How I Initially Manage CLL

John C. Byrd, MD

The Gordon and Helen Hughes Taylor Professor and Chair

Department of Internal Medicine

The University of Cincinnati

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March 3, 2025

• The most prevalent type of adult leukemia
• Median age of diagnosis of CLL is 72
• More frequent in men (2:1 ratio)
• Ethnic disposition: Caucasian>Black>Hispanic>>>Asian
• Environmental predisposition
• Only type of leukemia not associated with radiation exposure
• Modest association with farmers, chemical exposure, Round Up
• Agent Orange or Burn Pit exposure warrant “service-connected status” with VA (always ask about military history)

Chronic Lymphocytic Leukemia

Alfred Velpeau MD

1823

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Diagnosis of CLL

• Commonly identified by primary care or ER physician by increased WBC or differential evaluating something else

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• Diagnosis is made by flow cytometry as many other things can look like CLL on blood smear

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• Defined on flow by by > 5 x 10⁹/L CD5, CD19, CD20, CD23, CD200, sIg (dim) cells in blood

Monoclonal B-cell Lymphocytosis

• Rare under age 40 (1%) but increases proportionately with age (20% over age 80 years of age

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• < 5 x 10⁹/L cells with CLL immunophenotype or other monoclonal B-cell population in blood without cytopenias, LN enlargement or organomegaly

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• Outcome dichotomized based upon blood count
• Low count <0.5 x 10⁹/L) has normal life expectancy
• High-count ≥0.5 x 10⁹/L with 2% progression to CLL/yr

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• IPS score does predict risk, but great majority of patients will be low risk, value of CLL risk factors here only shown in 1 study to small proportion of individuals and may generate conflicting data

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• Infections and secondary cancers are more common than healthy individuals necessitating similar prophylaxis and screening

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Older Staging of CLL

Prof Kanti Rai

Prof Jacques-Louis Binet

How will this “bad” leukemia influence my quality of life and life expectancy?

• Stage not helpful to the individual with CLL unless high risk
• Many retrospective biomarkers predicting time to first treatment
• With new therapies, prognostic factors most relevant to identifying risk to progression requiring therapy versus prediction of survival—share this with patient

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The Big Question at Diagnosis in Asymptomatic Patient

CLL Outcome From Diagnosis by Fluorescence In Situ Hybridization (FISH) Interphase Chromosomal Abnormalities

Döhner H, et al. N Engl J Med. 2000; 343(26):1910-1916.

Overall Survival by IGHV Gene Mutation Status

Hamblin TJ, et al. Blood. 1999;94(6):1848-1854.

24.5 yrs

9.75 yrs

IGHV Unmutated

IGHV Mutated

Months

% Surviving

Prof Nicholas Chiorazzi

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Prof Terry Hamblin

Prof Freda Stevenson

Does TP53 mutated alone matter?

• 475 patients from CLL-01 study
• Prospective Observation study performed in Italy with all patients within 1 year of diagnosis
• All Binet Stage A patients; (136 have MBL by count)
• TP53 mutation done on purified B-cells using modern NGS method; del(17)(p13.1)

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TP53 mutation alone may not matter

Monti P, et al: Sci Rep 2020; 10: 18427

International Prognostic Score

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 Lancet, 17:779-790, 2016

Prof Michael Hallek

• All patients at diagnosis:
• Flow cytometry to confirm CLL diagnosis
• Informative for prognostic prediction if patients want to know:
• Interphase cytogenetics: del 17p, del 11q, t(11;14) to rule out mantle cell lymphoma and stimulated karyotype (when available)
• IGHV gene mutational status
• Beta-2-microglobulin (B₂M)
• Multi-gene NGS panel that includes TP53, CLL genes and clonal hematopoiesis genes

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• Immunoglobulin (IgG, IgA, IgM) levels
• No CT scan unless symptoms are present; PET scan if Richter’s suspected
• Bone marrow biopsy not necessary in absence of cytopenias

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My Initial Workup of CLL

• Anxiety over diagnosis—most common in younger males
• Time, education, and reassurance during first visit
• Fatigue in early-stage patients—very common
• If onset time of diagnosis, follow for 2-3 months to see if with extensive education and assurance this resolves
• Other causes - sleep apnea, cardiac, metabolic (thyroid, testosterone, menopause, vitamin D deficiency); depression
• Integrative medicine approaches
• Ritalin can sometimes help
• Night sweats
• Richter’s, viral reactivation (EBV, CMV), hormonal

