team 1 - rigshospitalet...venetoclax 20 mg, dag 1-7 0 venetoclax 50 mg, dag 8-14 0 venetoclax 100...

Hæmatologisk Team 1

NAVN: CPR: VIsion/HO141

ALLE Patientnummer _______________

BEHANDLINGS- OG UNDERSØGELSESSKEMA

SERIE (1 serie 4 uger/28 dage) 1 2 3 4 Dag 1 1 1 8 15 22 28 1 BEHANDLING Ibrutinib 420 mg, dag 1-28 0 011 0 0 0 0 0 0 Venetoclax 20 mg, dag 1-7 0 Venetoclax 50 mg, dag 8-14 0 Venetoclax 100 mg, dag 15-21 0 Venetoclax 200 mg, dag 22-28 0 Venetoclax 400 mg, dag 1-28 0 0 UNDERSØGELSER Anamnese/medical history 0 0 0 0 Objektiv undersøgelse 0 0 0 0 AE’er 0 0 0 0 TLS risiko vurdering1 01

Responsevaluering4 0 Livskvalitetsskema (QOL)(PET)-CT scan2 03 Knoglemarv aspirat og biopsi MRD Flowcytometri KM BLODPRØVER Hæmatologi7 0 0 0 0 0 0 0 0 Biokemi8 0 0 0 0 0 0 0 0 MRD Flowcytometri blod10

PROJEKTPRØVER Blodprøver 0 0 0 0

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SERIE (1 serie 4 uger/28 dage) 5 6 7 8 9 10 11 12

Dag 1 1 1 1 1 1 1 1 BEHANDLING Ibrutinib 420 mg, dag 1-28 0 0 0 0 0 0 0 0 Venetoclax 400 mg, dag 1-28 0 0 0 0 0 0 0 0 UNDERSØGELSER Anamnese/medical history 0 0 0 0 0 0 0 0 Objektiv undersøgelse 0 0 0 0 0 0 0 0 AE’er 0 0 0 0 0 0 0 0 TLS risiko vurdering1 Responsevaluering4 0 0 Livskvalitetsskema (QOL) (PET)-CT scan2

Knoglemarv aspirat og biopsi MRD Flowcytometri KM BLODPRØVER Hæmatologi7 0 0 0 0 0 0 0 0 Biokemi8 0 0 0 0 0 0 0 0 MRD Flowcytometri blod10 0 PROJEKTPRØVER Blodprøver 0 Knoglemarv






SERIE (1 serie 4 uger/28 dage)

13 14 155

• PB MRDpos efter serie 12 og/eller serie 15 – patienten fortsætterIbrutinib indtil progression/relaps (Arm A)

• PB MRDneg efter serie 12 OG PB og BM MRD neg efter serie 15randomisering mellem Arm A og Arm B (1:2). Arm A er Ibrutinibindtil progression/relaps. Arm B er observation indtil ”event”.

Dag 1 1 1 BEHANDLING Ibrutinib 420 mg, dag 1-28 0 0 0 Venetoclax 400 mg, dag 1-28 0 0 0 UNDERSØGELSER Anamnese/medical history 0 0 0 Objektiv undersøgelse 0 0 0 AE’er 0 0 0 TLS risiko vurdering1 Responsevaluering4 0 06

Livskvalitetsskema (QOL) 06 (PET)-CT scan2 0 Knoglemarv aspirat og biopsi 06+9

MRD Flowcytometri KM 06 BLODPRØVER Hæmatologi7 0 0 0 Biokemi8 0 0 0 MRD Flowcytometri blod10 0 06

PROJEKTPRØVER Blodprøver 0 06 Knoglemarv 06






1: TLS risikovurdering slutning af serie 2.

Risk categories for development of tumor lysis syndrome (TLS) Based on review of all currently available data, three risk categories for developing TLS were defined including the size of the enlarged lymph nodes and the absolute lymphocyte count (ALC). In addition, the creatinine-clearance (CrCl) of the patient needs to be taken into account by the investigator (see below).

The following risk categories were defined:

Low Risk Medium Risk High Risk

Lymph Nodes All measurable lymph nodes with the largest diameter <5 cm by radiographic

assessment

Presence of any single measurable lymph

node with the largest diameter

≥5 cm and <10 cm by radiologic assessment

A single measurable lymph

node with the largest diameter ≥5 cm by radiologic

assessment.

