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تعداد آیتم قابل مشاهده باقیمانده : -12 مورد

Evaluating response to treatment of chronic lymphocytic leukemia

Evaluating response to treatment of chronic lymphocytic leukemia
Author:
Stephan Stilgenbauer, MD
Section Editor:
Jennifer Woyach, MD
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Apr 2025. | This topic last updated: Apr 28, 2025.

INTRODUCTION — 

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a chronic lymphoproliferative disorder (lymphoid neoplasm) characterized by a progressive accumulation of a usually monoclonal population of functionally incompetent lymphocytes. CLL is considered to be identical (ie, one disease with different manifestations) to the mature B cell neoplasm SLL. The term CLL is used when the disease manifests primarily in the bone marrow and blood, while the term SLL is used when involvement is primarily nodal (ie, absolute B lymphocyte count in the peripheral blood <5000/microL [5 x 109/L] with lymphadenopathy). (See "Classification of hematopoietic neoplasms" and "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Treatment is indicated when there are disease-related symptoms or evidence of progression (ie, "active disease" (table 1)). Except for allogeneic hematopoietic cell transplantation (HCT) and possibly aggressive chemoimmunotherapy in a small minority of patients, both at the cost of increased toxicity, treatment options for CLL are not curative. The International Workshop Group on CLL (iwCLL) published a revised version of the guidelines for evaluating disease response that were published in 1996 by the National Cancer Institute Working Group (NCI/WG) (table 2) [1-4]. These efforts in developing standardized criteria for the evaluation of response have also allowed comparison of results from different therapeutic trials.

The response evaluation and criteria will be reviewed here. The initial treatment of CLL/SLL, the treatment of relapsed or refractory disease, and the management of the complications of CLL/SLL are discussed separately.

●(See "Overview of the treatment of chronic lymphocytic leukemia".)

●(See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

●(See "Overview of the complications of chronic lymphocytic leukemia".)

RESPONSE ASSESSMENT

Evaluation — Patients should be evaluated before each treatment cycle to determine how their disease is responding to therapy. The specific evaluation performed to assess the response to therapy differs depending on whether the patient is enrolled in a therapeutic research protocol (clinical trial) or is being treated in general practice [4]:

●For those treated in general practice, response evaluation should always include a history, physical examination, and complete blood count with differential. The history should include questions regarding constitutional symptoms such as unintentional weight loss, fatigue, fevers, and night sweats. The physical examination should pay particular attention to the evaluation of lymphadenopathy, hepatomegaly, and splenomegaly.

Although bone marrow biopsy with absence of CLL infiltrates on histology is required to confirm a complete remission (CR), it is not always recommended in general practice as it may not impact management. Bone marrow evaluation is indicated in patients with cytopenias of uncertain cause.

If the above clinical and hematologic parameters are compatible with a CR and the clinician chooses not to perform a bone marrow biopsy, the documented response can be either "partial remission" or "clinical CR, bone marrow biopsy not performed." The latter is not an official response category and is not used in clinical trials. However, this phrasing allows the patient to avoid bone marrow evaluation, limits ambiguity, and allows for more accurate data capture in registry studies or upon enrollment on a future clinical trial.

●For those treated as a part of a research protocol, the evaluation includes all that was just discussed. In addition, occult involvement is evaluated using computed tomography (CT) of the chest, abdomen, and pelvis. Patients should also undergo bone marrow aspirate and biopsy two months after all other findings are found to be compatible with CR. Assessment for measurable residual disease (MRD, also called "minimal residual disease") is often performed using four- to eight-color flow cytometry, polymerase chain reaction (PCR)-based methods, or next-generation sequencing. A lymph node biopsy should be obtained if transformation into an aggressive lymphoma is suspected (ie, Richter transformation). Richter transformation is suspected in patients who develop rapidly progressive lymphadenopathy or extranodal sites of disease, systemic symptoms, or elevated levels of serum lactate dehydrogenase. (See 'Measurable residual disease' below and "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Clinical features' and "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Image-directed biopsy'.)

The use of imaging studies is reserved for the research setting because it has not demonstrated a clinical benefit and is unlikely to change the management of most patients. This was demonstrated in a meta-analysis that included 1372 patients receiving initial therapy for CLL [5]. Of the 481 episodes of progressive disease, 77 percent were detected by clinical symptoms or changes in the blood counts. A decision to treat relapsed disease was made based on the results of CT or ultrasound alone in only two patients.

