet IV 19 mo 69 mo 104 mo Median OS Anno 1981 N= 295 Binet 10 Median OS Anno 2006 N=344 Sweden 12 A normal 100 mo B 7 y 55 mo C 2 y 45 mo

29 Lymphocyte doubling time < or > 12 months and mos Overleving B-CLL UZ Gent vgl >12m ( n= 164) verdubbelingstijd mos 233 mo <12m ( n= 61) en Binet mos staging 106 mo P < Percent Survival A en>12 m A en <12 m BC en >12m BC en <12m followup CLL database UZ Ghent

30 IGVH mutational status Remains stable over time Unmutated: 2% variation with germline Mutated: >2% variation with germline DNA sequencing was expensive, technically demanding, not widely available Search for surrogate markers Pepper et al. Br J Haematol 2011

31 CD38: surrogate marker for IGVH mutational status? Transmembrane protein Detected by flow cytometry CD38-IGV H discordance: 30% CD38 expression may vary: 25% Cut-off value not clearly defined ( %) Bimodal expression in some patients Pepper et al. Br J Haematol 2011

32 ZAP-70: surrogate marker for IGVH mutational status? Intracellular tyrosine kinase Detected by flow cytometry ZAP-70 -IGV H discordance: 7-30% ZAP-70 expression may vary: 5-10% Optimal cut-off value not defined No standardized test exist Pepper et al. Br J Haematol 2011

outcome if single vs complex aberrations FISH 13q14 deletion Trisomy 12 11q22

33 Genomic aberrations predict survival Conventional karyotyping Clonal aberrations in only 40-50% Better outcome if no vs clonal aberrations Better outcome if single vs complex aberrations FISH 13q14 deletion Trisomy 12 11q22 deletion 17p13 deletion Julliusson G et al. N Eng J Med 1990 Döhner H et al. N Eng J Med 2000

34 Genomic aberrations predict survival N= 325 untreated patients 100 % mttt mos 13q deletion 55 92m 133m trisomy m 114m 11q deletion 18 13m 79m Patients Surviving (%) q deletion 17p deletion 7 9m 32m 13q deletion 12q trisomy Normal 80% 0 17p deletion Mos Dohner et al. N Engl J Med 2000

techniques Clonal aberrations in 80% Worse outcome if translocations or complex karyotype?

35 Conventional karyotyping Clonal aberrations in only 40-50% Better outcome if no vs clonal aberrations Better outcome if single vs complex aberrations FISH 13q14 deletion Trisomy 12 11q22 deletion 17p13 deletion Conventional karyotyping with novel culture techniques Clonal aberrations in 80% Worse outcome if translocations or complex karyotype? Next generation sequencing p53, ATM NOTCH1, SF3B1, BIRC3 Julliusson G et al. N Eng J Med 1990, Döhner H et al. N Eng J Med 2000, Haferlach C et al. Leukemia 2007, Gaidano et al. Clin Invest 2012

36 Integrated mutational & cytogenetic analysis Rossi et al. Blood 2013

37 At diagnosis Chemorefractory 13q14 50% % ATM 15% P % NOTCH1 10% SF3B1 5-10% BIRC3 4% 13q14 50% % ATM 25% P53 40% NOTCH1 25% SF3B1 25% BIRC3 25% MYD88 3-5%

38 Response to treatment is a prognostic factor in first-line treatment Response to FCR as frontline treatment predicts OS Complete response Partial response Progressive disease Stable disease Hallek M, et al. Lancet 2010; 376: ; Hallek M, et al. CLL8 trial updated, Unpublished.

