Synthetic educational example. Do not self-treat: a qualified treating physician must verify the sources, patient data, contraindications, and final plan.
Patient
CLL-2L-VENR-MURANO-001 · Algorithm: ALGO-CLL-2L
Clinical significance of mutations (ESCAT)
Tumor-board context — the engine does not use these tiers to rank tracks
| Biomarker | Variant | ESCAT | Evidence | Clinical significance | Drugs | Sources |
|---|
| No clinically actionable variants matched in this profile. |
| Biomarker | Status |
|---|
| BIO-CLL-HIGH-RISK-GENETICS | BIO definition in KB; no ESCAT BMA entry — verify with clinician |
| BIO-CD20-IHC | BIO definition in KB; no ESCAT BMA entry — verify with clinician |
| BIO-CD5-IHC | BIO definition in KB; no ESCAT BMA entry — verify with clinician |
| BIO-CD23-IHC | BIO definition in KB; no ESCAT BMA entry — verify with clinician |
| BIO-NOTCH1-MUTATION | BIO definition in KB; no ESCAT BMA entry — verify with clinician |
Primary current-line option
- Indication
- IND-CLL-2L-VENR-MURANO
- Regimen
- Venetoclax + Rituximab (VenR), 24-month fixed-duration (MURANO schedule)
- Drugs + NSZU
- Venetoclax (DRUG-VENETOCLAX) 5-week ramp-up cycle 1: 20 → 50 → 100 → 200 → 400 mg PO daily (week 1-5); then 400 mg PO daily continuous for total 24 months from start of full dose
· PO daily, total 24 months therapy · PO ✓ NSZU covered
- Rituximab (DRUG-RITUXIMAB) 375 mg/m² (cycle 1) then 500 mg/m² (cycles 2-6) · IV day 1 of each 28-day cycle for 6 cycles total (start after venetoclax ramp completed) · IV ⚠ NSZU — not for this indication
- Allopurinol (DRUG-ALLOPURINOL) 300 mg PO daily · Start 72h before venetoclax ramp; continue ≥1 week after reaching 400 mg · PO ⚠ NSZU — not for this indication
- Supportive care
- SUP-TLS-PROPHYLAXIS, SUP-PJP-PROPHYLAXIS
- Hard contraindications
- CI-HBV-NO-PROPHYLAXIS
- Reason
- Primary current-line option selected by ALGO-CLL-2L at step 2; branch-driving red flag: RF-PRIOR-BTKI-PROGRESSION.
Other current-line alternatives (2 tracks)
Same treatment line; review when biomarker, access, contraindication, or patient-context assumptions change.
- Indication
- IND-CLL-1L-ZANUBRUTINIB
- Regimen
- Zanubrutinib monotherapy (continuous, ALPINE-style)
- Drugs + NSZU
- Zanubrutinib (DRUG-ZANUBRUTINIB) 160 mg PO twice daily OR 320 mg PO once daily · Continuous until progression or unacceptable toxicity · PO ⚠ NSZU — not for this indication
- Reason
- Current-line alternative presented for HCP consideration
- Indication
- IND-CLL-3L-PIRTOBRUTINIB
- Regimen
- Pirtobrutinib monotherapy (continuous, BRUIN schedule)
- Drugs + NSZU
- Pirtobrutinib (DRUG-PIRTOBRUTINIB) 200 mg PO once daily · Continuous until progression or unacceptable toxicity · PO ✗ Not registered in UA
- Reason
- Current-line alternative presented for HCP consideration
Why this branch was chosen
Triggers from the patient profile that fired and drove the chosen branch.
Step 2 → branch IND-CLL-2L-VENR-MURANO
- RF-PRIOR-BTKI-PROGRESSION ★ winner: Progression on covalent BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib). Triggers selection of non-covalent BTKi (pirtobrutinib), BCL2i (venetoclax-based regimens), CAR-T (lisocabtagene maraleucel, brexucabtagene autoleucel), or PI3Ki — depending on disease (CLL, MCL, WM). Resistance often driven by BTK C481S or PLCG2 mutation.
