Chronic Lymphocytic Leukemia and Hairy-Cell Leukemia

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia and one of the most common lymphoid malignancies in Western countries. The pathobiology of CLL is a result of the failure of apoptosis rather than uncontrolled proliferation. By definition, CLL is B-cell–derived and is also referred to as small lymphocytic lymphoma (SLL) when found in sites other than the blood and bone marrow. The prototypical CLL patient is an older, white man (2:1 male predominance, median age at diagnosis is 72 years) with lymphocytosis and possibly lymphadenopathy but no other symptoms. The management for such a prototypical patient is observation, because early initiation of cytotoxic therapy will expose the patient to toxicities and to date has never been shown to improve survival. Therapy may ultimately be needed for such a patient and for an improvement in symptoms; disease control and improved overall survival are possible with modern CLL regimens. A fraction of CLL patients do not behave like the prototypical patient and have short remissions and resistance to therapy that will require aggressive therapeutic options, including an allogeneic hematopoietic progenitor cell transplant.

Epidemiology

In the United States in 2015, there are an expected 14,620 new diagnoses of CLL and 4,650 CLL-related deaths. The age-adjusted incidence of CLL is 4.1/100,000 individuals. The median age at diagnosis is 72 years and the incidence of this disease continues to rise as the population ages. The male-to-female ratio is 2:1, with little change in relative risk as age increases. The incidence of the disease is higher in whites than in African Americans, and the diagnosis of CLL in Asian countries is infrequent. The shift in the global population has not changed the risk for any particular race or ethnicity.

Etiology and Risk Factors

Monoclonal B-cell lymphocytosis

It is surmised that nearly all cases of CLL are preceded by a monoclonal B-cell lymphocytosis (MBL). MBL is defined as a B-cell population with a CLL immunophenotype by flow cytometry that is not greater than 5 × 10⁹/L and no symptoms consistent with a diagnosis of CLL. This disorder is discovered incidentally or when patients are being evaluated for a possible diagnosis of CLL. The monoclonal B cell will invariably have a phenotype analogous to CLL. It is estimated that about 3% of the US population meets the criteria for MBL, and this incidence increases with age. Studies have shown that the rate of progression to CLL from MBL is approximately 1% to 2% per year.

Genetic factors

Approximately 17% of patients with a diagnosis of CLL have a first-degree family member who has MBL, and 5% to 10% of CLL patients have a family member with CLL.

Environmental factors

Exposure to herbicidal agents, such as “Agent Orange,” may be associated with CLL; however, this is not proven. Causality due to radiation exposure, alkylating chemotherapy, and other chemicals has not been confirmed.

Signs and Symptoms

In a prototypical patient, symptoms are typically absent, though some patients may have nonspecific complaints such as weakness and fatigue. Classic B symptoms are uncommon at diagnosis, but their presence may signal transformation to large cell lymphoma. Patients may notice enlarged lymph nodes, and abdominal distention may relate to enlarged mesenteric adenopathy, hepatomegaly, or splenomegaly. Infections such as reactivation of herpes simplex virus are common.

Splenomegaly is a common finding in CLL and typically progresses as the disease matures and becomes refractory to therapy. Hepatomegaly may present in 15% to 25% of patients and is usually mild and nontender. Because these cells circulate freely in the blood and are attracted to sites of inflammation, CLL cells are often found in biopsy specimens from almost any organ. It is important to recognize that in the vast majority of cases, the CLL is a bystander, not an instigator, and such findings rarely require anti-CLL therapy.

Laboratory Features

Peripheral blood

Lymphocytosis is the hallmark finding in CLL, with a typical lymphocyte count of 30–50 × 10⁹/L. Lymphocytes are small, mature-appearing cells with little cytoplasm and clumped chromatin. Smudge cells are frequently seen on peripheral blood smear; they may denote a more indolent course when present in high volumes. Larger cells, typically prolymphocytes, may also be seen on smear but they are usually less than 10% of the total lymphocyte pool. Diagnostic criteria for CLL defined by the National Cancer Institute and the International Workshop on Chronic Lymphocytic Leukemia are presented in Table 1.

TABLE 1: Diagnostic criteria for CLL according to the National Cancer Institute (NCI) and International Workshop on CLL (IWCLL)

A positive Coombs test is seen in as many as 30% of patients at some point during the disease course, although it is uncommon (< 5%) during early stages. Autoimmune phenomena are relatively frequent, with hemolytic anemia (lifetime risk, approximately 10% to 20%) and thrombocytopenia (lifetime risk, approximately 5% to 10%) occurring most commonly. Autoimmune neutropenia and other autoimmune sequelae are infrequent but more common than in the general population.