Timing — For patients treated with a therapy for a defined treatment duration, response assessment should be performed at least two months after the completion of therapy [4]. For those receiving continued therapies or treatment strategies that include a maintenance phase, response assessment should be performed at least two months after achieving "maximum response" defined as a treatment phase where no additional improvement is seen during at least two months of therapy.

RESPONSE CRITERIA

Response categories — In 2018, the International Workshop Group on CLL (iwCLL) published a revised version of the guidelines for evaluating disease response that were published in 1996 by the National Cancer Institute Working Group (NCI/WG) [1-4]. Response is categorized as complete remission (CR), CR with incomplete marrow recovery (CRi), partial remission (PR), stable disease, or progressive disease (table 2). An assessment for measurable residual disease (MRD, also called "minimal residual disease") is used in the context of clinical trials.

These guidelines rely on surrogate markers of tumor burden (eg, blood lymphocyte count, lymph node size, spleen size) that have predicted clinical benefit in patients treated with traditional chemotherapy agents. Some surrogate markers may not accurately predict clinical benefit in patients treated with newer agents [6].

CR categories

Complete remission — A CR requires all of the following to be present at least two months after completion of therapy (table 2) [4]:

●Absence of constitutional symptoms attributable to CLL. These include ≥10 percent unintentional weight loss within the previous six months, fatigue that interferes with work or usual activities, fevers greater than 100.5°F (>38°C) for ≥2 weeks, or night sweats for >1 month.

●No lymph nodes ≥1.5 cm in diameter by physical examination (or by computed tomography [CT] if on a clinical trial).

●No hepatomegaly or splenomegaly by physical examination. For patients enrolled on a clinical trial, CT can be used to assess hepatosplenomegaly if the physical examination is inconclusive.

●Absolute lymphocyte count <4000/microL (4 x 109/L).

●Absolute neutrophil count ≥1500/microL (1.5 x 109/L) without growth factor support.

●Platelet count ≥100,000/microL (100 x 109/L) without growth factor support.

●Untransfused hemoglobin concentration ≥11 g/dL (110 g/L) without growth factor support.

●A unilateral bone marrow aspirate and biopsy is required to confirm the CR. If a hypocellular marrow is found, the bone marrow aspirate and biopsy should be repeated in four to six weeks, provided the peripheral blood counts have recovered. The marrow should be at least normocellular for age and free of clonal CLL cells by morphology and immunohistochemistry. If nodules (lymphoid aggregates) are found on bone marrow biopsy, these may represent residual disease (ie, nodular PR) and so should be assessed by immunohistochemistry to determine if they are principally comprised of CLL cells or of lymphocytes other than CLL cells or T cells. If nodules are not composed of CLL cells, a CR can be documented provided all other criteria are met. (See 'Nodular PR' below.)

Although bone marrow biopsy is required to confirm a CR, it is not always recommended in general practice as it may not impact management. If the above clinical and hematologic parameters are compatible with a CR and the clinician chooses not to perform a bone marrow biopsy, the documented response can be either "partial remission" or "clinical CR, bone marrow biopsy not performed."

Complete remission with incomplete bone marrow recovery — A separate category is used for patients who fulfill all of the criteria for a CR yet have persistent neutropenia, anemia, or thrombocytopenia unrelated to their disease, but likely related to drug toxicity [4]. These patients must have a normal bone marrow aspirate and biopsy with no evidence of clonal infiltrates.

Measurable residual disease — Measurable residual disease (MRD, also called "minimal residual disease") testing has been incorporated into response assessment for patients enrolled in clinical trials. Its role in the routine care of patients with CLL is more uncertain. While MRD testing may provide prognostic guidance following the completion of therapy, it should not be used to direct treatment. Guidelines differ in their approach to MRD testing; iwCLL response criteria and other international guidelines reserve MRD testing for clinical trials and state that MRD has no role in the routine care of patients with CLL [4,7] while the National Comprehensive Cancer Network (NCCN) states that MRD may be useful for prognosis, but should not be used for treatment decisions [8].

In trials, MRD testing uses multicolor flow cytometry, real-time quantitative polymerase chain reaction, and/or next-generation sequencing to look for small malignant clones in patients following chemotherapy [7,9-11]. While the sensitivity depends on the technique used, modern assays for MRD can reliably detect approximately one CLL cell per 10,000 leukocytes [4,7]. Those who have less than one CLL cell per 10,000 leukocytes have undetectable MRD.

