OpenOnco · DIS-WM · Relapsed / 2nd line
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OpenOnco · Treatment Plan
Treatment plan — Waldenström Macroglobulinemia / Lymphoplasmacytic Lymphoma
PLAN-VAR-WM-RELAPSED-V1 · v1 · 2026-05-12
Patient
VAR-WM-RELAPSED · Algorithm: ALGO-WM-2L
DiagnosisWaldenström Macroglobulinemia / Lymphoplasmacytic Lymphoma
MOH / ICD-10C88.0
ICD-O-39671/3

Clinical significance of mutations (ESCAT)

Tumor-board context — the engine does not use these tiers to rank tracks
BiomarkerVariantESCATEvidenceClinical significanceDrugsSources
BIO-MYD88-L265PL265PIA
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

Standard plan
★ DEFAULT
Indication
IND-WM-2L-ZANUBRUTINIB
Regimen
Zanubrutinib monotherapy continuous for r/r WM (ASPEN schedule) — alternative to ibrutinib
Drugs + NSZU
  • Zanubrutinib (DRUG-ZANUBRUTINIB) 160 mg PO BID OR 320 mg PO once daily · Continuous until progression or unacceptable toxicity · PO ✓ NSZU covered
Reason
Primary current-line option selected by ALGO-WM-2L at step 3.

Other current-line alternatives (2 tracks)

Same treatment line; review when biomarker, access, contraindication, or patient-context assumptions change.
Standard plan
Indication
IND-WM-2L-VRD
Regimen
Bortezomib + Rituximab + Dexamethasone (BDR) × 6-8 cycles — chemo-free alternative for r/r WM (incl CXCR4-WHIM-mutated)
Drugs + NSZU
  • Bortezomib (DRUG-BORTEZOMIB) 1.3 mg/m² · SC days 1, 8, 15, 22 of each 35-day cycle (weekly × 4, then 13-day rest) · SC ⚠ NSZU — not for this indication
  • Rituximab (DRUG-RITUXIMAB) 375 mg/m² · IV day 1 OR weekly × 4 induction, then maintenance per protocol · IV ⚠ NSZU — not for this indication
  • Dexamethasone (DRUG-DEXAMETHASONE) 40 mg · PO/IV days 1, 8, 15, 22 of each 35-day cycle · PO ⚠ NSZU — not for this indication
Supportive care
SUP-PJP-PROPHYLAXIS, SUP-HSV-PROPHYLAXIS, SUP-HBV-PROPHYLAXIS
Hard contraindications
CI-HBV-NO-PROPHYLAXIS, CI-BORTEZOMIB-SEVERE-NEUROPATHY
Reason
Current-line alternative presented for HCP consideration
Aggressive plan
Indication
IND-WM-2L-CARFILZOMIB-CXCR4MUT
Regimen
Carfilzomib + Rituximab + Dexamethasone (CaRD) × 6 cycles — for CXCR4-WHIM-mutated WM (BTKi-resistant subset)
Drugs + NSZU
  • Carfilzomib (DRUG-CARFILZOMIB) 20 mg/m² days 1+2 of cycle 1, then 36 mg/m² days 1, 2, 8, 9, 15, 16 of subsequent cycles · IV days 1+2, 8+9, 15+16 of each 28-day cycle × 6 · IV ⚠ NSZU — not for this indication
  • Rituximab (DRUG-RITUXIMAB) 375 mg/m² · IV day 2 of each cycle · IV ⚠ NSZU — not for this indication
  • Dexamethasone (DRUG-DEXAMETHASONE) 20 mg · IV/PO before carfilzomib doses (premed + therapeutic) · PO ⚠ NSZU — not for this indication
Supportive care
SUP-PJP-PROPHYLAXIS, SUP-HSV-PROPHYLAXIS, SUP-HBV-PROPHYLAXIS
Hard contraindications
CI-HBV-NO-PROPHYLAXIS, CI-LVEF-LOW-FOR-ANTHRACYCLINE
Reason
Current-line alternative presented for HCP consideration

