 the treatment landscape for chronic lymphocytic leukemia (CLL) has changed significantly. For patients with CLL, including those with high-risk disease, the availability of novel targeted therapies and monoclonal antibodies offers an increased potential for improved outcomes.

 Several agents that inhibit CD20 have been developed because of the role of CD20 in the process of differentiation and growth of B cells

; obinutuzumab, ofatumumab, and rituximab have subsequently been approved.

 Additionally, several agents targeting the B-cell receptor pathway have achieved FDA approval,

 including the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, the phosphatidylinositol 3-kinase inhibitors idelalisib and duvelisib, and the B-cell lymphoma 2 inhibitor venetoclax.

 Initially, several of these agents were approved by the FDA in combination with other approved agents, such as idelalisib plus rituximab, obinutuzumab plus chlorambucil, and ofatumumab plus chlorambucil. The 

Positive results from clinical trials that explored additional combination regimens have led to expanded indications for agents already approved by the FDA, including ofatumumab plus fludarabine and cyclophosphamide, and ibrutinib plus obinutuzumab. Importantly, indications range among the various approved monotherapies and combination regimens. Despite the availability of several agents in multiple drug classes, therapeutic selection for optimized regimens can be challenging, particularly because new evidence continues to emerge that further elucidates the clinical profile of FDA approved therapies. In particular, 3 studies presented at the 2018 American Society of Hematology (ASH) meeting showed promising results for the role of ibrutinib in the frontline treatment landscape of CLL: the Alliance North American Intergroup Study A041202 (ALLIANCE A041202),

 the E1912 trial of the ECOG-ACRIN Cancer Research Group (ECOG E1912),

 The published results of these trials have already impacted the 2019 National Comprehensive Cancer Network guidelines for the patient populations who were evaluated in these trials.

 This article reviews these key findings.

The phase III ALLIANCE trial (ClinicalTrials.gov identifier: NCT01886872) evaluated the efficacy of ibrutinib treatment alone and in combination with the anti-CD20 monoclonal antibody rituximab against the standard-of-care chemoimmunotherapy in older patients with CLL: bendamustine (an alkylating agent) plus rituximab.

 Sponsored by the National Cancer Institute of the National Institutes of Health,

 ALLIANCE is the first head-to-head trial to compare ibrutinib against bendamustine/rituximab.

 Additionally, the benefit of adding rituximab to ibrutinib has not been established in previous trials.

ALLIANCE is the second trial to investigate ibrutinib treatment alone or in combination with rituximab in CLL; the first trial was done in previously treated patients with CLL and results showed no difference in progression-free survival (PFS) or overall survival (OS) outcomes between treatment arms.

ALLIANCE assessed patients 65 years and older who had previously untreated CLL as defined by the 2008 International Workshop on CLL criteria.

 Of the patients selected, 183 were given bendamustine plus rituximab, 182 were assigned ibrutinib, and 182 were administered ibrutinib plus rituximab.

 The median age was 71 years (range, 65-89).

 More than half of the patients (54%) had high-risk disease according to modified Rai stage.

 A quarter of patients had high-risk cytogenetics, including del(17p) (6%) and del(11q) (19%). The primary endpoint was PFS.

Researchers found that treatment with ibrutinib either alone or in combination with rituximab was more successful, in terms of PFS benefit, compared with

6 rounds of chemoimmunotherapy with bendamustine plus rituximab.

 No significant difference in median PFS was observed between the ibrutinib and ibrutinib-plus-rituximab groups (HR, 1.00; 95% CI, 0.62-1.62; 

This result suggests that adding rituximab to ibrutinib did not provide any additional benefit versus ibrutinib alone.

It was demonstrated that ibrutinib offers superior PFS compared with standard chemoimmunotherapy in this patient population.

The 2-year PFS was 74% for bendamustine plus rituximab, 87% for ibrutinib monotherapy, and 88% for ibrutinib plus rituximab.

Ibrutinib is a promising treatment option in CLL patients with high-risk cytogenetics (eg, del[17p] or 

 Although the ALLIANCE study did not have sufficient power to detect statistical differences among subgroups,

 results indicated a PFS benefit with ibrutinib treatment alone or in combination with rituximab in all cytogenetic factor—related subgroups and among patients regardless of their immunoglobulin heavy chain variable region gene (

 The strongest PFS benefit was observed in patients with del(17p13).

 An improved median PFS was seen in patients with mutated versus unmutated 

 PFS benefit was also shown in patients with a complex karyotype (defined as the presence of at least 3 unrelated abnormalities).