The most sensitive methods are eight-color flow cytometry and next-generation sequencing; both can detect up to one CLL cell per 1,000,000 leukocytes (sensitivity 10-6) [7]. Next-generation sequencing of the blood or bone marrow is available commercially and is the only method that has regulatory approval in the United States.    

Clinical trial data suggest that patients who have high levels of detectable MRD have inferior clinical outcomes when compared with those with low levels of MRD or with undetectable MRD [7,12-18], although it is unclear whether this correlation is maintained across all treatment regimens. As an example, in an analysis of data from three trials of first-line chemoimmunotherapy, MRD detection was associated with inferior progression-free survival (PFS) [15]. A greater treatment effect on MRD correlated with a larger impact on PFS. By contrast, the prognostic value of MRD with targeted therapies may depend on the regimen used and the genetics of the tumor. Studies of continuous treatment with a Bruton tyrosine kinase (BTK) inhibitor have demonstrated excellent PFS despite low rates of undetectable MRD (eg, ELEVATE-TN [19-21], ECOG-ACRIN E1912 [22,23]); whereas, a correlation between MRD status and PFS has been seen in some trials of fixed-duration targeted therapy regimens (eg, CLL13 [24,25], CLL14 [26-32], CAPTIVATE [33-35]), but others have demonstrated good PFS regardless of MRD achieved (eg, GLOW [36-38]). IGHV mutation status may impact the likelihood of achieving undetectable MRD and its prognostic impact in those treated with ibrutinib plus venetoclax. In the ibrutinib plus venetoclax containing arm of the Flair study, patients with mutated IGHV were less likely to achieve undetectable MRD but still had superior PFS as compared with those with unmutated IGHV [39]. Prospective trials are necessary to determine whether there is a significant clinical benefit from adjusting treatment based on MRD status (eg, additional therapy to convert a response from a CR with MRD to a CR with undetectable MRD).

PR categories

Partial remission — A PR requires demonstration of response both clinically and hematologically (table 2).

At least two of these clinical criteria must be documented [4]:

●A decrease in the peripheral absolute lymphocyte count by at least 50 percent from the level prior to therapy.

●A reduction in previously enlarged nodes by at least 50 percent with no increase in the size of any single lymph node and no new enlarged lymph nodes. For these purposes, the size of previously enlarged nodes is defined by the sum of the products of up to six lymph nodes. An increase of <25 percent in a lymph node <1.5 cm is not considered significant.

●A decrease in the size of the liver and/or spleen by at least 50 percent based upon palpation or ultrasound.

One of the following hematologic parameters must be met in addition to two of the above criteria in order to qualify for a PR:

●Platelet count ≥100,000/microL (100 x 109/L) or at least 50 percent improvement over baseline (if this value was abnormally low at baseline).

●Hemoglobin concentration ≥11 g/dL (110 g/L) or 50 percent improvement over baseline (if this value was abnormally low at baseline) without red blood cell transfusions or erythropoietin support.

Treatment with certain drugs (eg, antagonists of the B cell receptor signaling pathway) can result in tumor mobilization and lymphocytosis that is not thought to represent progressive disease. For patients treated with these drugs, the label "progressive disease" should be reserved for cases that demonstrate other definitive signs of progression (eg, anemia, thrombocytopenia, lymphadenopathy, hepatosplenomegaly) in addition to increased lymphocytosis. Lymphocytosis alone should not interfere with the identification of a partial response. (See 'Progressive disease' below.)

While not included as an official response category in the iwCLL, the term "partial response with lymphocytosis" has been used to describe a reduction in lymphadenopathy in the setting of persistent lymphocytosis [6]. This term was initially designated for use in trials of B cell receptor and adhesion-related kinase inhibitors (eg, ibrutinib, idelalisib). Treatment with these agents commonly results in tumor mobilization from tissues into the peripheral blood, characterized by the rapid development of lymphocytosis, often with a concomitant shrinkage of involved lymph nodes. The lymphocytosis usually resolves with continued treatment but may be persistent.