Any single measurable lymph

node with the largest diameter

≥10 cm by radiologic assessment

AND OR AND Absolute lymphocyte Count (ALC)

< 25 × 109/L ≥ 25 × 109/L ≥ 25 × 109/L

All patients enrolled in the trial will be assessed at screening and categorized based on their tumor burden, as described above. A repetition of imaging for evaluation of lymph node size before the administration of the first dosage of venetoclax is required for patients with high risk or CrCL 30-50ml/min. Patients can be restaged into a






lower TLS risk group at any time according to their ALC or repetition of imaging. Imaging is due to the investigator´s discretion; ultrasound may be accepted in case of clear results.

Please note: Patients with CrCl < 80 ml/min should be monitored very closely for signs of TLS, especially if they are in the intermediate or high risk TLS risk category (lymph node ≥ 5 and/or ALC ≥ 25× 109/L). Patients with CrCl 30-50 ml/min should be handled as high risk patients.

2: PET kun ved mistanke om transformation.

3: CT scan efter cyklus 2 hos patienter i høj risiko TLS eller med CrCl 30-50 ml/min

4: Response criteria

Response assessment will be based on the revised guidelines of the international workshop on CLL (IWCLL); these are as follows (see table on the next page) – a separate manual will be supplied to indicate the exact response assessment guidelines.

Complete remission (CR)1 : All below listed criteria must be fulfilled and no disease related symptoms should be present.

Complete remission with incomplete recovery of the bone marrow (CRi)1: All below listed criteria must be fulfilled, except for an incomplete recovery of the bone marrow with persisting anemia, thrombocytopenia and/or neutropenia (related to toxicity of treatment and not due to CLL) and no disease related symptoms should be present.

Partial response (PR):






Among the below listed criteria at least 2 from group A and 1 from group B must be fulfilled.

PR lymphocytosis: PR without a 50% decrease in blood lymphocytes

Stable disease (SD): Failure to achieve a PR and absence of PD.

Progressive disease (PD): Presence of at least 1 of the below enlisted criteria or appearance of new lymph nodes >1.5cm, hepato- or splenomegaly or organ infiltration by CLL.

Relapse: progressive disease more than 6 months after PR/CR was reached.

1 A clinical CR/CRi fulfills the same criteria as a CR or CRi but was not (yet) confirmed with a bone marrow examination. Parameter CR Cri PR PD Group A (indicating tumor load) Lymphadenopathy1 none >1.5cm decrease ≥50% increase by ≥50% or new

lymph nodes ≥1.5cm Hepatomegaly None decrease ≥50% increase by ≥50% Splenomegaly None decrease ≥50% increase by ≥50% Blood lymphocytes <4000/µl decrease of ≥50% from

baseline increase by ≥50% over baseline to ≥5000/µl

Bone marrow normocellular

hypocellular 50% reduction in BM infiltrates2

irrelevant

<30% lymphocytes, no B-lymphoid nodules

Group B (indicating function of the hematopoietic system)






Platelet count ≥100000/µl Irrelevant ≥100000/µl or increase by ≥50% from baseline

decrease by ≥50% due to CLL

Hemoglobin >11g/dl Irrelevant >11g/dl or increase by ≥50% from baseline

decrease by > 2g/dl

Neutrophil count >1500/ml Irrelevant >1500/ml or increase by ≥50% from baseline

1 Assessed as sum of the products of multiple lymph nodes, if available an indicator lymph node (the largest palpable) from every region should be compared in every staging. 2 In case of B-lymphoid nodules a 4-colour-flow cytometry is recommended to clarify if this is related to CLL, if flow cytometry is negative these patients can be rated as CR/CRi, if all other criteria are fulfilled

5: Efter cyklus 15, konsultation og medicin udlevering hver 3. mdr.

6: Slutningen af cyklus

7: Leukocytter (LEU), Hemoglobin (HB), Leucocytter diff. (DIFFMAS), Trombocytter (THROM)

8: Kreatinin (CREA), Bicarbonat (HCO3), Haptoglobin (…..), ASAT (ASAT), ALAT(ALAT), Bilirubin(BILI), LDH (LDH), Natrium (NA), Kalium (K), Calcium (CA), Fosfat (PHOS), Klodrid (CL), Urat (URAT), Total bilirubin (BILIFR), Basisk fosfatase (BASP), Carbamid (CARB).

9: BM only if necessary to define progressive disease and for MRD

10: Hvis patienten er MRD positive, skal der foreligge en ny prøve en måned senere.

