Expert Review of Hematology

ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20

Chronic lymphocytic leukemia and small

lymphocytic lymphoma: two faces of the same
disease

Michael T. Tees & Ian W. Flinn

To cite this article: Michael T. Tees & Ian W. Flinn (2016): Chronic lymphocytic leukemia and
small lymphocytic lymphoma: two faces of the same disease, Expert Review of Hematology

To link to this article: http://dx.doi.org/10.1080/17474086.2017.1270203

Accepted author version posted online: 12

Dec 2016.

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Download by: [Fudan University] Date: 13 December 2016, At: 19:37

Publisher: Taylor & Francis

Journal: Expert Review of Hematology

DOI: 10.1080/17474086.2017.1270203

Review

Chronic lymphocytic leukemia and small lymphocytic lymphoma: two faces of the

same disease

1,3 2,3
Authors: Michael T. Tees, M.D., M.PH. , Ian W. Flinn, M.D., Ph.D.
1
Colorado Blood Cancer Institute, Denver, CO; 2Tennesee Oncology, Nashville, TN;
3
Sarah Cannon Blood Cancer Network

Keywords: chronic lymphocytic leukemia, small lymphocytic lymphoma, CLL/SLL,

monoclonal B-cell lymphocytosis, TP53, ATM, NOTCH1, SF3B1, BIRC3

Abstract

1
Introduction: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma

(SLL) are considered indolent lymphocytic malignancies, more often requiring active

surveillance rather than intervention. Despite the indolent nature of CLL/SLL, treatment

is likely indicated in a patients' lifetime. Recent changes in the therapeutic landscape

have created more options to the clinician.

Areas Covered: The authors provide a broad assessment of the current state of

disease, including the work-up, prognostic features, and mutational aspects of the

disease that should be acknowledged when developing a rational treatment plan. Key

studies, guideline recommendations, and expert analysis are used to create this update

on CLL/SLL.

Expert Commentary: The recent pace of treatment additions in CLL/SLL is a welcome

addition. Moving forward, it is anticipated that treatment modalities will continue to

evolve, leading to additional management options that truly would define CLL/SLL as a

chronic disease.

Keywords: chronic lymphocytic leukemia, small lymphocytic lymphoma, CLL/SLL,

monoclonal B-cell lymphocytosis, TP53, ATM, NOTCH1, SF3B1, BIRC3

1.0 Introduction

CLL and SLL are indolent B-cell malignancies that are often considered to be different

clinical presentations of one disease, the major difference being whether a patient

presents with adenopathy alone or with an elevated lymphocyte count. While these

clinical differences can sometimes affect a patient’s symptoms as well as treatment

decisions, they are often treated similarly. In reality, the heterogeneity within CLL or

2
SLL is greater than the differences between CLL and SLL. Recent advances in our

understanding of the biology of CLL/SLL have prognostic implications that can affect the

treatment decisions in patients with CLL/SLL. This review will briefly highlight the

disease entity, the work-up, prognostic features, and therapeutic options available for

the management of CLL/SLL with attention to areas where there are meaningful

differences between CLL and SLL.

2.0 Work-up of CLL/SLL

CLL/SLL is classically a disease of the elderly, with the median age of diagnosis

approaching 71 years. Nearly 19,000 new cases were estimated in the U.S. for 2016,

with an estimated 5 year overall survival (OS) nearly 83% [1]. For unclear reasons,

there is a slight predominance of males (1.7:1) and Caucasians who are diagnosed with

this malignancy [2]. To maintain the consistent uptrend in survival rates, integrating

changes in the management is necessary to optimize patient care.

CLL often presents as an incidental finding on a routine complete blood count (CBC); in

SLL, lymphadenopathy may often be the first manifestation identified by the patient.

Despite the slight differences in presentation, CLL and SLL remain united as one

disease entity as re-emphasized in the 2016 revision of the World Health Organization

(WHO) classification of lymphoid neoplasms [3]. The non-specific “B” symptoms, which

include fever/chills, night sweats, weight loss, fatigue and/or malaise, may provide a

3
patient with an indication of disease and a provider a determination of whether

treatment should begin.

The criteria for diagnosis of CLL/SLL follows guidelines outlined by the International

Workshop on Chronic Lymphocytic Leukemia, which generally mirror the WHO 2008

and 2016 disease classifications [3, 4, 5]. The presence of at least 5.0 x 109/L

monoclonal B-cells in the periphery with an immunophenotype consistent with CLL is

diagnostic. In patients presenting only with lymphadenopathy, an excisional lymph

node biopsy is necessary to diagnose SLL. In both forms of the disease, the

immunophenotype is consistent. CD5, CD19, and CD23 are nearly always present,

while surface immunoglobulin (sIg), CD20, and CD79b have low expression compared

to healthy B-cells [6].

Immunophenotyping can help distinguish CLL/SLL from mantle cell lymphoma and

other lymphocytic diseases. When the classic markers for CLL/SLL are identified,

exclusion of mantle cell lymphoma is warranted as CD5 and CD19 are also seen in this

lymphocytic disease. Cyclin D1 expression with t(11;14), lack of CD23 expression, and

a more robust CD20 expression are associated with mantle cell lymphoma. If

inconclusive, CD200 expression can provide a more definitive diagnosis of CLL/SLL.

