Chronic lymphocytic leukemia&nbsp;(CLL) is a malignancy characterized by the clonal proliferation and accumulation of small, mature-appearing CD5-positive B lymphocytes in the blood, bone marrow, and secondary lymphoid tissues.

A CLL diagnosis is established by the presence of more than 5x109/L peripheral lymphocytes co-expressing CD5, CD19, and CD23, and weakly expressing CD20, CD79b, and surface immunoglobulin.

Small lymphocytic lymphoma (SLL), in which the same leukemic cell population is mostly restricted to the bone marrow and lymphoid tissues, represents a clinical variant of CLL and is similarly managed.

CLL is the most common adult leukemia in Western countries. Its incidence increases with age, and with aging populations, its prevalence and mortality in Western countries will continue to rise. Improved diagnostic methods and more frequent blood testing have also led to increasing identification of early-stage CLL among younger patients.

Approximately 10% to 15% of patients with CLL are younger than 55 years.

Recent years have seen major advances in diagnostic approaches in CLL, and disease assessment may now include analysis of multiple genetic mutations in addition to recurrent cytogenetic changes.

Furthermore, with the development of novel treatment approaches, the significance of prognostic markers is shifting. Awareness of current approaches to CLL diagnosis and assessment of disease criteria relevant to current risk stratification and treatment selection strategies is therefore prerequisite to tailor treatment for each patient.

The incidence of CLL varies between geographic locations and is lower in Eastern Asian populations, such as China, Korea, and Japan, than in Western countries.

Lower incidence of CLL is maintained in Asian individuals emigrating to Western countries and their progeny.

With an age-adjusted incidence of approximately 4 per 100,000 inhabitants in Europe and the United States, CLL is the most common adult leukemia in adults in Western countries.

In the United States, CLL accounts for approximately one-third of all annual new leukemia diagnoses (20,110 of 62,130 in 2017).

According to estimates based on the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database, CLL is most frequent in white populations in the United States (6.8 per 100,000 men and 3.5 per 100,000 women), followed by African Americans (4.9 per 100,000 men and 2.4 per 100,000 women).

Rates are lower among Hispanic Americans (2.7 per 100,000 men and 1.6 per 100,000 women), Indigenous Americans (1.7 per 100,000 men and 1.3 per 100,000 women), and individuals of Asian or Pacific Island descent (1.7 per 100,000 men and 0.3 per 100,000 women) (FIGURE 11,8).

The risk for CLL increases with age (FIGURE 27). More than 70% of patients are older than 65 years at diagnosis, the median age at diagnosis is 72 years, and the incidence rate increases to >30:100,000/year at an age of more than 80 years.

Men are at an approximately 2-fold higher risk for developing CLL than women (male:female ratio of 1.9).

A genetic contribution to CLL susceptibility has been clearly established. Family members of patients with CLL have an 8.5-fold increased risk for developing the disease compared with the general population.9,10 Genome-wide association studies have identified polymorphisms in more than 25 loci associated with familial CLL, including candidate genes involved in B-cell biology, apoptotic pathways, and regulatory microRNAs that may contribute to disease development.

Studies in veterans have established exposure to Agent Orange as an environmental risk factor for CLL.

Insecticide exposure and farming history have also been associated with a higher risk for developing CLL,

whereas blood transfusions and ionizing radiation have not.

The precursor state to CLL, characterized as monoclonal B-cell lymphocytosis (MBL), is defined by the presence of less than 5000 monoclonal B cells, in the absence of lymphadenopathy, organomegaly, cytopenia, and clinical symptoms.

Risk factors for MBL include increasing age and genetic disposition, including overlapping polymorphisms with those identified in CLL.

Population studies have shown that MBL is characterized by a bimodal distribution of clonal B cell counts that can be cat- egorized as low-count and high-count MBL (less than or equal to or greater than 0.5x109/L clonal B cells, respectively). Low-count MBL rarely progresses to CLL, whereas the annual rate of progression from high-count MBL to CLL requiring therapy is 1% to 2%.

Many patients with CLL are asymptomatic and diagnosis follows the detection of lymphocytosis in a routine complete blood count (CBC), ie, above the normal adult upper limit of approximately 3500 cells per &mu;L, typically &ge;10,000 cells per &mu;L.

If disease symptoms are present, they may include fatigue, involuntary weight loss, excessive night sweats, abdominal fullness with early satiety, increased frequency of infections, and symptoms of an autoimmune cytopenia, as well as enlarged lymph nodes, hepatomegaly, and splenomegaly, which can be detected by palpation.

Essential components of the CLL diagnosis include blood immunophenotyping by low cytometry and uorescence in situ hybridization (FISH), lymph node biopsy if a peripheral analysis is not sufficient, and absolute B monoclonal B lymphocyte counts.

The initial workup should include a physical exam with palpation of node-bearing areas, determination of liver and spleen size, performance status, complete blood count, differential blood counts, platelets, and a metabolic panel.

Immunophenotyping by low cytometry is required to establish CLL diagnosis based on cell identity, clonality, and quantity (<5x109/L peripheral CLL cells).2,3 CLL cells co-express CD5, CD19, and CD23 antigens, weakly express CD20, CD79b, and surface immunoglobulin, with each clone restricted to expression of either kappa or lambda immunoglobulin light chains, and are negative for cyclin D1. Flow cytometric analysis for these markers is therefore used to establish a differential diagnosis from other B-cell lymphoproliferative disorders such as marginal zone lymphoma, lymphoplasmacytic lymphoma, and mantle cell lymphoma (MCL), all of which express B-cell surface antigens, but usually do not express CD23 and have negative or low CD43 expression.

MCL cells express CD5 but also exhibit enhanced expression of the gene encoding cyclin D1 (CCND1) due to the (11;14) translocation (t[11;14]), which is absent from CLL cells.

