EHA-RSH-ROHS Tutorial on "Real world challenges and opportunities in

diagnostics and management of onco-hematological patients today"

Lali Babicheva

Russian Medical Academy for Postgraduate Education

Moscow, Russia

April 12-13, 2019

RSH

Clinical case 1

Follicular lymphoma, Grade I. Stage IVA.

Early relapse.

‒ Female, 58 years, consulted her GP early 2016

‒ Complaints: fatigue, discomfort in left hypochondrium, left sided chest pain, shortness of breath.

‒ At examination: left-sided pleuritis, generalized lymphadenopathy. Lymphoproliferative disease suspected.

‒ Consulted haematologist. In March 2016 biopsy of inguinal lymph node was performed.

‒ Comorbidities: essential hypertension stage 2

Histology (22.03.2016)

Diffuse proliferation of lymphoid elements with round moderately polymorphous nuclei and thin rim of cytoplasm. Morphological picture corresponds to lymphoproliferative disease.

Immunohistochemistry(IHC) is needed to define the diagnosis.

IHC (25.03.2016)

• CD20 pronounced diffuse cytoplasmatic expression in tumour cells

• CD10 pronounced diffuse membrane expression in tumour cells

• Bcl-6 pronounced diffuse nuclear expression in tumour cells

• Bcl-2 pronounced diffuse cytoplasmatic expression in tumour cells

• CD23 identifies the net of dendritic cells

• CD3, СD43, CD5, Cyclin D1 no expression in tumour cells

• Ki67 (%) positive in 10% of the tumour cells

Morphological and immunohistochemical pattern corresponds to follicular lymphoma grade 1 with diffuse-follicular growth.

Workup (24.03.2016)

FBP: Нb 123 g/l, RBC 4.3 × 1012/l, WBC 3.29 × 109/l, Platelets95 × 109/l, ESR 2 mm/h, banded neutrophils 10%, segmented neutrophils 55%, lymphocytes 20%, monocytes 11%, basophil 0%, eosinophil 4%.

Biochemistry: glucose 5.12 mmol/l, urea 5.18 mmol/l, creatinine 84.5 µmol/l, uric acid 291 µmol/l, total protein 60.16 g/l, albumin 41.64 g/l, bilirubin 14.85 µmol/l, ALT12.94 U/l, AST 22.28 U/l, LDH 202 U/l, alkaline phosphatase 75.72 U/l.

Urine: no abnormality

PET Scan 29.03.2016

On the series of tomograms – multiple hypermetabolic lesions in cervical, submaxillary, axillar, inguinal, retroperitoneal, iliac lymph nodes, mediastinum. Diffuse and focal uptake can be seen in all bones.

SUV in pathological lesions up to 6.0.

Thoracic, abdominal, and pelvic CT (contrast) 31.03.16

Generalized involvement of lymph nodes on both sides of diaphragm (the largest: right axillar – up to 3.7 × 2.5 cm, periportal – up to 3 × 1.5 cm, conglomerate around main abdominal vessels – up to 12.5 × 8 cm, in mesocolon – up to 7.5 × 4.5 cm, iliac lymph nodes 8.5 × 4.5 cm, inguinal lymph nodes – up to 5 × 3.5 cm)

Left-sided pleural effusion (layer up to 7 cm). Liver is moderately enlarged, with low density lesions in С4 and С2: 1.3; 1.2, and 0.8 cm.

Tumour lesion in the projection of the tail of pancreas, 4.5 cm in diameter, not differentiated from the pancreatic tissue.

Structure of L5 vertebra is non-homogeneous due to low density areas surrounded by a rim of sclerosis. Structure of vertebrae and ribs is vague.

Diagnosis in 2016

Follicular lymphoma, grade 1, with generalized involvement of lymph nodes on both sides of

diaphragm (bulky), bones, liver, pancreas, pleura. Left-sided pleuritis.

Stage IVА.

Treatment

First line:

• April – December, 2016 – 9 cycles of R-CHOP-21(with pegylated liposomal doxorubicin) with growing efficacy, partial remission was achieved.