Nodular PR — Persistent bone marrow nodules on bone marrow biopsy in patients achieving a CR or PR are classified separately as a nodular PR [4]. Lymphoid aggregates should be evaluated with immunohistochemistry to determine whether they are comprised of CLL cells, lymphocytes other than CLL cells, or T cells. Nodular PR is confirmed when the lymphoid aggregates are clonal lymphocytes with an immunophenotype consistent with CLL (monoclonal light chains, expression of B cell antigens, and CD5 expression). If nodules are not composed of CLL cells, a CR can be documented provided all other criteria are met. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Immunophenotype'.)

Progressive disease — Progressive disease (PD) is defined by the presence of one or more of the following (table 2) [4]:

●The appearance of a newly enlarged lymph node (≥1.5 cm), splenomegaly, hepatomegaly, or other organ infiltration.

●An increase of 50 percent or more in size of a previously involved site (eg, lymph nodes, spleen, or liver) measuring ≥1.5 cm.

●An increase of 50 percent or more in the total circulating lymphocyte count with at least 5000 lymphocytes per microL. For patients treated with therapies that may cause lymphocytosis (eg, kinase inhibitors), an increase in blood lymphocyte count, by itself, does not uniformly indicate an increased tumor burden, but may reflect redistribution of leukemia cells from lymphoid tissues to the blood. In such cases, increased lymphocytosis alone is not a sign of treatment failure or progressive disease.

●Development of neutropenia, anemia, or thrombocytopenia attributable to CLL. Cytopenias cannot be used to determine disease progression during active therapy since they may be due to administered cytotoxic agents. Cytopenias that occur at least three months after the completion of therapy and are accompanied by an infiltrate of clonal CLL cells on bone marrow biopsy can be used to define disease progression. Specific values that define progression include a decrease in hemoglobin level by more than 2 g/dL (20 g/L) or to less than 10 g/dL (100 g/L) or a decrease in platelet count by more than 50 percent or to less than 100,000/microL (100 x 109/L).

●Richter transformation (the development of a more aggressive lymphoma subtype) as documented by tissue biopsy. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Image-directed biopsy'.)

Surrogate markers of tumor burden (eg, blood lymphocyte count, lymph node size, spleen size) may not accurately predict clinical benefit in patients treated with newer agents (eg, immunomodulatory drugs, B cell receptor targeted drugs). Conclusions from a Lymphoma Research Foundation-sponsored workshop highlight the need to consider the following caveats with regard to PD [6]:

●Tumor flare – Tumor flare is a reaction to drug treatment, predominantly characterized by the rapid development of painful and swollen lymphadenopathy with or without fever, bone pain, rash, and lymphocytosis [40]. It is most commonly seen in patients with CLL treated with immunomodulatory drugs such as thalidomide and lenalidomide. Symptoms may resolve after a drug holiday and/or be mitigated by pretreatment with other agents (eg, nonsteroidal anti-inflammatory drugs, prednisone, rituximab). For patients receiving an immunomodulatory drug, clinicians should reserve the label PD for cases that demonstrate symptoms of PD not typical of tumor flare or that fail to resolve after the introduction of interventions known to mitigate tumor flare.

●Tumor mobilization – Tumor mobilization from tissues into the peripheral blood is characterized by the rapid development of lymphocytosis frequently persisting over months, often with a concomitant shrinkage of involved lymph nodes. It is most commonly seen in patients with CLL treated with B cell receptor and adhesion-related kinase inhibitors (eg, BTK and Pi3K inhibitors) [41-44]. The lymphocytosis usually resolves with continued treatment but may be persistent. For patients receiving a drug associated with tumor mobilization, clinicians should reserve the label PD for cases that demonstrate other definitive signs of PD (eg, anemia, thrombocytopenia, lymphadenopathy, hepatosplenomegaly). Lymphocytosis alone should not interfere with the identification of a partial response. (See 'Partial remission' above.)

These suggestions incorporate clinical trial experience using these novel agents into the evaluation of PD in an attempt to avoid underestimating the clinical benefit of these agents.

Stable disease — Patients who do not meet the criteria for a CR, PR, or PD, have stable disease. Stable disease is therapeutically equivalent to a nonresponse (ie, refractory disease) [4]. (See 'Refractory disease' below.)