Pre-treatment investigations

Investigations before treatment start · critical / standard / desired · merged across tracks
IDNamePriorityCategoryWhere to orderNeeded for
TEST-BM-ASPIRATEBone Marrow AspirateCriticalhistologyall tracks
TEST-BM-TREPHINEBone Marrow TrephineCriticalhistologyall tracks
TEST-CBCComplete Blood Count with DifferentialCriticallaball tracks
TEST-CECT-CAPCECT chest/abdomen/pelvisCriticalimagingall tracks
TEST-CMPComprehensive Metabolic PanelCriticallaball tracks
TEST-FLOW-CYTOMETRYFlow CytometryCriticalhistologyCSD Lab ✓ (code TBC)all tracks
TEST-HBV-SEROLOGYHepatitis B Serology Panel (HBsAg, anti-HBc total, anti-HBs)Criticallaball tracks
TEST-HCV-ANTIBODYHCV AntibodyCriticallaball tracks
TEST-HIV-SEROLOGYHIV Antibody/AntigenCriticallaball tracks
TEST-LFTLiver Function Tests (ALT, AST, bilirubin, ALP, GGT, albumin)Criticallaball tracks
TEST-PREGNANCYBeta-HCGCriticallabstandard
TEST-SPEP-UPEPSPEP / UPEP with IFECriticallaball tracks
TEST-ECHOEchocardiographyStandardimagingall tracks
TEST-IMMUNOGLOBULINSQuantitative ImmunoglobulinsStandardlaball tracks
TEST-NGS-LYMPHOID-PANELLymphoid NGS PanelDesiredgenomicCSD Lab ✓ (code TBC)all tracks

Red flags — PRO / CONTRA aggressive

PRO-AGGRESSIVE

Triggers that push toward the aggressive track
  • AITL with autoimmune hemolytic anemia (AIHA, DAT+) and/or immune thrombocytopenia (ITP) — paraneoplastic phenomenon needing concurrent immunosuppression alongside T-cell-directed therapyRF-AITL-AUTOIMMUNE-CYTOPENIA
  • CXCR4 WHIM-like nonsense or frameshift mutation in the C-terminal regulatory domain (e.g., S338X, R334X) in Waldenström macroglobulinemia (WM). CXCR4 WHIM-like mutations co-occur with MYD88 L265P in ~30-40% of MYD88-mutant WM and cause constitutive CXCR4 signaling via loss of the C-terminal regulatory domain. These mutations confer relative resistance to BTK inhibitor (BTKi) monotherapy — lower overall response rate and major-response rate, slower IgM decline kinetics compared to CXCR4-WT MYD88-mutant WM (Treon NEJM 2015; Castillo Blood 2020). Fires to route ALGO-WM-2L step 1 to carfilzomib-based therapy (IND-WM-2L-CARFILZOMIB-CXCR4MUT) rather than zanubrutinib BTKi monotherapy (IND-WM-2L-ZANUBRUTINIB), as BTKi efficacy is substantially attenuated in CXCR4-mutated WM. Detection: CXCR4 C-terminal sequencing by targeted PCR + Sanger or NGS panel with CXCR4 C-terminus coverage. Note: standard NGS panels frequently omit CXCR4 C-terminus; dedicated assay required. Bone marrow aspirate with CD138+ enrichment preferred for adequate WM clone representation. CXCR4 mutation testing is recommended at WM diagnosis per NCCN B-Cell Lymphomas 2025 (alongside MYD88 L265P) to guide initial therapy selection. In CXCR4-mutated patients, BTKi monotherapy response is attenuated; proteasome-inhibitor-based regimens or BR are preferred 1L per NCCN/ESMO. In 2L, carfilzomib-based regimens offer benefit in BTKi-refractory or BTKi-intolerant CXCR4-mutated WM. RF-WM-CXCR4-WHIM-MUTANT
  • Waldenström with symptomatic hyperviscosity syndrome (serum viscosity >4 cp typical, or symptomatic at any level): blurred vision, headache, retinal hemorrhage, mucosal bleeding, neurologic dysfunctionRF-WM-HYPERVISCOSITY

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
  • Pre-treatment LVEF <50% is an absolute contraindication to anthracycline-containing regimens (R-CHOP, Pola-R-CHP, ABVD, BV-AVD, etc.). Cardiotoxicity from doxorubicin is dose-cumulative and often irreversible; starting with already-impaired function risks acute decompensation.CI-LVEF-LOW-FOR-ANTHRACYCLINE