Bone Marrow

The bone marrow is usually hypercellular, and mature lymphocytes represent at least 30% of the marrow cellularity. Lymphocytic infiltration on the biopsy may be interstitial, nodular, mixed interstitial and nodular, or diffuse. The diffuse pattern (effacement of marrow architecture by a dense mass of CLL cells) was traditionally associated with a poor prognosis, but this is now less important with more modern therapies. Given the availability of malignant cells in the peripheral blood for flow cytometric immunophenotyping, routine bone marrow evaluation at presentation is no longer necessary for diagnosis. The authors do recommend bone marrow testing to assess the etiology of cytopenias, prior to initiating antileukemic therapy.

Other laboratory findings

Tests such as lactate dehydrogenase (LDH), indirect bilirubin, haptoglobin, and reticulocyte count are of help in diagnosing autoimmune hemolytic anemia, which is common in CLL. Progressive hypogammaglobulinemia is seen in more than 50% of patients, polyclonal gammopathy may be seen occasionally, and a monoclonal paraprotein is present in 5% to 10% of patients. Even patients with normal or elevated IgG levels who have an impaired repertoire of antibodies may still benefit from intravenous immunoglobulin-replacement therapy. Elevated levels of beta 2-microglobulin are a poor prognostic marker.

Immunophenotyping

Immunophenotyping by flow cytometry has become the most common method of diagnosing CLL, and since these cells are of B-cell origin, they commonly express CD19 and CD20. The expression level of CD20 is low compared with that of normal B cells. However, CLL is characteristically positive for CD5. Expression of CD23 helps differentiate CLL from mantle cell lymphoma. Expression of surface immunoglobulin is usually weak and lower than in normal B cells. CD38 expression is a poor prognostic marker in CLL.

Cytogenetic and Molecular Findings

Chromosomal abnormalities

Recurrent cytogenetic (karyotypic and more commonly on fluorescence in situ hybridization [FISH]) abnormalities have been found in CLL and are useful in assigning prognosis and prescribing therapy. The proliferative rate of CLL cells is low and thus the standard karyotype is less helpful than abnormalities identified by the FISH studies. Chromosomal abnormalities using FISH can be identified in 70% to 80% of patients with CLL. The most frequent and significant abnormalities found on FISH are deletion 13q14 (45% to 55%), deletion 11q (17% to 20%), trisomy 12 (10% to 20%), and deletion 17p (5% to 10%). Some deletions are found primarily at diagnosis (or before treatment), such as deletion 13q14, while other genetic lesions may evolve after therapy or at the time of progression (clonal evolution), such as deletion 17p. The presence of multiple genetic aberrations portends a poor prognosis even in the presence of otherwise favorable genetic abnormalities such as deletion 13q14. The sole finding of deletion 13q14 is associated with the best median overall survival (113 months) while the shortest median survival is in patients with deletion 17p (32 months). Characteristics of patients harboring deletion 11q may include age younger than 55 years, diffuse and bulky peripheral adenopathy, short disease remissions, and a median overall survival of approximately 79 months. Previously it was thought that a regimen combining a purine analog with cyclophosphamide may be particularly beneficial to patients with del11q. The recent introduction of small-molecule inhibitors of specific pathways as treatment for patients with CLL is rapidly changing the importance of traditional prognostic features.

Molecular abnormalities

No single gene has been implicated in the pathogenesis of CLL. However, several genetic abnormalities have important biologic and/or prognostic implications. The TP53 gene is located on the short arm of chromosome 17 and is deleted in the leukemia clone (or more typically in a subclone) of up to 10% of patients with CLL. Mutations of TP53 occur in a similar proportion of CLL cases, usually in association with TP53 deletion in the other TP53 allele. The 17p deletion involving TP53 is considered the most significant negative prognostic factor in CLL. The TP53 protein normally responds to DNA damage by inducing cell cycle arrest and facilitating DNA repair. It can also induce apoptosis in cells with damaged DNA and in this way mediates the cytotoxicity of many anticancer agents. Resistance to treatment is a particular characteristic of TP53 deletion and has been observed for agents including purine analogs. Further investigation of the common 13q deletion has revealed specific micro-RNA genomic sequence abnormalities expressed in patients with CLL. Further analysis suggests a micro-RNA signature profile may be associated with ZAP-70 expression and mutational status of IgVH (immunoglobulin heavy-chain variable), as well as disease progression. Although the exact significance of this finding is not known with certainty, the specific micro-RNA signature may be relevant to the pathogenesis of CLL. In addition, germline mutations affecting these micro-RNAs may be a predisposing factor in familial CLL.