• December, 2016 – radiotherapy to residual conglomerate in abdomen 24-26 Gy.

• Patient then followed-up

• Rituximab maintenance was not given

Lymphadenopathy on continued follow-up

LN on CT(size in cm)

End of treatment(December 2016)

February 2017 May 2017

Right axillar 1.0 2.0 2.8

Right iliac 2.0 × 1.3 3.0 × 2.3 6.7 × 3.3

Right inguinal 1.5 3.0 × 2.3 6.5 × 3.3

Left inguinal 1.8 1.8 3.0 ×1.8

Relapse

Consulted in N.N. Blokhin National Medical Research Center of Oncology, Moscow

Diagnosis: first early relapse of follicular lymphoma, rituximab-refractory (<6 months), involving peripheral and abdominal lymph nodes, bone marrow. Stage IVA

Workup

FBP: 19.05.17: Нb 128 g/l, RBC 4.46 × 1012/l, platelets 98 × 109/l, WBC 1.76 × 109/l

Blood biochemistry 19.05.17: glucose 5.3 mmol/l, creatinine 76 µmol/l, uric acid 291 µmol/l, bilirubin 14.8 µmol/l, ALT 18.7 U/l, AST 24 U/l, LDH 271 U/l

19.05.2017 bone marrow biopsy – bone marrow involvement confirmed.

Myelogram: myelopoietic cells 18000/µL, blasts 1200/µL, lymphocytes 13200/µL. Sample is hypocellular. Megakaryocytes in sufficient quantity

Bone marrow trephine: paratrabecular hypercellular foci with signs of “delicate” sclerosis: residual tumor?

CT 12.05.2017

• Small mediastinal lymph nodes up to 1.0 cm – no changes;

• Right axillar lymph node – increased up to 2.8 cm;

• The conglomerate around main abdominal vessels 7 × 4 cm – no change.

• Left iliac lymph node 2.5 cm – no change.

• Right iliac lymph node – increased up to 6.7 × 3.3 cm.

• Right inguinal lymph node – increased up to 6.5 × 3.3 cm.

• Left inguinal lymph node – 3 × 1.8 cm;

• Pararectal lymph node – 1.5 × 1.0 cm.

• Structure of L5 vertebra is non-homogeneous.

Progression

Treatment of relapse

Second line therapy:

• 29.05.2017 – 15.11.2017: 1 cycle of bendamustinemonotherapy (120 mg/m2) + 5 cycles of obinutuzumab + bendamustine with increasing tumour response.

• Regimen:

• Obinutuzumab

• 1000 mg i.v. on days 1, 8, 15 – cycle 1

• 1000 mg i.v. on day 1 – following cycles

• Bendamustine 90 mg/m2 i.v. on days 2, 3

CT 20.12.2017 (after 6 cycles of therapy)Compared with 12.05.17:• Right axillar lymph node decreased from 2.8 to 1.3 cm.

• Para-aortal conglomerate 1.3 cm in width – no changes.

• Right iliac lymph nodes decreased from 5.5 × 4 cm to 3.5 × 2 cm

• Left iliac lymph nodes decreased from 2.5 × 2 cm to 2 × 1.6 cm.

• Inguinal lymph nodes decreased to 1 cm.

Partial remission

February and April, 2018 – 2 injections of obinutuzumab maintenance

May, 2018 – bilateral lower lobe pneumonia (treated with antibacterial and antifungal therapy).

CT: 23.05.2018: in S9 and S10 of left lung – lesions of inflammatory infiltration. Similar abnormalities in the inferior lobe of right lung.

Lymph nodes are not enlarged except for the para-aortal conglomerate that remains unchanged.

Complete remission

Did not continue obinutuzumab maintenance due to infectious complications.

CT 25.09.18 – infiltration in S5 and S6 of right lung. Lymph nodes are not enlarged.

Recurring pneumonia diagnosed. Patient remains in complete remission.

Immunoglobulins 11.10.18: IgA-0.61 g/l (0.7-4), IgG –5.96 g/l (7-16), IgM – 0.36 g/l (0.4-2.3).

Patient received antibacterial and antifungal therapy.

November 2018 – cough, fatigue, sore throat, low grade fever up to 37.4ᵒ.

Sputum culture with a tests for antibiotic sensitivity 08.12.2018: pseudomonas auriginosa, candidaglabrata, enterobacteraerogenes.

Immunoglobulins 07.11.18: IgA-0.63 g/l, IgM-0.33 g/l, IgG-5.4 g/l.

Treatment: cefiximum (third generation cephalosporin) 500 mg/day, micafungin 100 mg/day, anidulafungin

100 mg/day, immunoglobulin 3 mg/kg.

Follow-up 24.01.2019

Patient remains in complete remission

(no treatment since April, 2018)

Clinical case 2

Follicular lymphoma, grade I. Stage IVA.

Intolerance to rituximab.

Presentation

Male, 52 years

‒ October 2011 – enlargement of cervical lymph nodes.

‒ Ultrasonography, December 2011 –generalized lymphadenopathy.

‒ Lymphoproliferative disease suspected.

Workup(Department of tumor diagnostics, N.N. Blokhin National Medical

Research Center of Oncology, Moscow):

‒ ECOG-1.

‒ In right supraclavicular region – lymph node conglomerate 5 cm, axillar lymph nodes up to 3 cm. Liver +3 cm below the rib cage, spleen 12 × 8 cm.

‒ FBP 15.02.12: WBC – 2.64 × 109/l, Нb – 96 g/l, platelets – 96 × 109/l

‒ Blood biochemistry: no clinically relevant abnormalities (LDH – 335 U/l)

Workup(Department of tumor diagnostics, N.N. Blokhin National Medical

Research Center of Oncology)

CT 20.01.12:

‒ Enlarged frontal mediastinal lymph nodes up to 2 cm. In S1 and S3 of right lung – focus-like shadows 2 mm and 3 mm.

‒ Conglomerate of lymph nodes up to 10 × 7 cm – retroperitoneal, from diaphragm, down to distal parts of iliac vessels on both sides; the largest diameter – in the projection of the kidney pelvis (bulky). Conglomerates of portal lymph nodes, in mesocolon.

‒ Liver is enlarged: right lobe – 20 cm, left – 9 cm, in both lobes – contrasting defects 3.7 mm. Spleen is enlarged – 23 × 18 × 8.5 cm.

Ultrasound of peripheral lymph nodes:

‒ Supraclavicular right – 5 × 1.5 × 2 cm, left – 4.2 × 3.1 × 2 cm. Axilla right –5.6 × 2.6 × 4.7 cm, left – 7.2 × 6.7 × 3.6 cm. Small up to 2 cm cervical lymph nodes on both sides and left inguinal lymph nodes.

Axillar lymph node biopsy 30.01.12: follicular lymphoma grade 1 with follicular growth pattern.

IHC: antigens used: CD3,CD5,CD10,CD20,CD21,CD23,CD43,BCL2,BCL6,Ki67. Tumour cells express CD20, CD10 (weak discrete reaction), BCL-2, BCL-6. Ki67 - 5-7%. In tumour nodules CD21+, CD23+follicular dendritic cells are detected. T-lymphocytes CD3+, CD5+, CD43 are prevalent in layers between nodules.

Conclusion: follicular lymphoma grade 1 with nodular and diffuse growth pattern.

Bone marrow biopsy: bone marrow is hypercellular due to interstitial diffuse, paratrabecular growth of lymphoma (follicular grade 1).

Diagnosis

Follicular lymphoma, grade 1, involving mediastinal, abdominal, retroperitoneal (bulky) lymph nodes, liver,

spleen, lungs, bone marrow – stage IVA

Follicular lymphoma international prognostic index (FLIPI) – 3 (involved areas > 4, stage IV, anemia)

Treatment: 1st line

‒ Since 07.02.12 – 1st cycle of R-CVP

‒ Complications: 15 minutes after the start of the infusion of rituximab – anaphylactic reaction: acute respiratory failure, low blood pressure, faint. Duration of infusion was 10 hours.