RELAPSED DISEASE — 

Relapsed disease occurs in patients who have previously achieved either a complete or partial remission by the above criteria but then develop progressive disease after a period of six months or more from end of last treatment [4]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

REFRACTORY DISEASE — 

Patients who fail to achieve either a partial or complete remission with therapy or those who develop disease progression within six months of therapy have refractory disease [4]. These treatment failures include patients with stable disease, nonresponsive disease, progressive disease, or death from any cause. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic lymphocytic leukemia/small lymphocytic lymphoma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)")

SUMMARY

●iwCLL 2018 guidelines – For evaluating disease response, the International Workshop on chronic lymphocytic leukemia (iwCLL) has published a revised version of the guidelines initially proposed in 1996 by the National Cancer Institute Working Group (NCI/WG) (table 2). These efforts in developing standardized criteria for the evaluation of response allow comparison of results from different therapeutic trials. (See 'Introduction' above.)

●Response assessment – For those treated in general practice, response evaluation should always include a history, physical examination, and complete blood count with differential. (See 'Response assessment' above.)

The history should include questions regarding constitutional symptoms such as unintentional weight loss, fatigue, fevers, and night sweats.

The physical examination should pay particular attention to the evaluation of lymphadenopathy, hepatomegaly, and splenomegaly.

Although bone marrow biopsy is required to confirm a complete remission, it is not always recommended in general practice as it may not impact management. Bone marrow evaluation is indicated in patients with cytopenias of uncertain cause.

●Response criteria – Response is categorized as (table 2) (see 'Response categories' above):

•Complete remission (CR)

•CR with incomplete marrow recovery (CRi)

•Partial remission (PR)

•Nodular PR

•Stable disease

•Progressive disease

If the clinical and hematologic parameters are compatible with a CR and the clinician chooses not to perform a bone marrow biopsy, the documented response can be either "partial remission" or "clinical CR, bone marrow biopsy not performed." The latter is not an official response category and is not used in clinical trials but is less ambiguous.

●Tumor mobilization and lymphocytosis – Treatment with certain drugs (eg, BTK or PI3K inhibitors) can result in tumor mobilization and lymphocytosis that is not thought to represent progressive disease. For patients treated with these drugs, the label "progressive disease" should be reserved for cases that demonstrate other definitive signs of progression (eg, anemia, thrombocytopenia, lymphadenopathy, hepatosplenomegaly) in addition to increased lymphocytosis. Lymphocytosis alone should not interfere with the identification of a partial response. (See 'Progressive disease' above.)

●Relapsed versus refractory disease – Relapsed disease occurs in patients who have previously achieved either a CR or PR but then develop progressive disease after a period of six months or more after last therapy. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

Patients who do not achieve either a CR or PR with therapy or those that develop disease progression within six months of therapy have refractory disease. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Michael J Keating, MD, and Kanti R Rai, MD, who contributed to earlier versions of this topic review.

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  44. Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014; 123:1810.
Topic 4501 Version 36.0

References

1 : National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment.

2 : Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia.

3 : Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines.

4 : iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.

5 : Limited clinical relevance of imaging techniques in the follow-up of patients with advanced chronic lymphocytic leukemia: results of a meta-analysis.

6 : Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia.

7 : Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations.

8 : Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations.

9 : Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.

10 : Novel flow-cytometric analysis based on BCD5+ subpopulations for the evaluation of minimal residual disease in chronic lymphocytic leukaemia.

11 : Detecting measurable residual disease beyond 10-4 by an IGHV leader-based NGS approach improves prognostic stratification in CLL.

12 : Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL.

13 : Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group.

14 : Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial.

15 : A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL.

16 : Prognostic value of MRD in CLL patients with comorbidities receiving chlorambucil plus obinutuzumab or rituximab.

17 : Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL after chemoimmunotherapy.

18 : Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study.

19 : Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia.

20 : Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia.

21 : Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial.

22 : Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.

23 : Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial.

24 : First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia.

25 : First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

26 : Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax.

27 : Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study.

28 : Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.

29 : Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial.

30 : High efficacy of venetoclax plus obinutuzumab in patients with complex karyotype and chronic lymphocytic leukemia.

31 : Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study.

32 : Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia.

33 : Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study.

34 : Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort.

35 : Outcomes in Patients with High-Risk Features after Fixed-Duration Ibrutinib plus Venetoclax: Phase II CAPTIVATE Study in First-Line Chronic Lymphocytic Leukemia.

36 : Impact of Minimal Residual Disease on Progression-Free Survival Outcomes After Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study.

37 : Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities

38 : Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

39 : Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease.

40 : Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study.

41 : Modeling absolute lymphocyte counts after treatment of chronic lymphocytic leukemia with ibrutinib.

42 : Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study.

43 : Lymphocytosis and ibrutinib treatment of CLL.

44 : Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy.