Patient
VAR-WM-HIGHRISK · Algorithm: ALGO-WM-1L
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 |
|---|
| BIO-MYD88-L265P | L265P | IA | Molecular evidence option - SRC-CIVIC: Level B (Supports, Better Outcome)
Trial or research option - SRC-CIVIC: Level D (Supports, Sensitivity/Response)
| MYD88 L265P present in >90% of WM. Activates NF-κB via BTK/IRAK signaling — rationale for BTKi. Ibrutinib monotherapy (iNNOVATE substudy 2 / arm A — Treon et al. NEJM 2015 R/R; iNNOVATE — Dimopoulos et al. NEJM 2018 1L+R/R with rituximab) and zanubrutinib (ASPEN — Tam et al. Blood 2020) FDA-approved. CXCR4 WHIM-like co-mutation reduces but does not abolish response. | zanubrutinib (preferred per ASPEN — fewer cardiac AE vs ibrutinib)
ibrutinib monotherapy
ibrutinib + rituximab
BR (chemo-immuno alternative) | - SRC-NCCN-BCELL-2025
- SRC-ESMO-WM-2024
|
Primary current-line option
- Indication
- IND-WM-1L-DRC
- Regimen
- Dexamethasone + Rituximab + Cyclophosphamide (DRC) × 6 cycles
- Drugs + NSZU
- Dexamethasone (DRUG-DEXAMETHASONE) 20 mg IV day 1 · IV day 1 each cycle · IV ⚠ NSZU — not for this indication
- Rituximab (DRUG-RITUXIMAB) 375 mg/m² day 1 · IV day 1 each cycle · IV ⚠ NSZU — not for this indication
- Cyclophosphamide (DRUG-CYCLOPHOSPHAMIDE) 100 mg/m² PO BID days 1-5 · PO twice daily, days 1-5 each cycle · PO ⚠ NSZU — not for this indication
- Supportive care
- SUP-PJP-PROPHYLAXIS, SUP-HBV-PROPHYLAXIS
- Hard contraindications
- CI-HBV-NO-PROPHYLAXIS
- Reason
- Primary current-line option selected by ALGO-WM-1L at step 2.
Other current-line alternatives (1 tracks)
Same treatment line; review when biomarker, access, contraindication, or patient-context assumptions change.
- Indication
- IND-WM-1L-BTKI
- Regimen
- Zanubrutinib monotherapy (continuous)
- Drugs + NSZU
- Zanubrutinib (DRUG-ZANUBRUTINIB) 160 mg PO BID OR 320 mg PO once daily · Continuous until progression or intolerance · PO ✓ NSZU covered
- 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 1 → branch 2
- RF-WM-MYD88-L265P-ACTIONABLE ★ winner: MYD88 L265P is the hallmark mutation of Waldenström macroglobulinemia, present in >90% of WM. Drives constitutive NF-κB activation through BTK. iNNOVATE (Dimopoulos NEJM 2018) and the iNNOVATE long-term follow-up established ibrutinib + rituximab > placebo + rituximab regardless of prior therapy; MYD88-L265P-positive disease has the highest response rate to BTKi monotherapy (ORR ~90%, major-response ~70%) while MYD88-WT WM responds poorly. Routes 1L symptomatic WM with MYD88-L265P toward BTKi-based therapy (ibrutinib, zanubrutinib per ASPEN, or ibrutinib + rituximab) over DRC chemoimmuno when chemo-avoidance is preferred (cardiac, frailty, hyperviscosity-controlled).