As such, FISH analysis for t(11;14) can help to distinguish MCL from CLL.

CLL cells in blood smears are small, mature lymphocytes with a narrow rim of cytoplasm and a dense nucleus without detectable nucleoli and with partially aggregated chromatin. Smudged cells, also known as Gumprecht nuclear shadows, are also mor- phologically characteristic for CLL.

Larger, atypical lymphocytes, cleaved cells, or prolymphocytes may be seen, but if the latter exceed 55%, prolymphocytic leukemia needs to be considered.

Bone marrow biopsy is not considered essential for the diagnostic workup in CLL but may be needed if immunophenotyping results are unclear. According to the International Workshop of Chronic Lymphocytic Leukemia (iwCLL) 2008 guidelines for the diagnosis and treatment of patients with CLL, a bone marrow asipirate and biopsy may be desirable in both practice and prior to enrollment in a clinical trial (TABLE 1).

If a biopsy is performed, 4 different patterns of infiltration may be observed, which are nodular, interstitial, mixed nodular/interstitial, or diffuse (advanced disease).

Imaging using computed tomography (CT) scans can be beneficial for assessing the tumor load, monitoring disease progression, and determining the effects of investigational treatments in clinical trials, but it&rsquo;s not recommended in asymptomatic patients or for staging.

More than 80% of patients with previously untreated CLL have cytogenetic abnormalities, most commonly a deletion in chromosome 13q14.3 (del[13q]; 55%), followed by del(11q) (18%), trisomy 12 (16%), and (del[17p]) (7%), and del(6q) (6%).

Recommended analyses include interphase cytogenetic analysis with FISH for the detection of the del(17p), which affects p53 expression, and if negative, molecular genetics is recommended for the detection of a TP53 mutation.2,3 While FISH testing for cytogenetic abnormalities is suggested for pretreatment evaluation by the iwCLL 2008 guidelines, the guidelines especially recommend these tests in patients being enrolled in clinical trials.

Molecular genetic analysis should also include mutational status of the immunoglobulin heavy chain variable region gene (IGHV). Additional analyses considered informative for prognosis and treatment selection are stimulated metaphase analyses to identify complex karyotypes, extended FISH for additional cytogenetic abnormalities, and polymerase chain reaction or sequencing for mutations in NOTCH1, SF3B1, TP53, or MYD88.

Two clinical staging systems, the Rai and Binet systems, are used predominantly in the United States and Europe, respectively, to group patients with CLL into broad prognostic groups.

Both systems combine the presence of specific physical parameters, such as lymph node involvement, enlarged spleen and/or liver and blood parameters, including anemia or thrombocytopenia, to determine tumor burden.

The Rai system, originally including 5 groups, has been modified to define low-risk disease (former stage 0) as lymphocytosis with leukemia cells in the blood and/or marrow. Intermediate risk disease (stage I/II) is defined as enlarged nodes in any site, and splenomegaly and/or hepatomegaly (lymph nodes being palpable or not), and high-risk disease (stage II/IV) as lymphocytosis and cytopenia (hemoglobin [Hb] level less than 11 g/dL and/ or platelet count of less than 100,000/&mu;L) (TABLE 23,23).

The Binet staging system relies on determining the number of involved areas, ie, enlarged lymph nodes of greater than 1 cm in diameter or organomegaly, and the presence anemia or thrombocytopenia. Binet stages are low risk (stage A), with less than 3 palpable enlarged sites without cytopenia; intermediate risk (stage B), with 3 or more palpable enlarged sites without cytopenia, and high risk (stage C) in all patients who have Hb of less than 10 g/dL and/or a platelet count of less than 100,000/&mu;L, irrespective of organomegaly (TABLE 3 24).

Available survival estimates linked with staging suggest similar survival to age-matched controls for patients with low-risk disease by Rai stage (median, 150 months), shorter survival for patients with intermediate-risk disease (median, 71-101 months), and poor survival for high-risk features (median, 19 months).

However, these estimates reflect treatment with chemotherapy or chemoimmunotherapy, and life expectancies are increasing with newer small molecule inhibitor-based therapy.

Newly diagnosed CLL is characterized by a highly variable clinical course, ranging from absence of symptoms for decades to the rapid development of symptoms or features of high-risk disease. Prognostic factors used for patient strati cation include patient factors and clinical features of the disease, and genetic, molecular, and biochemical characteristics of the CLL clone.

In addition to staging and lymphocyte doubling time, traditional prognostic factors or clinical features associated with poorer outcome are male sex, &ge;65 years, poor performance status due to medical comorbidities, high serum levels of beta-2 microglobulin (>3.5 mg/L), high absolute lymphocyte count (>50,000 cells/&mu;L), and/or late-stage disease at diagnosis.

Elevated serum &beta;2 microglobulin is an independent prognostic indicator for treatment-free interval, response to treatment, and overall survival (OS) in response to first-line chemoimmunotherapy regimens,

andif remaining after 6 months of treatment&mdash;for inferior progres- sion-free survival (PFS) with ibrutinib (Imbruvica)-based therapies.

The use of these diagnostic tests is encouraged by current treatment guidelines and managed care companies. John L. Fox, MD, MHA, the vice president of medical affairs of Priority Health, explained in an interview with the American Journal of Managed Care&reg;, &ldquo;The cost of the diagnostics themselves are really not an issue. Those are the upfront costs in trying to establish what the most appropriate therapy is for that particular patient.&rdquo;

Biological prognostic markers that reflect CLL cell characteristics and are used for risk stratification include cytogenetic abnormalities; IGHV mutational status; TP53 mutation; expression of ZAP-70, CD49d (also known as integrin alpha-4), or CD38; and mutations in NOTCH1, SF3B1, BIRC3, and MYD88.

Among these, del(17p) and TP53 mutations are considered pertinent for treatment selection, and multiple other markers are considered of predictive value.