‒ 26.03.12 – 2nd cycle of R-CVP: rituximab infusion was complicated with breath shortness and urticaria.

‒ April – August, 2012: 3-8 cycles of CVP chemotherapy. Due to anaphylactic reactions rituximab was not used.

Evaluation of response to 1st line therapy

‒ PET after cycle 6 of CVP: active residual tissue in left axillar, left iliac and both inguinal areas.

‒ Partial remission

‒ Additional 2 cycles of CVP administered (treatment finished on August 4, 2012)

‒ No rituximab maintenance was prescribed due to intolerance of rituximab

1st relapse after 1 year

‒ Ultrasonography 30.09.13: multiple enlarge peripheral lymph nodes:

• submaxillar left 2.1 × 1.0 cm, right 1.4 × 0.7 cm.

• cervical and supraclavicular on both sides up to 1.7 cm.

• subclavicular left 3.1 × 1.5 cm, right 1.5 × 1.2 × 2.0 cm.

• inguinal left 2.8 × 2.1 cm, right 1.9 × 1.0 cm.

• retroperitoneal up to 3.2 × 1.6 cm.

• iliac left 6.0 × 3.1 cm, right 3.3 × 2.3 cm.

• Splenomegaly 16.3 × 7.1 cm, with focal lesions.

• Portal lymph nodes merge into a conglomerate 6.2 × 4.0 cm.

2nd line treatment‒ October, 2013 – 2nd line treatment – bendamustine monotherapy

120 mg/m2 on days 1-2

• AEs: thrombocytopenia, grade 3 leukopenia. Interval increased for 3 weeks.

‒ On 21.11 13 and 27.12.13 – 2nd and 3rd cycles of bendamustinemonotherapy. AEs – prolonged grade 2 thrombocytopenia and grade 3 leukopenia.

‒ From 05.02.14 till 17.04.14 - cycles 4-6 – ВР (bendamustine + prednisolone)

‒ Ultrasonography 21.04.14: singular cervical and subclavian lymph nodes up to 0.9 cm, blurry, flat.

After 3 years (June, 2017) – 2nd late relapse of FL, involving all groups of peripheral, abdominal, retroperitoneal lymph nodes, spleen, bone

marrow.

After 3 years (June, 2017) – 2nd late relapse of FL, involving all groups of peripheral, abdominal, retroperitoneal lymph nodes, spleen, bone marrow. FLIPI2 = 4

• B-symptoms, lymph node enlargement

• FBP: WBC 10.0 × 109/l, Hb 152 g/l, platelets 78 × 109/l, neutrophils 95.6%, lymphocytes 2.1%, monocytes 1.9%, eosinophils 0.1.

• Biochemistry: LDH 350 U/l, creatinine 108 µmol/l, ALT 8 U/l AST 24 U/l, alkaline phosphatase 41 U/l.

• Bone marrow biopsy: nodular infiltration

• β2-microglobulin: 4.5 mg/l

3rd line of therapy

From 05.06.17 to 10.10.17 – 6 cycles of G-CHOP (the first cycle was complicated with grade 4 thrombocytopenia, grade 4 neutropenia; from cycle 2 patient received secondary prophylaxis with G-CSF )

‒ Obinutuzumab:

• Cycle 1: 1000 mg i.v. on day 1 (infusion in 2 days: 100 mg on day 1 and 900 mg on day 2), 8, 15

• Cycles 2-6: 1000 mg i.v. on day 1

‒ Doxorubicin 50 mg/m2 i.v. on day 1

‒ Cyclophosphamide 750 mg/m2 i.v. on day 1

‒ Vincristine 1.4 mg/m2 (not more than 2 mg) i.v. on day 1

‒ Prednisolone 100 mg p.o. on days 1-5

25.05.2017

23.01.2018

After 4 cycles – complete PET-negative remission, which continues

Last visit28.03.2019 –

remains in remission