Overexpression of BCL2

Abnormalities of the long arm of chromosome 14 frequently involve region 14q32, the site encoding for the immunoglobulin heavy-chain gene. However, gene translocations such as t(11;14)(q13;q32) and t(14;18)(q32;q21), which juxtapose genes CCND1 and BCL2 to the heavy-chain immunoglobulin gene, are not typical and should prompt consideration of alternative diagnoses (mantle cell or follicular lymphoma). Nevertheless, increased expression of BCL2 mRNA and protein is typical in CLL. Because overexpression of BCL2 inhibits apoptosis, it is possible that this gene participates in the pathogenesis of CLL.

Staging and Prognosis

Staging systems

CLL continues to be staged by the Rai and Binet staging systems, which correlate with median overall survival (Table 2).

TABLE 2: Staging systems for CLL

Other prognostic factors

Several markers have been associated with prognosis; however, only del 17p (and possibly 11q as indicated above) is predictive of therapeutic efficacy, because it has been associated with relative resistance to purine analogs. TP53 is a crucial tumor suppressor gene located on chromosome 17p13; this gene can be compromised by deletion of 17p13 or by a somatic mutation within the gene. Popular (yet uneconomical) prognostic markers include IgVH mutation status, CD38, and ZAP-70 expression. Other prognostic markers, such as beta2-microglobulin (> 3.5 mg/L), lymphocyte doubling time (< 12 months), and diffuse vs nodular or interstitial marrow involvement, are far less expensive. The authors find lymphocyte doubling time to be one of the best predictors of time to first cytotoxic therapy. Transformation to another lymphoid malignancy is a poor prognostic sign and is often a terminal event.

Somatic hypermutation of IgVH is a normal process in B-cell physiology and is responsible for the diverse immunoglobulin pool. CLL cells that retain this normal process have a better prognosis than CLL cells that lack this capability. Some studies suggest that for patients with an unmutated IgVH, the median survival is 5 to 10 years compared with 10 to 20 years for those who retain somatic hypermutation of IgVH. These results, however, may overstate the longevity of these patients because they are based on retrospective analysis and are biased toward patients who have already survived for some length of time.

ZAP-70 encodes a protein tyrosine kinase normally expressed by T cells and is involved in intracellular signaling. CD38 is a glycoprotein found on cell surfaces and is detectable by flow cytometry. Both ZAP-70 and CD38 are correlated with unmutated IgVH (approximately 70% for both), thus their expression is a poor prognostic sign.

Lymphocyte doubling time of less than 12 months is associated with a worse prognosis, and some believe this inexpensive evaluation may be a more reliable predictor than many of the more expensive tests listed above. Because clonal evolution is common in CLL, and prior therapy often selects for p53-deficient clones, we recommend that prior to initiating a new therapy patients should have repeated FISH testing.

As stated above, however, the recent introduction of small-molecule inhibitors of Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) as treatment for patients with CLL is rapidly changing the importance of traditional prognostic features.

Treatment

Treatment recommendations

Prior to the 1990s, alkylating chemotherapeutic agents were the standard of care for symptomatic CLL. These agents were supplanted by the purine analogs in the 1990s; subsequently, combination chemoimmunotherapy was introduced in the 2000s, which has become popular for young, fit patients with CLL. However, there is no standard front-line regimen for symptomatic or advanced-stage CLL. The choice of therapy depends on goals of therapy for the patient, the anticipated toxicities of the treatment regimen, and the biology of the CLL clone (deletion 17p13 positive or negative). Despite the cornucopia of new agents for CLL, there continues to be a paucity of head-to-head trials, and those that have been done compare modern therapy with chlorambucil-based regimens. For patients able to tolerate aggressive modern combination chemoimmunotherapy, there is a higher complete response rate, including molecular remissions that were not observed previously with older treatment strategies.

Asymptomatic and early-stage disease

Despite the high frequency of complete responses achieved with modern CLL therapy, it has never been shown that treatment of early-stage or asymptomatic CLL improves overall survival. In fact, a recent study from the Mayo Clinic suggests that deferring therapy may result in prolonged survival. Although some have advocated that localized SLL may be treated with involved-field radiation therapy, the authors believe that such therapy typically does not have a favorable risk/reward benefit. Patients with CLL or SLL who require treatment should receive systemic therapy in essentially all cases. Early-stage CLL, even in patients with high-risk features, should be monitored until there is an indication for treatment.