Del(17p), which causes the loss of 1 TP53 allele and is associated with inactivating mutations in the other allele in 80% of patients with CLL, is considered the most important prognostic marker in CLL, with predictive value on treatment. The presence of del(17p) and/or mutations in TP53 defines a group of patients with CLL not eligible for chemoimmunotherapy regimens due to poor outcomes.

Targeted inhibitors of the B-cell receptor pathway and apoptosis inhibitors can produce high response rates in patients with del(17p) and are the preferred regimens in the first and subsequent lines of therapy.

The deletion is relatively rare at diagnosis (approximately 7%)

but frequent in relapsed/refractory disease, indicating acquisition or expansion of del(17q)-harboring CLL clones during treatment.

Del(11q) has been linked to extensive lymphadenopathy, aggressive clinical course, and shorter median survival with traditional reg- imens (79 months).

However, the presence of del(11q) is not an adverse prognostic marker for response for treatment with ibrutinib.

Among cytogenetic abnormalities, del(13q) is the only one that confers a favorable prognosis and long median survival (133 months).

Trisomy 12 has been linked to shorter survival.

Unmutated IGHV (de ned as &ge;98% homology with the germline gene sequence) re ects CLL originating from B cells that have not undergone a somatic mutation. The presence of unmutated IGHV predicts a more aggressive disease type and has traditionally been associated with significantly decreased survival compared with mutated IGHV, irrespective of disease stage.

Recent analyses have con rmed unmutated IGHV as a predictor of shorter survival with chemoimmunotherapy regimens including udarabine and rituximab (Rituxan; FR), and udarabine, chlorambucil, and rituximab (FCR).

In patients with mutated IGHV, FCR was associated with an improved survival in all cytogenetic groups except del(17p).

Unmutated IGHV does not predict adverse outcomes with ibrutinib-based regimens.

Among prognostic surface markers detected by flow cytometry or immunohistochemistryincluding CD38, CD49d, and ZAP-70&mdash;CD49d is independent of FISH and IGHV.

Multiple studies have associated CD38 and/or ZAP-70 expression with shorter PFS and OS, but despite positive correlations with the presence of unmutated IGHV, these markers are not considered appropriate surrogate markersthe latter due to discordance and variable expression during the course of disease.

Expression of ZAP-70 may be a stronger predictor of time until treatment is needed than IGHV mutational status or CD38 levels

; however, standardized detec- tion of this nuclear marker is hampered by technical issues and it&rsquo;s use is not yet recommended outside clinical trials.

NOTCH1, SF3B1, and BIRC3 mutations are observed in approximately 4% to 15% of patients with newly diagnosed CLL, and 15% to 25% of patients with CLL refractory to udarabine.

These mutations have been associated with varying prognostic significance across studies, such that their impact on treatment selection remains to be established, particularly for targeted agents.

Del(17p) and TP53 mutations are currently the only disease-based predictive markers that affect treatment selection in CLL. With changing treatment options, particularly the inclusion of novel effective agents that prolong survival and have activity among patients considered high-risk in the era of chemotherapy-based regimens, the value of other prognostic markers continues to evolve.

As Steven E. Coutre, MD, professor of medicine (hematology) at the Stanford University Medical Center, summarized in an interview: &ldquo;A FISH test from the peripheral blood identifies patients who are at higher risk of progression and, in some cases like with del(17p), identifies patients who respond differently to different therapies. And so, those are the kinds of insights that we&rsquo;re looking for to help us better choose treatments for our patients. And I think that&rsquo;s where the eld is going. Hopefully, we&rsquo;ll be able to better tailor the choices we have toward specific patient groups."

Kipps TJ, Stevenson FK, Wu CJ, et al. Chronic lymphocytic leukaemia [published correction appears in Nat Rev Dis Primers. 2017;3:17008. doi:10.1038/nrdp.2017.8]. Nat Rev Dis Primers. 2017;3:16096. doi: 10.1038/nrdp.2016.96.

Eichhorst B, Robak T, Montserrat E et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5):v78-v84. doi: 10.1093/annonc/mdv303.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2017. NCCN website. www.nccn.org/professionals/physician_gls/ pdf/cll.pdf. Published February 21, 2017. Accessed May 15, 2017.

Scarfò L, Ferreri AJ, Ghia P. Chronic lymphocytic leukaemia. Crit Rev Oncol Hematol. 2016;104:169-182. doi: 10.1016/j.critrevonc.2016.06.003.

Pan JW, Cook LS, Schwartz SM, Weis NS. Incidence of leukemia in Asian migrants to the United States and their descendants. Cancer Causes Control. 2002;13(9):791-795.

Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67(1):7-30. doi: 10.3322/caac.21387

National Cancer Institute. Cancer stat facts: Chronic lymphocytic leukemia (CLL). NCI website. https://seer.cancer.gov/statfacts/html/clyl.html. Accessed May 15, 2017.

Li Y, Wang Y, Wang Z, Yi D, Ma S. Racial differences in three major NHL subtypes: descrip- tive epidemiology. Cancer Epidemiol. 2015;39(1):8-13. doi: 10.1016/j.canep.2014.12.001.

Goldin LR, Björkholm M, Kristinsson SY, Turesson I, Landgren O. Elevated risk of chronic lymphocytic leukemia and other indolent non-Hodgkin&rsquo;s lymphomas among relatives of patients with chronic lymphocytic leukemia. Haematologica. 2009;94(5):647-653. doi: 10.3324/haematol.2008.003632.

Articles

Clinical Articles

<p>CLL is a malignancy characterized by the clonal proliferation and accumulation of small, mature-appearing CD5-positive B lymphocytes in the blood, bone marrow, and secondary lymphoid tissues.</p>


Current Approaches to Diagnosis and Risk Stratification in Chronic Lymphocytic Leukemia

Except for allogeneic hematopoietic stem cell transplantation (HSCT), none of the current therapies are considered curative, but a subset of patients experience long-term remissions.

