MED B Form CLL. Johannes Schetelig. London 09/April/

www.ebmt.org MED B Form CLL Johannes Schetelig London 09/April/2013

Content Update on CLL (15 ) Experiment with mini MED B CLL Assessment of pre-treatment in CLL Cytogenetics in CLL What is the IGVH-Gene Mutations status? MED B CLL 2

Clinical presentation (CLL) Symptoms are mainly caused by cytopenia, lymphadenopathy, hepatosplenomegaly; B-Symptoms Fever Night sweats Weight loss Skin Pruritus Allergy

Diagnosis: CLL Differential blood count (microscopy): Lymphocytosis Smudge cells (Gumprecht) Confirmation of diagnose by immunophenotyping

1 1. Head and neck 2 2. Axillae 3 4 3. Hepatomegaly 4. Splenomegaly 5 5. Inguinal region

MED AB Manual Binet Stage Rai Stage 8

Percentage surviving patients Overall survival / Binet-Stage Overall survival / Rai-Stage 1.0 Binet-Stage A: median 14 years 1.0 Rai-Stage 0: median 17 years 0.8 Binet-Stage B: median 5 years Binet-Stage C: median 3 years 0.8 Rai -Stage I II: median 7 years Rai-Stage III IV: median 3 years 0.6 0.6 0.4 0.4 0.2 0.2 0 0 N = 970 5 10 15 20 25 30 35 N = 970 0 0 5 10 15 20 25 30 35 Time (years) Time (years) Hospital Clinic Provincial (HCP) Barcelona.

Watch & Wait for symptoms that require therapy Marrow failure (anemia, thrombocytopenia) Lymph nodes > 10 cm Lymphocyte doubling time < 6 months Refractory auto immune cytopenias Constitutional symptomes (B-symptoms or fatigue) Hallek M, et al. Blood 2008;111:5446-5456.

Chemotherapy Chlorambucil, Cyclophosphamide, Bendamustin, Fludarabine Antibodies Rituxan, Alemtuzumab, Ofatumumab Immune-Modulators Prednisolone, Dexamethasone, Revlimide Kinase Inhibitors Ibrutinib, Idelalisib

Shuffle Clb, R, R-Clb, R-Dexa, HDMP, R-HDMP, F, FR, FC, FCR, FCR-lite, FO, FCO, Flu-Cam, FCR, CFAR, BR, R-Benda, BO, BA, R 2, + lymphoma regimens CHOP, french-chop, DHAP, R-DHAP, radiation + Ibrutinib & Idelalisib &

Survival advantage? LRF CLL4 trial Catovsky, Lancet, 2007

Results of allogeneic HCT EFS @5yrs: 36% (95%CI, 32%-41%) OS @5yrs: 47% (95%CI, 43%-51%) 15

mini MED B MED B CLL 16

Problem - Approach Minimal Essential Data were missing in order to interpret registry results on allogeneic HSCT in CLL: Pre-treatment? Cytogenetics? We carefully designed a comprehensive questionnaire (mini MED B) for patients who received their 1 st allo HSCT between 2000 and 2011 Data on 2897 patients were requested Data Quality Initiative 17

Data Quality Initiative 18

Data Quality Initiative 19

Thank you! Data Quality Initiative 20

Participating Countries DQI CLL Czech Republic 98 Denmark 55 Finland 28 France 39 Germany 351 Israel 6 Netherlands 33 Norway 11 Russia 5 Spain 52 Sweden 27 Switzerland 36 UK 30 Total 771 Data Quality Initiative - CLL 21

First results Comparison NMA vs. RIC (NA, denmark) New concepts on how to present GVHD (Leiden) Long-term outcome in CLL (LdW & MvG, NL) Descriptive analysis (CM, Spain) Risk factor analysis Data Quality Initiative - CLL 22

Assessment of pre-treatment MED B CLL 23

Purine-analogue refractory disease (fludara, cladribine, pentostatin), defined as nonresponse or progression within 6 months after CT Relapse within 24 months after PA-based combination chemotherapy CLL with del(17p)