Alkylator- and purine analog–based regimens

Single-agent chlorambucil and, less commonly, cyclophosphamide are still commonly used regimens in patients with CLL who may not tolerate aggressive chemoimmunotherapy. These agents may improve symptoms but rarely lead to complete responses and have not been associated with an improvement of survival. Eichhorst et al published the results of a phase III German CLL Study Group (GCLLSG) trial that included 193 older patients with previously untreated symptomatic CLL, median age of 70, and Eastern Cooperative Oncology Group performance status of 2 or greater who were randomly assigned to receive single-agent fludarabine or chlorambucil. Despite the fact that patients assigned to fludarabine had higher response frequencies and higher complete response rates, grade 3/4 toxicities with fludarabine were high (myelosuppression) and, if anything, overall survival favored the chlorambucil arm (median survival, 46 months for fludarabine and 64 months for chlorambucil). Several studies strongly suggested that fludarabine or fludarabine combinations do not benefit patients older than 65 to 70 years.

Chlorambucil may be prescribed in several schedules, including daily dosing (0.1 mg/kg) and pulse-intermittent dosing, which may be every 3 to 4 weeks (20–40 mg/m² or 0.8 mg/kg). The dose of chlorambucil will need to be titrated based on myelotoxicity. Cyclophosphamide is an alternative to chlorambucil and is prescribed either alone or in combination with vincristine and prednisone. The common single-agent dose of cyclophosphamide is 0.5 to 1 g/m² every 3 to 4 weeks. Small daily doses of cyclophosphamide should be avoided because of the long-term risk of squamous cell bladder cancer. The addition of prednisone to either chlorambucil or fludarabine does not improve the frequency of response but does increase the risk of opportunistic infections.

Bendamustine is an alkylating agent (nitrogen mustard derivative) with a benzimidazole ring (purine analog) that demonstrates only partial cross-resistance (in vitro) with other alkylating agents. Knauf et al reported the results of a phase III randomized study of bendamustine compared with chlorambucil as first-line therapy in symptomatic CLL patients. The overall response rate (ORR), complete response (CR) rate, and progression-free survival for bendamustine vs chlorambucil were 68% vs 31% (P < .01), 31% vs 2%, and 21.6 months vs 8.3 months (P < .01), respectively. Fischer et al reported on the safety and efficacy of the combination of bendamustine and rituximab in 117 CLL patients. After a median follow-up of 27 months, the ORR, CR rate, and event-free survival were 88%, 23%, and 33 months, respectively. The GCLLSG CLL10 trial has recently completed enrollment of physically fit patients randomized to receive the combination of fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR). In an abstract by Eichhorst et al, FCR had more efficacy in terms of higher CR rate and longer progression-free and event-free survival than BR. But it was also noted that FCR was associated with a higher rate of severe adverse events, including neutropenia and infection, and authors concluded that there was no recommendation of one regimen over the other at this early point in the analysis. Bendamustine is FDA-approved for the treatment of previously untreated and relapsed CLL patients.

TABLE 3: Response criteria in CLL according to the IWCLL

Chemoimmunotherapy

Rituximab has perhaps been one of the most important additions to modern therapy. As a single agent, it has modest activity in terms of response, but when it is added to other treatments, it improves the quality and frequency of responses and, most importantly, improves survival. The Cancer and Leukemia Group B (CALGB) 9712 studied sequential vs the combination of rituximab and fludarabine in 104 patients with previously untreated CLL. With a median follow-up of 117 months, the ORR, CR rate, progression-free survival, and overall survival were 84%, 28%, 42 months, and 85 months, respectively. Investigators at MD Anderson evaluated FCR in a phase II study of 300 previously untreated patients. With a median follow-up of 6 years, the ORR, CR rate, and progression-free survival were 95%, 72%, and 80 months, respectively. These studies led to the GCLLSG CLL8 trial, which randomized 408 previously untreated patients to six cycles of either combination fludarabine and cyclophosphamide (FC) or FCR. The 3-year progression-free survival was 65% vs 45% (P < .01) and overall survival was 87% vs 83% (P = .01) in the FCR arm and FC arm, respectively. Adverse events were higher in the FCR arm and consisted primarily of neutropenia. Lamanna et al published the results of a sequential FCR regimen that produced a CR in 61%. Using a highly sensitive clonotypic polymerase chain reaction assay, the authors reported that 90% of patients achieving a molecular CR remained in a morphologic CR at 5 years. Other combinations, including pentostatin, cyclophosphamide, and rituximab (PCR) and cladribine, cyclophosphamide, and rituximab (CCR), may offer some advantages over FCR, with PCR perhaps being better tolerated and CCR possibly producing longer response durations.