39 Response duration after 1st line treatment affects outcome Patients who relapse early after 1 st -line FC or FCR have a very poor prognosis Remission duration after 1 st -line treatment Median OS from 2 nd -line treatment >24 months 44.6 months months 20.3 months <12 months 13.1 months FC: 14,5%-24,5% Cumulative survival Remission <12 months (n=47) Remission >24 months (n=32) Remission months (n=45) 0.0 FCR: 7,6%-16% Overall survival Months Stilgenbauer S, Zenz T. Am Soc Hematol Educ Program 2010

$Response to treatment is a prognostic factor in refractory patients Response$ $refractory patients Patient survival (%) m OS in responders 32 months Median$

40 Response to treatment is a prognostic factor in refractory patients Response to alemtuzumab in F-refractory patients Response to ofatumumab in F and A refractory patients Patient survival (%) m OS in responders 32 months Median OS all patients 16 months Keating et al. Blood, 2002 Wierda et al. Blood 2010

41 Minimal residual disease after 1 st line independent prognostic marker Moreno et al. Best Pract Res Clin Haematol 2010, Böttcher et al. J Clin Oncol 2012

Conclusion Part 1: Diagnostic and/or pretreatment work-up Mandatory Potential utility Personal and

CGA Complete blood cell count Peripheral blood smear CLL score Serum chemistry: LDH, IG, Cr

Rai-Binet CD38- ZAP-70 β2-microglobin IGV H mutational status FISH: 13q, t12, 11q Conventional

42 Conclusion Part 1: Diagnostic and/or pretreatment work-up Mandatory Potential utility Personal and familial history Physical examination Biological fitness: PS, comorbidities Biological fitness: CGA Complete blood cell count Peripheral blood smear CLL score Serum chemistry: LDH, IG, Cr Parameters for hemolysis FISH: 17p deletion Virology: hep B, hep C, CMV, HIV Clinical staging: Rai-Binet CD38- ZAP-70 β2-microglobin IGV H mutational status FISH: 13q, t12, 11q Conventional karyotyping with novel culture techniques Bone marrow aspirate and biopsy CT neck, thorax, abdomen, pelvis PET-scan

43 43 Part1 Diagnosis Prognostic factors Part 2 Complications Treatment

44 CLL and complications Advanced or active disease Relapsing to refractory disease Disease or therapy related cytopenia Infections, disease or therapy related Auto-immune phenomena AIHA, ITP, PRCA, AIN Secondary malignancies Melanoma and non-melanoma skin cancer, cancer of respiratory tract, prostate, kidney, Transformation Richter s syndrome Prolymphocytic transformation

45 Auto-immune phenomena in 4-10% of CLL patients Treatment Corticoiden AIHA AIN AITP PRCA Immunosuppressive agents: cyclosporine, mycophenolate mofetil, azathioprine Monoclonal antibodies Splenectomy Myeloid growth factors TPO-agonists 45

46 Secondary malignancies Risk of a sec malignancy 2x compared to age and sex matched controls Melanoma and non-melanoma skin cancers Respiratory cancer Prostate Renal Transformation to a higher grade lymphoma : Richter s syndrome 46

$bone marrow Characterized by a worsening of cytopenia, increasing lymphadenopathies and organomegaly and refractoriness to$

47 Richter s syndrome Prolymphocytic transformation (PLL) Transformation to DLBCL (95%) or Hodgkin s lymphoma (5%) Characterized by an abrupt change in patient s condition, rapid, asymmetric enlargment of lymph nodes, extranodal involvement, increasing LDH, and sometimes a monoclonal gammapathy Progressive increase of prolymphocytes in blood and bone marrow Characterized by a worsening of cytopenia, increasing lymphadenopathies and organomegaly and refractoriness to conventional treatment

At diagnosis Richter transformation 13q14 50% +12 15% ATM 15% P53 5-10% NOTCH1 10% SF3B1

48 At diagnosis Richter transformation 13q14 50% % ATM 15% P % NOTCH1 10% SF3B1 5-10% BIRC3 4% 13q14 20% % ATM 25% P53 60% NOTCH1 30% SF3B1 5% BIRC3 0% MYD88 3-5%

symptomatic lymphadenopathy Progressive marrow failure leading to cytopenia Auto-immune problems Disease related problems AIHA, AITP, PRCA