Data Quality Initiative 25

Treatment report 26

Treatment report 27

Assessment of pre-treatment I Regimen Date start Date stop Response 28

Assessment of pre-treatment I Regimen Date start Date stop Response CLB NN.NN.2004 NN.NN.2008 UK Bendamustin NN.09.2008 NN.04.2009 PR Rituximab NN.01.2009 NN.07.2009 PR... 29

Assessment of pre-treatment II TOTAL NUMBER OF LINES BEFORE THIS HSCT: 30

Assessment of pre-treatment III CIBMTR current disease status options for NHL and Hodgkins o Disease untreated o PIF res - Primary induction failure resistant: NEVER in COMPLETE remission but with stable or progressive disease on treatment. o PIF sen / PR1 - Primary induction failure sensitive: NEVER in COMPLETE remission but with partial remission on treatment. o PIF unk - Primary induction failure sensitivity unknown o CR1-1 st complete remission: no bone marrow or extramedullary relapse prior to transplant o CR2-2 nd complete remission o CR3+ - 3 rd or subsequent complete remission o REL1 unt - 1 st relapse untreated; includes either bone marrow or extramedullary relapse o REL1 res - 1 st relapse resistant: stable or progressive disease with treatment o REL1 sen - 1 st relapse sensitive: partial remission (if complete remission was achieved, classify as CR2) o REL1 unk - 1 st relapse sensitivity unknown o REL2 unt - 2 nd relapse untreated: includes either bone marrow or extramedullary relapse o REL2 res - 2 nd relapse resistant: stable or progressive disease with treatment o REL2 sen - 2 nd relapse sensitive: partial remission (if complete remission achieved, classify as CR3+) o REL2 unk - 2 nd relapse sensitivity unknown o REL3+ unt - 3rd or subsequent relapse untreated; includes wither bone marrow or extramedullary relapse o REL3+ res - 3 rd or subsequent relapse resistant: stable or progressive disease with treatment o REL3+ sen - 3 rd or subsequent relapse sensitive: partial remission (if complete remission achieved, classify as CR3+) o REL3+ unk - 3 rd relapse or greater sensitivity unknown 31

Assessment of pre-treatment IV Med-A June12 Status at HSCT: DISEASE HISTORY NUMBER OF PRIOR LINES OF TREATMENT unknown DISEASE STATUS: assessed at the time of HSCT TECHNIQUE used for the assessment: CT scan Cheson 1999: J Clin Oncol 17:1244-1253 sion (CR) Complete remission unconfirmed (CRU*) Number of this CR/CRu higher unknown *CRU complete response with persistent scan abnormalities of unknown significance, previously known as VGPR Partial response (PR) Number of this PR higher unknown Stable disease (SD) Chemorefractory progression Untreated relapse (from a previous CR)/progression (from a previous PR) Never treated Unknown TECHNIQUE used for the assessment: PET Cheson 2007: J Clin Oncol 25:579-586 Positive Negative Not done IF DISEASE STATUS IS NOT CR/CRU Did the patient ever achieve a CR/CRu before this HSCT? No Yes unknown Number of remissions (CR, CRu or PR) achieved by the patient prior to this HSCT Count all remissions including this one if applicable unknown 32

Assessment of pre-treatment IV Status at HSCT No. of lines of treatment? Status at HSCT? If status is not CR/CRu, has CR/CRu ever been achieved? Number of remissions (CR/CRu, PR) ever achieved prior to this HSCT? Options 1,2,3 or more, NK CR, PR. SD, PD, NK Yes/No/NK 1,2,3, Subtable if CR at HSCT no of this CR if PR at HSCT no of this PR Options 1 st, 2 nd, 3 rd or higher, NK 1 st, 2 nd, 3 rd or higher, NK 33

Which option do you think is best? Option 1: Collect raw data (regimen, start, stop, remission) Option 2: summarizing questions with underlying defs Option 3: combining information on status and no of previous remissions Option 4: counting lines of pre-treatment and number of remissions 34

Cytogenetic Report MED B CLL 35

Results from FISH screening in 325 patients with newly diagnosed CLL: 175 pts had a single abnormality, 67 had two and 26 > two abnormalities mir-15a/mir-16-1 located on 13q14.3 both downregulating Bcl2-expression Döhner, et al. NEJM 2000, 343, 1910-6.