11: Lige før start på T. Venetoclax skal pt. starte allopurinol mhp. Minimering af TLS




Arm A, OBSERVATION Patientnummer _______________


CYKLUS (1 cyklus 4 uger/28 dage)

18 21 24 27 30 33 36 391

Dag 1 1 1 1 1 1 1 1 UNDERSØGELSER Anamnese/medical history 0 0 0 0 0 0 0 0 Objektiv undersøgelse 0 0 0 0 0 0 0 0 AE’er 0 0 0 0 0 0 0 0 Responsevaluering5 0 Livskvalitetsskema (QOL) 0 0 (PET)-CT scan4 0 Knoglemarv aspirat og biopsi 08 MRD Flowcytometri KM 0 BLODPRØVER Hæmatologi6 0 0 0 0 0 0 0 0 Biokemi7 0 0 0 0 0 0 0 0 MRD Flowcytometri blod9 0 0 0 0 0 0 0 0 Flowcytometri PB (eller BM hvis PB not done) FISH/CGH og NGS PB 0 PROJEKTPRØVER Blodprøver 0 0 0 0 0 0 0 0 Knoglemarv 0

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CYKLUS (1 cyklus 4 uger/28 dage) 43 47 51 57 63 69 75 812

Dag 1 1 1 1 1 1 1 1 UNDERSØGELSER Anamnese/medical history 0 0 0 0 0 0 0 0 Objektiv undersøgelse 0 0 0 0 0 0 0 0 AE’er 0 0 0 0 0 0 0 0 Responsevaluering5 Livskvalitetsskema (QOL) 0 (PET)-CT scan4

Knoglemarv aspirat og biopsiMRD Flowcytometri KM BLODPRØVER Hæmatologi6 0 0 0 0 0 0 0 0 Biokemi7 0 0 0 0 0 0 0 0 MRD Flowcytometri blod9 0 0 0 0 0 0 0 0 Flowcytometri PB (eller BM hvis PB not done) FISH/CGH og NGS PB PROJEKTPRØVER Blodprøver 0 0 0 0 0 0 0 0 Knoglemarv







87 93 99 105 111 117 1233 Progression

Dag 1 1 1 1 1 1 1 1 UNDERSØGELSER Anamnese/medical history 0 0 0 0 0 0 0 0 Objektiv undersøgelse 0 0 0 0 0 0 0 0 AE’er 0 0 0 0 0 0 0 0 Responsevaluering5 0 Livskvalitetsskema (QOL) (PET)-CT scan4 0 Knoglemarv aspirat og biopsi 08 MRD Flowcytometri KM BLODPRØVER Hæmatologi6 0 0 0 0 0 0 0 0 Biokemi7 0 0 0 0 0 0 0 MRD Flowcytometri blod9 0 0 0 0 0 0 0 Flowcytometri PB (eller BM hvis PB not done) 0

FISH/CGH og NGS PB 0 PROJEKTPRØVER Blodprøver 0 0 0 0 0 0 0 0 Knoglemarv 0 Lymfeknude 010






1: Efter cyklus 39 konsultation hver 4. måned indtil måned 51

2: Hver 6. mdr. indtil 7 år efter registrering eller progression.

3: Fortsætter hver 6. måned indtil 7 år efter registrering eller progression






Partial response (PR): Among the below listed criteria at least 2 from group A and 1 from group B must be fulfilled.



Progressive disease (PD):






Presence of at least 1 of the below enlisted criteria or appearance of new lymph nodes >1.5cm, hepato- or splenomegaly or organ infiltration by CLL.


1 A clinical CR/CRi fulfills the same criteria as a CR or CRi but was not (yet) confirmed with a bone marrow examination.

Parameter CR Cri PR PD Group A (indicating tumor load) Lymphadenopathy1 none >1.5cm decrease ≥50% increase by ≥50% or new





irrelevant


Group B (indicating function of the hematopoietic system) Platelet count ≥100000/µl Irrelevant ≥100000/µl or increase

by ≥50% from baseline decrease by ≥50% due to CLL


decrease by > 2g/dl


1 Assessed as sum of the products of multiple lymph nodes, if available an indicator lymph node (the largest palpable) from every region should be compared in every staging. 2 In case of B-lymphoid nodules a 4-colour-flow cytometry is recommended to clarify if this is related to CLL, if flow cytometry






is negative these patients can be rated as CR/CRi, if all other criteria are fulfilled