49 INDICATIONS FOR TREATMENT «primary = second line decisions» High tumorload Stage Rai 3-4 or Binet C Disease progression Lymphocyte doubling time of less than 6m Massive (>6 cm below costal margin) or progressive or symptomatic splenomegaly Massive (>10cm) or progressive or symptomatic lymphadenopathy Progressive marrow failure leading to cytopenia Auto-immune problems Disease related problems AIHA, AITP, PRCA poorly responsive to corticosteroids 10% weight loss in 6m Fatigue ( PS>+2) Fever >38 C for >2w without infection Night sweats >1m Hallek et al., Blood 2008

50 Treatment 50

51 Frontline treatment CLL Active or advanced disease No active or no advanced disease Wait and See 51

52 Fit or unfit? 52

53 Fit for what? 53

gastrointestinal Liver Renal Genitourinary Musculoskeletal Endocrine/metabolic Neurological Psychiatric If illness/impairment

54 Assessment of co-morbidity by CIRS Cumulative Illness rating scale CIRS captures numbers and severity of comorbidities CUMULATIVE ILLNESS RATING SCALE (CIRS) Organ system Heart Blood pressure Vascular Respiratory Ear/nose/throat Upper gastrointestinal Lower gastrointestinal Liver Renal Genitourinary Musculoskeletal Endocrine/metabolic Neurological Psychiatric If illness/impairment present, please specify: Score Total Score: Linn B, et al. J Am Geriatr Soc 1968; 16: Parmelee P, et al. J Am Geriatr Soc 1995; 43:

55 CIRS score measures medical fitness 25 Fit Unfit 20 Patients (%) CIRS total score Extermann M, et al. J Clin Oncol 1998; 16:

56 If >70y : screening for a geriatric risk prophile Triage risk screening tool (2)History or evidence of cognitive impairment (poor recall or not oriented) (1)Lives alone and/or no available caregiver (1) Difficulty walking/transferring or recent falls (1)Five or more medications (1) ED use in previous 30 days or hospitalization in previous 90 days If 1: go for comprehensive geriatric assessment Meldon et al,

Tools to evaluate functional age Polypharmacy Activities of daily living Instrumental ADL comprehensive geriatric assessment Time & Man-power consuming, Not reimbursed Social support FIT

57 Tools to evaluate functional age Polypharmacy Activities of daily living Instrumental ADL comprehensive geriatric assessment Time & Man-power consuming, Not reimbursed Social support FIT VULNERABLE FRAIL Comorbidities Not used in routine clinical practice Psychological status Nutritional status Minimental state Need for simple screening test Pallis A et al, Eur J Cancer,

58 Frontline treatment CLL CLL 8: FCR vs FC OR 95,1% vs 88,4% CR 44,1% vs 21,8% Active or advanced disease mpfs 51,8 vs 32 mo 17p deletion or p53 defect Fit for FCR Unfit for FCR FCR 3y OS 87% vs 83% Clinical trial Hallek et al., Lancet 2010;376;

59 CLL 10: FCR vs BR in physically fit patients with no 17p deletion 561 patients evaluable hematological toxicity: 90% vs 67% neutropenia: 81.7% vs 56.8% infections: 39% vs 25.4% ( p= 0.001) Median age 62 (33-82)y, CIRS 2 (0-6) Binet A 22%, B 38%, C 40% CR ORR MRD mpfs OS 2y TRM R N=284 Fludarabine- Cyclofosfamiderituximab Bendamustine- Cyclofosfamide FCR 47.4% 97.8% 55.2 mo 90.6% 3.9% BR 38.1% 97.8% 41.7 mo 92.2% 2.1% p = <0.01 0,897 N=280 Untreated CLL > 18 years CIRS <=6 CrCl >70ml/ Eichorst et al., ASH 2014, abstract M follow-up: 27.9 mo

Frontline treatment CLL Active or advanced

FCR Unfit for FCR FCR BR Clinical trial 30%

60 Frontline treatment CLL Active or advanced disease Unfit for FCR? CIRS >6 CrCl <70 ml/ Active AIHA Recurrent infections 17p deletion or p53 defect Fit for FCR Unfit for FCR FCR BR Clinical trial 30% >65y 10% >70y Binet B or C CIRS 6 CrCl >70ml/ Janssens et al. Belg Hematol J, 2012

CIRS 6 CrCl >70ml/ Something better than Chl?