There was no significant difference in OS among the 3 treatment groups.

 panel, Susan O’Brien, MD, noted that the crossover design of the study may have contributed to the lack of observable OS difference.

Ibrutinib treatment alone or in combination with rituximab demonstrated a favorable safety profile compared with bendamustine plus rituximab. Grade 3, 4, or 5 hematologic adverse events (AEs) were reported at a higher rate with bendamustine plus rituximab versus ibrutinib or ibrutinib plus rituximab (61% vs 41% and 39%, respectively).

 However, the rates of grade 3, 4, or 5 nonhematologic AEs were higher in the ibrutinib-treated patients (74%) compared with those treated with bendamustine plus rituximab (63%).

Significantly higher rates of hypertension (

 = .05) were seen with ibrutinib-based treatments

investigators recommend closely monitoring this patient population.

These findings suggest that ibrutinib should be considered a standard-of-care treatment in older patients with CLL.

 Although the results show efficacy in patients treated with continuous ibrutinib therapy, they implicitly raise the question of whether indefinite BTK inhibitor treatment is necessary.

 This issue will be evaluated in upcoming clinical trials carried out by the National Cancer Institute’s National Clinical Trials Network.

E1912 (ClinicalTrials.gov identifier: NCT02048813) is a randomized, open-label, phase III study that compared the combination of ibrutinib plus rituximab with the gold-standard chemoimmunotherapeutic regimen of fludarabine, cyclophosphamide, and rituximab (FCR) in adult patients aged 18 to 70 years with previously untreated CLL.

 FCR, a primary treatment in patients younger than 65 years,

 is thought to be the most efficacious chemoimmunotherapeutic regimen.

 The trial was sponsored by the National Cancer Institute of the National Institutes of Health, designed by researchers with the ECOG-ACRIN Cancer Research Group.

Within the accrual period of January 31, 2014, to June 9, 2016, a total of 529 patients were assigned to either ibrutinib plus rituximab (n = 354) or FCR (n = 175).

The authors completed the first interim analysis in September 2018.

Patient characteristics were well balanced between the treatment arms, with a median age of 57 years in the ibrutinib-plus-rituximab group and 58 years in the FCR group.

 Those with del(17p) were excluded from the study.

The primary endpoint was PFS and the secondary endpoint was OS,

 and the median follow-up was 33.4 months.

 A total of 77 PFS events and 14 deaths were reported.

 Ibrutinib plus rituximab improved PFS and OS in this patient population.

 The hazard ratio favored the ibrutinib-plus-rituximab group for both PFS (HR, 0.352; 95% CI, 0.223-0.558; 

 <.0001) and OS (HR, 0.168; 95% CI, 0.053-0.538; 

Ibrutinib plus rituximab was superior to FCR across all subgroups in terms of PFS benefit, which was observed in patients independent of age, sex, performance status, disease stage, or del(11q23) status.

 mutation status was tested in 82% of patients; 71.1% of these did not have an 

 The results of the subgroup analysis showed an increased likelihood of PFS with the ibrutinib-plus-rituximab combination in patients without an 

 mutation (HR, 0.262; 95% CI, 0.137-0.498; 

 A trend toward PFS improvement with the ibrutinib-plus-rituximab combination was observed in patients with an 

 mutation (HR, 0.435; 95% CI, 0.140-0.1350; 

Ibrutinib demonstrated a favorable safety profile compared with FCR.

 Grade 3 and 4 treatment-related AEs were observed in 58% of the ibrutinib-plus-rituximab group and 72% of the FCR group (

 Grade 3 and 4 neutropenia developed in 23% of the ibrutinib-plus-rituximab group versus 44% of the FCR group (

 <.0001); grade 3 and 4 infectious complications developed in 7.1% of the ibrutinib-plus-rituximab group versus 17.1% of the FCR group (

The combination of ibrutinib plus rituximab was superior to standard chemoimmunotherapeutic treatments in CLL patients 70 years and younger.

It was also well tolerated in young patients.

Quality of life was measured throughout the study, but the data have not yet been published.

Compared with FCR, the combination of ibrutinib and rituximab provides superior PFS and OS and a preferential safety profile in patients 70 years and younger with previously untreated CLL.

 The results of this trial suggest practice changes that incorporate ibrutinib-based therapy as a frontline CLL regimen in young, previously untreated patients.

noted that the findings establish ibrutinib-based therapy as the most effective treatment option in this patient population.