SRC-NCCN-BCELL-2025SRC-ESMO-CLL-2024
Pre-treatment investigations
Investigations before treatment start · critical / standard / desired · merged across tracks
| ID | Name | Priority | Category | Where to order | Needed for |
|---|
| TEST-CBC | Complete Blood Count with Differential | Critical | lab | — | all tracks |
| TEST-CECT-CAP | CECT chest/abdomen/pelvis | Critical | imaging | — | all tracks |
| TEST-CMP | Comprehensive Metabolic Panel | Critical | lab | — | all tracks |
| TEST-FISH-PANEL | FISH (Fluorescence In Situ Hybridization) | Critical | genomic | CSD Lab ✓ (code TBC) | all tracks |
| TEST-HBV-SEROLOGY | Hepatitis B Serology Panel (HBsAg, anti-HBc total, anti-HBs) | Critical | lab | — | all tracks |
| TEST-HCV-ANTIBODY | HCV Antibody | Critical | lab | — | all tracks |
| TEST-HIV-SEROLOGY | HIV Antibody/Antigen | Critical | lab | — | all tracks |
| TEST-LDH | Lactate Dehydrogenase | Critical | lab | — | all tracks |
| TEST-LFT | Liver Function Tests (ALT, AST, bilirubin, ALP, GGT, albumin) | Critical | lab | — | all tracks |
| TEST-B2-MICROGLOBULIN | Beta-2 Microglobulin | Standard | lab | — | all tracks |
| TEST-ECHO | Echocardiography | Standard | imaging | — | all tracks |
| TEST-IMMUNOGLOBULINS | Quantitative Immunoglobulins | Standard | lab | — | all tracks |
| TEST-URIC-ACID | Serum Uric Acid | Standard | lab | — | standard |
| TEST-NGS-LYMPHOID-PANEL | Lymphoid NGS Panel | Desired | genomic | CSD Lab ✓ (code TBC) | all tracks |
Red flags — PRO / CONTRA aggressive
PRO-AGGRESSIVE
Triggers that push toward the aggressive track
- CLL with acquired BTK C481S (rarely C481R/F/Y) mutation after progression on covalent BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib). C481S abolishes covalent binding of cBTKi to BTK; non-covalent BTKi (pirtobrutinib) retains activity (BRUIN, Mato Lancet 2021; pirtobrutinib in cBTKi-pretreated CLL ORR 82%, mPFS 19.6 mo). Routes 2L+/3L+ post-cBTKi CLL with confirmed C481-axis resistance to pirtobrutinib over chemoimmunotherapy or alloHCT.
Distinguish from RF-PRIOR-BTKI-PROGRESSION (universal, broad) — that flag fires on any cBTKi PD; this flag is mutation-confirmed C481S resistance, the canonical mechanism of acquired cBTKi resistance (~80% of CLL patients with progressive…
RF-CLL-POST-BTKI-C481-ACTIONABLESRC-NCCN-BCELL-2025SRC-ESMO-CLL-2024 - CLL with clinical / biochemical features concerning for Richter transformation (to DLBCL or rarely Hodgkin variant): rapid LDH rise, asymmetric / rapidly enlarging nodal or extranodal mass, PET-CT SUVmax >10, B-symptoms in previously asymptomatic patient, or hypercalcemia. Mandates urgent excisional biopsy of PET-avid lesion.