8: BM only if necessary to define progressive disease and for MRD


10: Kun hvis der tages en lymfeknude biopsi




Arm B Patientnummer _______________



18 21 24 27 30 33 36 391

Dag 1 1 1 1 1 1 1 1 BEHANDLING Ibrutinib 420 mg, dag 1-28 0 0 0 0 0 0 0 0 UNDERSØGELSER Anamnese/medical history 0 0 0 0 0 0 0 0 Objektiv undersøgelse 0 0 0 0 0 0 0 0 AE’er 0 0 0 0 0 0 0 0 Responsevaluering5 0 Livskvalitetsskema (QOL) 0 0 (PET)-CT scan4 0 Knoglemarv aspirat og biopsi 08 MRD Flowcytometri KM 0 BLODPRØVER Hæmatologi6 0 0 0 0 0 0 0 0 Biokemi7 0 0 0 0 0 0 0 0 MRD Flowcytometri blod9 0 0 0 0 0 0 0 0 Flowcytometri PB (eller BM hvis PB not done) FISH/CGH og NGS PB 0 PROJEKTPRØVER Blodprøver 0 0 0 0 0 0 0 0 Knoglemarv 0

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43 47 51 57 63 69 75 812

Dag 1 1 1 1 1 1 1 1 BEHANDLING Ibrutinib 420 mg, dag 1-28 0 0 0 0 0 0 0 0 UNDERSØGELSER Anamnese/medical history 0 0 0 0 0 0 0 0 Objektiv undersøgelse 0 0 0 0 0 0 0 0 AE’er 0 0 0 0 0 0 0 0 Responsevaluering5 Livskvalitetsskema (QOL) 0 (PET)-CT scan4

Knoglemarv aspirat og biopsiMRD Flowcytometri KM BLODPRØVER Hæmatologi6 0 0 0 0 0 0 0 0 Biokemi7 0 0 0 0 0 0 0 0 MRD Flowcytometri blod9 0 0 0 0 0 0 0 0 Flowcytometri PB (eller BM hvis PB not done) FISH/CGH og NGS PB PROJETKPRØVER Blodprøver 0 0 0 0 0 0 0 0 Knoglemarv







87 93 99 105 111 117 1233 Progression

Dag 1 1 1 1 1 1 1 1 BEHANDLING Ibrutinib 420 mg, dag 1-28 0 0 0 0 0 0 0 0 UNDERSØGELSER Anamnese/medical history 0 0 0 0 0 0 0 0 Objektiv undersøgelse 0 0 0 0 0 0 0 0 AE’er 0 0 0 0 0 0 0 0 Responsevaluering5 0 Livskvalitetsskema (QOL) (PET)-CT scan4 0 Knoglemarv aspirat og biopsi 08 MRD Flowcytometri KM BLODPRØVER Hæmatologi6 0 0 0 0 0 0 0 0 Biokemi7 0 0 0 0 0 0 0 MRD Flowcytometri blod9 0 0 0 0 0 0 0 0 Flowcytometri PB (eller BM hvis PB not done) 0

FISH/CGH og NGS PB 0 PROJEKTPRØVER Blodprøver 0 0 0 0 0 0 0 0 Knoglemarv 0 Lymfeknude 010






1:Efter cyklus 39 konsultation og medicinudlevering hver 4. måned indtil måned 51

2: Hver 6. mdr. indtil 7 år efter registrering eller progression.

3: Fortsætter hver 6. måned indtil 7 år efter registrering eller progression.






Partial response (PR): Among the below listed criteria at least 2 from group A and 1 from group B must be fulfilled.








Progressive disease (PD): Presence of at least 1 of the below enlisted criteria or appearance of new lymph nodes >1.5cm, hepato- or splenomegaly or organ infiltration by CLL.


1 A clinical CR/CRi fulfills the same criteria as a CR or CRi but was not (yet) confirmed with a bone marrow examination. Parameter CR Cri PR PD Group A (indicating tumor load) Lymphadenopathy1 none >1.5cm decrease ≥50% increase by ≥50% or new





irrelevant


Group B (indicating function of the hematopoietic system) Platelet count ≥100000/µl Irrelevant ≥100000/µl or increase

by ≥50% from baseline decrease by ≥50% due to CLL


decrease by > 2g/dl







1 Assessed as sum of the products of multiple lymph nodes, if available an indicator lymph node (the largest palpable) from every region should be compared in every staging. 2 In case of B-lymphoid nodules a 4-colour-flow cytometry is recommended to clarify if this is related to CLL, if flow cytometry is negative these patients can be rated as CR/CRi, if all other criteria are fulfilled



8: BM only nif necessary to define progressive disease and for MRD


10: Kun hvis der tages en lymfeknude biopsi


team 1 - rigshospitalet...venetoclax 20 mg, dag 1-7 0 venetoclax 50 mg, dag 8-14 0 venetoclax 100...

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