CD200 is expressed on CLL/SLL cells as well as B-cell lymphoblastic leukemia and

plasma cell myeloma. The latter two malignancies can easily be excluded based on

clinical characteristics and by the initial immunophenotypic analysis [7].

4
Monoclonal B-cell lymphocytosis (MBL) has now been established as an early

manifestation of CLL, with the presence documented in 98% of patients who progressed

to disease (95% confidence interval (CI) 88 – 100) [15]. However, the peripheral count

of the monoclonal lymphocytic cells distinguishes those at risk. Patients with a low

count, defined as < 0.5 x 10^9 monoclonal lymphocytic cells in the periphery, have very

little risk of progressing to CLL/SLL and do not require further monitoring. Patients with

a high count MBL are recommended to be followed annually to assess for progression

[3].

Certain studies are necessary to develop an appropriate treatment plan for patients with

CLL/SLL. With clinical suspicion and physical examination, often a diagnosis can be

confirmed with routine peripheral labs and peripheral flow cytometry. In SLL patients

with lymphadenopathy alone, an excisional biopsy is mandatory. Other studies may be

indicated based on the presentation or treatment decision. For example, in a patient

with anemia out of proportion to expected, assessment for autoimmune hemolytic

anemia is warranted by obtaining a reticulocyte count, haptoglobin, and direct agglutinin

test [8].

2.1 Staging

Despite advancements in our understanding of the disease, CLL continues to be staged

using two systems over three decades old: Rai or Binet [8, 9]. Both systems utilize only

physical examination and CBC findings to stage (Table 1). The Ann Arbor staging

system may be utilized for patients with SLL, allowing the consideration of lymphocytic

5
mass associated with SLL [10]. While the staging systems have not changed over

several decades, knowledge of disease activity as well as available therapeutic

interventions have advanced. For these reasons, the staging systems cannot be

reliably used for prognostication as initially intended. The Rai and Binet systems remain

important tools; moving forward, staging should be incorporated into the CLL-

Interational Prognostic Index (CLL-IPI), to be discussed.

3.0 Confirmed and probable prognostic factors

Since the development of the Rai and Binet staging systems, there have been

significant advancement in our understanding of the biology of CLL/SLL. One of these

advancements is the understanding that the timing of the neoplastic transformation from

a normal b cell to a malignant cell is important with respect to the aggressiveness of the

disease and ultimately the prognosis. A poorer prognosis has been identified in patients

who express an unmutated immunoglobulin heavy chain (IgVh) and/or CD38 on the

diseased cells [16]. B-cells with mutated heavy chain variable regions are typically post-

germinal center memory B-cells. Unmutated IgVh is likely a marker of a cell locked

from maturing further. Likewise, CD38 on the surface of a diseased cell is not only

associated with the presence of unmutated IgVh, but also with augmenting favorable

survival and growth signals. ZAP-70 is a component of the cell signaling cascade

activated by the surface molecule CD38; ZAP-70 is a surrogate marker for its presence

and thus is an adverse prognostic marker [17]. While associated, the presence of CD38

cannot predict for IgVh non-mutational status, remaining as two related, but

6
independent prognostic markers [18]. Despite this confirmed adverse prognosis

portending a more aggressive disease, IgVh as well as the presence of CD38/ZAP-70

do not factor into the staging nor treatment decisions [19].

Deletions/mutations at chromosomes 17p and 11q are historically poor risk markers in

CLL/SLL [20]. The TP53 gene is located on chromosome 17p, encoding a common

tumor suppressor gene. The ATM gene is located on chromosome 11q, encoding a

protein involved in DNA double strand repair. Patients may have a chromosomal

mutation without demonstration of an abnormal genotype, although both remain

associated with inferior outcomes. The presence of a deletion at 17p or the

corresponding gene TP53 indicates a need to change the classic treatment paradigm;

history predicts these patients will respond poorly to standard chemotherapeutic agents.

Given the treatment adjustment, patients should be tested for these aberrations prior to

initiating any therapy. While not common, approximately 5-10% of those with CLL/SLL

harbor a 17p deletion, while approximately 12-18% will have an 11q deletion (see

Treatment: Therapeutic options) [21].

Deletions of chromosomes 17p and 11q are easily detected by FISH. Until recently

mutations in these and other genes were available only through research labs. Next

generation sequencing has now made this testing routine. In addition to TP53 and

ATM, NOTCH1, a promoter of survival with resistance to apoptosis, is a gene

associated with poor risk in CLL/SLL and is easily detectable with NGS [22]. NOTCH1

mutations are often associated with cells demonstrating unmutated IgVh. Regardless of

7
the mutational status of IgVh, the presence of a NOTCH1 mutation is associated with a

shorter time to treatment [23, 24]. A mutation that confers a more rapid disease

progression and shorter time to treatment is the presence of SF3B1 mutation.

Suspected to cause aberrant gene splicing, this mutation is identified later in the

disease course and has a strong association with del(11q). An additional defined

mutation to date associated with poor risk is BIRC3. In healthy cells, its role is to

maintain appropriate levels of TP53. If mutated, its inability to support this function

induces a pro-malignancy state [23].

A deletion at 13q is seen in approximately 55% of patients, identified as a favorable

mutation when not associated with other cytogenetic abnormalities. Another favorable

and relatively common finding is trisomy 12. Del(14q) may also be described on

cytogenetic analysis, and may be seen in association with trisomy 12 and del(13q) [25].

While most data suggest that SLL and CLL mirror each other in every way but clinical

characteristics, there is a suggestion that patients with SLL have a higher incidence of

demonstrating trisomy 12 [26]. The significance of this finding is unclear. Table 2

summarizes both confirmed and probable molecular risk factors in CLL/SLL.

Despite the advancement in our understanding of molecular markers for risk, examining

the peripheral blood smear can also be useful. The number of prolymphocytes found in

the peripheral blood is known to be an adverse predictor. These larger cells contain

auto-recmore cytoplasm, prominent nucleoli, and lymphoplasmacytoid features.

Patients having • 10% prolymphocytes have an association with being IgVh unmutated,

8
expressing CD38, not having a 13q deletion, and a higher rate of NOTCH1 mutations

[27].

The most clinically relevant prognostic factor is the presence of del(17p) or TP53

mutation, which adjusts therapeutic decisions. Additional known adverse prognostic

factors of high -2-microglobulin, unmutated IgVh status, and increased age [11]. To

utilize the established and vigorous prognostic data, the International Workshop for

Chronic Lymphocytic Leukemia (IWCLL) developed a prognostic model termed CLL-

International Prognostic Index (CLL-IPI) (Table 3) [12]. A predictive biomarker of

minimum residual disease (MRD) after initial therapy has also been identified as an

adverse feature, regardless of the agents used for therapy [13, 14]. The utility of this

information has yet to be defined.

4.0 Loss of indolence, or was it ever?

The goal of identifying molecular mutations, cytogenetic abnormalities, and morphologic

findings is to assist the clinician in predicting the disease course and how best to

manage therapy. However, some patients present with an aggressive or “accelerated”

CLL that acts entirely different from classic indolent CLL/SLL. These patients may often

present clinically like a diffuse large B-cell lymphoma. Rapidly enlarging

lymphadenopathy, B- symptoms, and high LDH are hallmarks of this sub-type. By

morphology, the malignant cells appear similar to classic CLL/SLL. However, the

proliferation centers are significantly larger and/or the proliferation rate of the malignant

cells is much higher than normal (Ki-67 > 40%) [28]. In the largest analysis on this

9
histologic sub-type, trisomy 12 and deletion 13q, neither of which are considered

adverse, were prevalent. These patients also expressed p53 more often compared to

classic CLL/SLL. A recent finding was the correlation in aggressive CLL/SLL with the

overexpression of EZH2, which is highly expressed in progenitor lymphocytes.

Facilitating progression of hematopoietic stem cells through the cell cycle, it is also

overexpressed when B-cells form germinal centers. This association is further

supported by identifying that diseased cells overexpressing EZH2 also were most likely

to be IgVh unmutated. Interestingly, the presence of EZH2 was inversely associated

with TP53 in the analysis, adding to the notion that similar diseases by morphology

have vastly different mechanisms of oncogenicity [29].

In comparison to “accelerated” CLL, Richter syndrome (RS) describes an event where a

sub-clone of the indolent CLL/SLL transforms acutely to an aggressive lymphoma. It is

estimated that approximately 15% of the patients with CLL/SLL will develop

transformation [30]. In patients who transform, diffuse large B-cell lymphoma (DLBCL)

is the most common disease entity, although Hodgkin lymphoma, lymphoplasmcytic

lymphoma, and others may rarely occur. While morphologically similar to de novo

DLBCL, patients with transformed DLBCL have a high incidence of TP53 mutations as

well as c-MYC, present in 33 - 47% and 13 - 26% of patients, respectively [30, 31].

Del(13q) and trisomy 12 have also been associated with RS. It has been established

that DLBCL transformed from CLL is more aggressive than de novo DLBCL [32]. The

IgVh sequences from the patient’s CLL and the suspected transformed disease should

10
be identical. However, in 20% of cases, the DLBCL develops unrelated to the CLL, and

outcomes are nearly identical to de novo DLBCL.

The non-indolent manifestation of Richter syndrome provides a clear rationale for

obtaining lymph node excisional biopsies. Because a transformed sub-clonal

population may not be present in all locations involving CLL/SLL, PET/CT has been

proven useful to identify an appropriate lymph node for biopsy. Lesions with

hypermetabolic uptake on PET/CT greater than SUV 5 have a sensitivity of 91% and

specificity of 80% [33]. The prognosis of the patient can be determined using the

validated RS prognosis scale. The prognosis scale uses the Eastern Cooperative

Oncology Group (ECOG) performance status, platelet count, LDH, number of prior

therapies, and size of the primary tumor (> 5 cm) [34, 35] (Table 4).

5.0 Unique Characteristics of CLL/SLL

CLL/SLL, in Western countries, is one of the most common B-cell lymphoid disorders.

In comparison, Asian populations have a significantly lower incidence of disease.

Interestingly, this disparity does not change when immigrating to Western countries [36].

While this clearly implicates genetic factors, there have not been any mutational

differences identified to date [37]. A short leukocyte telomeric length has been

associated with an increase in risk of malignancy and early death. However, a long

telomeric length is associated with an increased risk of developing CLL/SLL [38]. This

discrepancy is noted in other malignancies, and it is hypothesized that a long telomere

11
length may contribute to survival of pre-malignant cells, thus increasing the risk of

certain diseases [39]. The authors are not aware of any study comparing telomeric

lengths of these two populations and risk of developing CLL/SLL.

Autoimmune cytopenias are uncommon but notable disorders associated with CLL/SLL.

Autoimmune hemolytic anemia (AIHA) remains the most prevalent hematologic

autoimmune condition, identified in 4.5 – 11% of patients. Less frequent are immune

thrombocytopenic purpura (ITP) in 2 – 5%, and in < 1% each, pure red cell aplasia

(PRCA) and autoimmune agranulocythemia [40]. For all types of autoimmune

cytopenias, a bone marrow biopsy is warranted. In AIHA, generally accepted diagnostic

criteria are the presence of an elevated LDH, low haptoglobin, increased reticulocyte

count, unconjugated hyperbilirubinemia, and a positive direct agglutinin test (DAT). ITP

and PRCA follows classically accepted diagnostic criteria, and a diagnosis of

autoimmune agranulocythemia can be made when there is unexplainable neutropenia,

a lack of precursor granulocytes in the marrow, and the identification of anti-neutrophil

antibodies. The mechanisms are not entirely understood but the process is instigated

by the malignant B-cells aberrantly expressing auto-reactive B-cell receptors, which in

turn induces T-cells to signal for the production of polyclonal immunoglobulins.

Malignant B-cells and its interactions with T-cells are also associated with an increase in

inhibitory cytokines that may allow for self-reacting neoplastic B-cells to escape normal

means of apoptosis, thus providing an opportunity to develop the autoimmune response

[41].

12
The presence of an autoimmune disease, based on conflicting data, may not portend a

poorer prognosis [42]. However, those with advanced disease or more aggressive

disease by all measures have an increased risk of development, notably those with an

unmutated IgVh. This risk is exacerbated if fludarabine is received as part of his/her

treatment. This likely stems from fludarabine causing regulatory T-cell injury and death,

thus increasing the likelihood of developing an auto-reactive immune response [43, 44,

45].

Another unique characteristic of CLL/SLL is that the disease may present itself as both

a leukemic entity and as a lymphoid disease. In patients with SLL, the disease solely

congregates in lymphatic tissue. In CLL, both lymphadenopathy and leukocytosis is

present. One would suspect phenotypic differences between the two forms. However,

there are no clearly identifiable factors that make one disease predominant versus

another. While this appears irrelevant to outcomes and response to therapy, it

demonstrates an ongoing need to understand and exploit mechanisms of pathogenesis.

6.0 Treatment

The treatment for CLL/SLL has gone through a significant number of changes over the

past several years. Combined with historical therapeutic choices, the clinician now has

several options to fight the disease. Newer therapies target the B-cell receptor pathway

13
as well as cellular regulator proteins; available options are discussed and a simplified

approach is provided in Figure 1.

6.1 Watching and Waiting

One of the most important consideration a clinician should make is when treatment is

indicated. The factors used to decide when to treat predominantly are the symptom

burden and whether end-organ injury is impending or present. Symptom burden

includes weight loss, non-infectious fevers and/or night sweats, and significant fatigue.

Anemia, thrombocytopenia, progressive lymphadenopathy (nodes > 10 cm in size or

splenomegaly identified by spleen being > 6 cm below the costal margin) are indications

for treatment per IWCLL guidelines [4, 46, 47]. However, treatment decision remains

subjective and multifactorial. Considering the median age of diagnosis is over 70 years

of age, quality of life must hold significant weight. A recent prospective analysis

identified that quality of life decreased with all treatments, although novel therapies were

not evaluated [48]. Delaying therapy until treatment is warranted is termed the “watch

and wait” approach, one that has been adopted for other indolent lymphomas. At this

time, there is no evidence that early intervention provides benefit, and providers should

adhere to IWCLL treatment criteria. .

Once the decision has been made to begin treatment, the choice of therapy may vary

according to a patient’s age, co-morbidities, and prognostic factors. Certain screening

tools in geriatric patients may be helpful in identifying patients that are “fit” for

aggressive chemoimmunotherpy regimens versus those who are not [49]. Certain co-

14
morbities in patients of any age, such as inflammatory bowel disease or atrial fibrillation,

must be identified given the risks associated with novel agents. In addition, despite the

inferior survival outcomes associated with 17p or 11q deletion, chemotherapy is not

recommended when present due to lack of benefit. In these patients, novel therapies

should be considered.

Regardless of the therapeutic choice, it is important to check hepatitis B serologies prior

to initiating treatment. The goal is to identify those patients at risk for reactivation. Anti-

CD20 antibodies, such as rituximab and ofatumumab, are known to increase the risk of

hepatitis B reactivation and are a component of many regimens or used as

monotherapy. In addition, the phosphoinosotil-3 kinase (PI3K) inhibitors can cause

hepatotoxicity. It remains unclear if this risk is exacerbated in those with a prior history

of viral hepatitides [50].

6.2 Radiation

In some patients where systemic therapy is not indicated or there are co-mobidities that

preclude use, radiation therapy may provide local disease control with minimal side

effects. Often this treatment strategy is utilized in the setting of localized disease with

impending organ injury or with mild symptoms. Lymphocytes are quite sensitive to

radiation, making this a reasonable approach in the appropriate patient.

6.3 Chemoimmunotherapy

15
Chemotherapeutic options have been the mainstay approach for many years, and

continue to have a role. The use of fludarabine (F), a purine analog, in combination with

cyclophosphamide (C), an alkylating agent, and rituximab (R), a monoclonal antibody, is

the first-line approach in younger and fit patients without a 17p deletion. Monitoring for

unusual toxicities is warranted when using FCR; it is hypothesized that fludarabine is

associated with autoimmune complications [51, 52, 53]. Bendamustine (B), a nitrogen

mustard, in combination with rituximab, is a very common therapy, and should be

considered in older patients. In the German CLL study group trial CLL10, fit patients

with no prior therapy were randomized to receive BR or FCR. While there was less

severe neutropenia and infections seen with BR, the progression-free survival (PFS)

was inferior with BR compared to FCR (41.7 months (95% CI 34.9 – 45.3) with BR and

55.2 months (95% CI not evaluable) with FCR) [54]. As a consequence, FCR is

recommended in younger or fit patients receiving chemoimmunotherapy. Of note,

patients who are IgVh mutated have a significantly better PFS with FCR compared to

those IgVh unmutated or harboring del(17p). In addition, IgVh mutated patients who

achieve MRD post-FCR have profoundly better outcomes [55, 56]. Patients with

del(11q) also benefit from receiving FCR compared to BR with longer follow-up showing

a significant improvement in PFS [54]. For these reasons, the decision on utilizing BR

over FCR should not be minimized. BR should be used in the first-line setting only in

patients are considered unfit for FCR. Other chemotherapeutic options include the use

of pentostatin (P), another purine analog, with cyclophosphamide and rituximab.

16
The use of anti-CD20 antibodies in the treatment for CLL/SLL is somewhat surprising

considering that cell surface expression of CD20 is low. However, enough surface

expression exists on the malignant cells to attract the monoclonal antibodies and induce

complement-dependent and antibody-dependent cellular cytotoxicity [57]. Rituximab

remains the most studied and used anti-CD20 antibody; obinutuzumab and

ofatumumab are newer and fully humanized siblings that target different regions of the

surface molecule, causing more potent CDC and ADCC, respectively.

Anti-CD20 antibodies are typically combined with chemotherapeutic agents, although in

in the relapsed/refractory setting, may be used as monotherapy [58]. Obinutuzumab and

ofatumumab are not commonly used in the first-line setting due to its approvals in

combination with chlorambucil, a chemotherapeutic agent that is not commonly used in

the Unites States. However, in older patients in which FCR is contraindicated, this

combination may be considered. In comparison with chloambucil alone, ofatumumab

with chlorambucil demonstrated a median PFS of 22.4 months (95% confidence interval

(CI) 19.0 – 25.2) compared to 13.1 months (95% CI 10.6 – 13.8) [59, 60].

Obinutuzumab with chlorambucil was compared with rituximab and chlorambucil in the

first-line setting, demonstrating a 29.2 month PFS compared to 15.4 months, hazard

ratio (HR) of 0.40 (95% CI 0.33 – 0.50) [61, 62]. Interestingly, a phase II study in elderly

CLL patients receiving first-line chlorambucil and rituximab demonstrated a PFS of 34.7

months (95% CI 33.1 – 39.5) [63]. The discrepancy is unclear but cannot be interpreted

from one study to another. Regardless, chlorambucil in combination with either

17
obinutuzumab or rituximab are reasonable therapeutic options in elderly or unfit

patients.

In patients who develop Richter’s syndrome and transformation to diffuse large B-cell

lymphoma, treatment similar to de novo disease would be advised, including dose-

adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and

rituximab (DA-EPOCH-R) or cyclophosphamide, doxorubicin, vincristine, prednisone,

and rituximab (CHOP-R).

6.4 BTK Inhibition

The most influential recent addition to therapy for CLL/SLL is Bruton tyrosine kinase

(BTK) inhibition. BTK is part of the B-cell receptor pathway, known to be upregulated in

B-cell malignancies. Ibrutinib, the first-in-class oral BTK inhibitor, has demonstrated

efficacy in the first-line setting compared with chlorambucil; a median PFS was not

reached compared to 18.9 months. The overall response rate was 86% compared to

35% (p < 0.001) and the overall survival compared to chlorambucil was statistically

significant [64]. In the relapsed/refractory setting, efficacy has also been established

[65]. In the HELIOS study, in combination with BR, the PFS was not reached in the

ibrutinib group (95% CI not evaluable) compared to 13.3 months (95% CI 11.3 – 13.9),

HR 0.20 (95% CI 0.15 - 0.28) [66].

Ibrutinib has received approval for patients with 17p deletion. Given the poor response

to other therapies relative to toxicities, the use of chemotherapy is not advised.

18
However, in patients who previously received therapy, overall response rate (ORR) was

47.6% in patients receiving ibrutinib compared to 4.7% in patients receiving

ofatumumab monotherapy [65].

While many patients have an initial increase in peripheral lymphocyte count in the first

two to three months on treatment, some may have persistent lymphocytosis. In these

patients, there is no association with a decreased response to the treatment nor

increased risk of relapse [67]. Patients must also be monitored for certain side effects

that can be significant. The risk for both atrial fibrillation and hypertension are

increased. In patients who develop atrial fibrillation on ibrutunib, starting an anti-

coagulation is problematic as there is also an increased risk of hemorrhagic events.