Richter transformation occurs in 5-10% CLL lifetime risk; clonally related to underlying CLL ~80% (poor prognosis, median OS <12 mo on R-CHOP) vs clonally unrelated ~20% (de novo DLBCL biology, R-CHOP curable). PET-CT SUVmax >10 has ~70%…
RF-CLL-TRANSFORMATION-PROGRESSIONSRC-NCCN-BCELL-2025SRC-ESMO-CLL-2024
CONTRA-AGGRESSIVE
Hard contraindications to escalation
What NOT to do
Explicit prohibitive rules, each grounded in a regimen / supportive care / contraindication entity
Standard plan (IND-CLL-2L-VENR-MURANO)
- Do NOT skip the venetoclax 5-week ramp-up — fatal TLS documented.
- Do NOT prescribe with concomitant strong CYP3A4 inhibitor during ramp-up — fatal concentration increase.
- Do NOT start without HBV screening + entecavir prophylaxis if HBsAg+ or anti-HBc+ (anti-CD20 reactivation).
- Do NOT skip TLS prophylaxis (allopurinol + hydration) — especially with ALC >25K or bulky disease.
- Do NOT do ramp-up on an outpatient with high-burden disease — hospitalization with q6-8h labs required.
- Do NOT forget PJP prophylaxis on prolonged therapy.
- Do NOT use in prior BCL2i resistance — low efficacy; consider pirtobrutinib or CAR-T.
Standard plan (IND-CLL-1L-ZANUBRUTINIB)
- Do not prescribe ibrutinib instead of zanubrutinib without justification — ALPINE / ELEVATE-RR showed better safety of 2nd-gen BTKis.
- Do not skip baseline ECG + cardiology evaluation in atrial fibrillation history or HTN.
- Do not combine with warfarin without strict monitoring — bleeding risk (although lower than ibrutinib).
- Do not treat asymptomatic CLL without iwCLL indication — surveillance is the standard.
- Do not prescribe chemoimmuno (FCR / BR) in TP53-mut or del(17p) — survival impact substantial; BTKi is mandatory.
- Do not skip hold ≥3-7 days pre-major surgery — bleeding risk.
- Do NOT confirm the plan without funding pathway — zanubrutinib is NOT NSZU-reimbursed; ibrutinib (reimbursed) is fallback.
Aggressive plan (IND-CLL-3L-PIRTOBRUTINIB)
- Do NOT prescribe without verified prior cBTKi exposure — Cat 2A indication restricts use to post-cBTKi setting.
- Do NOT use in non-resistant 1L scenarios — slot for resistant disease only.
- Do NOT skip baseline ECG + cardiology evaluation — afib reduced but possible.
- Do NOT combine with anticoagulants without strict monitoring — bleeding risk persists.
- Do NOT prescribe with concomitant strong CYP3A4 inhibitor without dose reduction.
- Do NOT confirm the plan without funding pathway — drug not registered in Ukraine.
- Do NOT discontinue for transient AE without reassessment — for C481-mutated/TP53-mutated patients alternatives are few.
Monitoring schedule
Monitoring schedule by treatment phase
Standard plan · MON-CLL-BTKI
| Phase | Window | Tests | Checkpoints |
|---|
| Baseline | Within 2 weeks before start | TEST-CBC, TEST-CMP, TEST-LFT, TEST-LDH, TEST-B2-MICROGLOBULIN, TEST-FISH-PANEL, TEST-NGS-LYMPHOID-PANEL, TEST-IMMUNOGLOBULINS, TEST-HBV-SEROLOGY, TEST-HCV-ANTIBODY, TEST-HIV-SEROLOGY, TEST-CECT-CAP, TEST-ECHO | - Confirm CLL diagnosis: CD19+ CD5+ CD23+ flow on PB ≥5K monoclonal B-cells
- Risk stratification: del(17p), TP53, IGHV mutational status, karyotype
- iwCLL treatment indication documented (if asymptomatic — defer to surveillance)
