eha-rohs-nhs tutorial on real world challenges …eha-rohs-nhs tutorial on "real world...
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EHA-ROHS-NHS Tutorial on "Real world challenges and opportunities in
diagnostics and management of onco-hematological patients today"
Elena Stadnik
V.A. Almazov National Medical Research Center
Moscow, Russia
April 12-13, 2019
RSH
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Presentation: 2001‒ Male, 60 years
‒ Following a respiratory infection – an absolute lymphocytosis
No indication to commence specific therapy
Chronic lymphocytic
leukemia
Rai Stage I
Bone marrow biopsy: lymphocytosis 69%
IgHV not mutated
No autoimmune complications
Blood immunophenotyping:
CD5+CD23+CD19+ CD20+/-
Enlargement of peripheral lymph
nodes. Liver, spleen are nor enlarged.
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February 2004 – progression:
• Growth of lymph nodes, increase in leukocytosis
• Platelets <100 × 109/l, Rai stage IV
• Expression of CD38 >30%
• FISH – no mutations
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
?
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Терапия
O’Brien et al., 2001 (MDACC)• Fludarabine = 30 mg/m2 days 1-3
Cyclophosphamide = 300 mg/m2 days 1-3(FC)
• N = 34 • Response: 88% (CR 35%, PR+ nPR 53%)• Med. PFS: not reached after 41 months
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
1st line:“FC”, 6 cycles03.2004 – 12.2004Response: CR
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Keating et al., 2005 (MDACC)• Rituximab = 375-500 mg/m2
Fludarabine = 25 mg/m2 days 1-3Cyclophosphamide = 250 mg/m2 days 1-3
• N = 224• Response: 95% (CR 70%, PR+ nPR 25%)
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
1st line:“FC”, 6 cycles03.2004 – 12.2004Response: CR
+ rituximab 500 mg4 infusions 01.2005PFS: 1.5 years
Relapse 08.2006
CR
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Progression 09.2007 + massive lymphadenopathy
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
2nd line:“R-CVAD”, 6 cyclesRituximab 500 mg/m2 × 1, Cyclophosphamide 300 mg/m2 ×3, Vincristine 2 mg × 1, Doxorubicin 30 mg/m2 × 1, Dexamethasone 40 mg × 4
08.2006 - 01.2007Response: SDPFS: 8 months
CR SD
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Elter et al. 2005 • Fludarabine 30 mg/m2 days 1-3• Alemtuzumab 3-10-30 mg/m2 days 1-3• N = 36 (relapsed/refractory)• Overall response 83% (CR 30%, PR 53%)• PFS 13 months, OS 35.6 months
3rd line:• “FluCam”, 6 cycles (САМ314)
Flu 60 mg, Alem 3-10-30 mg10.2007 - 03.2008
• Complications: reactivation of CMV (hepatitis), herpes zoster
• Response: SD (-40%)• PFS: 4 months• Progression 07.2008 (resistance!)