Common adverse events include diarrhea, arthralgias, and myalgias which are usually

low grade. As the use of ibrutinib has increased, there is now evidence that mutations

to BTK or to PLC 2, a phospholipid enzyme that interacts with BTK, contributes to

ibrutinib resistence [81].

6.5 PI3K Inhibition.

Phosphoinositide-3 kinase (PI3K) is a component of the PI3K/AKT/mTOR pathway,

involved in critical cell cycle regulation. PI3K is upregulated in malignant cells. The

catalytic subunit p110 of class IA PI3K consist of three variants: - , - , and - . The delta

isoform is of particular interest in lymphoma and CLL as its expression is limited to cells

of hematopoetic origin. A PI3K p110 -specific inhibitor should not produce the same

toxicities seen with pan-PI3K inhibitors, such as issues with glucose metabolism.

19
Idelalisib is a first-in-class PI3K inhibitor targeting the p110 isoform. In a phase III study

of patients with relapsed CLL, idelalisib with rituximab was superior to rituximab alone in

terms of ORR 81% versus 13% (P<0.001), PFS at 6 months 93% versus 46% (HR 0.15

(95% CI 0.08 – 0.28)), and OS at 12 months 92% versus 80% (HR 0.28 (95% CI 0.09 –

0.86)) [68]. Idelalisib is now approved for this indication. The combination of idelaisib

with rituximab was also studied in elderly patients in the upfront setting with an overall

response rate approaching 97% [69]. Unfortunately, all large clinical studies in

previously untreated patients or patients with minimal prior therapy were discontinued

after an increase in infectious mortality from CMV and Pneumocystis jevovecii was

demonstrated. New recommendations advise all patients be screened monthly for CMV

and placed on Pneumocystis jevovecii prophylaxis dosing while on therapy.

Other than infection, notable side effects include the risk of increased

aminotransferases usually within the first ten weeks of therapy. Less common but

significant toxicities include immune colitis and pneumonitis. It is important to note that

early diarrhea can most often be managed with anti-motility agents and administration

modifications. However, diarrhea that develops months after initiating therapy may be

immune-mediated; this type of diarrhea classically does not respond to anti-motility

agents. Prompt initiation of steroids is often necessary. Similar to BTK inhibition, PI3K

inhibition is also associated with a transient lymphocytosis that typically begins to

downtrend by 3 months after initiation of therapy.

20
Little data exists on the sequence of dosing for these novel agents. As ibrutinib now

has a first line indication, it would be reasonable to administer the BTK inhibitor first,

followed by idelalisib. Patients with a 17p deletion also have an indication for treatment

first-line with ibrutinib. It is important to note that patients with a 17p deletion were

studied using idelalisib with favorable outcomes. There is little data on the relative

efficacy of these two agents in CLL patients compared to those presenting as SLL.

Interestingly, idelalisib has a specific indication in SLL whereas ibrutinib does not.

However, most clinicians are comfortable extrapolating the data from the CLL studies to

patients presenting as SLL. Similar to ibrutinib, time will provide additional data as to

the etiology of resistance to PI3K inhibition. At present, it is suspected that the ratio of

PI3K p110 to PI3K p110 isoform expression could predict response to therapy. It is

also suspected that upregulation of alternative PI3K classes for cell signaling may

support resistance [82, 83].

6.6 BCL2 Inhibition

Venetoclax is a novel BCL2 inhibitor that targets the regulator protein BCL2, which

normally acts to inhibit pro-apoptotic proteins. This first-in-class agent demonstrated

significant benefit in patients heavily pretreated and those with adverse disease

markers, including 17p deletion [70]. In a phase II study, patients with 17p deletion who

received one previous line of therapy received venetoclax. Overall response rate was

79.4% (95% CI 70.5 – 86.6), leading to Food and Drug Administration approval for use

in a similar patient population [71]. Tumor lysis syndrome may be significant; for this

reason, an uptitration over 5 weeks is necessary. Observation, hydration, and anti-

21
hyperuricemic therapy is also advised and those with a high tumor burden should be

admitted for the initial administration and first uptitration. Most common side effects

included anemia, infection, diarrhea, fatigue, and pyrexia [72].

6.7 Immunomodulating Agents

The use of lenalidomide for the treatment of CLL/SLL suffered a setback when the

ORIGIN trial, a phase III study assessing first-line therapy with lenalidomide compared

to chlorambucil, was halted due to a significant increase in mortality in the study arm.

Despite this, there have been several smaller studies demonstrating efficacy in both

first-line and in the relapsed/refractory setting. In elderly patients, an overall response

rate of 65% with 10% achieving a complete response has been reported; in another

study, it was identified that over half the patients receiving lenalidomide as first-line

therapy achieved a long term response lasting more than 36 months [73, 74]. When

lenalidomide was combined with rituximab in relapsed/refractory patients, the overall

response rate was 66% with 12% achieving a complete response [75]. There does

appear to be a benefit in patients, and appears to be a reasonable therapeutic option.

The clinician must be cognizant of the increased risk of thromboembolic events,

especially in older patients.