Treatment options for the management of patients with CLL have evolved significantly in the past decades. The historical stan- dard of initial chemotherapy with chlorambucil has been largely replaced with more effective chemoimmunotherapy regimens incorporating monoclonal antibodies (mAbs) targeting CD20 (rituximab [Rituxan], obinutuzumab [Gazyva], and ofatumumab [Arzerra]), and targeted therapy with the small-molecule inhibitor of Bruton&rsquo;s tyrosine kinase (BTK), ibrutinib (Imbruvica).

Current standards of care for patients with relapsed or refractory CLL are ibrutinib, the phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib (Zydelig) alone or with rituximab, and the B cell lymphoma 2 (BCL-2) inhibitor venetoclax (Venclexta) alone or with rituximab.

The availability of these agents has substantially changed outcomes for patients with relapsed CLL and adverse risk features, who had survival expectancies of less than 1 year in the past, but can now achieve progression-free survival (PFS) in the range of 24 months or longer.

Recent trial outcomes have shown the superiority of ibrutinib over chlorambucil as a front-line treatment in older patients.

Yet, novel kinase inhibitors are also becoming increasingly available in the frontline setting.

CURRENT ROLE OF CHEMOTHERAPY AND CHEMOIMMUNOTHERAPY

Findings from a phase II study in 300 patients,

followed by outcomes of the randomized German CLL study group CLL8

have established chemoimmunotherapy with udarabine, cyclophosphamide (FC), and rituximab (FCR) as the standard-of-care front- line therapy for patients under 65 years of age with CLL without a 17p deletion (del[17p]) or a TP53 mutation.

The landmark phase III CLL8 trial involving 817 physically fit previously untreated CLL patients demonstrated that the addition of rituximab to FC (6 courses of treatment) improved the overall response rate (ORR; 90% vs 80%, respectively) (TABLE 18), complete response (CR) rate (44% vs 22%; P <.0001), 3-year PFS (65% vs 45%; HR, 0.56; 95% CI, 0.46-0.69; P <.0001), and overall survival (OS; 87% vs 83%; P = .01).

Recently updated results show long-term remissions in patients treated with FCR, with a 5-year OS of 80.9% in patients less than 65 years of age versus 69.2% in patients treated with FC (HR, 0.63; 95% CI, 0.47-0.84; P = .002). The overall median PFS was 56.8 months with FCR versus 32.9 months for FC (HR, 0.59; 95% CI, 0.50-0.69; P <.001); the median OS was not reached for FCR and was 86.0 months for FC (HR, 0.68; 95% CI, 0.54-0.89; P = .001).

Long-term remissions were also shown in the phase II study, which reported an ORR of 95% (72% CR) at a median follow-up of 12.8 years, a median PFS of 6.4 years, and an overall 12.8-year PFS rate of 30.9% (53.9% and 8.7% for patients with mutated and unmutated IGHV, respectively).

Furthermore, 50.7% of patients with mutated IGHV had minimal residual disease (MRD) negativity after treatment, and a subset of 42 patients with mutated IGHV had no relapse after 10 years.

In an accompanying editorial, Farrukh Awan, MBBS, the assistant professor of internal medicine, The Ohio State University Wexner Medical Center, commented: &ldquo;This represents the first time in the history of CLL that a nontransplant therapeutic option has resulted in sustained disease-free intervals and raises the possibility of a cure for a subset of patients with generally good-risk disease and excellent response to therapy.&rdquo;

Benefits of FCR come at the cost of higher toxicity, with 76% of patients treated with FCR experiencing a grade 3/4 adverse event (AE) compared with 63% among those treated with FC, particularly notable is grade 3/4 neutropenia in 34% of patients and a significant increase in infectious complications with FCR.

Prophylactic measures include supplementation with myeloid growth factors and antimicrobial therapy.

Treatment with FCR has also been associated with a 6% to 10% incidence of secondary hematologic malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

A combination regimen of the alkylating agent bendamustine (Treanda) and rituximab (BR) is an alternative, less myelotoxic frontline treatment option in fit patients with CLL without del(17p) or a TP53 mutation. The CLL10 trial compared FCR with BR in this patient population, and found similar ORR and OS rates (TABLE 212). In patients treated with FCR compared with those treated with BR, the ORR was 95% versus 96%, respectively and the 3-year OS rate was 91% versus 92%. However, FCR produced a higher CR rate (40% vs 31%; P = .034), more MRD negativity (59% vs 26% at 12 months; P <.0001; 55% vs 27% at 18 months; P = .002), and longer median PFS (55.2 months vs 41.7 months; P = .0003). The 3-year PFS favored FCR over BR in patients 65 years or younger (53.6 vs 38.5 months); however, for patients over the age of 65, the outcome was similar for both regimens with less toxicity for BR. More patients experienced a grade 4/5 AE with FCR, most of which were hematologic, including neutropenia, leukocytopenia, and thrombocytopenia; grade 3/4 neutropenia was also common in the BR arm.

An update analysis with a median follow-up of 58.2 months reported a decreased risk of secondary AML or MDS following BR treatment (0.7%) versus FCR (4.3%).

FCR is also considered suitable for the treatment of patients with relapsed/refractory CLL without high-risk features based on phase II and III study outcomes showing high response rates.

TARGETED THERAPIES: INHIBITION OF BRUTON&rsquo;S TYROSINE KINASE MOVING TO THE FOREFRONT

Ibrutinib, an oral small-molecule irreversible inhibitor of BTK, which is central to the B-cell antigen receptor (BCR) survival pathway, was first approved for the treatment of patients with CLL who had received at least 1 previous therapy, and became available as a frontline therapy in 2016 for patients both with and without del(17p).

