Hematology POCKET GUIDELINE. of Chronic Lymphocytic Leukemia in Belgium. Practical management

Transcription

1 POCKET GUIDELINE Hematology Practical management of Chronic Lymphocytic Leukemia in Belgium 1

2 2 POCKET GUIDELINE Hematology Practical management of Chronic Lymphocytic Leukemia in Belgium

3 This pocket guideline is based on: Janssens et al., Updated BHS guidelines for the treatment of CLL anno 2016, BJH 2015;6: Publisher Ariez International BV, Nieuweweg 108 A, 1531 AH Wormer, The Netherlands Tel.: +31(0) , Fax: +31(0) , adres: Website: Copyright Copyright 2016 Ariez International B.V., Wormer, The Netherlands. This publication or parts of this publication may not be used, copied or reproduced for commercial purposes by other parties than the publisher. The opinions stated in this publication do not reflect the opinion of the publisher and are not the responsibility of the publisher. The responsibility of the content of this publication rests solely with the authors. The publisher cannot be held responsible and is not liable for any damage caused to third parties by this publication and rejects any claims with regards to damage that might be caused or inflicted to third parties following the content of this publication. The authors have written this publication with the utmost attention and care; despite this fact, errors in the text could occur. The publisher cannot be held responsible or is not liable for any textual errors or potential damage or claims concerning damage inflicted to other parties following the use of this publication. This pocket guideline was made possible through funding from Gilead.

4 Index Introduction 4 Differential diagnosis CLL vs. other chronic B-cell 6 lymphoproliferative diseases MBL vs. SLL vs. CLL 7 Morphology of CLL 8 Immunophenotype of CLL 9 Diagnostic and/or pretreatment work-up 10 Clinical staging systems 11 Assessment of comorbidity 12 CLL-International prognostic index (CLL-IPI) 13 1

5 Indications for treatment 14 Treatment algorithm for frontline CLL 15 Treatment algorithm for relapsing/refractory CLL 16 Treatment schemes for CLL 17 Prevention of infection in CLL during treatment 18 Choice between available BCR-inhibitors 19 Ibrutinib drug interactions 20 Idelalisib drug interactions Posttreatment work-up 23 Abbreviations 24 References

6 POCKET GUIDELINE Hematology Practical management of Chronic Lymphocytic Leukemia in Belgium

7 Introduction The BHS lymphoproliferative working party reviewed the recent literature on treatment of SLL/CLL in 2015 to update the 2012 recommendations on best strategies for front-line and subsequent-line treatment. The incorporation of novel agents as obinutuzumab, ibrutinib and idelalisib have changed the natural history of CLL. A lot of ongoing trials combine first or second generation BCR-inhibitors with monoclonal antibodies, chemotherapy, bcl-2 antagonists, etc. to improve depth of response, duration of response and overall survival without compromising quality of life and will challenge our proposed guidelines shortly. Due to safety alerts appearing in 2016 the first line treatment of patients with a 17p del/p53 mutation has been slightly adapted and recommendations to prevent infections proposed. Prof. Ann Janssens, MD, PhD Hematology UZ Leuven Chair of the BHS Lymphoproliferative working group 4

8 LPD subcommittee members 2015 Marc André Virginie De Wilde Jan Lemmens Christophe Bonnet Vanessa Delrieu Marie Maerevoet Dominique Bron Daan Dierickx Fritz Offner Alessandra Camboni Radu Firescu Wilfried Schroyens Charlotte Caron Pierre Heimann Cécile Springel Sarah Debussche Caroline Jacquy Thomas Tousseyn Hilde Demuynck Ann Janssens Eric Van Den Neste Janssens et al., Updated BHS guidelines for the treatment of CLL anno 2016, BJH 2015;6: Vanessa Van Hende Achiel Van Hoof Gregor Verhoef Inge Vrelust Ka Lung Wu 5

9 CLL vs. other chronic B-LPD Chronic lymphocytic leukemia/ Small lymphocytic lymphoma CLL/SLL B-cell prolymphocytic leukemia B-PLL Mantle cell lymphoma MCL Follicular lymphoma FL Hairy cell leukemia HCL Lymphoplasmacytic lymphoma LPL Marginal zone B-cell lymphoma MZL Extranodal MZL (gastric and non-gastric MALT) Splenic MZL Nodal MZL 6

10 MBL vs. SLL vs. CLL Monoclonal B cell lymphocytosis Clonal B cells < 5000/ml Hallek et al. Blood 2008 Small Lymphocytic Lymphoma Clonal B cells < 5000/ml Lymphadenopathies + Organomegaly +/- Cytopenia due to marrow infiltration +/- Constitutional symptoms +/- 7 Chronic Lymphocytic Leukemia Clonal B cells > 5000/ml Lymphadenopathies +/- Organomegaly +/- Cytopenia due to marrow infiltration +/- Constitutional symptoms +/-

11 Morphology of CLL Courtesy: Dr C. Brusselmans, UZ Leuven Hallek et al. Blood 2008 CLL cell characteristics small mature narrow border of cytoplasm dense nucleus with partially aggregated chromatin no discernible nucleoli Gumprecht nuclear shadows or smudge cells < 55% prolymphocytes 8 Microscopy blood smear: easy, rapid and inexpensive

12 Immunophenotype of CLL CLL score > 3/5 CD5 CD19, CD23 CD20, CD79b sig, k or l FMC7 typical CLL atypical CLL B-PLL HCL FL, SLVL, MCL nv Roche sa Moreau, Am J Pathol 1997 CD200 and CD43 can help to differentiate atypical CLL from other LPD positive positive low expression low expression negative 4 to 5/5 2 to 3/5 0 to 1/5 0 to 1/5 0 to 2/5 9

13 Diagnostic and/or pretreatment work-up Mandatory Potential utility Personal and familial history Biological fitness: CGA Physical examination Biological fitness: PS, comorbidities Complete blood cell count Peripheral blood smear CLL score LDH, immunoglobulines, renal function Parameters for hemolysis 17p deletion/p53 mutation hep B, hep C, CMV, HIV Clinical staging: Rai-Binet CD38-CD49d β2-microglobulin IGV H mutational status FISH: 13q, t12, 11q Conventional karyotyping with novel culture techniques Bone marrow aspirate and biopsy Rx-thorax, echo abdomen CT neck, thorax, abdomen, pelvis ECG 10

14 Clinical staging systems Staging system Clinical features Lab results 0 low risk Lymphocytosis Rai I-II intermediate risk Lymphadenopathy Splenomegaly/Hepatomegaly III-IV high risk Anemia (Hb <11g/dl) Thrombocytopenia (<100000/μl) A <3 areas of lymphadenopathies Binet B 3 areas of lymphadenopathies C Anemia (Hb <10g/dl) Thrombocytopenia (<100000/μl) Rai et al. Blood 1975 & 1987; Binet et al. Cancer

15 Assessment of comorbidity CIRS (Cumulative Illness Rating Scale) captures numbers and severity of comorbidities Organ system If illness/impairment present, please specify: Score Heart Blood pressure Vascular Respiratory Ear/nose/throat Upper gastrointestinal Lower gastrointestinal Liver Renal Genitourinary Musculoskeletal Endocrine/metabolic Rating strategy 0: no problem 1: current mild problem or past significant problem 2: moderate disability or morbidity requiring first line treatment 3: severe/constant significant disability/ uncontrollable with first line treatment 4: extremely severe/immediate treatment required end organ failure/severe impairment in function Neurological Psychiatric Total Score: Parmelee P et al, J Am Geriatr Soc

16 CLL - International Prognostic Index (CLL-IPI) Variable HR Grading 17p del/p53 mut No or Yes IGV H Mut or Unmut B2 microglobulin or > 3.5 mg/dl 2 2 Stage Rai 0 vs 1-4 Binet A vs B-C Age or > 65y Risk group % 5y TTFT 5y OS low % 94% intermediate % 91% high % 68% very high % 21% International CLL-IPI working group, Lancet Oncol

17 Indications for treatment (advanced and/or active disease) High tumorload Rai 3-4 or Binet C Disease progression Lymphocyte doubling time of less than 6 months 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 AIHA, AITP, PRCA poorly responsive to corticosteroids Disease related problems 10% weight loss in 6 months Fatigue ( PS 2) Fever >38 C for >2w without infection Night sweats >1m Hallek et al. Blood

18 Treatment algorithm for frontline CLL Unfit for FCR? CIRS >6 CrCl <70 ml/ Active AIHA Recurrent infections Advanced/ Active CLL CLL frontline 17p del/ p53 mut No 17p del/ p53 mut Fit for AlloBMT Unfit for AlloBMT Fit for FCR Ibrutinib/ R-idelalisib* (A/FCR) Allo-BMT Ibrutinib/ R-idelalisib* (A/FCR) 65y: FCR >65y: FCR/BR Janssens et al., Updated BHS guidelines for the treatment of CLL anno 2016, BJH 2015;6: *: R-idelalisib if contra-indication for ibrutinib treatment 15 no Advanced/ Active CLL Wait & See Unfit for FCR BR/Ob-Chl R-Chl (Chl)

19 Treatment algorithm for relapsing/refractory CLL CLL relapse/ refractory Early vs. Late relapse: relapse <24 mo after the end of previous treatment Early relapse 17p del/p53 mut F/A refractory Late relapse Unfit Fit Unfit Ibrutinib/ R-idelalisib (A) Ibrutinib/ R-idelalisib Allo-BMT Ibrutinib/ R-idelalisib (A) Janssens et al., Updated BHS guidelines for the treatment of CLL anno 2016, BJH 2015;6: Fit CIT 16

20 17 Treatment schemes for CLL dosage Days(d)/weeks(w) Cycles (C) FCR Fludarabine Cyclophosphamide Rituximab 25 mg/m mg/m (C1)-500(C2-6) mg/m 2 d1-3 d1-3 d1 6 BR Bendamustine Rituximab 90 (Frontline)-70 (Relapse) mg/m 2 d (C1)-500(C2-6) mg/m 2 d1 6 Ob-Chl Obinutuzumab Chlorambucil 100(d1)-900 (d2)-1000 (d8-15)mg (C1) 1000mg (C2-6) 10 mg/m 2 or 0.5 (till 0.8) mg/kg d d1 d1-7 d1 & (12) 6 (12) R-Chl Rituximab Chlorambucil 375 (C1)-500(C2-6) mg/m 2 10 mg/m 2 or 0.5 (till 0.8) mg/kg d1 d1-7 d1 & (12) 6 (12) Ibrutinib 420 mg/d, once daily Continuous treatment R-Idelalisib Rituximab Idelalisib 375 (w1)-500(w3-21) mg/m mg twice daily w Continuous treatment

21 Prevention of infection in CLL during treatment pneumocystis jirovecii (PCJ) prophylaxis herpes simplex virus (HSV) prophylaxis Cytomagalovirus (CMV) PCR moni toring Hepatits B screening Prophylaxis/ monitoring When, how long >2 months after treatment completion and CD4 >200/µl >2 months after treatment completion and CD4 >200/µl Every 4 weeks untill 2 months after treatment completion Before start of treatment Drug choice Co-trimoxazol 400/80 mg 1 tabl/d Co-trimoxazol 800/160 mg 1 tabl/d 3 times a week (Pentamidine 300 mg aerosol once a month) (Dapsone 100 mg/d) (Atovaquone 1500 mg/d) Acyclovir 2 x 400mg/d History of PCJ/HSV/ CMV infection prior any immunosuppressive treatment x x x FCR x x x BR x if CD4 <200/µl x if CD4 <200/µl x Ob-Chl, R-Chl x Ibrutinib R-idelalisib x x if CMV serology pos x Alemtuzumab x x x if CMV serology pos x Prednisone > 20mg/d for 4 weeks x x Maertens et al., J Antimicrob Chemother 2016; Baden et al., NCCN

22 19 Choice between available BCR-inhibitors Patient preference Once daily 3 to 4 capsules: ibrutinib Twice daily 1 tablet: idelalisib Frontline treatment ibrutinib > idelalisib Renal impairment CrCl >25 ml/min: ibrutinib or idelalisib CrCl ml/min: idelalisib Auto-immune colitis Ibrutinib > idelalisib Cardiac impairment/ arrhytmia Idelalisib > ibrutinib ECG and cardiac check up if cardiovascular risk factors or disease before start ibrutinib Bleeding Congenital bleeding disorders: idelalisib > ibrutinib Antiplatelet agents: idelalisib > ibrutinib Anticoagulant agents: idelalisib > ibrutinib Assess indication of antiplateletanticoagulant therapy Serious pulmonary impairment Ibrutinib > idelalisib Janssens. Ibrutinib and idelalisib, the BCR antagonists available for use in daily clinical practice. BJH 2015;6:

23 Ibrutinib drug interactions Ibrutinib Ibrutinib Increased bleeding risk Strong CYP3A4 inhibitors Moderate CYP3A4 inhibitors CYP3A4 inducers clarithromycin aprepitant carbamazepine Heparine & LMWH telithromycin ciprofloxacin phenytoin Vit K antagonists ketoconazole erytromycin rifampicin NOACs itraconazole fluconazole rifabutin Aspirin posaconazole diltiazem phenobarbital NSAID voriconazole verapamil dexamethasone thienopyridines HIV medication amiodarone St John s wort SSRIs Grape fruit (juice) Fish oil Herbals Assess necessity of concomitant drugs 20

24 Idelalisib drug interactions Idelalisib Idelalisib Strong CYP3A4 inhibitors CYP3A4 inducers clarithromycin carbamazepine telithromycin phenytoin ketoconazole rifampicin itraconazole rifabutin posaconazole phenobarbital voriconazole dexamethasone HIV medication St John s wort Grape fruit (juice) 21 Assess necessity of concomitant drugs

25 Idelalisib drug interactions Contraindicated The metabolite of idelalisib (GS ) is a strong CYP3A4 inhibitor and may increase the concentration (check SMPC and consider alternative if possible) simvastatine Antidepressants Sedatives Neuroleptica trazodone diazepam, flurazepam, zolpidem quietapine, pimozide amiodarone Anti-gout colchicine midazolam, triamzolam Cardiovascular drugs amlodipine, felodipine, diltiazem, nifedipine, nicardipine disopyramide, lidocaine sildefanil, tadalafil (PAH) Anticoagulants NOACs, warfarine Analgetics morfine, buprenorphine, fentanyl, cocaine, methadone Glucocorticoids oral budesonide Anti-infectives clarithromycine, telitromycine, rifabutin, HCV protease inhibitors ketoconazole, itraconazole, voriconazole, posaconazole Phosphodiesterase inhibitors Anticonvulsants carbamazepine sildefanil, tadalafil (erectile dysfunction) Immunosuppressants cyclosporine, tacrolimus, everolimus 22 Assess necessity of concomitant drugs

26 23 Posttreatment work-up Complete Response outside a clinical trial (at least 2 mo after completion of therapy) Partial Response (at least one of the following parameters documented for a minimal duration of 2 mo) Absence of clonal lymphocytes in the peripheral blood Decrease in blood lymphocytes by at least 50% Absence of significant lymphadenopathy (<1.5cm) by physical examination Reduction lymphadenopathy >50% (no new node, no increase in any node) No spleno- or hepatomegaly by physical examination Reduction hepato-, splenomegaly > 50% Blood counts above: (without transfusion - growth factors) Neutrophils >1500/µl Platelets >100000/µl Hemoglobin >11g/dl Blood counts: Neutrophils >1500/µl or 50% improvement over baseline Platelets >100000/µl or 50% improvement over baseline Hemoglobin >11g/dl or 50% improvement over baseline Absence of constitutional symptoms Hallek et al. Blood 2008

27 Abbreviations A AIHA CGA CIRS CIT CLL CLL-IPI CrCl F/A refractory HR ITP LPD MALT MBL MZL OS PRCA PS SLL SSRI TTFT alemtuzumab auto-immune hemolytic anemia complete geriatric assessment cumulative illness rating scale chemo-immunotherapy chronic lymphocytic leukemia CLL international prognostic index creatinine clearance fludarabine/alemtuzumab refractory hazard ratio immune thrombocytopenic purpura lymphoproliferative disorder mucosa associated lymphoid tissue monoclonal B-cell lymphocytosis marginal zone B-cell lymphoma overall survival pure red cell aplasia performance status small lymphocytic lymphoma selective serotonin re-uptake inhibitor time to first treatment 24

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