Obinutuzumab is a humanized bioengineered monoclonal antibody to CD20 that has a higher binding affinity and leads to increased antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The FDA granted approval of obinutuzumab in 2013 for the treatment of patients with pre-existing comorbidities in combination with chlorambucil. The CLL11 (BO21004) is a phase III trial that compared the combination of obinutuzumab and chlorambucil with the combination of chlorambucil and rituximab and chlorambucil alone in patients with previously untreated CLL and pre-existing comorbidities. The overall response frequency, complete response frequency, and median progression-free survival with the combination of obinutuzumab and chlorambucil was higher than that of the combination of chlorambucil and rituximab: 75.5% vs 65.9%, 22.2% vs 8.3%, and 23 months vs 15.7 months, respectively. There were more grade 3-5 adverse events for the combination of obinutuzumab and chlorambucil, which mostly consisted of infusion reactions (21%) and neutropenia (34%). The FDA-approved dosing of obinutuzumab is 100 mg IV on day 1, then 900 mg on day 2, and 1,000 mg on days 8 and 15 for cycle one. For subsequent cycles, obinutuzumab is given on day 1 at 1,000 mg IV on a 4-week schedule. The chlorambucil is given at 0.5 mg/kg PO on days 1 and 15 of each 4-week cycle.

Ofatumumab is a fully humanized antibody targeting CD20 that was initially approved for CLL in fludarabine- and alemtuzumab-refractory patients. More recently, a prospective randomized trial demonstrated the superiority of ofatumumab over chlorambucil as initial treatment of patients with CLL, which led to FDA approval for this indication.

Alemtuzumab is a recombinant, humanized monoclonal antibody against CD52 that is FDA-approved for treatment of upfront and relapsed CLL patients. Keating et al presented the results of alemtuzumab in 93 patients with relapsed CLL who were fludarabine-resistant. The ORR was 33%, CR was seen in only 2%, and 30% of patients died within 6 months of starting therapy. Hillmen et al studied alemtuzumab in a randomized study of 297 patients in the first-line setting in symptomatic CLL, with chlorambucil as the control arm. The ORR, CR rate, and progression-free survival in the alemtuzumab and chlorambucil arms were 83% vs 55%, 24% vs 2%, and 14.6 months vs 11.7 months, respectively. Lozanski et al described their results with alemtuzumab in 36 patients with fludarabine-refractory CLL and either mutations or deletions of p53. The ORR was 40% and the response duration was 8 months. On the basis of these results, many believe that alemtuzumab may be the drug of choice for patients with CLL and del17p. Of particular note is the risk of cytomegalovirus reactivation in patients treated with alemtuzumab. The recent development of ibrutinib (below) appears likely to supplant alemtuzumab as the preferred therapy for patients with deletion of p53.

Immunomodulatory agents

Lenalidomide, characterized as an immunomodulatory agent with an unknown mechanism of action, has important activity in CLL. Studies at Roswell Park and MD Anderson initially demonstrated the important clinical activity of lenalidomide alone or combined with rituximab. Interestingly, the use of lenalidomide in CLL has been complicated by lethal tumor lysis and tumor flare. Accordingly, the typical starting dose is 5 mg daily and every dose increment needs very close follow-up to recognize and treat tumor lysis and tumor flare.

Novel agents under study

Although the prior section describes the paradigm of CLL therapy for the last 10-15 years, the authors note that the therapeutic approach to CLL is shifting dramatically. This has occurred because of the introduction of new classes of drugs including those that impact inhibition of signaling through the B-cell receptor and inhibition of BCL-2. Multiple agents are currently in development, and below we highlight three of the most studied agents, two of which are now FDA-approved and are rapidly becoming the agents of choice.