6.8 Hematopoietic Cell Transplant

Allogeneic stem cell transplantation is a treatment option in certain patients with

CLL/SLL. Previously, those who lacked a response to first- and second-line therapy, or

in those who developed disease recurrence within 12 months of fludarabine-based

22
therapy, would be recommended for transplant [76]. However, these recommendations

are not reflective of the novel agents now available for for disease treatment. Given the

median age of CLL/SLL diagnosis, transplant may not be an appropriate treatment

option when necessary. With this in mind, it is recommended that a transplant

hematologist assesses a patients under treatment with del(17p) or TP53, del(11q), or

who had disease recurrence shortly after concluding chemoimmunotherapy [77].

6.9 Maintenance Therapy

Maintenance therapy, defined as treatment after first-line therapy, remains

controversial. The most common maintenance agents investigated are anti-CD20

antibodies. Unfortunately, many studies on maintenance therapies have lumped

together all indolent lymphomas. In one trial, the therapy utilized first-line treatment

consisting of FCR with mitoxantrone, followed by rituximab every 3 months for 2 years.

This uncommon regimen and maintenance therapy demonstrated a prolonged PFS,

particularly in patients who had minimum residual disease after induction [78].

Another study assessed ofatumumab maintenance compared to observation after

receiving two or three lines of therapy and in a partial response. While the outcomes

demonstrated a prolonged PFS, it remains difficult to label this as maintenance therapy

as opposed to prolonged therapy [79].

As BTK inhibitors and PI3K inhibitors find a place closer to first-line therapy, a question

on when to discontinue these oral therapies is raised. At this time, continuing therapy

23
indefinitely is advocated until response is lost. Hesitant to call this maintenance

therapy, it may be more appropriate to label this as prolonged or persistent therapy.

6.10 Future Therapies

While many novel agents are under investigation, immunotherapeutic options are

attractive. Autologous chimeric antigen receptor (CAR) T-cell therapy, novel

monoclonal antibody targets with or without conjugated small molecule therapies, bi-

specific molecules assisting the linkage between a diseased cell and a cytotoxic T-cell,

and checkpoint inhibition are several therapeutic strategies being employed [80].

Targeting signals upregulated in malignant cells follows a familiar approach utilized by

BTK and PI3K inhibitors, and epigenetic targets are also desirable for investigation.

7.0 Conclusion

CLL/SLL remains a disease with a heterogeneous clinical course. At present, we have

several tools to assist in identifying those that may transform. However, this does not

change the overall treatment strategy, which is to first watch and wait. Upon the need

to treat, we have several new therapies added to the arsenal, and several more in the

pipeline. There are many causes of mortality, but as we look forward, CLL/SLL may not

be one of them.

24
8.0 Expert Commentary

This review on the current state of CLL/SLL emphasizes several elements of the

disease and current therapeutic options that have changed how we treat this indolent

malignancy. So many aspects of this malignancy continue to spark interest. On the

one hand, the disease may slowly advance without requiring therapy. On the other

hand, the disease may necessitate several lines of therapy to decrease disease burden.

And between the two, the disease can transform to an aggressive malignancy, requiring

intensive chemotherapy to attempt disease control. While certain mutations are known

to predict more indolent and less indolent types, the transformative processes have yet

to be well defined. To date, we have little to predict those with the potential for sub-

clonal transformation.

Prior to the availability of BTK, BCL2, and PI3K inhibitors, patients were considered for

allogeneic stem cell transplant earlier in the treatment plan. In just a few short years,

the number of patients proceeding to allogeneic transplant for CLL has fallen. It is

expected that transplant for CLL will soon be similar to transplant for CML: rare and

when mutations render therapies less effective. But considering that fewer patients may

proceed to a “curative” transplant for CLL, is it possible that we may see an increase in

patients with transformed lymphoma? If so, it would be expected to be later in the

disease course. In a disease with a median diagnosis is the early seventh decade, the

management of transformed lymphoma may be particularly difficult. In this regard,

identifying disease with a predisposition to transform may be helpful, as perhaps these

patients may still benefit from early disease eradication made possible with an

25
allogeneic transplant. But would transplant in its current sense be the treatment option

in the future? Autologous CAR-T cell infusion is an exciting prospect under

investigation that may allow a sustained response to disease.

Can CLL/SLL be cured? Perhaps in the future, with additional therapeutic options, we

will be able to maintain indefinite disease control. Again, it is important to acknowledge

the older median age of diagnosis of CLL/SLL. All treatments, both current and future,

must heavily weigh the tolerability of agents in addition to the efficacy. Idelalisib may

serve as a long-standing example. The slight increase in risk of CMV and

Pneumocystis jerovecii pneumonia, as well as a trend for increased autoimmune

manifestations in a less treated population, responsibly prompted a discontinuation of

studies for use in the first-line setting. While the study discontinuations have no

reflection on the value of this agent in the current management of CLL/SLL, it

demonstrates the ongoing need to balance the benefits and risks for all novel therapies.

Venetoclax is a potent oral therapy with a high risk of tumor lysis syndrome. For this

reason, some patients who would benefit from this agent require hospitalization for

initiation and uptitration. Without minimizing the value of this additional agent, the

potency of this new oral therapeutic option is alarming if prescribed in a setting where

knowledge and management of tumor lysis is deficient.

The authors remain excited about novel treatment strategies in CLL/SLL and are

encouraged by the recent advancements that are prolonging the overall survival in

affected patients. Treatment approaches in the future should be directed towards

26
additional disease risk reduction, notably the potential for disease transformation. For

this intervention, identification of the molecular markers of risk is necessary. While

rapid changes have occurred over the past several years, additional options are

currently under investigation, assuredly leading to management changes in the near

future.