61 Frontline treatment CLL CLL 5: Chl vs F Active or advanced disease Median age y PFS 18 vs 19m OS 64 vs 46m Fit for FCR Unfit for FCR FCR OS 30% >65y 10% >70y Binet B or C CIRS 6 CrCl >70ml/ Something better than Chl??? Eichhorst, B. F. et al. Blood 2009;114:

62 First-Line Bendamustine vs Chl Response % B Chl Overall 62% 33% CR 27% 2% PR 35% 31% PFS (%) Log-rank test stratified according to Binet B/C: P <.0001 Gr 3-4 neutropenia: 43 vs 21% Gr 3-4 infections: 7 vs 3% Months 24 mpfs 21.5m mpfs 8.3m Median 40 Bendamustine (n = 162) Chlorambucil (n = 157) Knauf et al. Br J Haematol, 2012

63 CLL 11 for the slow go OR/CR mpfs 30/0% Chlorambucil 10.8 mo 66/8% CIRS >6 Or Cr Cl <70ml/ R Chlorambucil- Rituximab 15.7mo 75/22% Chlorambucil- GA mo Goede et al, ASCO, EHA, ICML, ASH

64 CLL 11: PFS GA 101 vs Chl Goede et al, NEJM, 2013

65 CLL 11: OS GA-101 vs Chl Goede et al, ASCO, EHA, ICML, ASH 2013 plenary

66 Results at ASH 2013 mpfs: 22.4 vs 13.1 mo N=525 18y, contraindication for fludarabine active disease, Not previously treated ECOG 0-2

67 OMB : PFS (IRC assessed) Hillmen et al, Lancet, accepted

68 Frontline treatment CLL Active or advanced disease 17p deletion or p53 defect Fit for FCR Unfit for FCR Novel agents Clinical trial A A + HDMP FCR-FCA-CFAR FCR BR ( >65y) BR Chl / B Chl-R, Chl-GA-101 Chl-0 Clinical trial F / FR / FC RIC-alloBMT Clinical trial 68

$Treatment at Late relapse Refractory CLL$ any clinical trial!

69 Treatment at Late relapse Refractory CLL Relapsing CLL Clinical trial Not confirmed by any clinical trial! Repeat previous treatment FC/FCR (Ib) FA (Ib)/ FCA (Iia/b abstract) BR (IIa) 69

$Refractory or early relapse CLL 17p deletion - p53 defects Fludarabine refractory Fludarabine and Alemtuzumab refractory$ FCR-FA-FCA Ofatumumab (IIa) Clinical trial Repeat previous treatment if CR/nCR Go for another CIT combination Unmed

FCR-FA-FCA Ofatumumab (IIa) Clinical trial Repeat previous treatment if CR/nCR Go for another CIT combination Unmed

70 Refractory or early relapse CLL 17p deletion - p53 defects Fludarabine refractory Fludarabine and Alemtuzumab refractory Relapse <24m after CIT Clinical trial A (IIa or b) A + HDMP (IIb) R + HDMP (IIb) Clinical trial Alemtuzumab (IIa) FCR-FA-FCA Ofatumumab (IIa) Clinical trial Repeat previous treatment if CR/nCR Go for another CIT combination Unmed medical need OS 13m PFS 4,5m Fit: RIC Allo-transplant (IIb or III) Not eligible for transplant: consider consolidation in clinical trial 70

$Refractory or early relapse CLL 17p deletion - p53 defects Fludarabine refractory Fludarabine and Alemtuzumab refractory Relapse <24m after CIT Clinical trial A (IIa or b) A + HDMP (IIb) R + HDMP$