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
CR SD SD
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5th line:• Chlorambucil (dose variation)
11.2008 – 01.2009• Response: SD• PFS: 1 month
Progression from 02.2009
4th line:• GCS-100 (trial PR-CS008)
Galectin-3 inhibitor3 cycles (each 375 mg х5) 08.2008 - 11.2008
• Response: progression
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM GCS-100 Chlorambucil
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
CR SD SD
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Wierda et al. 2005 (MDACC)Rituximab = 375-500 mg/m2
Fludarabine = 25 mg/m2 days 1-3Cyclophosphamide = 250 mg/m2
days 1-3
N = 177 (R/R)Overall response: 73% (CR 25%)
PFS 28 months
• 6th line:“FCR”, 2 cycles
03.2009 - 04.2009
• Response: SD (-30%)
• Fludarabine-associated haemolysis:
• Decrease in Hb to 40 g/• Hyperbilirubinemia grade I• Reticulocytes 49%
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM GCS-100 Chlorambucil FCR
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
CR SD SD
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Kaufman et al. 2008
• Rituxumab = 375 mg/m2 day 1Cyclophosphamide= 0,75-1 g/m2 day 2Dexamethasone = 12 mg days 1-7
• N = 21 (20 AIHA)
• Hb response: 100%
• Median time to response: 22 months
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM GCS-100 Chlorambucil FCR RCD
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
“RCD”, 6 cyclesRituxumab 700 mg × 1, Cyclophosphamide 400 mg× 3, Dexamethasone 40 mg× 4
05.2009 - 10.2009
Response: SD (-50%),AIHA arrestedPFS: 7 months
CR SD SD SD
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0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM GCS-100 Chlorambucil FCR RCD RD
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
7th line:• Rituximab + dexamethasone
Rituxumab 700-1000 mg × 1, Dexamethasone 40 mg ×406.2010 - 07.2010
• Response: SD (-30-40%)• PFS: 6 months
CR SD SD SD
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Fischer et al., 2011 (CLL2M)Bendamustine = 70 mg/m2 days 1-2Rituximab = 375/500 mg/m2
N = 78 (22 refractory to Fludarabine)Response: 59% (CR 9%, PR+ nPR 50%)Median PFS: 14.7 months
8th line:
• “BR”, 6 cyclesRituximab 1000 mg × 1, Bendamustine 140 mg × 2
02.2011 - 07.2011
• AEs: neutropenia grade 3-4
• Response: PR (-80%)
• PFS: 5 months(progression 01.2012)
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM GCS-100 Chlorambucil FCR RCD RD BR
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
PRCR SD SD SD SD
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Wierda et al., 2010 (Hx-CD20-406)• Ofatumumab = 300/2000 mg (24 weeks)• N = 138 (refractory to F and A = 59)• Response in refractory pts 58% (all PR)• Median PFS 5.7 months;
median OS 13.7 months
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM GCS-100 Chlorambucil FCR RCD RD BR Ofatumumab
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
9th line
:Ofatumumab (trial OMB114242)10.2012 – 02.2013
• AEs: invasive mycosis of lungs, serous meningoencephalitis, pneumonia
• Response: PR• PFS: 11 months
PRPRCR SD SD SD SD
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Visco et al., 2010 (Vicenza)
N = 13 (R/R, 9 del17p)
Rituximab 375 mg/m2 day 1Bendamustine 70 mg/m2 days 1-2Cytarabine 800 mg/m2 days 1-3
Overall response: 84% (CR 38%)
Median PFS: 16 months
• RESONATE trial• HELIOS trial (BR+Ibr)
John C. Byrd et al NEJM 2014
Day 1 Day 2 Day 3 Day 4
Rituximab 1000
Bendamustine 140 140
Cytarabine 1600 1600 1600
Ibrutinib 480 mg/day * * * *
0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM GCS-100 Chlorambucil FCR RCD RD BR Ofatumumab R-BAC Ibrutinib
PR
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
del11q 86%
10th line:• “R-BAC+Ibr”, 4 cycles
Rtx 1000 mg х1, Bend 140 mg х2, Ara-C 1600 mg х3
02.2014 – 05.2014,• Following ibrutinib monotherapy• AEs: anaemia gr. 3, neutropenia gr. 4,
thrombocytopenia gr. 4• Response: PR
PRPRCR SD SD SD SD
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September – October, 2017‒ Growth of all groups of peripheral lymph nodes, constitutional
symptoms, anaemia grade 3-4 with symptoms of anemic hypoxia
‒ Bone marrow histology and PET/CT with 18-FDG performed – no signs of Richter’s syndrome.
‒ Genesis of anaemia:
• 1 – tumor infiltration of bone marrow?
• 2 – AIHA (↑ indirect bilirubin, ↑ LDH, Coombs test +++)?
• 3 – PRCA (decreased number of erythroid elements in bone marrow, reticulocytopenia, parvovirus В19+) ?