- Cardiac baseline (atrial fibrillation history, hypertension control)
- HBV status + entecavir prophylaxis if HBsAg+ or anti-HBc+ (anti-CD20 in VenO regimen)
|
| On treatment (BTKi) | Monthly × 3 months, then every 3 months | TEST-CBC, TEST-CMP, TEST-LFT | - ALC trend (lymphocytosis early on BTKi is expected — not progression)
- Bleeding events; major bleed → hold BTKi
- AF symptoms → ECG; if AF → cardiology + anticoagulation strategy
|
| On treatment (venetoclax) | Per CLL14 schedule during 12-month VenO course | TEST-CBC, TEST-CMP, TEST-LFT, TEST-URIC-ACID | - TLS labs (K+, phosphate, calcium, uric acid, creatinine) per ramp-up schedule
- ANC + platelets pre each obinutuzumab dose
- Infusion reactions to obinutuzumab (especially first dose)
|
| Response assessment | After cycle 6 (VenO) or every 6 months on BTKi | TEST-CBC, TEST-CECT-CAP, TEST-FLOW-CYTOMETRY | - iwCLL response criteria (CR, PR, PR-L on BTKi, SD, PD)
- MRD assessment by flow on PB at end of VenO 12-month course
|
| Follow-up | Every 3-6 months after treatment / continuously on BTKi | TEST-CBC, TEST-CMP, TEST-LFT | - Surveillance for relapse (median PFS years for both regimens)
- Watch for Richter transformation (rapid LDH rise, new B-symptoms, isolated mass) — re-biopsy
- Second primary malignancy screening
|
Timeline
Treatment timeline — derived from regimen + monitoring schedule
Standard plan
Baseline
Within 2 weeks before start
Induction · Venetoclax + Rituximab (VenR), 24-month fixed-duration (MURANO schedule)
28-day cycles × 6 rituximab + 24 months total venetoclax
Response assessment
After cycle 6 (VenO) or every 6 months on BTKi
Follow-up
Every 3-6 months after treatment / continuously on BTKi
Standard plan
Baseline
Within 2 weeks before start
Induction · Zanubrutinib monotherapy (continuous, ALPINE-style)
28-day cycles × Continuous
Response assessment
After cycle 6 (VenO) or every 6 months on BTKi
Follow-up
Every 3-6 months after treatment / continuously on BTKi
Aggressive plan
Baseline
Within 2 weeks before start
Induction · Pirtobrutinib monotherapy (continuous, BRUIN schedule)
28-day cycles × Continuous
Response assessment
After cycle 6 (VenO) or every 6 months on BTKi
Follow-up
Every 3-6 months after treatment / continuously on BTKi
MDT brief
Discussion questions (1, 0 blocking)
MDT talk tree (3 steps)
| # | Owner | Topic | Action |
|---|
| 1 | hematologist | Staging / disease burden | What is the current LDH? Marker of tumor burden and transformation. |
| 2 | clinical_pharmacist | Specialist review | Chemoimmunotherapy regimen — drug-drug interactions, dose adjustments, premedication. |
| 3 | molecular_geneticist | Specialist review | Indication references an actionable genomic biomarker — mutation / target / actionability interpretation needed. |
Skills (recommended) — for consideration (2)
- Clinical pharmacist recommended
Chemoimmunotherapy regimen — drug-drug interactions, dose adjustments, premedication.
- Molecular geneticist / molecular oncologist recommended
Indication references an actionable genomic biomarker — mutation / target / actionability interpretation needed.
Data quality
Usable with caveats. No critical default-track gap was found, but the MDT should review the listed caveats before final sign-off.