The approval of single-agent ibrutinib for the treatment of patients with relapsed and refractory CLL was based on data from the phase III randomized RESONATE study demonstrating ORR, PFS, and OS benefits with ibrutinib, including a 57% reduction in risk of death, compared with the anti-CD20 mAb ofatumumab in patients with advanced and high-risk disease, including del(17p) CLL.

Updated results at 16 months&rsquo; follow-up reported significantly better ORR with ibrutinib compared with ofatumumab (90% vs 25%, respectively; P <.0001), as well as median PFS (not reached vs 8.1 months; HR, 0.106; 95% CI, 0.073-0.153; P <.0001) and OS rates (18-month, 85% vs 78%).

The frontline indication of ibrutinib is supported by outcomes of the randomized phase III RESONATE-2 study in 269 patients aged 65 years or higher with untreated CLL without del(17p) demonstrating a significantly higher ORR (86% vs 35%; P <.001) and PFS (90% vs 52% by independent review committee; P <.0001) with ibrutinib compared with those treated with chlorambucil at 18 months&rsquo; median follow-up.

By investigator review, patients treated with ibrutinib showed an 89% PFS rate at 18 months in both the subgroup with mutated IGHV and in those without an IGHV mutation. A recent update at a median follow-up of 28.6 months reported that PFS benefits were sustained across high-risk groups, including those with del(11q) and in those with unmutated IGHV, with an overall 88% reduction in risk for progression or death with ibrutinib versus chlorambucil.

At 24 months, the overall PFS rate was 89% with ibrutinib compared with 34% with chlorambucil (HR, 0.121; 95% CI, 0.074-0.198; P <.0001), and estimated OS rates in the intent-to-treat population were 95% and 84%, respectively, despite high crossover rates to ibrutinib (41%).

According to Steven E. Coutre, MD, professor of medicine (hematology) at Stanford University Medical Center, and co-investigator of the RESONATE-2 study, &ldquo;We&rsquo;re fortunate that we have a body of experience now from our trials, where we&rsquo;ve used ibrutinib in a variety of clinical settings for CLL; heavily pretreated, refractory patients. We have trials in the upfront setting...and what we&rsquo;ve learned is that you see efficacy across a broad range of patients. In fact, I can&rsquo;t think of a subgroup who doesn&rsquo;t benefit from treatment.&rdquo;

Ibrutinib was generally well tolerated in clinical trials; AEs included cytopenias, pneumonia, rash, diarrhea, fatigue, and nausea, and notable AEs were bleeding (4%), hypertension (all-grade, 14%; grade 3, 4%), and atrial brillation (6%).

In the RESONATE-2 trial, 9% of patients discontinued treatment due to AEs compared with 23% in the chlorambucil arm.

Treatment with ibrutinib results in rapid reduction of lymphadenopathy associated with a concomitant transient increase in absolute lymphocyte count; this lymphocytosis does not signify disease progression and subsides with continued therapy.

In addition, an incomplete resolution of lymphocytosis does not seem to affect PFS rates.

According to Coutre, &ldquo;It&rsquo;s well tolerable across many different types of patients; patients who are fit, patients who are unfit. We have a fair amount of long-term follow-up now to understand the safety profile.&rdquo;

PHOSPHOINOSITIDE 3-KINASE INHIBITOR THERAPY

PI3K is a key component of BCR survival signaling downstream of BTK, and inhibition of the PI3K-delta isoform leads to increased apoptosis.

The oral PI3K-delta inhibitor idelalisib is the first PI3K inhibitor to become available for the treatment in CLL and is indicated for the treatment of relapsed/refractory CLL in combination with rituximab, based on outcomes of a phase III trial, demonstrating significantly higher ORR (81% vs 13%; P <.001) and significantly longer median PFS and OS (12-month OS, 92% vs 80%; HR, 0.28; P = .02) with the combination versus with rituximab alone.

Comparable efficacy was also observed across all subgroups with idelalisib and rituximab, including in those with del(17p), TP53 mutations, unmutated IGHV, or del(11q).

The benefit of the combination was also consistent in those with an advanced Rai stage or high levels of beta-2 microglobulin.

AEs associated with idelalisib include hepatotoxicity causing transaminitis, pneumonitis, and colitis that may require treatment cessation, and is of major concern in younger patients treated with idelalisib.

Therapy with idelalisib can also produce a rapid reduction in lymphadenopathy leading to transient lymphocytosis that does not signify disease progression. Febrile neutropenia and infections, including reactivation of cytomegalovirus, can also be associated with treatment of idelalisib, which is increased with the addition of a CD20 mAb or chemoimmunotherapy. Due to high numbers of infections and deaths in clinical trials investigating idelalisib and rituximab in patients with untreated CLL, it is not indicated for frontline treatment.

Venetoclax is a small-molecule BCL-2 inhibitor promoting CLL cell apoptosis.

Phase II study outcomes have demonstrated clinical activity in patients with relapsed/refractory CLL with del(17p), including an ORR of 79.4%, estimated 12-month PFS and OS rates of 72% and 86.7%, respectively per independent review commit- tee assessment.21 Across all subgroups with additional risk features, such as udarabine-refractory status, bulky disease, del(17p), or a TP53 mutation, the ORR was higher than 70%.

Updated results from the M13-982 trial showed that 40% of evaluable patients achieved MRD-negative status.

Of 32 patients who achieved a CR with or without complete hematologic recovery, 22 had MRD-negative peripheral blood by flow cytometry and an estimated 24-month PFS of 100%.

Venetoclax has shown promising activity among patients who are intolerant of ibrutinib or idelalisib or failed previous therapy with either agent, and can also be combined with rituximab.

In the phase III MURANO study of patients with relapsed/refractory CLL treated with venetoclax and rituximab, the ORR was 86%, and 41% achieved a CR or a CR with incomplete bone marrow recovery; the 2-year PFS rate was 84%.