Überleben (%) 100 Ausschließlich 13q-Deletion 80 60 40 11q-Deletion Trisomie 12q 20 17p-Deletion Normal 0 0 24 48 72 96 120 144 168 Zeit (Monate) Döhner NEJM 2000

Cytogenetic Report 38

Karyotype Formula Karyotype (ISCN): 46, XY,?inv(12)(p11.2q13)[2]/46,XY [8].nuc ish 11q22.3(ATMx2) [200],(D12Z3x2) [200], 13q14(D13S319x2) [200], 13q34(SHGC- 146516,PROZ,CUL4A,LAMP1,D13S1020[200], WI-9415)x2[200],14q32(IGHx2)[200],(D17Z1x2) [200],17p13(TP53x2)[200] 39

Conventional Banding Technique 41

Report on FISH analysis 46

Cytogenetic Report Distinguish between banding & FISH The banding analysis is comprehensive but less sensitive to specific lesions (microdeletions) FISH analysis is more sensitive, but you see only what you are looking for (which probes you use) 47

Cytogenetic Report in MED B 48

Summary Brief update on CLL Report on DQI in CLL How should pre-treatment information be collected? Cytogenetic reports IGVH mutations status 49

Thank you! MED B CLL 50

IGHV Mutationstatus MED B CLL 51

Chiorazzi, NEJM, 2005

Result IGVH sequencing 53

Report on IGVH mutation status 54

Report on IGVH mutation status 55

Among 77.469 healthy adults enrolled in the PLCO Cancer Screening Trial 45 subjects were identified in whom CLL was diagnosed later. Samples from these patients were re-analysed by FACS for MBL or by RT-PCR for IgV(h)-rearrangement 44 of 45 patients had a prediagnostic B-cell clone by either FACS or PCR and 41 patients by both methods. Time between collection of pre-diagnostic sample and diagnosis of CLL median 32 months (3 to 77 ) Landgren, NEJM, 2009, 360, 659-667.

Rawstron, NEJM, 2008, 359, 575-583.

Age group [years] Prevalence of MBL 40 49 5.1% 50 59 5.3% 60 69 17.5% 70 79 21.7% 80 89 27.3% > 89 75% Nieto, Blood, 2009, 114, 33-37.

Minimal residual disease MED B CLL 60

Clearance of CLL-cells 5000 skin GVHD 4000 3000 2000 1000 0 0 100 200 300 400 500 600 Days after allogeneic HCT

Report on MRD 62

Minimal Residual Disease FISH: Reported as being present: Yes / No Reported as percentage of lymphocytes with CLL immunophenotype or as absolute number PCR: Reported as being present: Yes / No Reported as percentage of lymphocytes with CLL immunophenotype or as absolute number 63

Remission Status MED B CLL 64

Reference Document: 65

Remission Criteria iwcll 66

Complete Remission CR Absence of clonal lymphocytes in the peripheral blood and absence of significant lymphadenopathy (e.g. LN >1,5 cm in diameter) and absence of hepatomegaly or splenomegaly and absence of constitutional symptoms. This definition of CR refers to clinical response. Not included are results obtained by immunophenotyping, cytogenetics and/or molecular biology. CR incomplete All CR criteria fulfilled except for anemia, thrombocytopenia and neutropenia. 67

Partial Remission To define a PR, at least two of the following parameters need to be documented for a minimal duration of 2 months: Decrease in blood lymphocytes 50% Decrease in lymph node size 50% (SPD or largest diameters) Decrease in size of the spleen/liver 50% Decrease of BM infiltration 50% The blood count should show one of the following results if abnormal prior to therapy: Neutrophils >1.500/μL or 50% improvement without G-CSF support Platelets >100.000/μL or 50% improvement over baseline; Hemoglobin >11.0 g/dl or 50% improvement without transfusions or EPO support. 68

Stable Disease 69

Clinical Staging (CLL) Staging according to Binet (1981) Stage LK-Regions Hemoglobin Thrombocytes Survival A <3 6,5 mmol/l 100 Gpt/l > 10 years B 3 6,5 mmol/l 100 Gpt/l 5 years C any < 6,5 mmol/l < 100 Gpt/l 2 years LK-Regions: cervical, axillär, inguinal, liver, spleen (palpation) Alternative classification according to Rai: stage 0-IV