- Biomarker coverage: 3/3 known (100%), 0 missing, 0 default-track gaps
- Unevaluated RedFlags: RF-BINET-A, RF-BINET-B-C, RF-CLL-FRAILTY-AGE, RF-CLL-HIGH-RISK, RF-CLL-INFECTION-SCREENING, RF-CLL-ORGAN-DYSFUNCTION, RF-CLL-POST-BTKI-C481-ACTIONABLE, RF-CLL-TP53-DELETION-ACTIONABLE, RF-CLL-TRANSFORMATION-PROGRESSION, RF-CLL-VEN-RESISTANT-ACTIONABLE, RF-RAI-HIGH, RF-RAI-LOW, RF-RICHTER-TRANSFORMATION
Technical MDT skill metadata (2/16 activated in this plan)
All registered virtual specialists. ✓ — activated for this case; ○ — not activated (available for other clinical scenarios).
| Specialist | skill_id | Version | Last reviewed | Sign-offs | Domain |
|---|
| Cellular therapy specialist (CAR-T) | cellular_therapy_specialist | v0.1.0 | 2026-04-25 | 0 | cellular_therapy |
| Clinical pharmacist | clinical_pharmacist | v0.1.0 | 2026-04-25 | 0 | clinical_pharmacy |
| Hematologist / oncohematologist | hematologist | v0.1.0 | 2026-04-25 | 0 | hematology_oncology |
| Hematopathologist (lymphoma / leukemia / myeloma) | hematopathologist | v0.1.0 | 2026-04-25 | 0 | hematopathology |
| Infectious disease / hepatology | infectious_disease_hepatology | v0.1.0 | 2026-04-25 | 0 | infectious_diseases |
| Medical oncologist (solid-tumor chemotherapist) | medical_oncologist | v0.1.0 | 2026-04-25 | 0 | solid_oncology |
| Molecular geneticist / molecular oncologist | molecular_geneticist | v0.1.0 | 2026-04-25 | 0 | molecular_oncology |
| Palliative care | palliative_care | v0.1.0 | 2026-04-25 | 0 | palliative_care |
| Pathologist (general) | pathologist | v0.1.0 | 2026-04-25 | 0 | pathology |
| Primary care / family physician | primary_care | v0.1.0 | 2026-04-25 | 0 | primary_care |
| Psycho-oncologist | psychologist | v0.1.0 | 2026-04-25 | 0 | psychosocial |
| Radiation oncologist | radiation_oncologist | v0.1.0 | 2026-04-25 | 0 | radiation_oncology |
| Radiologist | radiologist | v0.1.0 | 2026-04-25 | 0 | diagnostic_imaging |
| Social worker / case manager | social_worker_case_manager | v0.1.0 | 2026-04-25 | 0 | psychosocial |
| Surgical oncologist | surgical_oncologist | v0.1.0 | 2026-04-25 | 0 | surgical_oncology |
| Transplant specialist (BMT) | transplant_specialist | v0.1.0 | 2026-04-25 | 0 | cellular_therapy |
Sources cited
- SRC-ESMO-CLL-2024: ESMO Clinical Practice Guideline on Chronic Lymphocytic Leukaemia (2024)
- SRC-MURANO-SEYMOUR-2018: Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia (2018)
- SRC-NCCN-BCELL-2025: NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas (v.2.2025)
Experimental options (clinical trials)
Last synced: 2026-08-17 · ctgov.
No active trials matched this scenario in ctgov.
Option availability in Ukraine
Per-track UA registration · NSZU · cost · access pathway. Render-time metadata; engine selection does not depend on these fields (CHARTER §8.3).
| Option | UA registration | NSZU | Cost orientation | Access pathway |
|---|
| Standard plan Venetoclax + Rituximab (VenR), 24-month fixed-duration (MURANO schedule) (REG-VENETOCLAX-RITUXIMAB) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Standard plan Zanubrutinib monotherapy (continuous, ALPINE-style) (REG-ZANUBRUTINIB-CONTINUOUS) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Aggressive plan Pirtobrutinib monotherapy (continuous, BRUIN schedule) (REG-PIRTOBRUTINIB) 1/1 component drug(s) not registered in Ukraine +1 | ✗ not registered | ✗ out-of-pocket | ₴-? — verify pathway | not recorded |
Cost information is orientation. Verify with a specific pharmacy / foundation / trial site. Status updated: 2026-08-17.