My Approach to Common Symptoms at Diagnosis

• Autoimmune hemolytic anemia and thrombocytopenia common in CLL (10-25%); often when disease is active
• Cytopenias due to autoimmune complication does not impact staging survival
• ITP and AIHA can occur concomitantly (Evan’s Syndrome)
• Most common presentation of AIHA or ITP is at disease progression or trigger event (infection, initiation of new treatment, etc)
• Pathophysiology
• Most common etiology of auto-antibody is polyclonal IgG (from autoreactive B-cell)
• Approximately 10% of patients (more commonly with AIHA) will have monoclonal IgM antibody and cold agglutinin (diagnosis can be tricky)
• Rarely will lack antibody and have T-cell mediated autoimmune destruction (LGL or polyclonal)

Autoimmune Cytopenias of CLL

My Approach to Treatment

AIHA

• Treat in presence of anemia and diagnosis
• If patient symptomatic/unstable and can not cross-match, transfuse
• Initial: prednisone (1mg/kg/d) +/- rituximab (375 mg/m² Qwk x 4)
• Salvage: IVIG, cyclosporin, cyclophosphamide, mycophenolate, splenectomy
• BTKi (ibrutinib or acalabrutinib) almost always enables withdraw of immune suppression

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ITP

• Treat when platelets are < 50 x10⁹/L
• Generally do bone marrow to rule out alterative diagnosis
• Initial: prednisone (1mg/kg/d) +/- rituximab (375 mg/m² Qwk x 4)
• Salvage: splenectomy, TPO-RA (romiplostim and eltrombopag), cyclosporin, and IVIG
• BTKi (ibrutinib or acalabrutinib) almost always enables withdraw of immune suppression

• Most common cause of morbidity and mortality in CLL with bacterial, viral and later opportunistic infections being problematic
• Preventative strategies should include:
• Pneumococcal vaccine (Prevnar 20) at diagnosis and Q5 years (Suboptimal response versus control population)
• Influenza and Covid vaccine yearly (poor response); aggressive treatment for both
• Shingrex vaccine at diagnosis and boster (sub-optimal response versus control population)
• RSV vaccine at diagnosis (60 yrs and over is approval indication)
• No live vaccines due to risk of systemic dissemination
• IVIG use:
• Although expensive, this is very effective to augment treatment of recurrent infections not cleared with multiple antibiotic courses
• Post influenza if serum IgG low

Infections in CLL and Management

Diagnosis and Management?

Pain and burning on left side of face with tearing

Secondary Malignancies

• Overall incidence more common CLL
• Skin (squamous, basal cell, melanoma, merkel cell carcinoma)
• Solid tumor (head/neck, lung, renal, prostate, and colon cancer) Heme (treatment related myeloid malignancy, clonally unrelated DLBCL, and Hodgkin’s disease)
• My approach
• Yearly dermatology skin exam; avoid unprotected sun exposure
• Aggressive prevention efforts to include colonoscopies, yearly PSA, mammogram, PAP smears, Chest CT screening (for prior smokers)
• Avoid chemotherapy (risk factor for trMN)

Merkel Cell Carcinoma

Rapidly growing mass that is hard and fixed

Transformation of CLL

• Types
• Diffuse large B-cell lymphoma (Richter’s transformation)
• Hodgkin’s Disease
• Prolymphocytic leukemia (PLL) [>55% prolymphocytes in blood or node] which behaves clinically different than DLBCL
• DLBCL most common and has pathophysiology not fully explained but driven by TP53 mutation and MYC in some
• Typical presentation includes asymmetric node enlargement, B-symptoms, and elevated LDH
• PET scan in this setting is helpful to localize biopsy

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Richter’s Transformation

Lymph Node

Blood

Richter’s Look Alike: HSV Lymphadenitis

CLL Transformation Treatment

Richter’s Transformation

• Clonally un-related—treat as de novo DLBCL with curative intent
• Clonally related—poor outcome with chemotherapy
• Consider non-chemotherapy bridge or trial to CAR-T cells or allogeneic SCT
• Preliminary data suggest venetoclax + BTKi or chemo may offer benefit

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Hodgkin’s Disease

• Unclear if clonally related status matters
• Treat as de novo Hodgkin’s Disease with curative intent
• More common escape pattern for BTKi?
• Rarely can be EBV driven where immune suppression withdrawal can be considered