Additionally, 53% of the patients achieved negative marrow MRD with acceptable toxicity, which was seen in 75% of patients who had a CR/CRi. The combination received a breakthrough therapy designation from the FDA in January 2016.

Side effects of venetoclax include gastrointestinal toxicity, infections, and neutropenia, and tumor lysis syndrome (TLS), requiring gradual dose increases, monitoring, and TLS prophylaxis.

The National Comprehensive Cancer Network recommends initiating treatment with venetoclax at 20 mg and, after 1 week, stepping up treatment over 5 weeks until reaching the target dose of 400 mg daily.

Available targeted mAbs against the transmembrane receptor CD20 include rituximab, ofatumumab, and obinutuzumab. These agents have modest activity as single agents but are widely used in combination with purine analogues and alkylating agents.

Based on outcomes from the CLL11 study, obinutuzumab in combination with chlorambucil was approved for the frontline treatment of CLL, and is the current standard of care for elderly patients and patients with comorbidities and absence of del(17p).

A study in 781 patients with medical comorbidities demonstrated superior median PFS with the combination versus with chlorambucil alone (26.7, 16.3, and 11.1 months, respectively, for obinutuzumab plus chlorambucil, rituximab plus chlorambucil, and chlorambucil alone; P <.001), including in all subgroups except del(17p).

Updated survival data after a mean 39 months follow-up showed significantly longer PFS with obinutuzumab plus chlorambucil versus rituximab plus chlorambucil (28.7 vs 15.7 months; HR, 0.46; 95% CI, 0.38-0.55; P <.0001), and a trend to OS benefits with obinutuzumab plus chlorambucil (P = .0932).

Single-agent obinutuzumab has also shown activity in previously untreated patients (2000 vs 1000 mg dose, respectively; ORR, 67% vs 49%; CR, 20% vs 5%).

AEs occurred more frequently with the addition of obinutuzumab, especially grade 3/4 neutropenia.

Ofatumumab, a CD20 mAb first approved for patients with fludarabine- and alemtuzumab-refractory CLL, was recently approved for frontline therapy in CLL, based on the ndings of the open-label, phase III COMPLEMENT study in 447 patients ineligible for udarabine-based therapy due to age or comorbidities. Patients randomized to ofatumumab plus chlorambucil had significantly higher ORR (82% vs 69%, respectively; P = .001) and median PFS (22.4 vs 13.1 months; P <.0001) than patients in the chlorambucil arm at 29 months median follow-up; median OS was not reached in either arm.

AEs were higher in the combina- tion arm compared with the chlorambucil alone arm for all-grade (94% vs 87%, respectively) and grade &ge;3 events (50% vs 43%) across all age groups, including higher rates of neutropenia.

Ofatumumab is also indicated in relapsed disease in combination with FC, supported by data from the COMPLEMENT-2 study showing improved PFS with ofatumumab versus with FC alone (28.9 vs 18.8 months, respectively; HR, 0.67; P = .0032).

Single-agent ofatumumab can be used for post second-line maintenance therapy, with outcomes of the PROLONG study showing improved PFS versus observation in patients with relapsed CLL after second- or third-line therapy.

In a randomized phase II CALGB 9712 study comparing concurrent or sequential rituximab with udarabine, a higher ORR was shown with the concurrent regimen (90% vs 77%; CR, 47% vs 28%), and similar median PFS (42 months) and OS (85 months) rates between the 2 arms.

IMMUNOMODULATORY AGENTS FOR MAINTENANCE REGIMENS: LENALIDOMIDE

The immunomodulatory agent lenalidomide (Revlimid) is approved for various hematologic malignancies, and is evolving as a maintenance therapy option for patients with high-risk CLL after first-line therapy. Recent reports from the CLL M1 and CONTINUUM trials have shown prolonged PFS with maintenance lenalidomide following first- and second-line treatment, respectively.

In the CLL M1 study of the German CLL Study Group, patients with a high risk for disease progression after first-line treatment with BR or FCR were randomized to lenalidomide (n = 56) or placebo (n = 29) based on MRD levels and the presence of unmutated IGHV, del(17p), or mutated TP53 at baseline.

Interim results at a medium follow-up of 17.7 months, demonstrated significantly longer median PFS with lenalidomide (not reached vs 14.6 months for placebo; P <.00001). Lead author Anna Fink, MD, of the Department of Internal Medicine and the Center of Integrated Oncology at the University of Cologne, Germany, commented, &ldquo;We saw conversion to MRD-negative status in the lenalidomide group. Thus far, there is no difference in survival at this interim analysis. The study confirms the prognostic significance of achieving MRD.&rdquo;

The CONTINUUM trial investigated lenalidomide vs placebo in patients with CLL who achieved at least a partial response to second-line therapy. Patients reported a significant increase in median PFS with lenalidomide at a median follow-up of 31.

months (33.9 vs 9.2 months for placebo; HR, 0.4; 95% CI, 0.29-0.55; P <.001).

In both studies, neutropenia, gastrointestinal, nervous system, respiratory, and skin disorders were more common in the lenalidomide arms,

but the CONTINUUM study noted that a clinically meaningful difference in quality of life was not found between the 2 arms.

As a frontline therapy, single-agent lenalidomide showed an ORR of 72% in a phase II study with a 20% CR rate.

At 3 years, the PFS rate was 65% and the OS rate was 85%. AEs of note included grade 3/4 neutropenia (76%) and thrombocytopenia (28%) and grade 1/2 tumor are reaction occurred at a rate of 88%. However, tumor are reaction is correlated with a response in patients receiving lenalidomide.

Allogeneic HSCT can result in long-term PFS and has traditionally been considered in patients with high-risk disease in first remission.

With the availability of effective targeted therapies, this paradigm has recently shifted.