What NOT to do

Explicit prohibitive rules, each grounded in a regimen / supportive care / contraindication entity
Standard plan (IND-WM-2L-ZANUBRUTINIB)
  • Do NOT prescribe in MYD88-WT WM (rare) — BTKi not active; chemoimmuno (DRC, BDR) preferred.
  • Do NOT skip CXCR4 sequencing — WHIM-mutated subset (~30%) has weaker depth of response; consider proteasome-inhibitor alternative.
  • Do NOT prescribe rituximab with symptomatic hyperviscosity without plasmapheresis first — rituximab causes IgM flare in subset.
  • Do NOT combine with warfarin without strict monitoring — bleeding risk.
  • Do NOT prescribe with concomitant strong CYP3A4 inhibitor without dose reduction to 80 mg PO BID.
  • Do NOT skip baseline ECG — afib reduced but possible.
  • Do NOT skip baseline LFTs — Child-Pugh C avoid; severe impairment dose-reduce.
Standard plan (IND-WM-2L-VRD)
  • Do not start BDR without HBV screening + entecavir prophylaxis if HBsAg+ or anti-HBc+.
  • Do not prescribe rituximab with symptomatic hyperviscosity without plasmapheresis first — IgM flare risk.
  • Do not use bortezomib with pre-existing Grade ≥2 peripheral neuropathy — absolute CI; switch to carfilzomib (CaRD).
  • Do not use twice-weekly IV bortezomib — weekly SC substantially reduces peripheral neuropathy.
  • Do not skip acyclovir HSV/VZV prophylaxis throughout proteasome inhibitor therapy.
  • Do not skip dexamethasone dose reduction to 20 mg if age >75 or frail — steroid toxicity (infection, hyperglycemia, falls).
  • Do not forget PJP prophylaxis throughout ≥6 months after last anti-CD20 dose.
  • Do not ignore new peripheral neuropathy — reduce bortezomib or switch to CaRD if Grade ≥3 or painful.
Aggressive plan (IND-WM-2L-CARFILZOMIB-CXCR4MUT)
  • Do not prescribe without CXCR4 status check — drug particularly justified for WHIM-mutated subset (informational stratification).
  • Do not skip baseline ECHO + LVEF assessment — carfilzomib cardiotoxicity signal substantial.
  • Do not ignore new dyspnea / chest pain / hypertension >180/110 — cardiology consult immediately.
  • Do not skip pre-carfilzomib hydration (NS 250-500 mL IV) — TLS + cardiac protection.
  • Do not start without HBV screening + entecavir prophylaxis.
  • Do not prescribe rituximab with symptomatic hyperviscosity without plasmapheresis first.
  • Do not skip acyclovir HSV/VZV prophylaxis throughout proteasome inhibitor therapy.
  • Do not ignore TLS prophylaxis cycle 1 in high-burden disease.
  • Do not forget off-label disclosure — carfilzomib registered for r/r MM; WM off-label.

Monitoring schedule

Monitoring schedule by treatment phase

Standard plan · MON-CLL-BTKI

PhaseWindowTestsCheckpoints
baselineWithin 2 weeks before startTEST-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_btkiMonthly × 3 months, then every 3 monthsTEST-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_venoPer CLL14 schedule during 12-month VenO courseTEST-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_assessmentAfter cycle 6 (VenO) or every 6 months on BTKiTEST-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_upEvery 3-6 months after treatment / continuously on BTKiTEST-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 · Zanubrutinib monotherapy continuous for r/r WM (ASPEN schedule) — alternative to ibrutinib
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

Standard plan

Induction · Bortezomib + Rituximab + Dexamethasone (BDR) × 6-8 cycles — chemo-free alternative for r/r WM (incl CXCR4-WHIM-mutated)
35-day cycles × 6-8 cycles induction; rituximab maintenance optional based on response/depth

Aggressive plan

Induction · Carfilzomib + Rituximab + Dexamethasone (CaRD) × 6 cycles — for CXCR4-WHIM-mutated WM (BTKi-resistant subset)
28-day cycles × 6 cycles induction; rituximab maintenance optional based on response

MDT brief

Discussion questions (4, 1 blocking)

MDT talk tree (5 steps)

#OwnerTopicAction
1pathologistPathology confirmation BLOCKINGIs CD20+ status confirmed by histology (IHC)? Without CD20+, rituximab/obinutuzumab are not indicated.
2hematologistStaging / disease burden What is the current LDH? Marker of tumor burden and transformation.
3molecular_geneticistBiomarker status What is the status of CXCR4 WHIM-like mutation (BIO-CXCR4-WHIM)? It is required by track(s): IND-WM-2L-CARFILZOMIB-CXCR4MUT. Expected value: positive (WHIM-mutated) preferred — BTKi response weaker; OR bortezomib-intolerant patient with neuropathy.
4radiologistStaging / disease burden Has complete staging been done (Lugano + PET/CT or CT)?
5clinical_pharmacistSpecialist review Chemoimmunotherapy regimen — drug-drug interactions, dose adjustments, premedication.