BTK inhibitor: ibrutinib

Bruton tyrosine kinase (BTK) plays a role in signal transduction of the B-cell receptor, which is a necessary driver for CLL pathogenesis. Ibrutinib is a small-molecule inhibitor of BTK that has dramatic activity in CLL. In a study by Byrd et al, 85 CLL/SLL patients were treated with either 420 mg or 840 mg of ibrutinib once daily. The therapy was well tolerated, and although CR was infrequent (2%), overall response with disease control was seen in the vast majority of patients (> 70%). Given these initial data, the FDA granted accelerated approval to ibrutinib for CLL in early 2014. On average, patients were diagnosed with CLL 6.7 years prior to the study and had received four previous therapies. Results revealed an overall response rate of 58%. At the time of the study, the duration of response ranged from 5.6 to 24.2 months. An improvement in survival or disease-related symptoms had not been established. Subsequently, the FDA granted approval of ibrutinib for patients with 17p deletion based on the results seen in this subgroup from the RESONATE study. This study was a randomized, international, multicenter, open-label phase III trial in 391 patients with CLL or SLL, who had received at least one prior therapy. Thirty-two percent of patients in the trial had del 17p. Patients were administered either 420 mg oral ibrutinib (n = 195) once daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n = 196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). Results revealed ibrutinib significantly prolonged progression-free survival (median not reached vs 8.1 months; hazard ratio [HR] = 0.22, 95% CI, 0.15–0.32; P < .0001) and overall survival (HR = 0.43; 95% CI, 0.24–0.79; P = .05) vs intravenous ofatumumab in previously treated patients with CLL or SLL. The overall survival results represents a 57% statistically significant reduction in the risk of death in patients receiving ibrutinib vs those in the ofatumumab arm. Progression-free survival was the primary endpoint of the RESONATE study, with overall survival, ORR, and safety as key secondary endpoints. Treatment with ibrutinib was associated with a 78% statistically significant reduction in the risk of death or progression vs ofatumumab. ORR was shown to be 42.6% in the ibrutinib arm vs 4.1% in the ofatumumab arm. There are many ongoing studies of ibrutinib in combination with chemoimmunotherapy, as well as investigations of other novel agents that are currently in progress.

PI3k inhibitor: idelalisib

The class I PI3Ks regulate B-cell proliferation and survival. Idelalisib is an oral inhibitor of an isoform of the this enzyme that promotes apoptosis of CLL cells. A phase I study reported by Brown et al treated 54 refractory CLL patients with idelalisib with a resulting ORR of 56%; there were no dose-limiting toxicities and only mild adverse effects including rash, fevers, fatigue, diarrhea, and respiratory infections. Because of the activity of idelalisib as a single agent and in combination with other agents, including rituximab, a phase III randomized, double-blind, placebo-controlled trial of combination therapy with idelalisib and rituximab in patients with relapsed CLL was recently reported by Furman et al. The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P < .001). Patients receiving idelalisib compared with those receiving placebo had improved rates of overall response (81% vs 13%; odds ratio, 29.92; P < .001) and overall survival at 12 months (92% vs 80%; HR for death 0.28; P = .02). Serious adverse events occurred in 40% of patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. This study led to the FDA approval of idelalisib and rituximab for the treatment of patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to other comorbidities.

BCL-2 inhibitor: ABT-199

The BCL-2 family of anti-apoptotic proteins is a target in various B-cell malignancies. A phase I study of ABT-199 by Seymour et al included 56 patients with refractory CLL. The dose-limiting adverse events were tumor lysis syndrome and neutropenia, and the ORR was 85%, with 13% CRs.

Importance of achieving a minimal residual disease state

Minimal residual disease (MRD) can be detected by multiparameter flow cytometry and real-time polymerase chain reaction (PCR). With the popularization of chemoimmunotherapy and the resultant high rates of CRs, it now possible to achieve a depth of remission that is undectable by these sensitive tests. Böttcher et al from the GCLLSG CLL8 trial concluded that MRD levels independently predict progression-free survival and overall survival in CLL. However, MRD is not a mandatory assessment for routine clinical practice. Furthermore, this may be more complicated than previously thought because an MRD-negative state may be a biomarker of clinically favorable disease rather than a goal to be achieved through even more aggressive treatment. Finally, the paradigm noting the importance of an MRD-negative state may not be valid in the new era of small-molecule inhibitors of vital pathways.

Cellular therapy

Autologous transplant. An autologous progenitor cell transplant aims at delivering high-dose chemotherapy yet limits the associated duration of neutropenia by autologous progenitor cell rescue. Although autologous transplant is curative in some lymphomas, its role in CLL is less well defined. The European Bone Marrow Transplant Chronic Leukemia Working Party conducted a phase III randomized study offering an autologous transplant with conditioning with BEAM (BCNU, etoposide, cytarabine, and melphalan) after first- or second-line therapy or observation. The event-free survival time was doubled for patients in the autologous transplant arm compared with the observation arm (51.2 vs 24.4 months) and the 5-year event-free survival was 42% vs 24% (P < .01). Despite this impressive improvement in event-free survival, the overall survival was statistically similar in the two arms. A second randomized trial by Sutton et al confirmed this improvement in event-free survival yet no benefit in overall survival. Currently the authors believe there is no role for autologous transplant in CLL and that such transplants should not be offered outside of a clinical trial.