The FDA approval of the combination of ibrutinib plus obinutuzumab (an anti-CD20 monoclonal antibody) for the first-line treatment of CLL was based on the results of the phase III iLLUMINATE study (ClinicalTrials.gov identifier: NCT 02264574).

 In iLLUMINATE, investigators compared ibrutinib plus obinutuzumab against standard chemoimmunotherapy.

 This study was presented at the 2018 ASH Meeting and published simultaneously in 

. iLLUMINATE is the first study to prospectively evaluate a nonchemotherapy regimen with ibrutinib against a chemoimmunotherapy regimen in treatment-naïve patients with CLL, including those with high-risk cytogenetics (eg, del[17p] or 

This randomized, open-label, multicenter study was completed at 74 academic and community hospitals in Australia, Canada, Israel, New Zealand, Russia, Turkey, the European Union, and the United States.

The study population consisted of previously untreated patients with CLL or small lymphocytic leukemia in 2 cohorts: those older than 65 years, and those 65 years and younger who had considerable comorbidities or high-risk cytogenetics (ie, Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del[17p] or 

A total of 229 patients were either administered ibrutinib plus obinutuzumab (n = 113) or chlorambucil plus obinutuzumab (n = 116). The median age was 71 years; 65% of patients in both groups had high-risk disease (del[17p], 

 iLLUMINATE met its primary endpoint and improved PFS.

At 30 months, the PFS rate was 79% in the ibrutinib-plus-obinutuzumab group and 31% in the chlorambucil-plus-obinutuzumab group.

 Patients treated with ibrutinib plus obinutuzumab had a significantly improved PFS compared with those treated with chlorambucil plus obinutuzumab (median PFS, not reached vs 19 months; 

 Similar trends were observed comparing median PFS of patients with high-risk features in the ibrutinib-plus-obinutuzumab group versus the chlorambucil-plus-obinutuzumab group (unmutated 

, not reached vs 14.6 months; del11q: not reached vs 15.2 months; del[17p]: not reached vs 11.3 months).

 Findings showed a 77% reduction in risk of progression or death compared with chlorambucil plus obinutuzumab (HR, 0.23; 95% CI, 0.15-0.37), which led to the combination’s FDA approval.

 Patients with high-risk disease (del[17p]/

) experienced an 85% reduction in risk of progression or death (HR, 0.15; 95% CI, 0.09-0.27) with ibrutinib plus obinutuzumab.

 The overall response rate was 88% (complete response/complete response with incomplete hematologic recovery [CR/CRi], 19%) in the ibrutinib-plus-obinutuzumab group and 73% (CR/CRi, 8%) in the chlorambucil-plus-obinutuzumab group.

Similar percentages of patients in each group developed grade 3 or grade 4 AEs (68% in the ibrutinib-plus-obinutuzumab group vs 70% in the chlorambucil-plus-obinutuzumab group).

 The most common grade 3 or 4 AEs were pneumonia (4%), atrial fibrillation (3%), febrile neutropenia (3%), and decreased neutrophils (3%) in the ibrutinib-plus-obinutuzumab group, and febrile neutropenia (6%), hypertension (4%), pneumonia (3%), hyperglycemia (3%), and leukopenia (3%) in the chlorambucil-plus-obinutuzumab group.

 Serious AEs were reported in 58% of patients who were treated with ibrutinib plus obinutuzumab and 35% who received chlorambucil plus obinutuzumab.

This study provides evidence that adding a monoclonal antibody to ibrutinib can improve the efficacy of the drug. This combination is an alternative first-line option and a safe chemotherapy-free treatment in previously untreated CLL.

Currently, several studies of novel combination therapy with ibrutinib are underway, including 2 phase III trials that are assessing ibrutinib plus obinutuzumab with or without venetoclax (EA9161; ClinicalTrials.gov identifier: NCT03701282 and A041702; ClinicalTrials.gov identifier: NCT03737981).

The results of ALLIANCE, iLLUMINATE, and ECOG E1912 could have a significant impact on broad treatment approaches to CLL. Ibrutinib monotherapy is, potentially, more beneficial than bendamustine plus rituximab in patients 65 years and older, while the combination of ibrutinib plus rituximab appears to show more benefit than FCR does in patients 70 years and younger. Additionally, the efficacy of ibrutinib plus obinutuzumab has been validated by the FDA approval of the combination regimen. Collectively, these findings suggest that ibrutinib, both in combination with other agents and as a monotherapy, will play an integral role in the evolving treatment spectrum of CLL.