71 Refractory or early relapse CLL 17p deletion - p53 defects Fludarabine refractory Fludarabine and Alemtuzumab refractory Relapse <24m after CIT Clinical trial A (IIa or b) A + HDMP (IIb) R + HDMP (IIb) Clinical trial Alemtuzumab (IIa) FCR-FA-FCA Novel agents Ibrutinib Idelalisib/rituximab Venetoclax Ofatumumab (IIa) Clinical trial Repeat previous treatment if CR/nCR Go for another CIT combination Fit: RIC Allo-transplant (IIb or III) Not eligible for transplant: consider consolidation in clinical trial 71

$guidelines for TX -Refractory CLL$ -Early relapse (within 12-24

72 Allotranplantation in CLL EBMT guidelines for TX -Refractory CLL -Early relapse (within months) after purine analogue or combination therapy -p53 deletion/mutation requiring treatment Dreger et al, Blood, 2014 Don t use as a last desperate measure! Moreno, EHA 2012, educational 72

73 Dreger et al, Blood

74 BCR- antagonists Oral Inhibition of proliferation, migration, adhesion AMG 319 IPI-145 BAY TGR-1202 XL147 (panpi3k) RP6530 d+y GS-9820 CC-292 ONO

75 R/R no del 17p PFS = 81% 95% CI = [64%, 91%] R/R del 17p PFS = 53% 95% CI = [28%, 72%] Historical data: Median PFS 3-7 months R/R CLL patients by 17p status treated with ibrutinib (PCYC-1102-CA): Median PFS not reached (median f/u 22 mo)

76 R/R no del 17p OS = 87% R/R del 17p OS = 67% Historical data: Median OS months Survival in R/R CLL patients by del 17p status (PCYC-1102-CA): Median OS not Reached (median f/u 22 mo)

77 Byrd et al, NEJM 2013

78 Ibrutinib and response pattern 78

79 Ibrutinib: Aes in treatment naive CLL patients 79

80 Idelalisib+Rituximab in naive CLL, >65y Median age 71y Rituximab 8 weeks Idelalisib 2 x 150 mg/d continuously All patients ORR: 97% (CR 19%, PR 78%) 17 p del (n=9) ORR: 100%, CR 33%, PR 67% O Brien, ASCO 2013

81 Idelalisib+Rituximab in naive CLL, >65y O Brien, ASCO 2013

82 Idelalisib in Rel/Ref CLL Flinn et al, ICML 2013, abstract 297 & Brown, ASCO 2013

83 Lenalidomide and 17p deletion N=103 Median age 63.6y 17p del 24% and p53 mut 39% ORR 38.5% ORR 40% for pat without and 35% for pat with p53 mut ORR 22.7% for pat with a 17pdel No difference in ORR for pat with or without p53 mutation Buhler et al, ICML 2013, abstract 058

84 ABT-199 in Rel/Ref CLL ABT-199: selective bcl-2inhibitor N=56 Median age 67y Median n of therapies: 3.5 (1-10) 17p deletion 29%, F ref 32% ORR 85% (17p 88%, F Ref 75%) TLS 10%: dosing and sheduling modifications ongoing Nausea, diarrhea, fatigue, infections ( also tested in FL, WM, MCL, DLBCL) Seymour et al, ICML 2013, abstract 057

85 CLL treatment: a chemotherapy-free road? Cytostatic agents Antibodies New anti- CD20 antibodies BCR antagonists Chimeric antigen receptors Immunomodulatory agents Bcl 2 inhibitors

86 86

CLL & SLL: Current Management & Treatment. Dr. Isabelle Bence-Bruckler

CLL & SLL: Current Management & Treatment Dr. Isabelle Bence-Bruckler Chronic Lymphocytic Leukemia Prolonged clinical course Chronic A particular type of white blood cell B lymphocyte Lymphocytic Cancer