‒ Treatment: rituximab no. 4 (once per week), IVIg (3 injections)
‒ Response: clinically significant anaemia resolved, lymph nodes decreased in size by 40%
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↓
↓
↓
Rituximab
Rituximab
Rituximab
↓ ↓
↓IVIg
IVIg
IVIg
Haemoglobin changes during therapy
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0 10 19 29 39 49 58 68 78 88 97 107 117 127 136 146
Месяцы
FC Rituximab R-CVAD FluCAM GCS-100Chlorambucil FCR RCD RD BROfatumumab R-BAC Ibrutinib Venetoclax
PR
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
del11q 86%
PRPRCR SD SD SD SD PR
11th line:
Venetoclax
Risk of tumour lysis syndrome (TLS)High tumour burden >10 cm(mass at bifurcation and aortopulmonary lymph nodes 72× 57 ×131 mm)
High risk TLS• Hydration 1.2-2 L• Allopurinol 300 mg in 3 days• Laboratory monitoring before therapy, after 4, 8,
12, and 24 hours after start of therapy, after 6, 8, and 24 hours after dose escalation
Ramp-up
Week 1 Week 2 Week 3 Week 4 Fromweek 5
20 mg 50 mg100 mg
200 mg
400 mg
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Low risk Median risk High risk
Additional comorbidity ortumour burden
Normal kidney functionCrCl >80 ml/min
Kidney disfunctionCrCl <80 ml/min
Additional comorbidity ortumour burden
Risk of TLSTLS prophylaxis:• Adequate hydration• Anti-hyperuricemia therapy
(allopurinol, rasburicase)• Laboratory monitoring (depending
on the risk group)
Venetoclax Prescribing Information Abbvie Inc & Genetech Inc, April 2016
Ramp-up
Week 1 Week 2 Week 3 Week 4 Fromweek 5
20 mg 50 mg100 mg
200 mg
400 mg
Lymph node ≤5 cm + lymphocyte count
<25 × 109/l
Lymph node ≥5 cm, but <10 cm
orlymphocyte count
>25 × 109/l
Lymph node ≥10 cmor
Lymph node ≥5 cm +Lymphocyte count
>25 × 109/l
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Restaging
Patient achieved partial response
FBP 26.03.2016:
HB 135.2 g/l (130-160)RBC 4.9 × 1012/L (4.0-5.0)Platelets 90 × 109/l (180-320)WBC 4.8 × 109/l (4.0-9.0)Neu 2.66 × 109/l (2.0-5.8)Lymph 1.68 ×109/l (1.2-3.2)
CT 27.03.2018• Lymphadenopathy regressed
>50%• Residual solitary enlarged
lymph nodes in abdomen and pelvis:• Right axillar 19 × 10 mm• Bifurcation 21 × 7 mm• Right iliac 15 × 19 mm
Examination: axillar lymph nodes 2 × 1.5 cm, liver and spleen not enlarged
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Complete blood count 31.05.2018
Haemoglobin 135 g/l (130-168)
RBC 4.39 × 1012/l (4.0-5.0)
Haematocrit 36.9% (40-48)
Platelets 130 × 109/l (150-400)
WBC 7.1 × 109/l (4.0-9.0)
Relative Absolute
Neutrophils 50 % (45 - 72) 3.55 × 109/l (2 - 5.5)
Eosinophils 0.1 % (0 - 5) 0.01 × 109/l (0 - 0.3)
Basophils 0.6 % (0 - 1) 0.04 × 109/l (0 - 0.1)
Monocytes 23.6 % (3 - 11) 1.68 × 109/l (0.1 - 0.7)
Lymphocytes 25.7 % (19 - 37) 1.82 × 109/l (1.20 - 3.2)
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Restaging – March, 2019(16 months of therapy)
‒ Myelogram – lymphocytes 9.5%
‒ Bone marrow immunophenotyping – MRD not detected
‒ CT – right axillar lymph node 23 × 14 mm, periportal lymph node 22 ×7 mm
‒ At palpation – no lymph nodes detected
‒ Patient remains MRD-negative: partial response (lymph nodes >1.5 cm)