Allogeneic transplant. Unlike the autologous transplant, allogeneic transplant can produce durable complete responses not only because it enables patients to receive higher-dose chemotherapy but also, more importantly, because it imparts a potent graft-vs-leukemia effect. Historically, the allogeneic transplant was preceded by a myeloablative conditioning regimen that only patients under the age of 55 to 60 years could tolerate. After the introduction of the reduced-intensity and nonmyeloablative conditioning regimens, older patients more representative of the CLL population were able to tolerate the transplant. In fact, most groups have now abandoned myeloablative transplants for patients with CLL, even for younger, fit patients.

The largest prospective study using a nonmyeloablative conditioning regimen is by Sorror et al, who transplanted using either a matched related “r” or matched unrelated donor in patients who proved refractory to chemotherapy between 1997 and 2003. The 5-year incidence of treatment-related mortality, progression-free survival, and overall survival were 23%, 39%, and 50%, respectively. Similar results were reported by Dreger et al from the GCSG CLL3X study, which used a reduced-intensity conditioning, matched related donor, or matched unrelated donor in high-risk patients with CLL between 2001 and 2007. The 4-year treatment-related mortality, event-free survival, and overall survival were 23%, 42%, and 65%, respectively. These results support the utility of reduced-intensity transplants as treatment for CLL but also highlight the risks of this therapy, thus requiring careful patient selection.

Chimeric antigen receptor (CAR) T cells. Targeted cellular therapy is in its infancy, and patient case reports using CARs have generated tremendous excitement. Genetic modifications of T cells to identify and kill B cells form the basis of these therapeutic modalities. Porter et al reported the first successful cases in which three patients with CLL were given a conditioning regimen of bendamustine or pentostatin plus cyclophosphamide followed by the infusion of CAR-modified T cells. They described the immune reaction, now referred to as cytokine release syndrome, consisting of fevers, rigors, diarrhea, and even tumor lysis. Two patients achieved a CR and one had a partial response. To date, there is too little experience and too few follow-up data to decipher the duration of remission and the overall survival outcomes achieved with this expensive technology. Moreover, the development of the novel small-molecule inhibitors is likely to markedly reduce the utility of CAR therapy and allogeneic transplantation for patients with CLL.

Hypersplenism

Historically, as CLL progressed and became more refractory to therapy, some patients developed cytopenias related to pronounced splenomegaly that can be associated with worsening cytopenias. The two methods for improving symptoms due to hypersplenism are irradiation of the spleen and surgical splenectomy. Splenectomy is the more definitive choice; irradiation is a temporizing option in patients who are not surgical candidates. The mortality associated with splenectomy is variable and dependent on the experience of the surgeon. Therefore, if necessary, we recommend that splenectomy should be done in experienced centers. Vaccination against pneumococcus, Haemophilus influenzae type B, and meningococcus should be administered prior to surgery, however it needs to be recognized that patients with CLL have a reduced response to such vaccines. Despite the benefits previously seen with splenectomy it should be noted that with more modern and effective therapies, the role of spleen-targeted therapy has been greatly reduced.

Complications of CLL

Infections

As with all hematologic malignancies, CLL is associated with a compromised immune system and an increased incidence of infections. The infectious complications may be due to either the underlying disease or the associated therapy. Patients have a quantitative and qualitative compromise in immunoglobulin that can be improved by the administration of immunoglobulin replacement therapy; typically 400 to 500 mg/kg administered every 3 or 4 weeks. Despite this beneficial treatment, up to 50% of patients are projected to die as a result of infection, which makes infection the leading cause of death in patients with CLL.

Autoimmune cytopenias

Autoimmune hemolytic anemia is reported to occur in 5% to 10% of patients with CLL. If one were to include low-level hemolysis, the authors believe the fraction would be higher still. The diagnosis is usually evident by a sudden worsening of anemia and an elevated indirect bilirubin level, LDH level, and reticulocyte count. However, the direct Coombs test may be negative in the vast majority of patients or results might be quite subtle; in this setting, a haptoglobin test result that is low-to-absent is the most sensitive clinical test. Patients with a sudden fall in hemoglobin level and a near-absent reticulocyte count may have pure red cell aplasia. Although most cases of autoimmune hemolytic anemia will improve with corticosteroids and/or rituximab, pure red cell aplasia typically requires therapy with cyclosporine (3 to 6 mg/kg/d).

Transformation and secondary malignancies

The most common hematologic malignancies encountered in patients who have received therapy for CLL include transformed disease, such as evolution to a large cell lymphoma, prolymphocytic leukemia (PLL), or Hodgkin lymphoma. Secondary malignancies include myelodysplastic syndrome and acute myeloid leukemia. There is some evidence that patients may also have a higher risk of developing secondary solid malignancies, perhaps related to the immune dysfunction inherent in CLL.