Skills (required) — mandatory virtual specialists (1)

  • Hematologist / oncohematologist required
    Lymphoma diagnosis — leading specialty for treatment management.
    Owns: OQ-LDH-CURRENT

Skills (recommended) — for consideration (3)

  • 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.
    Owns: OQ-BIOMARKER-CXCR4-WHIM
  • Pathologist (general) recommended
    Confirm lymphoma histology + assess transformation risk (DLBCL/Richter).
    Owns: OQ-CD20-CONFIRMATION

Data quality

Incomplete for MDT sign-off. MDT sign-off is incomplete until critical clinical data gaps are resolved.
  • Biomarker coverage: 1/2 known (50%), 1 missing, 0 default-track gaps
  • Missing critical: cd20_ihc_status, lugano_stage
  • Missing recommended: ldh_ratio_to_uln, 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

PriorityClinical itemOwnerWhy it mattersNext actionBlocks
CRITICALCD20 IHC status
cd20_ihc_status
pathologistConfirms CD20-directed therapy is biologically appropriate.Verify CD20 IHC result, specimen, method, and report date.-
CRITICALLugano stage
lugano_stage
radiologistDefines lymphoma extent and supports tumor-burden and response-assessment decisions.Document Lugano stage from PET/CT or contrast CT staging.-
RECOMMENDEDLDH ratio to ULN
ldh_ratio_to_uln
medical_oncologistSupports prognostic scoring and aggressive-biology flags.Enter LDH with local upper limit of normal.-
RECOMMENDEDFIB-4 liver fibrosis index
fib4_index
infectious_disease_hepatologyScreens hepatic fibrosis risk before hepatotoxic therapy or antiviral coordination.Calculate FIB-4 from age, AST, ALT, and platelet count.-
RECOMMENDEDPET/CT date
pet_ct_date
radiologistShows whether baseline staging is recent enough for treatment planning and later response comparison.Document baseline PET/CT date or explain alternative staging modality.-
Missing biomarkerLabelMDT ownerDefault trackRequired byNext action
BIO-CXCR4-WHIMCXCR4 WHIM-like mutationmolecular_geneticistnoIND-WM-2L-CARFILZOMIB-CXCR4MUTVerify result, method, specimen, and report date before sign-off. Expected/constraint: positive (WHIM-mutated) preferred — BTKi response weaker; OR bortezomib-intolerant patient with neuropathy
Technical MDT skill metadata (4/16 activated in this plan)
All registered virtual specialists. ✓ — activated for this case; ○ — not activated (available for other clinical scenarios).
Specialistskill_idVersionLast reviewedSign-offsDomain
Cellular therapy specialist (CAR-T)cellular_therapy_specialistv0.1.02026-04-250cellular_therapy
Clinical pharmacistclinical_pharmacistv0.1.02026-04-250clinical_pharmacy
Hematologist / oncohematologisthematologistv0.1.02026-04-250hematology_oncology
Hematopathologist (lymphoma / leukemia / myeloma)hematopathologistv0.1.02026-04-250hematopathology
Infectious disease / hepatologyinfectious_disease_hepatologyv0.1.02026-04-250infectious_diseases
Medical oncologist (solid-tumor chemotherapist)medical_oncologistv0.1.02026-04-250solid_oncology
Molecular geneticist / molecular oncologistmolecular_geneticistv0.1.02026-04-250molecular_oncology
Palliative carepalliative_carev0.1.02026-04-250palliative_care
Pathologist (general)pathologistv0.1.02026-04-250pathology
Primary care / family physicianprimary_carev0.1.02026-04-250primary_care
Psycho-oncologistpsychologistv0.1.02026-04-250psychosocial
Radiation oncologistradiation_oncologistv0.1.02026-04-250radiation_oncology
Radiologistradiologistv0.1.02026-04-250diagnostic_imaging
Social worker / case managersocial_worker_case_managerv0.1.02026-04-250psychosocial
Surgical oncologistsurgical_oncologistv0.1.02026-04-250surgical_oncology
Transplant specialist (BMT)transplant_specialistv0.1.02026-04-250cellular_therapy

Sources cited

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.
NCTTitlePhaseStatusSponsorUASignalsEligibility (excerpt)
NCT05640102Observational Study Evaluating the Efficacy and Safety of Zanubrutinib in Participants With Waldenström MacroglobulinemiaN/ARECRUITINGBeiGeneBiomarker: 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).
OptionUA registrationNSZUCost orientationAccess pathway
Standard plan
Zanubrutinib monotherapy continuous for r/r WM (ASPEN schedule) — alternative to ibrutinib (REG-ZANUBRUTINIB-WM-RELAPSED)
✓ registered✓ covered₴-? — verify pathwayNSZU formulary
Standard plan
Bortezomib + Rituximab + Dexamethasone (BDR) × 6-8 cycles — chemo-free alternative for r/r WM (incl CXCR4-WHIM-mutated) (REG-VRD-WM)
✓ registered✓ covered₴-? — verify pathwayNSZU formulary
Aggressive plan
Carfilzomib + Rituximab + Dexamethasone (CaRD) × 6 cycles — for CXCR4-WHIM-mutated WM (BTKi-resistant subset) (REG-CARFILZOMIB-WM)
✓ registered✓ covered₴-? — verify pathwayNSZU 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.