SRC-NCCN-BCELL-2025SRC-ESMO-WM-2024
Pre-treatment investigations
Investigations before treatment start · critical / standard / desired · merged across tracks
| ID | Name | Priority | Category | Where to order | Needed for |
|---|
| TEST-BM-ASPIRATE | Bone Marrow Aspirate | Critical | histology | — | all tracks |
| TEST-BM-TREPHINE | Bone Marrow Trephine | Critical | histology | — | all tracks |
| 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-FLOW-CYTOMETRY | Flow Cytometry | Critical | histology | CSD Lab ✓ (code TBC) | all tracks |
| TEST-FREE-LIGHT-CHAINS | Serum Free Light Chains | Critical | lab | — | aggressive |
| TEST-HBV-SEROLOGY | Hepatitis B Serology Panel (HBsAg, anti-HBc total, anti-HBs) | Critical | lab | — | all tracks |
| TEST-HCV-ANTIBODY | HCV Antibody | Critical | lab | — | aggressive |
| TEST-HIV-SEROLOGY | HIV Antibody/Antigen | Critical | lab | — | aggressive |
| TEST-LFT | Liver Function Tests (ALT, AST, bilirubin, ALP, GGT, albumin) | Critical | lab | — | all tracks |
| TEST-SPEP-UPEP | SPEP / UPEP with IFE | Critical | lab | — | all tracks |
| TEST-IMMUNOGLOBULINS | Quantitative Immunoglobulins | Standard | lab | — | all tracks |
| 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
CONTRA-AGGRESSIVE
Hard contraindications to escalation
- Active or latent HBV without antiviral prophylaxis is an absolute contraindication to starting B-cell-depleting / immunomodulatory monoclonal antibody therapy (anti-CD20, anti-CD30 ADC, anti-CD38). Severe HBV reactivation hepatitis risk including fulminant hepatic failure.CI-HBV-NO-PROPHYLAXIS
What NOT to do
Explicit prohibitive rules, each grounded in a regimen / supportive care / contraindication entity
Aggressive plan (IND-WM-1L-DRC)
- Do not start rituximab without plasmapheresis in symptomatic hyperviscosity — IgM flare worsens.
- Do not skip HBV screening + entecavir prophylaxis.
Standard plan (IND-WM-1L-BTKI)
- Do not prescribe in MYD88-WT WM — BTKi not active; chemoimmuno (DRC) preferred.
- Do not skip CXCR4 sequencing — WHIM-mutated subset has weaker response.
- Do not prescribe rituximab with symptomatic hyperviscosity without plasmapheresis first.
Monitoring schedule
Monitoring schedule by treatment phase
Aggressive plan · MON-RITUXIMAB-MONO
| Phase | Window | Tests | Checkpoints |
|---|
| baseline | Within 2 weeks before first dose | TEST-CBC, TEST-LFT, TEST-LDH, TEST-CD20-IHC, TEST-HBV-SEROLOGY, TEST-HCV-ANTIBODY, TEST-FLOW-CYTOMETRY | - Confirm CD20+ histology
- HBV status + entecavir prophylaxis if HBsAg+ or anti-HBc+
|
| induction | Day 1 of each weekly induction × 4 | TEST-CBC, TEST-LFT | - Infusion reactions especially first dose
|
| maintenance | Every 2 months × 2 years | TEST-CBC, TEST-LFT, TEST-LDH | - HBV-DNA quarterly during therapy and 12 mo post
- Disease assessment clinically; imaging if concern
|
| follow_up | Every 6 months × 5 years post-treatment | TEST-CBC, TEST-LFT, TEST-LDH | - Surveillance for relapse + transformation
|
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_veno | 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
Aggressive plan
Baseline
Within 2 weeks before first dose
Induction · Dexamethasone + Rituximab + Cyclophosphamide (DRC) × 6 cycles
21-day cycles × 6
Maintenance
Every 2 months × 2 years
Follow-up
Every 6 months × 5 years post-treatment
Standard plan
Baseline
Within 2 weeks before start
Induction · Zanubrutinib monotherapy (continuous)
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 (2, 1 blocking)
BLOCKING OQ-CD20-CONFIRMATION
Is CD20+ status confirmed by histology (IHC)? Without CD20+, rituximab/obinutuzumab are not indicated.
Anti-CD20 therapy is the backbone of most lines of treatment; absence of CD20 expression fully changes the regimen.
→ pathologist
OQ-STAGING-COMPLETE
Has complete staging been done (Lugano + PET/CT or CT)?
Prognosis and track selection depend on stage and tumor burden.
