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

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.

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

?

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

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

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

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

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

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

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

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

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

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

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

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%

↓

↓

↓

Rituximab

Rituximab

Rituximab

↓ ↓

↓IVIg

IVIg

IVIg

Haemoglobin changes during therapy

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

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

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

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)

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)