Treatment plan — Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

OpenOnco · DIS-CLL · BIO-BCL2-EXPRESSION-IHC (ESCAT IA)

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OpenOnco · Treatment Plan

Treatment plan — Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

PLAN-BMA-BCL2_EXPRESSION_CLL-V1 · v1 · 2026-08-17

Patient

BMA-BCL2_EXPRESSION_CLL · Algorithm: ALGO-CLL-1L

DiagnosisChronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

MOH / ICD-10C91.1

ICD-O-39823/3

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
ESCAT: clinical review pendingBIO-BCL2-EXPRESSION-IHC	BCL2 high expression (universal in CLL)	IA	Resistance or avoidance signal SRC-CIVIC: Level C ⚠ Resistance SRC-CIVIC: Level D ⚠ Resistance	CLL universally expresses BCL2 (no rearrangement needed; driven by miR-15/16 deletion at 13q14). Venetoclax-based fixed-duration (CLL14: VenO 1L; MURANO: VenR R/R) is FDA/EMA-approved and disease-defining as a target. Not biomarker-selected per se — BCL2 is a CLL-class marker.	venetoclax + obinutuzumab (1L) venetoclax + rituximab (R/R) venetoclax + ibrutinib (CAPTIVATE / GLOW)	SRC-NCCN-BCELL-2025 SRC-ESMO-CLL-2024

Primary current-line option

Standard plan

★ DEFAULT

Indication

IND-CLL-1L-BTKI

Regimen

Acalabrutinib monotherapy (continuous, until progression or intolerance)

Drugs + NSZU

Acalabrutinib (DRUG-ACALABRUTINIB) 100 mg · PO twice daily continuous · PO ⚠ NSZU — not for this indication

Hard contraindications

CI-HBV-NO-PROPHYLAXIS

Reason

Primary current-line option selected by ALGO-CLL-1L at step 3.

Other current-line alternatives (3 tracks)

Same treatment line; review when biomarker, access, contraindication, or patient-context assumptions change.

Aggressive plan

Indication

IND-CLL-1L-VENO

Regimen

Venetoclax + Obinutuzumab (VenO), 12 months fixed-duration (CLL14 schedule)

Drugs + NSZU

Obinutuzumab (DRUG-OBINUTUZUMAB) 100 mg cycle 1 day 1; 900 mg day 2; 1000 mg days 8 + 15; then 1000 mg day 1 of cycles 2-6 · IV monthly (28-day cycles), 6 cycles total · IV ✓ NSZU covered
Venetoclax (DRUG-VENETOCLAX) 5-week ramp starting cycle 1 day 22: 20 → 50 → 100 → 200 → 400 mg PO daily, then 400 mg daily continuous through cycle 12 · PO daily, total 12 months from start of ramp · PO ✓ NSZU covered
Allopurinol (DRUG-ALLOPURINOL) 300 mg PO daily · Start 72h before venetoclax ramp; continue ≥1 week post highest dose · PO ⚠ NSZU — not for this indication

Supportive care

SUP-TLS-PROPHYLAXIS, SUP-PJP-PROPHYLAXIS

Hard contraindications

CI-HBV-NO-PROPHYLAXIS

Reason

Current-line alternative presented for HCP consideration

Standard plan

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

Aggressive plan

Indication

IND-CLL-1L-AVO

Regimen

Acalabrutinib + Venetoclax + Obinutuzumab (AVO), fixed-duration 14 cycles (AMPLIFY)

Drugs + NSZU

Acalabrutinib (DRUG-ACALABRUTINIB) 100 mg PO BID · Continuous twice daily, cycles 1-14 (entire duration) · PO ⚠ NSZU — not for this indication
Venetoclax (DRUG-VENETOCLAX) 5-week ramp-up starting cycle 3 day 1: week 1 20 mg → week 2 50 mg → week 3 100 mg → week 4 200 mg → week 5 400 mg; then 400 mg QD maintenance through cycle 14 · PO daily, cycles 3-14 (ramp begins cycle 3 day 1) · PO ✓ NSZU covered
Obinutuzumab (DRUG-OBINUTUZUMAB) Cycle 2 day 1: 100 mg IV; cycle 2 day 2: 900 mg IV; cycle 2 days 8+15: 1000 mg IV; cycles 3-7 day 1: 1000 mg IV · IV monthly (28-day cycles), cycles 2-7 (6 cycles total) · IV ✓ NSZU covered

Supportive care

SUP-TLS-PROPHYLAXIS, SUP-PJP-PROPHYLAXIS

Hard contraindications

CI-HBV-NO-PROPHYLAXIS

Reason

Current-line alternative presented for HCP consideration

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	—	aggressive
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

Fit performance status (ECOG 0-1): patient is fully active or restricted in physically strenuous activity but ambulatory and able to carry out light work. Eligible for full-dose chemotherapy and intensive regimens (CHOEP, BEACOPP-escalated, HD-MTX, ASCT consolidation, CAR-T).
Pan-disease eligibility gate. ECOG 0-1 is the canonical entry criterion for intensified regimens across DLBCL (CHOEP-21 in age ≤60 with elevated LDH per German High-Grade NHL Study Group), Hodgkin (BEACOPP-escalated), Burkitt…
RF-FITNESS-ECOG-FITSRC-NCCN-BCELL-2025SRC-ESMO-DLBCL-2024

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
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

Standard plan (IND-CLL-1L-BTKI)

Do not prescribe chemoimmuno (FCR / BR) in high-risk CLL — survival impact substantial.
Do not start ibrutinib instead of acalabrutinib without justification — ELEVATE-RR showed better safety of acalabrutinib.
Do not skip baseline ECG + cardiology evaluation in atrial fibrillation history or HTN.
Do not combine BTKi with warfarin without strict monitoring — bleeding risk.
Do not treat asymptomatic CLL without iwCLL indication — surveillance is the standard.

Aggressive plan (IND-CLL-1L-VENO)

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 obinutuzumab therapy.

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.

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 · Acalabrutinib monotherapy (continuous, until progression or intolerance)

28-day cycles × Continuous until progression or intolerance

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 · Venetoclax + Obinutuzumab (VenO), 12 months fixed-duration (CLL14 schedule)

28-day cycles × 6 obinutuzumab + 12 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 · Acalabrutinib + Venetoclax + Obinutuzumab (AVO), fixed-duration 14 cycles (AMPLIFY)

28-day cycles × 14 (fixed-duration)

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 (4, 3 blocking)

OQ-LDH-CURRENT
What is the current LDH? Marker of tumor burden and transformation.
LDH is part of the prognostic indices of indolent lymphomas.
→ hematologist
BLOCKING OQ-BIOMARKER-CD23-IHC
What is the status of CD23 expression by IHC / flow cytometry (BIO-CD23-IHC)? It is required by track(s): IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB. Expected value: positive (CD23+) — part of CLL diagnostic immunophenotype panel (Matutes score); distinguishes from MCL.
A treatment-track biomarker requirement is missing from the patient profile; the MDT should verify the test result, method, specimen, and date before relying on this option.
→ pathologist
BLOCKING OQ-BIOMARKER-CD5-IHC
What is the status of CD5 expression by IHC / flow cytometry (BIO-CD5-IHC)? It is required by track(s): IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB. Expected value: positive (CD5+) — part of CLL diagnostic immunophenotype panel (Matutes score).
A treatment-track biomarker requirement is missing from the patient profile; the MDT should verify the test result, method, specimen, and date before relying on this option.
→ pathologist
BLOCKING OQ-BIOMARKER-NOTCH1-MUTATION
What is the status of NOTCH1 mutation (PEST domain) (BIO-NOTCH1-MUTATION)? It is required by track(s): IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB. Expected value: NOTCH1-mutated CLL has poorer prognosis but does not exclude BTKi; useful prognostic stratifier.
A treatment-track biomarker requirement is missing from the patient profile; the MDT should verify the test result, method, specimen, and date before relying on this option.
→ molecular_geneticist

MDT talk tree (5 steps)

#	Owner	Topic	Action
1	molecular_geneticist	Biomarker status BLOCKING	What is the status of NOTCH1 mutation (PEST domain) (BIO-NOTCH1-MUTATION)? It is required by track(s): IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB. Expected value: NOTCH1-mutated CLL has poorer prognosis but does not exclude BTKi; useful prognostic stratifier.
2	pathologist	Biomarker status BLOCKING	What is the status of CD23 expression by IHC / flow cytometry (BIO-CD23-IHC)? It is required by track(s): IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB. Expected value: positive (CD23+) — part of CLL diagnostic immunophenotype panel (Matutes score); distinguishes from MCL.
3	pathologist	Biomarker status BLOCKING	What is the status of CD5 expression by IHC / flow cytometry (BIO-CD5-IHC)? It is required by track(s): IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB. Expected value: positive (CD5+) — part of CLL diagnostic immunophenotype panel (Matutes score).
4	hematologist	Staging / disease burden	What is the current LDH? Marker of tumor burden and transformation.
5	clinical_pharmacist	Specialist review	Chemoimmunotherapy regimen — drug-drug interactions, dose adjustments, premedication.

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.
Owns: OQ-BIOMARKER-NOTCH1-MUTATION

Data quality

Incomplete for default-track review. Default-track review is incomplete until required biomarker gaps are resolved.

Biomarker coverage: 0/3 known (0%), 3 missing, 3 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

Missing biomarker	Label	MDT owner	Default track	Required by	Next action
`BIO-CD23-IHC`	CD23 expression by IHC / flow cytometry	pathologist	yes	IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB	Verify result, method, specimen, and report date before sign-off. Expected/constraint: positive (CD23+) — part of CLL diagnostic immunophenotype panel (Matutes score); distinguishes from MCL
`BIO-CD5-IHC`	CD5 expression by IHC / flow cytometry	pathologist	yes	IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB	Verify result, method, specimen, and report date before sign-off. Expected/constraint: positive (CD5+) — part of CLL diagnostic immunophenotype panel (Matutes score)
`BIO-NOTCH1-MUTATION`	NOTCH1 mutation (PEST domain)	molecular_geneticist	yes	IND-CLL-1L-BTKI, IND-CLL-1L-VENO, IND-CLL-1L-ZANUBRUTINIB	Verify result, method, specimen, and report date before sign-off. Expected/constraint: NOTCH1-mutated CLL has poorer prognosis but does not exclude BTKi; useful prognostic stratifier

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-CLL14-FISCHER-2019: Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions (2019)
SRC-ELEVATE-TN-SHARMAN-2020: Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN) (2020)
SRC-ESMO-CLL-2024: ESMO Clinical Practice Guideline on Chronic Lymphocytic Leukaemia (2024)
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 Acalabrutinib monotherapy (continuous, until progression or intolerance) (REG-ACALABRUTINIB-CONTINUOUS)	✓ registered	✓ covered	₴-? — verify pathway	NSZU formulary
Aggressive plan Venetoclax + Obinutuzumab (VenO), 12 months fixed-duration (CLL14 schedule) (REG-VENETOCLAX-OBINUTUZUMAB)	✓ registered	✓ covered	₴-? — verify pathway	NSZU formulary
Standard plan Zanubrutinib monotherapy (continuous, ALPINE-style) (REG-ZANUBRUTINIB-CONTINUOUS)	✓ registered	✓ covered	₴-? — verify pathway	NSZU formulary
Aggressive plan Acalabrutinib + Venetoclax + Obinutuzumab (AVO), fixed-duration 14 cycles (AMPLIFY) (REG-AVO-CLL-1L)	✓ registered	✓ covered	₴-? — verify pathway	NSZU formulary

Cost information is orientation. Verify with a specific pharmacy / foundation / trial site. Status updated: 2026-08-17.

plan_id: PLAN-BMA-BCL2_EXPRESSION_CLL-V1 | version: 1 | generated: 2026-08-17T08:06:31.537889+00:00

Per FDA non-device CDS positioning (CHARTER §15): Outpatient oncology treatment planning to support tumor-board discussion. Not a medical device; not for autonomous clinical decision-making.

Per FDA non-device CDS positioning (CHARTER §15): Both treatment options below are presented for review. The engine's selection of a 'recommended' default does not constitute a clinical decision. Final treatment selection requires HCP judgment incorporating information not available to the system.

This document is an informational resource supporting tumor-board discussion (per CHARTER §11). It is not a system that makes clinical decisions. Every recommendation must be verified by the treating physician.