→ radiologist
MDT talk tree (5 steps)
| # | Owner | Topic | Action |
|---|
| 1 | pathologist | Pathology confirmation BLOCKING | Is CD20+ status confirmed by histology (IHC)? Without CD20+, rituximab/obinutuzumab are not indicated. |
| 2 | radiologist | Staging / disease burden | Has complete staging been done (Lugano + PET/CT or CT)? |
| 3 | hematologist | Specialist review | Lymphoma diagnosis — leading specialty for treatment management. |
| 4 | clinical_pharmacist | Specialist review | Chemoimmunotherapy regimen — drug-drug interactions, dose adjustments, premedication. |
| 5 | molecular_geneticist | Specialist review | Indication references an actionable genomic biomarker — mutation / target / actionability interpretation needed. |
Skills (required) — mandatory virtual specialists (1)
Skills (recommended) — for consideration (4)
- 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.
- Pathologist (general) recommended
Confirm lymphoma histology + assess transformation risk (DLBCL/Richter).
Owns: OQ-CD20-CONFIRMATION
- Radiologist recommended
Imaging findings present — radiologist needed for staging/restaging.
Owns: OQ-STAGING-COMPLETE
Data quality
Incomplete for MDT sign-off. MDT sign-off is incomplete until critical clinical data gaps are resolved.
- Biomarker coverage: 1/1 known (100%), 0 missing, 0 default-track gaps
- Missing critical: cd20_ihc_status, lugano_stage
- Missing recommended: fib4_index, pet_ct_date
- Unevaluated RedFlags: RF-WM-CXCR4-WHIM-MUTANT, RF-WM-FRAILTY-AGE, RF-WM-HIGH-RISK-BIOLOGY, RF-WM-HYPERVISCOSITY, RF-WM-INFECTION-SCREENING, RF-WM-MYD88-L265P-ACTIONABLE, RF-WM-TRANSFORMATION-PROGRESSION
Missing data for doctor action
| Priority | Clinical item | Owner | Why it matters | Next action | Blocks |
|---|
| CRITICAL | CD20 IHC status cd20_ihc_status
| pathologist | Confirms CD20-directed therapy is biologically appropriate. | Verify CD20 IHC result, specimen, method, and report date. | - |
| CRITICAL | Lugano stage lugano_stage
| radiologist | Defines lymphoma extent and supports tumor-burden and response-assessment decisions. | Document Lugano stage from PET/CT or contrast CT staging. | - |
| RECOMMENDED | FIB-4 liver fibrosis index fib4_index
| infectious_disease_hepatology | Screens hepatic fibrosis risk before hepatotoxic therapy or antiviral coordination. | Calculate FIB-4 from age, AST, ALT, and platelet count. | - |
| RECOMMENDED | PET/CT date pet_ct_date
| radiologist | Shows whether baseline staging is recent enough for treatment planning and later response comparison. | Document baseline PET/CT date or explain alternative staging modality. | - |
Technical MDT skill metadata (5/16 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-WM-2024: ESMO Clinical Practice Guideline on Waldenström Macroglobulinaemia (2024)
- SRC-NCCN-BCELL-2025: NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas (v.2.2025)
Experimental options (clinical trials)
Third plan track — open-enrollment trials from ClinicalTrials.gov. Render-time metadata; engine selection is not affected by this block (CHARTER §8.3). Last synced: 2026-05-12.
| NCT | Title | Phase | Status | Sponsor | UA | Signals | Eligibility (excerpt) |
|---|
| NCT05640102 | Observational Study Evaluating the Efficacy and Safety of Zanubrutinib in Participants With Waldenström Macroglobulinemia | N/A | RECRUITING | — | Biomarker: enriched Surrogate endpoint only | |
Verify recruitment status directly with the trial site. ctgov data can lag behind current UA-site status.
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 |
|---|
| Aggressive plan Dexamethasone + Rituximab + Cyclophosphamide (DRC) × 6 cycles (REG-DRC-WM) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Standard plan Zanubrutinib monotherapy (continuous) (REG-ZANUBRUTINIB-WM) | ✓ registered | ✓ covered | ₴-? — verify pathway | NSZU formulary |
| Trial · NCT05640102 Observational Study Evaluating the Efficacy and Safety of Zanubrutinib in Participants With Waldenström Macroglobulinemia No UA site listed — international referral required | — unknown | — unknown | self-pay: ₴0/course | Trial sponsor |
Cost information is orientation. Verify with a specific pharmacy / foundation / trial site. Status updated: 2026-05-12.