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Articles

For patients with chronic lymphocytic leukemia, including those with high-risk disease, the availability of novel targeted therapies and monoclonal antibodies offers an increased potential for improved outcomes.

The Shifting Therapeutic Spectrum for Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults in Western countries, with an estimated 20,720 people in the United States expected to be diagnosed in 2019.

 The disease is characterized by an accumulation of leukemic cells often appearing as small, mature lymphocytes in the peripheral blood, bone marrow, and lymphoid tissues.

Over the past decade, diagnosis, testing, and prognostic stratification have substantially improved,

 leading to revisions in guidelines from both the International Workshop on Chronic Lymphocytic Leukemia and the National Comprehensive Cancer Network (NCCN). Among the most significant changes is the increasing essential prognostic role of the immunoglobulin heavy-chain variable (IGHV) mutational status and the clinical relevance of genomic alterations found in CLL.

 This article reviews updates in CLL prevalence and diagnosis, with an emphasis on testing options.

The majority of patients diagnosed with CLL receive diagnosis when absolute lymphocytosis is discovered incidentally during a routine blood count.

 Some patients, however, may exhibit painless lymphadenopathy or present with symptoms caused by splenomegaly or cytopenias.

 The median survival of patients with low-risk disease is 150 months, which is similar to the survival rate of age-matched controls.

 Intermediate-risk disease is associated with a median survival of 71 to 101 months, while high-risk disease is associated with a poorer prognosis and a median survival of 19 months.

Patients with asymptomatic early-stage disease (low-risk Rai 0 or Binet A) or intermediate-risk disease (Rai I-II or Binet B) can be closely observed without therapy.

 For this patient population, evidence of progressive disease or the development of symptomatic disease would be indications for initiating treatment.

 Therapy is necessary for patients with advanced-stage or high-risk CLL with progressive cytopenia, while patients with mild, stable cytopenia may continue to be monitored in selected cases.

Disease-related symptoms include severe fatigue, weight loss, night sweats, and fever without evidence of infection.

 Additional signals for treatment include progressive or symptomatic splenomegaly or lymphadenopathy, progressive anemia or thrombocytopenia, autoimmune complications, or thrombocytopenia unresponsive to corticosteroids.

 According to the NCCN guidelines, in the absence of other signs or symptoms, absolute lymphocyte count is an indication for treatment only if it is above 200 to 300 x 10

/L or if symptoms related to leukostasis develop.

DIAGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA

For a patient with suspected CLL, it is crucial to rule out other lymphoproliferative diseases, such as hairy cell leukemia or leukemic manifestations of various lymphomas, which may appear similar to CLL.

 Assessments of the blood smear, the immunophenotype, and, in some cases, the genetic features of the circulating lymphoid cells are necessary to assess to differentiate CLL from other lymphoproliferative diseases.

 According the NCCN guidelines, the presence of at least 5 x 10

/L B lymphocytes in the peripheral blood for 3 or more months is required for a CLL diagnosis, and the clonality of B lymphocytes must be verified by flow cytometry.

 Small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus are distinctive of CLL, as are smudge cells.

The immunophenotype for CLL is typically CD5+, CD10—, CD19+, CD23+, cyclin D1–, CD43 +/–, CD20 dim, and surface immunoglobulin.

 Flow cytometry of peripheral blood is adequate to establish diagnosis, with biopsy of the bone marrow normally not needed.

 According to the NCCN guidelines, flow cytometric studies should include cell surface markers kappa/lambda, CD19, CD20, CD5, CD23, and CD10.

 It is also recommended, if flow cytometry is used for diagnosis, to include cytospin for cyclin D1 or fluorescence in situ hybridization (FISH) for t(11;14);t(11q;v);

if the diagnosis is not established by flow cytometry, lymph node biopsy should be performed.

 Immunophenotyping by immunohistochemistry should include CD3, CD5, CD10, CD20, CD23, and cyclin D1.

 A fine needle aspiration or core needle biopsy by itself is typically not suitable to determine initial diagnosis.

 However, a combination of core biopsy and fine needle aspiration biopsy, along with supplemental techniques (ie, flow cytometry and immunohistochemistry), may be a sufficient option to establish a diagnosis if a lymph node is not easily accessible for biopsy.

 for a listing of diagnostic testing options for CLL.

Although both CLL and mantle cell lymphoma are CD5+ B-cell tumors, the absence of cyclin D1 expression is a key differentiator.

 Assessment of cyclin D1 or FISH for t(11;14), CD200 by flow cytometry, and lymphocyte enhancer-binding factor 1 (LEF1) by immunohistochemistry are useful in distinguishing CLL from mantle cell lymphoma.

