Ace the Case: A 62-Year-Old Man Presents With Increasing Fatigue, Weight Loss, and Night Sweats for the Past 8 Months

Clinical Review

Chronic lymphocytic leukemia is a monoclonal disorder characterized by progressive accumulation of functionally incompetent lymphocytes.1 Chronic lymphocytic leukemia is the most prevalent lymphoid malignancy among US adults and the most common form of leukemia in Western countries.2,3 The American Cancer Society estimates that 20,940 new cases of CLL will be diagnosed in the United States in 2018.3

Chronic lymphocytic leukemia may be associated with a wide range of symptoms.5 Enlarged lymph nodes are the most common presenting symptom, observed in 87% of patients.1 Other symptoms can include enlargement of the liver or spleen, recurrent infections, loss of appetite or early satiety, fatigue, or night sweats.6,7 However, because the onset is insidious, 25% to 50% of patients are asymptomatic at the time of presentation.1 Chronic lymphocytic leukemia is often detected incidentally after a higher-than-normal lymphocyte complete blood count has been performed for another purpose.1 Peripheral blood flow cytometry is the most helpful test for confirming a diagnosis of CLL. Immunophenotyping of circulating B lymphocytes will identify a clonal B-cell population carrying CD5 antigen and B-cell markers.3

The prognosis of patients with CLL varies at the time of diagnosis. Some patients with CLL die within 2 to 3 years of diagnosis due to complications.1 However, the majority survive for 5 to 10 years, with an initial course of CLL that is relatively benign but is followed by a terminal, progressive, resistant phase lasting 1 to 2 years.2,3 The prognosis depends on the disease stage at diagnosis, as well as the presence or absence of markers of high risk.8.9

Two staging tools—the revised Rai system and the Binet system—are used to assess the prognosis of patients with CLL based on physical examination and blood counts (Table 1).10,11

Table 1. Staging Tools

Staging System

Stage

Characteristics

Revised Rai system

Low risk (formerly stage 0)a

Lymphocytosis, lymphocytes in blood >15,000 μL, and >40% lymphocytes in the bone marrow

 

Intermediate risk (formerly stages I and II)

Lymphocytosis as in low risk with enlarged node(s) in any site, splenomegaly or hepatomegaly, or both

 

High risk (formerly stages III and IV)

Lymphocytosis as in low risk and intermediate risk with disease-related anemia (hemoglobin level <11 g/dL or hematocrit <33%) or platelets <100,000 μL

Binet system

Stage A

Hemoglobin ≥10 g/dL, platelets ≥100,000/mm3, and <3 enlarged areas (ie, lymph nodes involved)

 

Stage B

Hemoglobin ≥10 g/dL, platelets ≥100,000/mm3, and ≥3 enlarged areas

 

Stage C

Hemoglobin <10 g/dL, platelets <100,000/mm3, and any number of enlarged areas

aStage in original version of the Rai system published in 1975.12

Certain genetic markers also hold important prognostic implications in CLL.3 Deletion in the short arm of chromosome 17 (del[17p]) is associated with rapid progression, short remission, and reduced survival.1 17p deletions are present in approximately 7% of previously untreated patients and 30% of relapsed/refractory patients and are associated with a more rapidly progressive course and shorter survival in both groups.13 17p deletions are linked to loss of function of TP53, a tumor suppressor gene associated with resistance to available chemotherapies.3 TP53 mutations can also occur in the absence of 17p deletions and are strong predictors of treatment refractoriness and poorer survival. Deletions of bands 11q22-q23 are seen in 19% of patients and are associated with extensive involvement of the lymph nodes, aggressive disease, and shorter duration of survival.1 Studies have also shown overexpression of the proto-oncogene bcl2, which suppresses apoptosis and results in prolonged life of involved cells.14

Recently, a new comprehensive prognostic score incorporating genetic, biological, and clinical variables was introduced that facilitates the classification of patients with CLL into distinct risk groups.15 The CLL-International Prognostic Index (IPI) is a staging system that was developed by an international group of researchers to provide greater discrimination of prognostic status than is obtained with the Rai and Binet systems, which were developed more than 30 years ago.15 The International CLL-IPI Working Group analyzed 27 prognostic factors for overall survival identified in 13 prospective trials.15 From these factors, 5 emerged as independent prognostic markers for overall survival in CLL (Table 2).15 Each variable was then assigned an individual weight, yielding a possible prognostic score ranging from 0 to 10.

Table 2. CLL-IPI Grading of Prognostic Indicators in CLL15

Variable

Grade

Age >65 years

1

Clinical stage: Binet B/C or Rai I-IV

1

del(17p) and/or TP53 mutation

4

Immunoglobulin heavy chain variable gene unmutated

2

Serum β2-microglobulin concentration >3.5 mg/L

2

Abbreviation: CLL-IPI, Chronic Lymphocytic Leukemia International Prognostic Index

Four risk groups were identified with significantly different rates of overall survival at 5 years (P<.001 for all), as shown in Table 3.15

Table 3. CLL-IPI staging system for CLL15

Risk Classification

CLL-IPI Score

5-Year Survival Rate (95% CI)

Low risk

0-1

93.2% (90.5-96.0)

Intermediate risk

2-3

79.3% (75.5-83.2)

High risk

4-6

63.3% (57.9-68.8)

Very high risk

7-10

23.3% (12.5-34.1)

Abbreviations: CI, confidence interval; CLL-IPI, Chronic Lymphocytic Leukemia International Prognostic Index

The International CLL-IPI Working Group believes that the CLL-IPI will allow a more targeted management of patients with CLL in clinical practice and in trials of novel drugs.16 However, it is currently unknown how newly developed CLL therapies and newly identified molecular mutations might be incorporated into this staging system in the future.16

First-line Treatment

Patients with low-risk CLL whose disease is stable can be managed with periodic follow-up only.1 Numerous studies have found that early initiation of chemotherapy does not produce a survival benefit and may actually increase mortality.1 However, patients with active or symptomatic disease or with advanced Rai or Binet stages require treatment.3 Symptoms and findings of concern include >10% weight loss over 6 months; extreme fatigue; fever related to leukemia for >2 weeks; night sweats for >1 month; progressive marrow failure (anemia or thrombocytopenia); autoimmune anemia or thrombocytopenia not responding to glucocorticoids; progressive or symptomatic splenomegaly; massive or symptomatic lymphadenopathy; and progressive lymphocytosis (an increase of >50% in 2 months or a doubling time of <6 months).1

Chemotherapy with fludarabine, cyclophosphamide, and rituximab is considered the standard of care for first-line treatment of CLL in younger, physically fit patients with few comorbidities.3 In a randomized, phase III, open-label trial involving fit patients with CLL who were treatment-naïve was shown to significantly improve progression-free survival when compared with fludarabine and cyclophosphamide alone (median durations of 56.8 and 32.9 months, respectively).17 However, the use of this regimen in unfit or older patients is limited, particularly due to a high risk of toxicity (such as myelosuppression, hematologic toxicity, and infections).17,18 In a trial that compared the combination of fludarabine, cyclophosphamide, and rituximab versus fludarabine and cyclophosphamide, toxicity occurred more frequently and was more severe in patients age >65 years.17,19 In a subsequent study, first-line therapy with this combination proved superior to bendamustine and rituximab, but no difference was observed among patients >65 years old.20 On the basis of these and other recent trials, first-line treatment with bendamustine and rituximab, a combination associated with fewer side effects, albeit lower efficacy, is recommended for elderly patients who are physically fit.18

Among patients who are unfit, have comorbidities, and/or are elderly, current evidence supports the first-line use of chlorambucil plus an anti-CD20 monoclonal antibody (such as rituximab, obinutuzumab, or ofatumumab).3,21 For example, in one trial chlorambucil plus ofatumumab significantly improved complete response rates, progression-free survival, and overall survival when compared with chlorambucil alone in patients who were elderly or had comorbidities, in whom fludarabine-based treatment was not possible.21 However, in another study, treatment with chlorambucil plus an anti-CD20 monoclonal antibody was associated with an increase in adverse events among patients with comorbidities (median age, 73 years), suggesting the need for novel therapies with both improved safety and efficacy.22,23 Combination treatment with obinutuzumab plus venetoclax, a BCL-2 inhibitor, has proven safe and effective in previously untreated patients, although the sample size was small.24

A novel targeted therapy, ibrutinib, is a first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase (BTK).25 Bruton’s tyrosine kinase has a well-characterized role in the B-cell receptor signaling pathway that leads to proliferation and cell survival.23 Ibrutinib was approved by the US Food and Drug Administration (FDA) in 2014 for the first-line treatment of patients with CLL and 17p deletion, as well as for the second-line treatment of CLL.25 In 2016, the indications for ibrutinib were expanded to first-line treatment of CLL regardless of cytogenetics, risk status, or age.25 These expanded indications were based on the results of the phase III, randomized, open-label RESONATE-2 trial, which found that ibrutinib was significantly superior to chlorambucil, reducing the risk of progression or death by 84% (P<.001) in patients aged >65 years.26 Toxicity was reported to be modest in most patients treated with ibrutinib, with 87% continuing to take this therapy at a median follow-up of 18.4 months. The combination of ibrutinib with fludarabine, cyclophosphamide, and rituximab was studied as first-line therapy in a recent phase II trial involving 49 young, fit patients with CLL.27 Patients received combination treatment for up to 6 months, followed by 2 years of ibrutinib maintenance therapy.27 The primary endpoint was the rate of clinical response with bone marrow minimal residual disease negativity 2 months after the completion of combined therapy.27 Among 35 patients evaluable for efficacy, the overall response rate was 100%.27 Ibrutinib in combination with venetoclax is also being investigated in patients with high-risk disease, with promising safety and efficacy.24

Ibrutinib can be associated with drug resistance due to incomplete blockade of the BTK receptor, as well as a risk of Richter’s transformation (evolution of CLL into large-cell lymphoma).28,29 Acalabrutinib is a second-generation, irreversible inhibitor of BTK that is currently under investigation as both first- and second-line therapy for CLL.28 Preliminary findings from a phase I/II study of acalabrutinib in 74 treatment-naïve patients with CLL showed that the overall response rate was 96% and the treatment was well tolerated, with 97% of patients continuing on the drug during median follow-up of 11 months.30

Relapsed/Refractory Disease

Despite improvements in response rates and disease control with first-line treatments for CLL, most patients will relapse.15 Treatment decisions for these patients should be guided by the same factors that determine first-line therapy, including patient age and concurrent comorbidities.13 In addition, cytogenetic assessment should be repeated because the presence of 17p deletion is crucial to treatment decisions. In patients who have received first-line treatment with fludarabine, cyclophosphamide, and rituximab, consideration may be given to retreatment with this combination if the treatment-free interval is longer than 3 years.3,13 However, impaired marrow reserve following this treatment and the emergence of 17p deletion may limit the efficacy of this regimen.13 If relapse occurs earlier, the treatment should be changed to agents such as bendamustine (plus rituximab), alemtuzumab (for patients refractory to fludarabine), or ofatumumab (for patients refractory to fludarabine and alemtuzumab) or to newer targeted agents such as ibrutinib, idelalisib, or venetoclax.3 Patients with 17p deletions or TP53 mutations can be treated with ibrutinib, a combination of idelalisib and rituximab, or venetoclax.

The BTK inhibitor ibrutinib is approved for patients with relapsed/refractory CLL, as well as in the first-line treatment setting.25 The efficacy of this agent as second-line therapy was demonstrated in the phase III RESONATE trial, which enrolled patients aged >70 years who had received at least one previous therapy and were ineligible for treatment with purine analogs (eg, fludarabine) due to comorbidities, 17p deletions, or a short duration of response after chemoimmunotherapy.31 The patients were randomized to receive ibrutinib or ofatumumab, and the primary endpoint was the duration of progression-free survival.31 However, the trial was terminated after a pre-planned interim analysis identified significantly improved outcomes with ibrutinib.31 At a median follow-up of 9.4 months, median progression-free survival in the ofatumumab group was 8.1 months but had not been reached in the ibrutinib group, with a hazard ratio for progression or death with ibrutinib of 0.22 (P<.001).31 Ibrutinib also significantly improved overall survival, with 12-month rates of 90% in patients treated with this agent as opposed to 81% with ofatumumab (P=.005).31

As noted above, ibrutinib can be associated with drug resistance and Richter’s transformation (evolution of CLL into large-cell lymphoma).28,29 The second-generation agent acalabrutinib, an irreversible inhibitor of BTK, has been evaluated as second-line treatment for CLL in addition to investigations in the first-line treatment setting.30 In a phase I/II trial involving 60 relapsed/refractory patients with CLL, the overall response rate was 95% in the study population as a whole and was 100% among patients with del(17p).30 No cases of Richter’s transformation were reported, and only 1 patient experienced disease progression.30

Idelalisib is a phosphatidylinositol 3-kinase δ inhibitor that targets the B-cell receptor signaling pathway.32 This agent was approved by the FDA in 2014 for the treatment of relapsed CLL in combination with rituximab.32 In a phase III, randomized trial, idelalisib plus rituximab was compared to rituximab plus placebo in patients (median age, 71 years) who had progressed within 24 months after their last treatment (which must have included an anti-CD20-based therapy or at least 2 prior cytotoxic regiments) and were not candidates for cytotoxic agents due to 1 or more of the following reasons: impaired marrow reserve as a consequence of prior myelosuppressive therapy, creatinine clearance <60 mL/min, or a Cumulative Illness Rating Scale score of more than 6 for coexisting illnesses not related to CLL.33 More than 40% of patients had 17p deletions or TP53 mutations.33 The primary endpoint was progression-free survival. At 24 months, 93% of patients in the idelalisib-rituximab group were progression free compared to 46% in the rituximab-placebo group, and the study was halted at a prespecified stopping point for efficacy.33 Median progression-free survival was 5.5 months in the rituximab-only arm and had not yet been reached with the combination of idelalisib and rituximab (P<.001).33 The clinical benefit of the idelalisib-rituximab combination was observed in all prespecified subgroups, including high-risk patients with 17p deletions and/or TP53 mutations.33 Serious adverse events occurred in 40% of patients receiving idelalisib and rituximab and in 35% of those receiving rituximab and placebo.33 The combination of idelalisib and ofatumumab was compared with ofatumumab alone in an open-label phase III study in patients with relapsed CLL.34 The combination demonstrated superior median progression-free survival and overall response rates (each P<.0001).34 Serious infections were more common in the combination therapy group.

Ibrutinib and idelalisib have each been evaluated in combination with bendamustine plus rituximab in phase III clinical trials.35,36 In both cases, the addition of the new agent resulted in significantly improved outcomes.35,36 Two-year results from the HELIOS trial, which assessed ibrutinib with bendamustine and rituximab, showed that this triple combination was superior to bendamustine-rituximab alone regarding the primary endpoint of progression-free survival (P<.0001).35

Although ibrutinib and idelalisib have improved outcomes in patients with CLL, there is still potential for relapse and resistance, especially in patients with 17p deletions.28 Moreover, these treatments have limitations such as intolerability and poor outcomes in patients who progress while on treatment or discontinue therapy.37 Venetoclax is a first-in-class oral inhibitor of BCL-2, an anti-apoptotic protein implicated in the pathology of CLL.38 This agent was approved by the FDA in 2016 for the treatment of patients with 17p deletions who have received at least one previous course of therapy.39 A phase I trial, single-arm, open-label, dose-escalation study involving 56 patients with relapsed/refractory CLL or small lymphocytic lymphoma who received venetoclax monotherapy was suspended to reassess dosing of the drug when laboratory evidence of tumor lysis syndrome (TLS) was observed in the first 3 patients treated, with 1 death.40 The trial was resumed, with 60 additional patients enrolled, using a weekly stepwise ramp-up dosing schedule, and TLS did not occur in any of these patients.41

A multicenter, single-arm, open-label phase II trial using a weekly ramp-up dosing schedule evaluated venetoclax in 107 patients with relapsed or refractory CLL and 17p deletions.37 The patients continued ventoclax until disease progression or unacceptable toxicity occurred. At a median follow-up of 12.1 months, the overall response rate (primary endpoint) was 79% and the rate of complete response was 8%.37 The most common grade 3/4 adverse events were neutropenia, infection, anemia, and thrombocytopenia.37 On laboratory testing, TLS was reported in 5 patients during the ramp-up period but resolved without clinical sequelae.37 Despite the lack of clinical TLS after the initiation of the slow, stepwise dose increase, it remains important to monitor patients for laboratory abnormalities indicating TLS, particularly those considered to have a higher risk due to a significantly elevated blood lymphocyte count (>25 Gi/L) or with bulky adenopathy (>5 cm).13 Hospitalization for dose escalations should be used in appropriate cases.

Recently reported results from the phase III MURANO trial, which enrolled nearly 400 patients with relapsed/refractory CLL, showed that the combination of venetoclax and rituximab markedly reduced the risk of CLL progression compared with bendamustine plus rituximab.42 The study population included patients with or without 17p deletions who had either relapsed after at least one course of chemotherapy or had failed to respond to previous regimens.42 At the planned interim analysis, the median progression-free survival was 17 months for patients treated with bendamustine plus rituximab but had not yet been reached for patients treated with venetoclax and rituximab.42 Rates of 2-year progression-free survival (the primary endpoint) were estimated to be 84.9% in the venetoclax/rituximab group as opposed to 36.3% in the bendamustine/rituximab groups.42 After the interim analysis, the trial was stopped early due to these positive results to make venetoclax available to patients in the control arm.42

Interim results from a phase II, multicenter, open-label trial have also been recently reported, showing that venetoclax was effective in patients with relapsed/refractory CLL who had failed treatment with ibrutinib.43 The trial enrolled 127 patients who had relapsed or refractory disease after previous treatment with a B-cell receptor signaling pathway inhibitor, 91 of whom had received ibrutinib as the last such therapy. Of the latter group, 43 patients were initially enrolled in the main cohort and 48 were enrolled after a protocol amendment (expansion cohort). At a median follow-up of 14 months, overall response was achieved in 70% of patients in the main cohort and 60% in the expansion cohort.43

Emerging Options

Numerous other treatment regimens for CLL are currently being investigated for relapsed/refractory patients and/or as first-line therapy.13,28 For instance, lenalidomide, an immunomodulatory agent, has been associated with overall response rates of 56% and 58% when used as monotherapy in untreated and relapsed/refractory patients, respectively.44,45 The addition of rituximab to lenalidomide produced overall response rates of nearly 83% in the first-line setting and 61% in the relapsed/refractory setting.46,47 Examples of combination regimens under investigation include venetoclax plus ibrutinib and obinutuzumab, ibrutinib plus obinutuzumab, ibrutinib plus nivolumab, ibrutinib plus lenalidomide, ibrutinib plus lenalidomide and rituximab, and ibrutinib plus selinexor.

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What is the prognosis for this patient with a 17p deletion?
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Correct Answer: A.

Rationale: Deletion in the short arm of chromosome 17 (del[17p]) is associated with rapid progression, short remission, and reduced survival.1 17p deletions are present in approximately 7% of previously untreated patients and 30% of relapsed/refractory patients and are associated with a more rapidly progressive course and shorter survival in both groups.13 17p deletions are linked to the loss of function of TP53, a tumor suppressor gene associated with resistance to available chemotherapies.3 The presence of a 17p deletion is crucial to treatment decisions. In patients who have received first-line treatment with fludarabine, cyclophosphamide, and rituximab, consideration may be given to retreatment with this combination if the treatment-free interval is longer than 3 years.3,13

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