Large-cell lymphoma. Maurice Richter initially described transformation to large cell lymphoma in 1928. Typically this is diffuse large B-cell lymphoma (DLBCL) and, rarely, Hodgkin and even T-cell lymphomas. Although not always included under the umbrella term of “Richter transformation,” PLL represents a biologically similar event and should be viewed as “transformed disease.” The incidence of Richter’s transformation is approximately 0.5% to 1% of patients per year, and presenting symptoms include fever and other B symptoms and accelerated enlargement of adenopathy. Laboratory signs include a sharp rise in serum LDH level, hypercalcemia, and the discovery of a monoclonal protein. Positron emission tomography may be very helpful in diagnosing Richter transformation, but biopsy of an enlarged hypermetabolic lymph node is the diagnostic procedure. If the biopsy proves DLBCL, therapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) should be considered. Patients who have had significant prior therapy typically do not respond to this or other regimens. Patients who have not had cytotoxic therapy often respond well to R-CHOP and may have durable responses.

PLL and Hodgkin lymphoma. PLL is characterized by more than 55% prolymphocytes in the peripheral blood, which is accompanied by a rapidly enlarging spleen and, thus, cytopenias that prove refractory to therapy. The Hodgkin lymphoma associated with CLL is typically more aggressive than de novo Hodgkin lymphoma and is resistant to traditional treatment for Hodgkin lymphoma. The authors recommend that all patients with transformed disease be treated with R-CHOP regardless of the histologic subtype. Consolidation with allogeneic transplant should be considered for patients with transformation to Hodgkin lymphoma and for any patient who received chemotherapy for their CLL before transformation.

Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disease that often comes to medical attention when affected patients are found to have unexplained cytopenias and/or splenomegaly. Atypical of a rare disease, there is a plethora of effective therapy for HCL.

Epidemiology and Etiology

There are approximately 600 to 800 cases of HCL diagnosed per year in the United States. HCL accounts for 2% of all leukemias and less than 1% of all lymphoid neoplasms. The median age at diagnosis is 52 years, with a male predominance of about 4:1. The BRAF V600E mutation is characteristic in HCL and is present in almost every case of the disease. However, BRAF mutations are present in other malignancies, including malignant melanoma, for which a BRAF inhibitor (vemurafenib) is now FDA-approved. Recent clinical experience by Dietrich et al of vemurafenib in a patient with refractory HCL proves the concept that BRAF mutation is critical in driving the proliferation of HCL.

Differential Diagnosis

The differential diagnosis of HCL includes other mature, small-cell lymphoproliferative neoplasms, such as CLL, PLL, splenic marginal zone lymphoma, and mantle cell lymphoma in leukemic phase. The diagnosis of HCL is made by bone marrow biopsy and aspirate, with flow cytometry revealing B-cell markers in addition to CD103, CD11c, and CD25. Aberrant expression of CD5 may be encountered, but staining for cyclin D1 is negative.

Treatment

Similar to patients with CLL, patients with HCL may be asymptomatic and can be observed without therapy for months or years. Early institution of therapy has not been shown to improve survival, and the goal of therapy is to alleviate symptoms. Such goals may include improvements in cytopenias (absolute neutrophil count > 1,500/µL, platelet count > 100,000/µL, and hemoglobin level > 12 g/dL), regression of organomegaly, and clearance of hairy cells from the peripheral blood and bone marrow.

Purine analogs are the first line of therapy, and resistance to one agent does not mean resistance to all such agents. The most common purine analog used is cladribine at 0.1 mg/kg/d as a continuous infusion for 7 days. However, pentostatin at 4 mg/m² given every 14 days for 4 to 6 months has excellent activity and may be less toxic than cladribine.

A small fraction of patients may develop disease refractory to treatment with the purine analogs; such patients may be treated with rituximab, the BRAF inhibitor vemurafenib, the anti-CD22 antibody BL22, the anti-CD25 antibody LMB-2, or interferon-alpha. BL22 is a recombinant immunotoxin containing an anti-CD22 variable domain fused to a truncated Pseudomonas exotoxin. A phase II study by Kreitman et al of BL22 in 36 patients with relapsed/refractory HCL revealed an ORR of 50% and a CR in 25% after one cycle of treatment. Toxicities were sometimes serious and included hemolytic uremic syndrome, cytokine-release syndrome, and elevated liver enzyme levels. The recent development of BRAF inhibitors will likely challenge these potentially severely toxic therapies and may become the treatment of choice in purine analog–refractory HCL.

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