 CD200 has a moderate-to-strong expression in both typical and atypical CLL cells, with a negative expression in cases of mantle cell lymphoma.

 Although LEF1 is a specific diagnostic marker for CLL, it is expressed in only about 30% of positive tumor cells in other lymphoma entities.

The clinical course of patients with CLL is highly variable.

 Clinical staging of CLL does not transparently interpret the observed variations in response to therapy and survival.

 The mutational status of IGHV, cytogenetic abnormalities detected by FISH, flow cytometry—based prognostic markers, and serum markers may provide additional prognostic information.

 However, these prognostic factors were generated using data of patients treated with chemotherapy or chemoimmunotherapy.

 Survival outcomes for patients treated with newer small molecule inhibitor—based therapy have substantially improved, but follow-up data with the use of these treatments are limited.

 Therefore, the NCCN guidelines recommend caution when interpreting the survival data associated with these identified prognostic factors.

Recommended testing for proper prognosis and/or guidance on therapy selection include FISH, stimulated metaphase karyotype, 

 sequencing, and molecular genetic analysis (

 Although indications for initiating treatment in patients are independent of these results, they are useful for the selection of treatment.

 Patient age, performance status or fitness level, assessment of 

 mutation status, del(17p) status, and IGHV mutation status should be evaluated prior to initiating therapy.

Approximately 80% of patients with previously untreated CLL present with cytogenetic abnormalities that can be found using FISH,

 with the most common irregularities being del(11q), del(13q), trisomy 12, and del(17p).

 Longest median survival (133 months), as well as longest median treatment-free interval (92 months), are observed in patients with del(13q) as the sole abnormality.

 Shorter median survival times are observed in patients with del(17p) or del(11q) in CLL cells, compared with patients with leukemic cells with other abnormalities or a normal karyotype.

 Treatment regimens that contain fludarabine, cyclophosphamide, and rituximab appear to improve the poor prognosis associated with del(11q).

 gene and is often associated with mutations in the remaining allele of 

 have also been observed in the absence of del(17p).

 mutations in CLL cells is linked with poor prognosis and a relative resistance to standard chemotherapy regimens using alkylating drugs and/or purine analogues.

 mutations is independent of the presence of del(17p).

 mutations in CLL cells experience better outcomes when treated with small molecule inhibitors of Bruton tyrosine kinase, phosphatidylinositol 3-kinase, or BCL-2 protein, compared with standard chemotherapy regimens.

 The treatment algorithms suggested by the NCCN guidelines are based on the presence or absence of del(17p) or 

The leukemic cells in CLL have a very low in vitro proliferative activity, making conventional metaphase cytogenetics challenging.

 Interphase cytogenetic analysis with FISH represents the standard method to detect specific chromosomal abnormalities.

 Cytosine—phosphate –guanosine (CpG) oligonucleotide stimulation has been used successfully to detect cytogenetic defects, allowing for a more in-depth chromosome analysis compared with FISH.

NCCN guidelines recommend CpG-stimulated metaphase karyotype for the identification of complex karyotype, which is characterized by the presence of at least 3 independent chromosomal abnormalities in more than 1 cell

 and is an independent predictor of a substantially shorter overall survival (OS) in patients with CLL.

 In addition, complex karyotype may have stronger prognostic implications than del(17p) or TP53 mutations in patients with CLL who are treated with ibrutinib-based regimens.

 In a multivariate analysis among patients with relapsed or refractory CLL treated with ibrutinib-based regimens, the presence of complex karyotype was associated with shorter survival, while independent relationships were identified between del(17p) and OS.

 genes, which distinguishes 2 disease groups with substantially different behavior, is an important prognostic marker in CLL.

 Molecular genetic analysis, by polymerase chain reaction or sequencing, should be performed to detect the mutational status of 

 have a more dismal clinical course and shorter survival compared with patients with mutated 

There have been updates in chronic lymphocytic leukemia prevalence and diagnosis, with an emphasis on testing options.

The Changing Chronic Lymphocytic Leukemia Treatment Paradigm | Special Issues

The Shifting Therapeutic Spectrum for Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia: Updates in Diagnosis and Testing

New Directions in Chronic Lymphocytic Leukemia Care: A Review of 2019 Treatment Guideline Updates

An Investigator's Perspective on the Chronic Lymphocytic Leukemia Research Front

Optimizing Treatment Approaches for Chronic Lymphocytic Leukemia