• No advantage to treating CLL until symptoms develop, irrespective of genomic features
• NCCN criteria for treatment (primary and in relapse)
• Enlarging, symptomatic lymph nodes (> 10 cm)
• Enlarging, symptomatic spleen (> 6 cm)
• Cytopenias due to CLL (hemoglobin < 11, platelets < 100)
• Constitutional symptoms due to disease (fatigue, B-symptoms)
• Poorly controlled AIHA or ITP
• Lymphocyte count < 300 x 109/L not an indication for Rx
• Lymphocyte doubling time < 6 months or 50% increase over a 2-month time period is NOT an indication for Rx

When to Treat CLL Patients

History of Therapy of CLL

• Alkylator therapy (chlorambucil, cyclophosphamide)—1950’s palliative therapy
• Intensive chemotherapy-disease free survival (DFS) but not overall survival (OS) increase
• Nucleoside analog therapy (fludarabine)—1991 minimal OS
• CD20 antibody therapy (rituximab and obinutuzumab) with chemotherapy (CLB or FC)—2001 modest OS
• New targeted therapy ibrutinib (2014), venetoclax (2016), and acalabrutinib (2019) significant increase in OS

Initial Management of CLL in 2025

• Chemo-immunotherapy
• Fit/younger patients: Fludarabine, cyclophosphamide, and rituximab (FCR)

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• Bruton’s tyrosine kinase inhibitor
• Acalabrutinib+/- CD20 antibody
• Zanabrutinib

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• BCL2 interfering molecule
• Venetoclax + obinutuzumab

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MDA FCR Long Term Follow Up: Cure of IGHVH Mutated CLL?

(56%)

(10%)

Median F/U 12.8 years

Thompson and Keating, Blood 127:303-9, 2016

Reasonable for young IgVH mutated patients; concern includes long-term side effects of chemotherapy

Prof Michael Keating

Targeting BCR: Where BTK Fits (2^nd Generation Only)

All Three Axis are Important to CLL: only target to hit all three

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Bruton’s Tyrosine Kinase (BTK)

• Member of the Tec family of kinases
• Roles in signaling (e.g. BCR, TLR), as well as transcription
• Leads to activation of PI3K, PLCγ2, MAPK, and NF-kB pathways
• BTK-deficient models have predominantly a B-cell phenotype
• XID (BTK mutant) mouse: Diminished B-cells, B1 lymphocytes, and impaired BCR signaling. Modest effect on other immune effector cells (NK, monocyte, macrophage, dendritic cells) due to redundancy of TEC family members
• BTK knockout mouse: More profound B-cell defect due to loss of chaperone and transcriptional function
• BTK mutations in humans give rise to X-linked agamma-globulinaemia, an inherited disorder with decreased IgG and absence of B-cells

Ibrutinib: First Potent Irreversible BTK Inhibitor

29

• Forms a specific and irreversible bond with cysteine-481 in BTK with IC₅₀ = 0.5 nM
• Alternative irreversible targets include EGFR, ERB3, ERB4, BMX, ITK, TEC and BLK; many reversible targets

Honigberg et al: PNAS 2010; 107:13075

Ibrutinib Pivotal Phase II Study

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O’Brien S and Byrd JC: Lancet Oncol 15:48-58, 2014

Byrd JC and O’Brien S: N Engl J Med 369:32- 2042, 2013

Byrd JC and O’Brien S: Blood 125:2497-506, 2015

O’Brien S and Byrd JC: Blood 131: 1910-1919, 2018

Byrd JC and O’Brien S: Clin Cancer Res 2020

• 132 patients with CLL enrolled onto this study
• 31 pts age > 65 years with symptomatic disease but no prior therapy
• 101 pts of any age with relapsed/refractory disease
• Median 4 prior therapies
• 57% Advanced (Stage 3 or 4) disease
• 35% Del(17)(p13.1)
• Dosed at 420 mg or 840 mg dose Qd with similar response and PFS (data therefore merged)
• Early lymphocytosis noted but ignored

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Progression Free Survival: PCYC-1102-1103 (9-yrs)

Progression-Free Survival

Overall Survival

Byrd JC and O’Brien S: Clin Cancer Res 2020

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Onset of Most Grade ≥3 Adverse Events Decreased Over Time

*

Byrd JC and O’Brien S: Clin Cancer Res 2020

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Phase 3 Studies of Ibrutinib vs Chemotherapy or Chemoimmunotherapy: All Superior

Resonate 2: Chlorambucil versus Ibrutinib---Improved response, PFS and OS (Burger JA et al. NEJM 373:2425-2437, 2015)

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Alliance Study: Bendamustine + Rituximab versus Ibrutinib + Rituximab versus Ibrutinib alone in CLL pts >64 years—Improved response and PFS with Ibrutinib regimens and no benefit to Rituximab (Woyach et al: NEJM 379:2517-2528 2019)

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ECOG Study: Fludarabine + Cyclophosphamide + Rituximab versus Ibrutinib + Rituximab in CLL pts < 70 years --improved response, PFS, and OS with ibrutinib + Rituximab regimen (Shanafelt et al, NEJM 381:432-443, 2019)

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CLL 14: Chlorambucil + Obinutuzumab versus Ibrutinib + Obinotuzumab in unfit CLL pts—Improved response and PFS with Ibrutinib combination (Moreno et al, Lancet Onc 20:43-56, 2019)

First (Ibrutinib) versus Second Generation (Acalabrutinib or Zanabrutinib) Covalent BTKi

1

Potential off-target effects of Ibrutinib include:

Acalabrutinib my general choice—more selective and novel pharmacophore

An Alternative to Ibrutinib:�Acalabrutinib in Treatment-Naïve CLL

• Primary endpoint: PFS

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Obinutuzumab + chlorambucil

N = 535 randomized

• Patients with treatment-naïve CLL per iwCLL criteria, aged ≥65 y or <65 y with coexisting conditions (CIRS score >6, creatinine clearance <70 mL/min)

Acalabrutinib + obinutuzumab

Acalabrutinib monotherapy

• Acalabrutinib: 100 mg twice daily continuously
• Obinutuzumab: 1,000 mg on d 1, 2, 8, and 15 of cycle 2, and d 1 of subsequent cycles
• Chlorambucil: 0.5 mg/kg on d 1 and 15 of each cycle

• Patient demographics and typical of other initial Rx studies

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Sharman J and Byrd JC Lancet 395:1278-1291, 2020

ELEVATE-TN 6-Yr Update: PFS (Primary Endpoint)

Sharman J et al: Blood (in revisión)

Slide credit: clinicaloptions.com

ELEVATE-TN 6-Yr Update: Adverse Events

Sharman J et al: Blood 2025 (in revisión)

ELEVATE-TN: Investigator-Assessed ORR

Sharman. ASCO 2022. Abstr 7539. Reproduced with permission.

Sharman J et al: Blood 2025 (in revisión)

Slide credit: clinicaloptions.com

ELEVATE-TN 6-Yr Update: OS

• 72 patients (41%) in the O+Clb arm crossed over to acalabrutinib monotherapy arm.

Sharman J et al: Blood 2025 (in revisión)

�

Slide credit: clinicaloptions.com

SEQUOIA: Study Design and Outcome

^aDefined as Cumulative Illness Rating Scale > 6, creatinine clearance < 70 mL/min, or a history of previous severe infection or multiple infections within the last 2 years. ^bOne prespecified interim analysis was planned at approximately 86 events; efficacy analyses were ITT. ^cIRC and investigator response assessments per modified iwCLL criteria for CLL^2,3 and Lugano criteria for SLL.⁴

bid, twice daily; C, cycle; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; CYP3A, cytochrome P450, family 3, subfamily A; D, day; del(17p), chromosome 17p deletion;

FCR, fludarabine, cyclophosphamide, and rituximab; FISH, fluorescence in-situ hybridization; IGHV, gene encoding the immunoglobulin heavy chain variable region; IRC, independent review committee; ITT, intent to treat; iwCLL, International Workshop on CLL; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; R, randomized.

1. Tedeschi A, et al. ASH 2021. Abstract 67; 2. Hallek M, et al. Blood. 2008;111:5446-5456; 3. Cheson BD, et al. J Clin Oncol. 2012;30:2820-2822; 4. Cheson BD, et al. J Clin Oncol. 2014;32:3059-3067.

Cohort 1

without del(17p) by central FISH (n=479)

open-label

Arm C: Zanubrutinib

Cohort 2

(n=111)

Arm D: Zanubrutinib + Venetoclax

Cohort 3¹

planned n ~110

R 1:1

Key Eligibility Criteria

• Untreated CLL/SLL
• Met iwCLL criteria for treatment
• ≥ 65 y of age OR unsuitable for treatment with FCR^a
• Anticoagulation and CYP3A inhibitors allowed

ClinicalTrials.gov: NCT03336333

Stratification Factors

Age, Binet stage,

IGHV status, geographic region

Arm A: Zanubrutinib

160 mg bid until PD, intolerable toxicity, or end of study

Arm B: Bendamustine (90 mg/m² D1 & D2)

+ Rituximab (375 mg/m² C1, then 500 mg/m² C2-C6)

x 6 cycles

• PFS (investigator)^c
• ORR (IRC and investigator)^c
• OS
• Safety

95% ORR 7% CR

85% ORR 15% CR

95% ORR 7% CR

Tam CS, et al: Lancet Oncol 2022; 23: 1031–43

SEQUOIA PFS Per IRC Assessment

BR, bendamustine + rituximab; CI, confidence interval; IRC, independent review committee; PFS, progression-free survival.

3 6 9 12 15 18 21 24 27 30 33 36 39 42

Months

20

10

0

69.5% (95% CI, 62.4–75.5)

BR

Censored

Hazard ratio: 0.42 (95% CI, 0.27–0.63); 2-sided P < .0001

0

Progression-Free Survival Probability

^aDefined as Cumulative Illness Rating Scale > 6, creatinine clearance < 70 mL/min, or a history of previous severe infection or multiple infections within the last 2 years. ^bOne prespecified interim analysis was planned at approximately 86 events; efficacy analyses were ITT. ^cIRC and investigator response assessments per modified iwCLL criteria for CLL^2,3 and Lugano criteria for SLL.⁴

bid, twice daily; C, cycle; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; CYP3A, cytochrome P450, family 3, subfamily A; D, day; del(17p), chromosome 17p deletion;

FCR, fludarabine, cyclophosphamide, and rituximab; FISH, fluorescence in-situ hybridization; IGHV, gene encoding the immunoglobulin heavy chain variable region; IRC, independent review committee; ITT, intent to treat; iwCLL, International Workshop on CLL; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; R, randomized.

1. Tedeschi A, et al. ASH 2021. Abstract 67; 2. Hallek M, et al. Blood. 2008;111:5446-5456; 3. Cheson BD, et al. J Clin Oncol. 2012;30:2820-2822; 4. Cheson BD, et al. J Clin Oncol. 2014;32:3059-3067.

Tam CS, et al: Lancet Oncol 2022; 23: 1031–43

Overall survival superimposable

Adverse Events of Interest

Tam CS, et al: Lancet Oncol 2022; 23: 1031–43

Conclusions from These Studies Relative to Initial Therapy Recommendations for CLL

• Second generation BTKi (Acalabrutinib or Zanabrutinib) should be used when starting new patients on BTKi

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• Acalabrutinib has extended long-term follow up data and combination experience that justify its use in most cases
• When use of Obinutuzumab is appropriate
• In patients with a risk of or active hypertension

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• Zanubrutinib has less follow up, minimal combination data, and resistance pattern of concern; my use is in
• Patients with significant migraine headaches
• Patients needing proton pump inhibitors

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• Zanabrutinib and acalabrutinib both irreversibly inhibit 5 targets (some immunosuppressive) providing opportunity to improve

BCL-2 as a Target in CLL

• BCL-2 is involved in multiple cellular pathways including
• Preventing apoptosis
• Mitochondrial shape and localization
• Cellular calcium flux (via IP3 complex)
• Autophagy
• BCL-2 is highly over-expressed in CLL cells and these cells are primed for apoptosis based upon interruption of bcl-2 interaction with BAX and BIM proteins
• Venetoclax, the first BH3 mimetic that disrupts interaction with BAX and BAK highly active clinically in CLL with dose limiting toxicity tumor lysis

Venetoclax: A New CLL Drug That Interferes with BCL-2 interaction with binding partners

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On target mechanistic side effects

Immune suppression (B-cells >NK cells > CD8 T-cells)

Causes clonal hematopoiesis in stem cells (BAX mutations)

• Second-generation selective BCL2 BH3 domain inhibition

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• 116 previously-treated patients treated in Phase 1 dose escalation (n=56) or expansion (n=60) administered venetoclax until progressive disease

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• Toxicity included mainly diarrhea (mild), nausea, and neutropenia (responsive to G-CSF); tumor lysis syndrome manageable
• Risk mitigation for tumor lysis requires stepped up dosing schedule over 5 weeks with close monitoring for this side effect and hospitalization for first dose if high risk

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• 79% ORR with 20% CR (5% MRD-negative by flow cytometry) with 15 month PFS of 69% for patients dosed at 400 mg/m²; remissions shorter for del(17p13.1)

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Response lower in pts with ibrutinib resistant disease (65% ORR) and PFS less durable (24 months) versus no ibrutinib

Venetoclax in Relapsed CLL/SLL

Roberts et al., New Engl J Med 374:311-22, 2016

Jones et al, Lancet Oncology 19:65-75, 2018

CLL14: Initial Treatment with Venetoclax + Obinutuzumab

Patients with previously untreated CLL and coexisting medical conditions (N = 432)

Venetoclax PO 5-wk ramp up from 20 to 400 mg/day starting

on Day 22 of cycle 1, then 400 mg/day until end of cycle 12

+ Obinutuzumab IV 1000 mg Days 1, 8, 15 of cycle 1,*�then 1000 mg Day 1 of cycles 2-6�(n = 216)

Chlorambucil PO 0.5 mg/kg Days 1, 15 of cycles 1-12

+ Obinutuzumab IV 1000 mg Days 1-2, 8, 15 of cycle 1,*�then 1000 mg Day 1 in cycles 2-6�(n = 216)

• Open-label, multicenter, randomized phase III trial

• Primary endpoint: investigator-assessed PFS
• Secondary endpoints: IRC-assessed PFS, ORR, MRD negativity, OS, safety

Total 28-day cycles

• Venetoclax: 12
• Chlorambucil: 12
• Obinutuzumab: 6

This trial in previously untreated patients supported by multiple phase 2/3 studies in relapse disease

Fischer, K et al: NEJM 380:2225, 2019

Al-Sawaf, O, et al: Blood 144: 1924, 2024

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CLL14: Investigator-Assessed PFS (Primary Endpoint)

Fischer, K et al: NEJM 380:2225, 2019

Al-Sawaf, O, et al: Blood 144: 1924, 2024

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 HR 0.33 [95% CI 0.25-0.45] p < 0.0001

CLL 14 Overall Survival: A Lesson for FDA

CLB + Obin

↓

↑

Ven + Obin

HR, 1.24; 95% CI, 0.64 to 2.40, 3-years

C+ O 4% Rx related death

V + O 8% Rx related deaths

Fischer K et al: NEJM. 380:2225, 2019

Al-Sawaf, O, et al: Blood 144: 1924, 2024

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HR, 0.69 [0.48-1.01] p= .052, 6 years 

Ven + Obin

↓

↑

CLB + Obin

Venetoclax + Obinutuzumab Less Effective in del(17)(p13.1)

Al-Sawaf, O, et al: Blood 144: 1924, 2024

Where Does This Bring Us?

• IgHV mutated, young patient with CLL
• FCR offers opportunity of cure; 2^nd generation BTKi ± Obinotuzumab or VO time limited therapy suggested as an alternative but no curative data as of yet
• For all other CLL patients
• BTKi has 5 randomized trials against chemo or chemoimmunotherapy demonstrating
• Progression-free survival advantage in all trials
• Overall survival advantage against FCR, CLB, CLB + Obinutuzumab
• Long-term follow up exists for this class of drugs
• Venetoclax + Obinutuzumab
• Progression-free survival in one trial, but hazard ratio for overall survival only crosses 1 at 4 years and still not statistically significant versus CLB + Obinutuzumab at 6 years
• Less reliable follow up for secondary cancers and other late morbidity due to nature of study

Use of BTKi + Venetoclax Off study?

• While high CR and extended PFS exists with combination therapies, possible concern exists for
• Extended immune suppression, long-term infections, and 2^nd cancers
• Clonal hematopoiesis and trMN from venetoclax

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• Until Phase 3 combination data of VEN/BTKi are out with extended follow up showing safety and/or salvage data, I do not combine these off trials
• Phase 3 study of IVR versus IR shows no PFS benefit due to higher risk of covid deaths (Woyach J, et al: ASCO 2023)
• Phase 3 study of AV but not AVO versus FCR/BR shows PFS benefit due to high risk of covid deaths (Brown et al: N Engl J Med 392: 748, 2025)

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Conclusions

• CLL is defined by both immunophenotype and sufficient malignant lymphocytosis in blood or presence of lymph node enlargement (by exam), organomegaly, or cytopenias
• Therapy for CLL is best initiated based upon symptoms of patients and not lab or exam findings
• BTKi (2^nd generation) have the most relevant data for CLL therapy and are my first choice in most patients
• Time limited therapy with Venetoclax + Obintuzumab represents an alternative option for non-del(17p)/TP53 mutated patients
• Combination data with Acalabrutinib + Venetoclax has improved PFS versus chemoimmunotherapy (FCR or BR) but lacks OS due to confounding covid-19 data; with extended follow up may be approved as initial therapy making it another time limited therapy.