Susan M. O&rsquo; Brien, MD, associate director for clinical science at the Chao Family Comprehensive Cancer Center at the Univer- sity of California Irvine Health, explained in an interview with the American Journal of Managed Care

: &ldquo;Some of our newer thera- pies are improving the outcomes even in the high-risk subsets which traditionally had been patients with 17p deletion or 11q deletion.... Now we have approved treatments including ibrutinib, idelalisib, and, most recently, venetoclax for patients with 17p. So, since we have all these effective targeted therapies, we&rsquo;d no longer recommend stem cell transplant in first remission.&rdquo;

HSCT remains a treatment option for patients with relapsed or refractory CLL, but despite the development of nonmyeloablative reduced-intensity conditioning (RIC) regimens, many patients with CLL are not eligible due to age or comorbidities, and graft- versus-host disease (GVHD) remains a major issue. A summary of prospective studies using RIC HSCT in CLL patients with a median follow-up of up to 6 years reported a 40% median PFS and a median OS of 50% to 60%, and chronic GVHD in almost 50% of patients.

According to Coutre, the current treatment landscape in CLL is &ldquo;changing dramatically, largely because of the introduction of the new oral therapies. And so, it&rsquo;s really a transformative time in managing CLL...clearly we are able to better treat this disease for a longer period of time with drugs that are better tolerated for many of our patients.&rdquo;

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Chronic Lymphocytic Leukemia/Small Lymphocytic Lym- phoma. Version 2.2017. NCCN website. www.nccn.org/professionals/physician_gls/pdf/cll. pdf. Published February 21, 2017. Accessed May 15, 2017.

Thompson PA, Tam CS, O&rsquo;Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303-309. doi: 10.1182/blood-2015-09-667675.

Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42. doi: 10.1056/NEJMoa1215637.

FurmanRR,SharmanJP,CoutreSE,etal.Idelalisibandrituximabinrelapsedchroniclym- phocytic leukemia. N Engl J Med. 2014;370(11):997-1007. doi: 10.1056/NEJMoa1315226.

Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322. doi: 10.1056/NEJMoa1513257.

Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi: 10.1056/NEJMoa1509388.

Tam CS, O&rsquo;Brien S, Wierda W, et al. Long-term results of the udarabine, cyclophospha- mide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975-980. doi: 10.1182/blood-2008-02-140582.

Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to udarabine and cy- clophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174. doi: 10.1016/S0140-6736(10)61381-5.

Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215. doi: 10.1182/blood-2015-06-651125.

Awan FT. Cure for CLL? Blood. 2016;127(3):274. doi: 10.1182/blood-2015-11-678532.

Kipps TJ, Stevenson FK, Wu CJ, et al. Chronic lymphocytic leukaemia [published correction appears in Nat Rev Dis Primers. 2017;3:17008. doi:10.1038/nrdp.2017.8]. Nat Rev Dis Prim- ers. 2017;3:16096. doi: 10.1038/nrdp.2016.96.

Eichhorst B, Fink AM, Bahlo J, et al; German CLL Study Group. First-line chemoimmunother- apy with bendamustine and rituximab versus udarabine, cyclophosphamide, and ritux- imab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942. doi: 10.1016/S1470-2045(16)30051-1.

Eichhorst B, Bahlo J, Maurer C, et al. Favorable toxicity pro le and long term outcome of elderly, but physically t CLL patients (pts) receiving rst line bendamustine and rituximab (BR) frontline chemoimmunotherapy in comparison to udarabine, cyclophosphamide, and rituximab (FCR) in advanced chronic lymphocytic leukemia (CLL): Update analysis of an international, randomized study of the german CLL study group (GCLLSG) (CLL10 study). Blood. 2016;128: (Abstract 4382).

Byrd JC, Brown JR, O&rsquo;Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi: 10.1056/NEJMoa1400376.

Current treatment strategies for chronic lymphocytic leukemia (CLL).

Current Treatment Strategies in CLL

With changing treatment paradigms, particularly the use of oral targeted agents, predictive value and use of prognostic factors to determine treatment choice are shifting. Traditional risk factors, including disease stage and lymphocyte doubling time, are becoming less relevant for treatment selection, and the predictive value of cytogenetic and molecular markers on response to treatment with novel agents is being rede ned based on the outcomes of recent trials.

In 2008, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) published revised guidelines for the diagnosis and treatment of CLL.

These revised guidelines acted as an update to the National Cancer Institute sponsored Working Group's (NCI-WG) 1996 guidelines,

which sought to create recommendations for the design and conduct of clinical trials for patients with CLL. The iwCLL updates these guidelines following significant progress in determining prognostic markers, diagnostic parameters, treatment options, and more for the diagnosis and response to treatment for patients with CLL.

When assessing the level of response to treatment in patients with CLL, a physical exam is required, along with evaluation of the blood and marrow. Unlike response assessment in solid tumors, imaging studies, particularly CT scans, are not usually necessary.

The characterization of a complete remission (CR) as defined by the iwCLL requires the absence of clonal lymphocytes in the peripheral blood, no hepatomegaly or splenomegaly, and the absence of constitutional symptoms, all within 3 months of the completion of therapy.

Additionally, polymorphonuclear leukocyte levels should be above 1500/&mu;L, platelets above 100,000/&mu;L, and hemoglobin above 11 g/dL untransfused (TABLE 12). Previously, a CR according to the NCI-WG still had detectable minimal residual disease (MRD). A partial remission (PR) depends upon at least 1 parameter relating to the tumor load and another relating to the function of the hematopoietic system or marrow improving, with 1 of these factors lasting for at least 2 months. Progressive disease (PD) is also determined by a change in the tumor load and/or a decrease in platelet or hemoglobin levels. Additionally, the guidelines define a CR in the absence of MRD as the complete eradication of the leukemia, where blood or marrow expresses less than 1 CLL cell per every 10,000 leukocytes.