9.0 Five Year View

The authors believe that novel therapeutic options will drastically change the landscape

of treatment. Much like other malignancies, newer treatments will target the specific

cellular processes the malignancy has exploited, leading to therapies will toxicities and

more efficacy. It is highly likely that hematopoietic cell transplantation, in its current

form, will become a rare necessity in a minority of patients.

10.0 Key Issues

- While CLL and SLL are the same malignancy with different presentations, the

main difference with clinical implications is in how a diagnosis is achieved. In

CLL, a tissue biopsy is often not required. In SLL, given its normal peripheral

lymphocyte count, a lymph node biopsy allows differentiation between other

lymphocytic diseases.

27
 - When treatment is indicated, the presence of a 17p deletion has both prognostic

and treatment implications. Identification of a 17p deletion and the age of the

patient remain the two most important decision tools in choosing therapy.

- A watch and wait approach is mandatory in patients without disease symptoms

or lymphadenopathy causing organ dysfunction.

- No evidence supports maintenance therapy after initial therapy. However,

maintenance therapy with ofatumumab after two lines of therapy was shown to

prolong the progression free survival.

- Ibrutinib, venetoclax, and idelalisib have improved the overall survival in

CLL/SLL. In particular, 17p deleted CLL/SLL, previously with limited therapeutic

options, now have agents more effective than chemoimmunotherapy.

Funding

This paper was not funded.

Declaration of Interest

M Tees has received Speakers’ Bureau for Gilead and Celgene. I Flinn has received

institutional research funding from Acerta, Beigene, Celgene, Constellation, Curis, Forty

Seven, Genentech, Gilead, ImmunoGen, Infinity, Janssen, KITE, Novartis, Portola,

Seattle Genetics, Takeda, TG Therapeutics and Trillium. The authors have no other

relevant affiliations or financial involvement with any organization or entity with a

28
financial interest in or financial conflict with the subject matter or materials discussed in

the manuscript apart from those disclosed.

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*Article of interest

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7.
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34
83. Woyach JA, Johnson AJ. Targeted therapies in CLL: mechanisms of resistance
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35
Figure 1. CLL/SLL treatment algorithm. All patients should be screened for clinical
trials, represented as a dashed line. Active disease is defined by IWCLL 2008
guidelines. Older is defined as 65 years of age. * Ofatumumab is approved for
maintenance therapy by the United States Food and Drug Administration, but it does not
have approval by the European Medicines Agency.

New First Line Second Line Third Line

Diagnosis

Del(17p) Ibrutinib Venetoclax Change to other

or TP53 second line therapies
Idelalisib +/-
Rituximab Lenalidomide +/-
No Chlorambucil +
Active Rituximab
Active Anti-CD20 antibody
Disease* Disease* Unfit
Older Ibrutinib Anti-CD20
Antibody
Bendamustine +
Rituximab Bendamustine +
No Allogeneic Stem
Watch & Wait Del(17p) Rituximab Cell Transplant
or TP53
Young Fludarabine +
Fit Cyclophosphamide +
Rituximab Maintenance
Ofatumumab*

36
Table 1. CLL/SLL staging systems.*for Binet staging, the presence of hepatomegaly and/or
splenomegaly must be accompanied by lymphadenopathy in 2 or more lymph node chains in
order to be classified as stage B [8, 9].

Factor Rai Binet

Lymphocyte 0 A
count > 15 x
109/L
Lymphadenopathy I B
of cervical,
axillary, and
inguinal regions
Splenomegaly II B
and/or
hepatomegaly*
Hemoglobin ≤ 11 III C
g/dL (< 10 g/dL
for Binet)
Platelets < 100 x IV C
9
10 /L

Table 2. MConfirmed and probable molecular risk factors in CLL/SLL. Highlighted features
indicates factors included in the CLL-IPI.

Good Intermediate Poor

13q Trisomy 12 17p/TP53
IgVh mutated Normal cytogenetics IgVh unmutated
ZAP-70/CD38
presence
11q/ATM
NOTCH1
SF3B1
BIRC1
10% or more of pro-
lymphocytes in
periphery

37
Table 3A and 3B. CLL-International Prognostic Index (CLL-IPI). OS = Overall survival. [12]

Prognostic Marker Point(s)

Age > 65 1
Stage: Rai I-IV or Binet B/C 1
IgVh unmutated 2
Β-2-microglobulin > 3.5 mg/dL 2
Del(17p) or TP53 mutation 4

Total Risk 5 year OS, % (95%

Category CI)
0-1 Low 93.2 (90.5-96.0)
2-3 Intermediate 79.3 (75.5-83.2)
4-6 High 63.3 (57.9-68.8)
7-10 Very high 23.3 (12.5-34.1)

Table 4. Richter syndrome prognostication. [31, 34, 35]

Pre-Treatment Assessment Post-Treatment Assessment

ECOG performance status > 1
LDH > 1.5 upper limit of normal
Chemotherapies for CLL > 1
Platelets < 100 x 109/L
Tumor size > 5 cm
ECOG performance status > 1 (3 points)
TP53 mutation
Lack of complete response to induction

Points 0-1 2 3 4-5 0 1-2 3+

Median overall 1.1 0.9 0.3 0.1 Not reached 2.0 0.7
survival
(years)

38