Treatment of patients with CLL is initiated at the time of symptomatic progressive disease. The specific criteria for initiating therapy have been detailed in the IWCLL-2008 guidelines.1 This recommendation is primarily based on older studies that failed to demonstrate a survival advantage in patients treated early in the course of disease.159,160 These results were validated by a large study of fludarabine treatment in patients with early stage disease conducted by the German CLL study group, which failed to show a survival advantage with early treatment using conventional chemotherapeutic agents.161 Trials are currently underway with kinase inhibitors to determine if early intervention can alter the natural history of the disease. We recommend initiating treatment when patients fulfill the IWCLL-2008 criteria for treatment, regardless of the prognostic factors.
Patients with autoimmune complications of CLL can be managed accordingly with steroids and immunosuppressive therapies prior to proceeding with definitive therapy for the underlying disease. Patients with CLL rarely exhibit evidence of leukostasis resulting from profound leukocytosis, therefore, an elevated white cell count should not be used as a sole criteria for initiating treatment. Similarly, hypogammaglobulinemia should not be used as a reason to treat the disease. Periodic intravenous immunoglobulin infusions can be used in patients with hypogammaglobulinemia and recurrent life-threatening infections with encapsulated organisms. The IWCLL-2008 criteria should also be used when determining the timing of therapy for patients with relapsed disease.
One of the most important factors to consider prior to initiating treatment is the functional state of the patient. Historically, age cutoff has been successfully used in developing specific therapies. Because the median age of diagnosis for CLL is 72 years, the vast majority of patients treated in the community are older and with multiple comorbid conditions. Unfortunately, there is limited data available in this patient population and until recently they had very limited options for therapy. Most of the clinical trial participants have been younger patients who are in their 50s and 60s. The gradual functional decline, decrease in organ function, especially renal and hepatic function, and an increase in the comorbid conditions in the majority of patients older than age 65 years significantly increases the risks and toxicities of conventional chemotherapeutic regimens especially nucleoside analogues. To address these issues, different approaches are being used to treat patients older than 65 years versus younger patients. A cumulative illness rating scale (CIRS) has been proposed and used primarily by the German CLL study group. It allows patients to be stratified based on an aggregate score derived from multiple factors including age, comorbid conditions and organ function.162
DEVELOPMENT OF CHEMOTHERAPY FOR THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA
Chlorambucil has been used as the prominent alkylating agent for the treatment of CLL for the last 60 years. Chlorambucil is taken orally and is generally well-tolerated but does have multiple side effects, including nausea, vomiting, and cytopenias. Various doses and schedules have been used with different responses and tolerability profiles. Older studies compared chlorambucil to conventional high-grade lymphoma therapy, including cyclophosphamide, vincristine, and prednisone (CVP) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and found no improvement in survival outcomes with the use of high-grade lymphoma-like therapies.159 Multiple doses of chlorambucil have been evaluated in various clinical trials with differing but similarly modest overall response rate (ORR) and PFS. No single-dosing regimen has been shown to be superior to another. One dosing regimen that has been used in cooperative group studies is 40 mg/m2 oral dose every 28 days for 12 cycles.163 An argument, however, can be made that escalating the dose of chlorambucil in younger patients might result in a higher response rate.164 Despite its ease of use and reasonable tolerability, chlorambucil is not very commonly used today because of the availability of better and potentially safer alternatives. Moreover, responses observed with chlorambucil are modest and not durable.165 Nevertheless, chlorambucil is potentially an option for treatment of elderly patients with multiple comorbidities and limited other options for treatment. It should, however, not be used for asymptomatic patients with early stage disease.160
Cyclophosphamide is also approved for the use in patients with CLL and has moderate efficacy and reasonable tolerability. Care should be taken to avoid nighttime dosing and aggressive hydration should encouraged to avoid hemorrhagic cystitis.166 Low-dose etoposide, either as a single agent or in combination with cladribine, also shows modest responses in patients with relapsed and refractory disease. Treatment with etoposide is associated with significant myelosuppression and resultant infectious complications.167,168
Bendamustine was approved for the treatment of patients with CLL in 2008. This was based on a phase III trial that demonstrated the superior efficacy of bendamustine as compared to chlorambucil with regards to response rate and PFS.169 Structurally, bendamustine has features common with alkylating agents and purine analogues, but its activity is primarily derived from the alkylating agent moiety.170 Bendamustine appears to be generally better tolerated than fludarabine but causes significant myelosuppression, requiring dose reductions, especially in elderly and infirm. Tolerability is better in patients with impaired renal function since excretion is primarily through the feces.171
Nucleoside analogues have also been used for the treatment of patients with CLL for the last 25 to 30 years. Fludarabine has been the most commonly used agent from this class of drugs. Fludarabine has moderate activity especially in the younger patients with good nutritional status and with untreated, early stage disease.172 After demonstrating promising activity as a single agent in early phase clinical trials, fludarabine was compared to chlorambucil in a randomized phase III study for the initial treatment of patients with CLL. Patients treated with fludarabine demonstrated improvement in PFS and OS compared to chlorambucil, albeit with a higher rate of infectious complications; however, all patients ultimately had recurrent disease.163 Similar to chlorambucil, fludarabine was also more effective compared to combination chemotherapy regimens like cyclophosphamide, doxorubicin, and prednisone (CAP).173 However, PFS and OS advantage was not shown in another randomized trial of elderly patients older than age 70 years treated with fludarabine on chlorambucil despite the higher overall and complete response (CR) rate in the fludarabine-treated patients.174
The use of fludarabine and similar nucleoside analogues is associated with significant hematologic and immunologic toxicities. Patients can experience prolonged cytopenias and especially neutropenia, which can result in a significant increase in the risk of infectious complications. These drugs are also exquisitely toxic to T cells, especially to CD4+ T cells. This effect may last for an extended period of time and predisposes patients to acquiring opportunistic infections.175,176 Neurologic toxicities have also been observed in patients receiving the usual dose of fludarabine.177 Patients treated with fludarabine occasionally develop autoimmune hemolytic anemia. In this situation, further use of fludarabine is contraindicated.178,179,180 Fludarabine is also poorly tolerated in patients with compromised renal function as a significant percentage of the metabolites are cleared via the renal system. Hemodialysis is a useful tool to limit fludarabine toxicity in patients who develop acute renal failure while receiving treatment.181 Moreover, fludarabine treatment in patients older than age 65 years was poorly tolerated and did not result in improvements in PFS and resulted in a trend toward inferior OS outcome when compared to chlorambucil.174
Other nucleoside analogues used in the treatment CLL include cladribine and pentostatin which have similar outcomes and toxicities as fludarabine.182,183,184,185 A phase III trial comparing fludarabine, cladribine, and chlorambucil showed similar ORR and CR rate with all three agents, but median PFS was superior with cladribine (25 months) versus 10 and 9 months with fludarabine and chlorambucil, respectively.186 No advantages, however, were observed in OS. Cytarabine has also shown modest activity, especially in combination with oxaliplatin, fludarabine, and rituximab (OFAR regimen) in patients with refractory disease and patients with Richter transformation.187,188
Multiple chemotherapeutic combinations have been studied in patients with CLL. One of the earlier combinations to be used was chlorambucil and prednisone with ORR of approximately 80 percent with CR rates of approximately 10 to 15 percent.165,189 This regimen was also found to be as effective as other combination regimens like CVP, cyclophosphamide, melphalan, and prednisone (CMP), CAP, or CHOP.159,190,191,192 A meta-analysis comparing lymphoma-like combination therapies found no improvements in survival outcomes over chlorambucil alone.159 High-dose combination therapies like CAP, CHOP, and CVP have no role in the routine management of patients with CLL.
Given the improvement in outcomes with single-agent fludarabine as compared to chlorambucil, multiple combinations were developed with fludarabine to improve on its efficacy. Both the combination of fludarabine and chlorambucil and fludarabine and prednisone were found to be similar to fludarabine and not developed further.172,193,194 Fludarabine was combined with cyclophosphamide (FC) and resulted in encouraging responses even in patients with heavily pretreated disease.195 Multiple phase III trials were subsequently conducted in predominantly younger patients, comparing fludarabine with FC and revealed an ORR of 74 to 94 percent with CR rates of 23 to 38 percent and median PFS of 33 to 48 months, all significantly better with the combination.87,196,197 Early toxicities were mostly related to cytopenias secondary to myelosuppression and the resultant increase in infectious complications resulted in a slight dose adjustment and a dose of fludarabine 25 to 30 mg/m2 for 3 days and cyclophosphamide 250 mg/m2 for 3 days every 28 days for six cycles was used for subsequent studies. Notably, the combination of FC was the first regimen that was able to overcome the adverse prognostic impact of del 11q.86
Similarly, other combinations of alkylating agents with nucleoside agents have been tested with varying success. These include cladribine and prednisone, which combination was shown to be better than chlorambucil and prednisone in terms of responses, but without improvements in OS and with a higher incidence of infectious complications in the cladribine-treated arm.198,199 Similarly, the addition of cyclophosphamide and prednisone to cladribine resulted in higher responses but more myelosuppression and related complications.200,201,202 Pentostatin was also combined with cyclophosphamide and resulted in ORR of 74 percent and CR rates of 17 percent in patients with fludarabine refractory disease.203 Pentostatin in combination with chlorambucil and prednisone also resulted in promising responses but was extremely immunosuppressive and resulted in an unacceptably high incidence of infectious complications.204
Fludarabine was also combined with mitoxantrone without significant improvements in outcome. Although mitoxantrone appeared to improve outcomes when added to cladribine, it came at the cost of significant toxicity.205,206 Likewise, the combination of fludarabine, cyclophosphamide, and mitoxantrone resulted in an ORR of 78 percent and CR rates of 50 percent in patients with relapsed disease and an ORR of 90 percent with a CR rate of 38 percent in patients with previously untreated disease. The major toxicity was myelosuppression.206,207
The advent of antibodies for the treatment of patients with CLL has been a major advance in the management of this disease with the first true consistent evidence of improving survival. Numerous antibodies targeting different receptors have been developed and are at various stages of development. Four antibodies are currently approved for routine management. Unfortunately, one of these (alemtuzumab) is no longer actively marketed for this indication.
Alemtuzumab is a CD52-targeting, humanized, monoclonal antibody that mediates its efficacy through direct cytotoxicity, complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). CD52 is ubiquitously expressed on lymphocytes (including B and T cells) and monocytes and this explains the efficacy and toxicity of the antibody. Alemtuzumab is extremely effective in clearing the blood and marrow of disease and is also active in patients with del 17p disease which is generally refractory to conventional chemotherapy.208 However, alemtuzumab has limited efficacy in patients with bulky lymphadenopathy, especially in patients with lymph nodes that are greater than 5 cm in diameter.209,210,211 Alemtuzumab was initially approved in 2001 by the FDA for the treatment of patients who had failed prior therapy with nucleoside analogues. This was primarily based on small trials that administered alemtuzumab intravenously three times a week for 12 weeks and showed modest response rates of approximately 30 to 40 percent and CRs in less than 5 percent of patients.209,210,211 Responses were short-lived in this cohort of patients and the median response duration was approximately 9 months. Treatment was also complicated by infusion-related toxicities in the vast majority of patients. To minimize these reactions, alemtuzumab is started at a dose of 3 mg and escalated to 10 mg for the second dose and 30 mg for the third dose, as tolerated. Another major toxicity was immunosuppression that resulted in multiple recurrent infections especially with opportunistic organisms that are commonly seen in patients with chronic immunocompromised states like HIV/AIDS such as CMV, pneumocystis, or varicella zoster.209,210,211 Patients also experienced prolonged cytopenias, especially of natural killer (NK) and T cells, which can persist for more than 9 months following therapy.212 Consequently, antiviral and antimicrobial prophylaxis therapy should be initiated in all patients receiving alemtuzumab and should be continued for at least 6 months after completing therapy.
A subsequent large phase III (CAM307) clinical trial was performed that compared alemtuzumab to chlorambucil as first-line therapy.213 Two hundred ninety-seven patients were randomized to chlorambucil 40 mg/m2 every 4 weeks for 12 cycles or alemtuzumab 30 mg intravenous infusion three times per week for 12 weeks. Overall response with alemtuzumab was 83 percent, with 24 percent CRs and with time to next treatment of 23 months. This was significantly better than the results observed with chlorambucil, which resulted in an ORR of 55 percent with 2 percent CRs and time to next treatment of 14 months. Moreover, approximately one-third of patients treated with alemtuzumab achieved a minimal residual disease (MRD)-negative CR that was later shown to correlate with OS. Both agents were well-tolerated but alemtuzumab resulted in a higher incidence of CMV infections. This trial resulted in the approval of alemtuzumab as initial therapy for CLL in 2007.
Infusion reactions and infectious complications are the major issues observed with the use of alemtuzumab. Infusion reactions can be diminished with a subcutaneous administration which appears to be equally efficacious but with similar toxicity profiles.214,215 Despite the encouraging results and approvals by the FDA, alemtuzumab never gained mass popularity and was not used by practicing physicians very often. It is no longer being marketed by the company for CLL but (as of 2015) can be obtained upon written request at no cost. The limited future prospects of alemtuzumab precludes exhaustive discussion. Alemtuzumab has been studied in combination with chemotherapy and as consolidative therapy after chemotherapy and has shown some benefit, but is generally associated with significant serious infectious morbidity.216,217,218,219
CD20 Targeting Antibodies
Rituximab Rituximab is a chimeric, murine, CD20-targeting, monoclonal antibody that has been extensively used for the treatment of patients with CD20+ lymphoid malignancies. CD20 is a calcium channel that interacts with BCR complex and is ubiquitously expressed on B-cell non-Hodgkin lymphomas and has a weak expression on CLL cells. Rituximab exerts its efficacy through direct CDC and ADCC.220,221,222
The dose and schedule of treatment with rituximab was determined empirically and has since been modified repeatedly. Initial trials were performed with four weekly infusions at 375 mg/m2 and showed limited efficacy in patients with CLL.223,224 Responses were higher when higher doses (up to 2250 mg/m2) or dose-dense regimens (375 mg/m2 three times a week) were used but was primarily limited to the blood and nodal areas.225,226 Nonetheless, these studies established the efficacy of rituximab and supported combination trials with chemoimmunotherapy where their impact has been most impactful.
Rituximab is generally tolerated very well with the most common toxicity being infusion reactions that are predominantly observed primarily with the first dose. These are generally mild fevers or chills, but occasionally may result in serious reactions that mimic severe allergic or anaphylactic reactions or cytokine release syndrome. The infusion reactions can be minimized with the routine use of prophylactic acetaminophen, antihistamine, and corticosteroids, glucocorticoid, and by slowing the infusion rate. Patients may also experience transient, severe thrombocytopenia, the mechanism of which is poorly understood. Therefore, rituximab should be used with caution in patients with a preexisting thrombocytopenia. Another important and potentially severe toxicity is tumor lysis syndrome, which is generally observed in patients with a high circulating peripheral lymphocyte count. These patients should be monitored closely and should receive prophylactic hydration, allopurinol, and electrolyte monitoring during and after the infusion. Other uncommon toxicities include delayed neutropenia, hepatitis B reactivation, interstitial pneumonitis, rash, and serum sickness. Patients with a prior history of hepatitis B infection should receive monitoring for reactivation while being treated with rituximab or similar agents, with rapid implementation of antiviral therapy if reactivation is observed. Fatal cases of progressive multifocal leukoencephalopathy from JC polyomavirus infection has also been reported with the use of rituximab and similar monoclonal antibodies. These infections typically occur during treatment or soon after, with virtually all cases observed during the first year posttherapy.227,228
Ofatumumab Ofatumumab is a fully human, type 1, IgG1, CD20-targeting, monoclonal antibody that binds more effectively to a different epitope of CD20 than rituximab.229 In vitro it was shown to have improved CDC and ADCC as compared to rituximab.230,231 Ofatumumab is given as a test dose of 300 mg followed by eight weekly intravenous infusions of 2000 mg, after which patients can go on a maintenance schedule of four monthly infusions of 2000 mg. The half-life of ofatumumab is 21 days, but the B-cell–depleting effects may last for up to 7 months after the last infusion.232
Early results with ofatumumab as a single agent in patients who were refractory to alemtuzumab and/or fludarabine showed encouraging ORR of 58 percent in the double refractory group and 47 percent in the fludarabine refractory cohort with bulky disease. Responses were all partial except for one CR in the fludarabine refractory group. Response was also short lived and the median duration of response was 7 months in the fludarabine refractory group and 5.6 months in the double refractory group with most patients progressing during treatment.233 These results led to the approval of ofatumumab in patients with relapsed disease refractory to alemtuzumab and/or fludarabine in 2009. Subsequent studies compared ofatumumab (300 mg on day 1 followed by eight weekly infusions of 1000 mg, followed by 1000 mg on day 1 of subsequent 28-day cycles, for a maximum of 12 cycles) given in combination with oral chlorambucil (10 mg/m2 on days 1 to 7 of each 28-day cycle) versus chlorambucil alone, in patients with previously untreated CLL who required treatment and were not considered candidates for conventional chemoimmunotherapy. The combination resulted in an ORR of 82 percent versus 68 percent with chlorambucil alone. However, CR rates were 12 percent versus 1 percent and median duration of response was 22 months versus 13 months in the combination versus chlorambucil arms, respectively.234 Based on these results, the combination of ofatumumab and chlorambucil was granted approval in 2014 for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.
Ofatumumab has also been studied in the upfront setting in combination with FC in smaller phase II studies of a relatively young patient population (median age: 56 years). This study revealed an ORR of 75 percent with 41 percent CRs.235 The combination of ofatumumab with pentostatin and cyclophosphamide resulted in a 96 percent ORR with 46 percent complete remission rate.236,237 This compares favorably to the results seen with the combination of rituximab and chemotherapy, but large multiinstitution randomized trials are lacking.
Ofatumumab is generally well-tolerated, with the most common reaction being an infusion-related reaction that typically occurs with the first infusion and includes fevers, rash, fatigue, chills, and diaphoresis. These reactions tend to get better with subsequent infusions. Infectious complications are similar to those reported with other CD20 monoclonal antibodies.
Obinutuzumab Obinutuzumab is a CD20-targeting antibody that was approved in combination with chlorambucil for the initial treatment of patients with CLL in 2014. Obinutuzumab is a fully humanized, type II, IgG1 antibody238 with additional structural modifications that explain its enhanced activity. It binds selectively to the extracellular domain of CD20 with reduced internalization. This persistence of the antibody on the cell surface along with a fucosylation in its Fc region allow for enhanced ADCC through robust engagement of Fc-gamma receptor type III on effector cells. Another modification in the hinge region allows for more potent direct cytotoxicity.239,240,241 Together, these modifications translate into a higher efficacy as compared with rituximab in both preclinical and clinical studies.239,240,241,242,243
Obinutuzumab in combination with chlorambucil was compared to rituximab and chlorambucil and chlorambucil alone in patients with untreated CLL in the CLL-11 trial conducted by the German CLL study group.244 Patients had a median age of 73 years, which is closer to the median age of 72 years at diagnosis for CLL patients, and significantly higher than the median ages of 58 to 62 years which have historically been the population that has been enrolled in chemotherapy-based clinical trials for CLL. More importantly, these patients had clinically meaningful comorbid conditions. Treatment of this patient population has historically been challenging and no prior chemotherapeutic option, including fludarabine, has improved survival outcomes as compared to chlorambucil alone.174 The combination of obinutuzumab and chlorambucil improved ORRs (77.3 percent [obinutuzumab and chlorambucil] vs. 65.7 percent [rituximab and chlorambucil] vs. 31.4 percent [chlorambucil]), CR rates (22.3 percent [obinutuzumab and chlorambucil] vs. 7.3 percent [rituximab and chlorambucil] vs. 0 percent [chlorambucil]) and median PFS (26.7 months [obinutuzumab and chlorambucil] vs. 16.3 months [rituximab and chlorambucil] vs. 11.1 months [chlorambucil]). Obinutuzumab with chlorambucil also prolonged OS over that which was observed with chlorambucil. Notably, the combination also resulted in significant improvement in the rate of MRD-negative status in both marrow (19.5 percent vs. 2.6 percent) and blood (37.7 percent vs. 3.3 percent) as compared to rituximab and chlorambucil.
Obinutuzumab is generally well-tolerated, but has a high incidence of infusion reactions that are seen primarily with the first infusion. Unlike rituximab or ofatumumab where infusion events occur 1 to 2 hours into therapy, those with obinutuzumab typically occur within the first 5 to 10 minutes of starting therapy. These may be minimized by a test dose, slower infusion rate, and prophylactic steroids, acetaminophen, and antihistamines. Tumor lysis is also seen in a small number of patients, reflecting the higher efficacy of obinutuzumab. Hematologic toxicities, like neutropenia and thrombocytopenia, are also observed. All CD20-targeting antibodies increase the risk of hepatitis B virus reactivation and progressive multifocal leukoencephalopathy.
The activity of obinutuzumab in patients with untreated CLL is very exciting and this antibody is being combined with other novel agents and chemotherapy to further improve outcomes in patients with CLL.
Other Antibodies and Antibody-Like Compounds
Multiple antibodies targeting various antigens like CD19 and CD37 are at various stages of development for the treatment of CLL.245,246,247 Advances in antibody manufacturing technology are enabling us to synthesize more potent and bispecific antibodies like blinatumomab, which has already shown promising activity in patients with acute lymphoblastic lymphoma (ALL) and CLL.248
Glucocorticoids are effective agents in the management of patients with relapsed CLL and especially patients with del 17p and fludarabine refractory disease. High-dose methylprednisolone, either as a single agent or in combination with multiple other chemotherapeutic agents, produced sustained responses in the majority of patients with refractory and high-risk disease.249 High-dose methylprednisolone at 1 g/m for 5 days with weekly rituximab for three cycles induces response rates as high as 93 percent with a CR of 36 percent.250 Therapy, however, is complicated by significant hyperglycemia, fluid retention, and immune suppression resulting in increased incidence of opportunistic infections requiring close followup and aggressive supportive care with prophylactic antibiotics. The addition of weekly rituximab and decreasing the duration of methylprednisone dose to 3 days resulted in similar responses and reduction in the incidence of adverse events.250,251 Similar results were observed when methylprednisolone was substituted for dexamethasone 40 mg weekly or every 2 weeks for 4 days.252 Glucocorticoids at lower doses are also very useful in the management of patients with autoimmune complications as a result of their CLL.
The combining of chemotherapy with targeted antibodies has been a major advance in the management of patients with CLL. Multiple therapeutic combinations have been developed and validated for use and are summarized below.
The impact of sequential or concurrent administration of rituximab with fludarabine (FR) was assessed in the Cancer and Leukemia Group B (CALGB) 9712 randomized study of 104 previously untreated CLL patients.253 Fludarabine was given at 25 mg/m2 days 1 to 5 every 4 weeks for six cycles, with or without concurrent rituximab 375 mg/m2 on day 1 of each cycle, and an additional dose on day 4 of cycle 1. Patients in both arms received rituximab 375 mg/m2 weekly for four doses beginning 2 months after completion of fludarabine; thus, patients in the concurrent arm received 11 total doses of rituximab, compared to four in the sequential arm. ORR was 90 percent versus 77 percent and CR rates were 47 percent versus 28 percent in the concurrent versus sequential arm, respectively. A retrospective comparison to a fludarabine-only treatment (CALGB 9011) demonstrated improved PFS and OS with the use of FR.254 This regimen had limited efficacy in patients with del 17p and del 11q. The median PFS was 42 months and 27 percent were progression free at 5 years. Notably, there were no cases of treatment-related-myeloid neoplasms occurring before disease relapse.255
Fludarabine, cyclophosphamide, and rituximab (FCR) chemotherapy has been studied extensively in patients with previously treated and untreated CLL.256,257,258,259 Fludarabine was administered at 25 mg/m2, cyclophosphamide at 250 mg/m2 on days 2 to 4 of cycle 1 and on days 1 to 3 of cycles 2 to 6, and rituximab at 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 to 6. In the initial single institution, phase II experience of 300 untreated CLL patients, this combination resulted in exciting ORR of 95 percent with CR rate of 72 percent with median time to progression of 80 months in patients with untreated CLL.259 However, despite a younger patient population with a median age of 57 years, FCR resulted in significant and sustained myelosuppression, with 35 percent of patients experiencing cytopenias 3 months after completing therapy.260 Notably, therapy-related myeloid neoplasms/myelodysplastic syndromes occurred in 5.1 percent of patients and Richter transformation in 9 percent.261 FCR was subsequently compared to FC in a large multicenter trial of 817 young patients (median age: 61 years) with previously untreated CLL.262 The responses observed with FCR were more modest in larger phase III trials. Patients treated with FCR had a significantly higher ORR of 90 percent with a CR rate of 44 percent as compared to FC, which resulted in an ORR of 80 percent and a CR rate of 22 percent. More importantly, this study established the improvement in OS with the addition of rituximab to chemotherapy. As a result, rituximab was approved for the treatment of patients with CLL in combination with chemotherapy in 2010. The use of FCR was also associated with a significantly higher risk of cytopenias that did not result in a higher incidence of serious infectious complications which were similar in both arms as was the treatment-related mortality. All genomic groups appear to benefit from the addition of FCR, except for those without any common interphase cytogenetic abnormalities and those with del 17p.263 Long-term followup of FCR by both the MD Anderson group and the German CLL Study Group suggests that the patients benefiting most from FCR may be those with IGHV mutated disease where prolonged complete remissions can be obtained. For patients with IGHV unmutated disease there does not appear to be any evidence of sustained stable remission, with all eventually relapsing and requiring additional therapy.263,264
Given the poor tolerability and increased toxicity observed with the use of FCR in elderly patients and patients with compromised renal function and to enhance efficacy of FCR, multiple variations of the regimen were tested with similar results in small cohorts of patients.265,266 None of these regimens are commonly used and the advent of alternative agents have made these regimens of limited utility.
The combination of bendamustine and rituximab (BR) has been tested both in patients with relapsed and in patients with untreated CLL. In the first BR study with relapsed CLL bendamustine was administered to 78 patients at a dose of 70 mg/m2 on days 1 and 2 with rituximab 375 mg/m2 on day 0 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 to 6. The ORR was 59 percent with a CR rate of 9 percent and a median PFS of 14.7 months. Minimal activity was observed in patients with del 17p.267 In the subsequent followup study, 117 patients with previously untreated CLL were treated at the same schedule but with a higher dose of bendamustine at 90 mg/m2 on days 1 and 2 and resulted in ORR of 91 percent with CR rate of 33 percent.268 In the large, multicenter, CLL10 trial, 564 patients with previously untreated CLL, good performance status, and low comorbidity burden were randomized to FCR or BR.269 ORR was similar in both arms at 97 percent but CR rates were higher in the FCR arm at 40 percent versus 31 percent with BR. MRD rates were also higher with FCR (74 percent vs. 62 percent). Median PFS was 53 months in the FCR arm and 43 months in the BR arm. FCR was more toxic and severe neutropenia was more often observed in the FCR arm (87 percent vs. 67 percent) as were severe infections (39 percent vs. 25 percent). Treatment-related mortality was 3.9 percent with FCR and 2.1 percent with BR. Given these results, FCR appears to be the more effective therapeutic option for younger patients and patients without significant comorbid conditions, and BR can be used for older and unfit patients.
Other Chemoimmunotherapeutic Regimens
Pentostatin and rituximab and pentostatin, cyclophosphamide, and rituximab (PCR) both resulted in promising ORR (91 percent vs. 76 percent) and CR rates (41 percent vs. 27 percent).237,270 Importantly, the PCR regimen appeared to be generally well-tolerated in young and older patients and in patients with high-risk genetic features. Levels of Mcl-1, an antiapoptotic protein, were also shown to be predictive of response and OS.34 The most common toxicity was neutropenia and thrombocytopenia. Similarly, cladribine and cladribine plus cyclophosphamide were also combined with rituximab and resulted in predictable efficacy and toxicity.271,272,273
The introduction of BCR kinase inhibitors has significantly improved the management options for patients with CLL and represents a group of agents that very likely will change the natural history of this disease. Early results with these agents including ibrutinib and idelalisib that target BTK and PI3K, respectively, have shown promising efficacy and excellent tolerability but long-term data is limited to 4 years of followup and decision rules need to be developed that allow for eventual treatment discontinuation.72 Much of what was learned from the transition of chemoimmunotherapy management of chronic myeloid leukemia will likely become relevant to CLL as additional follow up develops with the use of BCR antagonists in this disease.
Ibrutinib is a first-in-class, irreversible inhibitor of BTK and covalently binds to Cys-481 near the ATP binding domain of the BTK molecule, and abrogates enzyme activity and BCR-mediated survival signals. Ibrutinib also has the ability to irreversibly target ITK in T cells and other Tec family of kinases.274
A 420-mg daily oral dose of ibrutinib has been used in the treatment of patients with relapsed CLL and demonstrated an ORR of 71 percent with an additional 20 percent of patients experiencing partial response (PR) with lymphocytosis (PR+L), which, interestingly, does not appear to predict for inferior PFS.275 The responses observed with ibrutinib are sustained and resulted in PFS of 75 percent at 26 months.92 Patients with del 17p had an ORR of 55.9 percent with a median duration of response of 25 months.276 Historical comparisons reveal a significantly improved response rate and PFS when ibrutinib was compared to either cyclin-dependent kinase (CDK) inhibitors or other conventional therapies used in the past for patients with del 17p.91 Similar exciting results were reported in elderly, treatment-naïve patients treated with ibrutinib with ORR of 71 percent and 13 percent PR+L. These responses also appear to be sustained over time with PFS of 96.1 percent at 2 years.277 Ibrutinib in general is well-tolerated, with the most common side effects being mild diarrhea, nausea, and fatigue. A randomized study comparing ibrutinib to ofatumumab in relapsed CLL confirmed the benefits of ibrutinib with improved response rate, PFS, and OS.278 However, this study also demonstrated a higher incidence of both minor bleeding and atrial fibrillation with ibrutinib. The bleeding diathesis observed with ibrutinib is possibly caused by a collagen-mediated platelet aggregation defect.278,279 Caution should be taken to avoid the use of ibrutinib in patients on concurrent anticoagulation with warfarin and treatment should be held 3 to 7 days before and after surgical procedures. The pathophysiologic reason for increased risk of atrial fibrillation with ibrutinib is uncertain. Ibrutinib treatment also results in a progressive decline in the incidence of infectious complications with ongoing therapy, primarily as a result of disease control.92 Most patients do not require routine antimicrobial prophylaxis commonly used with chemoimmunotherapy. Moreover, improvements are also observed in stress, depressive symptoms, fatigue, and quality-of-life in patients treated with ibrutinib.280 Based on these exciting data, ibrutinib was approved in 2014 for the treatment of all patients with relapsed CLL and for the treatment of all patients with del 17p CLL regardless of prior therapy.
Treatment with ibrutinib does not result in CRs in most patients and discontinuing this treatment in heavily pretreated patients often results in patients experiencing rapid disease progression. Therefore, we currently recommend that ibrutinib be continued in responding patients until disease progression or unacceptable toxicity. However, this chronic exposure to kinase inhibitors might result in the emergence of resistant malignant cell clones, although this has been quite rare.72 Data derived from whole-exome sequencing of paired samples at baseline and at the time of relapse while being treated with ibrutinib identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib and three distinct mutations in PLCγ2.281 Functional analysis revealed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous BCR activity. Interestingly, these mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib, suggesting an alternative and as yet unidentified mechanism for the persistence of lymphocytosis in those patients. Furthermore, the clinical impact of this persistent lymphocytosis was not demonstrated, with individuals having persistent lymphocytosis actually having similar outcome to those patients with PRs or better.
Ibrutinib is being combined with various other agents to improve the depth of response and outcomes. The combination of ibrutinib and rituximab in patients with high-risk CLL was generally well-tolerated and resulted in an ORR of 95 percent and a PFS of 78 percent at 18 months.282 PFS was 72 percent at 18 months in patients with del 17p. Multiple trials are ongoing with ibrutinib in the frontline setting and in comparison to chemoimmunotherapy. These trials and the development of newer BTK inhibitors have the potential to change the treatment paradigms for CLL.
Idelalisib is an orally bioavailable, first-in-class isoform selective PI3K-δ inhibitor that promoted apoptosis of CLL B cells ex vivo, along with abrogating the survival signals provided by the microenvironment.283 The PI3K family of enzymes are involved in an extraordinarily diverse group of cellular functions, including cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking.284 Many of these functions relate to the ability of class I PI3Ks to activate the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway.285 The p110δ isoform regulates different aspects of cellular proliferation and survival and is constitutively overexpressed in CLL B cells286; consequently, targeting it with specific inhibitors has become a useful therapeutic option.72
In a phase I trial of 54 patients, with relapsed/refractory high-risk CLL patients, idelalisib resulted in an ORR of 72 percent (including PR+L).71 The median PFS was 15.8 months. Therapy was generally well- tolerated with the most commonly observed grade 3 or greater adverse events being pneumonia (20 percent), neutropenic fever (11 percent), and diarrhea (6 percent). The combination of idelalisib and rituximab was also compared to rituximab and placebo in a phase III trial and resulted in an ORR of 81 percent versus 13 percent and PFS at 1 year in excess of 90 percent versus 5.5 months in the rituximab and placebo arms, respectively.287 Serious toxicities observed with idelalisib included transaminase elevations, diarrhea with colitis, and pneumonitis that were primarily observed after continued drug exposure. Based on these results, idelalisib was approved in 2014 in combination with rituximab for the treatment of patients with relapsed CLL with significant comorbid conditions that would make them ineligible for treatment with standard chemotherapy.
Lenalidomide is an immunomodulatory analogue of thalidomide and is approved for the treatment of multiple myeloma and myelodysplastic syndrome.288 Lenalidomide has also shown exciting efficacy in patients with previously treated and untreated CLL in multiple studies.289,290,291,292,293 Multiple dose levels and schedules have been tested in CLL with varying responses. From compilation of all the data it appears that 5 mg daily continuous dose of lenalidomide appears to be the best-tolerated dose in the vast majority of patients with CLL.294 The responses observed with CLL are mostly PRs in 40 to 60 percent of patients, with approximately 10 percent of the patients experiencing a CR. However, response improves with ongoing therapy. Cytopenias are the most common, and dose-limiting, side effect. Patients can also experience tumor flare and tumor lysis, especially at the start of therapy. Care should be taken to minimize these reactions with the early use of steroids and aggressive hydration and uricosuric agents. In a recent phase III study, lenalidomide was shown to increase mortality in patients older than 80 years of age and thus is not recommended for the elderly. Combination of lenalidomide with monoclonal antibodies has also resulted in improved sustained responses.295,296,297 Despite the advent of kinase inhibitors, lenalidomide continues to be an exciting agent for the treatment of CLL as it is one of the only agents that appears to have the potential to reverse the immune dysfunction associated with CLL; it also appears to have efficacy in patients with del 17p disease.49,298,299,300,301
CHIMERIC ANTIGEN RECEPTOR T CELLS
Chimeric antigen receptor T (CAR-T) cells are engineered autologous lentiviral modified T cells that contain an altered TCR targeting a surface antigen (e.g., CD19) on the surface of CLL B cells. The modified TCR has a higher affinity and specificity toward the target antigen and is not major histocompatibility complex (MHC) restricted. Multiple CAR-T cells have been developed and tested in clinical trials with exciting results.302,303 These modified T cells persisted in vivo for an extended period and were able to induce prolonged clinical responses in the majority of patients.304 The treatment is associated with severe cytokine release syndrome and macrophage activation syndrome that require aggressive and intensive supportive care and anti–IL-6–directed therapy. These modified CAR-T cells also result in the sustained elimination of normal B cells and subsequent sustained hypogammaglobulinemia that require ongoing supportive care and infection prophylaxis to limit the incidence of infectious complications in these patients.303 Development of these agents on a larger scale is ongoing to allow for larger studies to confirm their promising effect.
Venetoclax (ABT-199) is an oral Bcl-2–targeting agent that has shown impressive activity with deep remissions in patients with relapsed and refractory CLL, including those who have del 17p.305 Bcl-2 is an antiapoptotic protein overexpressed in CLL and causes disruption of apoptosis in CLL cells. Early efforts with the first-generation compound navitoclax, demonstrated single-agent activity, but also resulted in profound thrombocytopenia as a result of off-target effects on Bcl-xl expressed in platelets. Venetoclax is significantly more potent and more specific to Bcl-2 with limited off-target effects.306 Combination studies are already underway with kinase inhibitors and monoclonal antibodies to improve outcomes. Therapy with venetoclax has been complicated by fulminant tumor lysis syndrome, especially in patients with a high burden of disease that has greatly slowed down clinical development of this agent.
Blinatumomab is an engineered bi-specific T-cell engaging (BiTE) antibody that has shown promising activity in CD19+ B-cell malignancies, including CLL and ALL.248 It was approved in 2014 for the treatment of relapsed ALL. Blinatumomab engages the CD19+ cell and brings it in close proximity to a CD3+ T-cell that is also activated upon binding to the bi-specific antibody. The resultant interaction leads to the apoptosis of the CD19+ B cells. The antibody has shown promising and durable responses and is currently in clinical trials for CLL. Therapy is complicated by hypogammaglobulinemia, cytokine release and neurologic symptoms.307
CDK inhibitors like flavopiridol and dinaciclib have also demonstrated promising activity in patients with CLL, and are able to induce durable remissions even in patients with high-risk del 17p disease with or without concomitant chemotherapy.308,309,310,311 Therapy with CDK inhibitors is complicated by fulminant hyperacute tumor lysis that requires aggressive supportive care including hemodialysis. Diarrhea and fatigue are also seen as off target effects.
STEM CELL TRANSPLANTATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA
With the advent of effective therapy for patients with relapsed and refractory disease and even for patients with high-risk disease, the role of stem cell transplantation (SCT) for the routine management of patients with CLL is diminishing. Autologous transplantation has the ability to induce deeper and more frequent remissions that may result in longer disease-free remission, but does not translate into an OS advantage and is associated with significantly higher morbidity and mortality and secondary cancers, including therapy-related myeloid neoplasms that may impact long-term survival.312,313,314 Moreover, autologous transplantation, which is essentially high-dose chemotherapy, is unable to overcome the chemoresistance conferred by del 17p or TP53 mutation. Consequently, autologous transplantation has no role in the routine management of patients with CLL.
Allogeneic SCT potentially offers a curative approach for patients with CLL, but its utility and timing is currently under considerable debate given the availability of multiple novel agents. Myeloablative conditioning prior to allogeneic SCT is associated with an unacceptably high transplant-related mortality (TRM) in excess of 30 percent and is not generally recommended.314,315,316 Nonmyeloablative conditioning regimens afford the opportunity to reduce TRM without impacting the graft-versus-leukemia (GVL) effect. Long-term disease-free survival is generally in the 30 to 45 percent range. However, nonrelapse mortality (NRM) is still in the 15 to 30 percent range, but decreasing with improvements in supportive care techniques. Moreover, chronic graft-versus-host disease still impacts long-term quality-of-life after nonmyeloablative allogeneic SCT in approximately 25 percent of survivors.317,318,319,320 Various patient-, disease-, and transplant-specific factors at the time of transplantation impact SCT outcomes.321 In particular, the number of prior treatments and the presence of a complex karyotype contribute to success and also toxicity observed after transplantation.322,323,324 Studies have identified that implementation of an effective quality management system and experience of the transplantation center are associated with a significant decrease in NRM.325,326,327 Patients who relapse after SCT can sometimes be effectively salvaged with the use of currently approved novel therapeutic agents. Given the availability of kinase inhibitors such as ibrutinib, we recommend that patients be offered therapy with these novel agents and nonmyeloablative SCT evaluation should be reserved for those failing ibrutinib unless no other cytoreductive therapy is available after receipt of this agent. Moreover, we recommend that patients who progress after treatment with kinase inhibitors be referred to a treatment center with established expertise for treating CLL, as this can significantly impact their therapeutic options and outcomes.325,326,327
Splenectomy is rarely used today given the availability of effective therapeutic agents to treat CLL. It can be an effective option for ameliorating refractory autoimmune hemolytic anemia and thrombocytopenia for which medical management has been unsuccessful.328 It can also be used to provide relief to patients with symptomatic splenomegaly secondary to refractory disease.329,330,331
Involved field radiation therapy is an extremely useful treatment modality for the management of locally symptomatic lymphadenopathy and isolated Richter transformation. Splenic irradiation can be used in patients with symptomatic splenomegaly, but its efficacy is limited and short-lived with significant and sometimes prolonged myelosuppression.332,333,334 Systemic radiation or extracorporeal photopheresis has no role in the routine management of patients with CLL.335,336,337
Patients with CLL will very rarely experience hyperviscosity-related signs and symptoms secondary to hyperleukocytosis. However, this modality can be used for the occasional patient who becomes symptomatic from hyperleukocytosis. When this is initiated, it should be performed in conjunction conventional therapy, to cytoreduce the CLL. Leukapheresis has been used in the past for patients with refractory disease as a therapeutic option, but it results in modest and transient benefits.338,339,340 With the advent of modern therapeutic options, the role of leukapheresis is limited in the management of routine CLL patients with hyperleukocytosis. While the BCR signaling agents can cause profound hyperleukocytosis in some patients, it virtually never results in symptoms mandating leukapheresis.