DISEASE CHARACTERISTICS AFFECTING PROGNOSIS AND GUIDING TREATMENT SELECTION

The presence of a deletion of chromosome 17p (del[17p]) and mutated TP53 represent the most relevant disease characteristics that guide the choice of therapy in patients with CLL.

Del(17p) causes the loss of 1 TP53 allele and is associated with mutations in the remaining TP53 allele in more than 80% of patients, resulting in loss or dysfunction of TP53. Both del(17p) and mutated TP53 are associated with poor response to chemotherapy-based regimens, short progression-free survival (PFS), and poor overall survival (OS), independently of IGHV mutation status (TABLE 2).

Recent trials have demonstrated activity of novel targeted agents in patients with del(17p)/TP53-mutant CLL, who are considered a distinct subgroup who require a specific therapeutic approach.

This has significantly changed outcomes for this subgroup for whom previous options to increase the duration of response were largely limited to stem cell transplant in eligible patients.

Ibrutinib (Imbruvica), a first-in-class oral covalent inhibitor of Bruton&rsquo;s tyrosine kinase (BTK), blocks an essential component of the B-cell receptor cascade, inhibiting survival signaling between CLL cells and the tumor microenvironment. The agent was approved by the FDA in 2014 for the treatment of patients with relapsed/refractory CLL, supported by outcomes of phase II and III studies demonstrating high response rates (71%),12 higher objective response rates (ORR; 43% vs 4%), and significantly improved PFS compared with treatment with ofatumumab (Arzerra); (not reached vs 8.1 months at median follow-up of 9.4 months), and OS benefit (1-year OS, 90% vs 81%; HR for death, 0.43; P = .005) (TABLE 33). Importantly, the phase III RESONATE study showed that efficacy differences were retained in patients carrying del(17p) and in those resistant to purine analogues.

The CLL indication of ibrutinib has recently been expanded to include frontline therapy, in part based on outcomes from the phase III RESONATE-2 study comparing ibrutinib with chlorambucil in 260 elderly treatment-nai&Igrave;&circ;ve patients with CLL.

Ibrutinib induced a signi cantly higher ORR (86% vs 35%), longer median PFS (not reached vs 18.9 months), and a longer OS (98% vs 85% at 2 years) (TABLE 413).This study specifically excluded patients with known del(17p) CLL; however, a recently published single-arm phase II study also demonstrated activity in previously untreated patients and in those with relapsed/ refractory CLL with del(17p) or TP53-mutant disease, with an objective response rate of 97% among untreated patients and 80% among relapsed/refractory patients after a median follow-up of 2 years.

Ibrutinib is considered the preferred first-line therapy for patients with del(17p)/TP53-mutant CLL and is a category 1 recommendation for patients with CLL without del(17p)/TP53 mutation who are frail or, are &ge;65 years, or younger with significant comorbidities, according to the National Comprehensive Cancer Network (NCCN) guidelines on CLL.

As Steven E. Coutre, MD, a hematologist with Stanford University and co-investigator of the RESONATE-2 trial, explained in an interview with the American Journal of Managed Care

, &ldquo;We had patients between the ages of 65 and 70, and then we had those 70 years and older. Again, those patients 70 years and older would be an average CLL patient who&rsquo;s starting therapy. And we saw benefit in both groups. There really was no distinction. It also speaks to the fact that it&rsquo;s well tolerated. So, often patients who are older, of course, have more comorbiditiesdiabetes, hypertension, the usual things that we see. And that didn&rsquo;t impact either the ef cacy or the tolerability of the treatment.&rdquo;

The long-term outcomes with first-line ibrutinib remain to be determined. Coutre added, &ldquo;The real value is going to be to see how those patients do as they continue on ibrutinib.... In the RESONATE-2 trial, there are only 3 patients who came off ibrutinib because of progressive disease. And, although follow-up of them is still shortmeasured in months, not years&mdash;none of those patients have gone on to subsequent treatment yet.

We have a limited experience from our very first trial. I have a few patients on that trial who have been receiving ibrutinib for more than 6 years now.&rdquo;

With the availability of targeted therapies, which also include idelalisib (Zydelig) and venetoclax (Venclexta) for the treatment of patients with relapsed/refractory CLL, the question how to optimally sequence agents has become highly pertinent. Findings of a retrospective study evaluating outcomes with targeted therapies suggest better outcomes with ibrutinib as the first kinase inhibitor compared with idelalisib, superior outcomes with an alternate kinase inhibitor or venetoclax than with chemoimmunotherapy combinations after kinase inhibitor failure, and possibly better outcomes with venetoclax after ibrutinib failure.

Consequently, the authors emphasized the need for trials testing sequencing strategies to optimize treatment algorithms.

DEL(11Q) IS NOT A NEGATIVE PROGNOSTIC PREDICTOR FOR RESPONSE TO IBRUTINIB

The del(11q22.3) cytogenetic abnormality, which is detected in up to 20% of patients with CLL at diagnosis and at a higher frequency in relapsed/refractory CLL, has traditionally been considered an unfavorable cytogenetic alteration associated with extensive lymphadenopathy, disease progression, and shorter median survival (79 months).

The presence of del(11q) predicts poor response to chlorambucil-, udarabine-, or FCR ( udarabine, chlorambucil, rituximab [Rituxan])-based regimens, with shorter duration of remission and OS compared with other cytogenetic groups.

An overview of the factors affecting prognosis and treatment in chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia

Current Approaches to Diagnosis and Risk Stratification in Chronic Lymphocytic Leukemia

Current Treatment Strategies in CLL

Factors Affecting Prognosis and Treatment in CLL

Emerging Targeted Therapies and Immunotherapies in CLL

Experts Share Insight on Ibrutinib's Bright Future in CLL Landscape