Chronic Lymphocytic Leukemia and Hairy-Cell Leukemia

Treatment

Treatment recommendations

Traditionally, the initial therapy for CLL has been chlorambucil(Drug information on chlorambucil) (Leukeran) with or without prednisone(Drug information on prednisone). However, accumulating data suggest that fludarabine has significantly greater activity than these agents. This agent produces higher overall and complete remission (CR) rates and provides a longer remission duration than chlorambucil. Newer data suggest that combination chemotherapy, particularly a nucleoside analog combined with an alkylating agent, produces higher response rates, and the addition of monoclonal antibodies to such regimens appears to increase CR rates.

The development of nonmyeloablative transplants has provided the possibility of allogeneic transplantation for CLL, where the median age of patients is near 70 years, but this new technique should only be performed in the context of a clinical trial. An effort should be made to enroll patients in clinical trials that offer them the possibility of receiving some of the new alternatives, which may eventually achieve the goal of curing CLL.

Early-stage disease

Since patients with early-stage CLL have a good long-term prognosis, and early therapy has not yet been shown to change the outcome of the disease, patients in the early stages should not be treated unless specific indications exist. Randomized trials comparing chlorambucil vs no therapy have documented no advantage for patients with early-stage CLL who received immediate therapy with chlorambucil. New alternatives for treatment of high-risk early-stage CLL (ZAP-70–positive, unmutated IgH status) are being investigated.

Conventional chemotherapy

Single-agent chemotherapy

Historically, the initial agent used for CLL has been chlorambucil, given as either 0.1 mg/kg daily or 20 to 40 mg/m² every 2 to 4 weeks. Therapy is continued until the signs or symptoms requiring therapy are controlled.

Chlorambucil is frequently combined with oral prednisone (30–100 mg/m²/day), although there is no clear evidence that the combination improves responses or overall survival over chlorambucil alone. Prednisone is of value, however, in the management of autoimmune cytopenias.

Cyclophosphamide(Drug information on cyclophosphamide) is an alternative to chlorambucil. The usual dose is 0.5 to 1 g/m² every 3 to 4 weeks alone or together with vincristine and steroids (eg, COP [cyclophosphamide, Oncovin (vincristine), and prednisone] regimen).

A 2009 study by Eichhorst et al randomized patients > 65 years of age to monotherapy with either fludarabine or chlorambucil. More responses, including CRs, were seen in patients randomized to fludarabine therapy. Despite this improvement in response, there was no difference in progression-free survival (fludarabine, 19 months; chlorambucil, 18 months). However, median survival appeared to favor the chlorambucil arm (fludarabine, 53 months; chlorambucil, not reached), although this result did not reach statistical significance (P = .07).

Combination chemotherapy

Various drug combinations have been used in CLL, mostly in patients with advanced-stage disease. Historically, the most frequently employed combinations have been COP and these three drugs plus doxorubicin(Drug information on doxorubicin) (CHOP). The dose of doxorubicin used is usually low (25 mg/m²). A higher dose of doxorubicin (50 mg/m²) has been employed in some regimens, such as CAP (cyclophosphamide, doxorubicin [Adriamycin], and prednisone).

Response rates have been 40% to 85% with these combinations. In randomized studies, COP was no better than chlorambucil plus prednisone. Although CHOP initially achieved better survival than COP (in patients with Binet stage C disease) or chlorambucil plus prednisone, longer follow-up has not confirmed this survival advantage.

TABLE 3Response criteria in CLL according to the IWCLL

Nucleoside analogs

Fludarabine, now frequently the drug of choice for treating CLL, has been demonstrated to be more effective than chlorambucil for the treatment of CLL in younger patients. When given to previously treated patients at a dose of 25 to 30 mg/m²/day for 5 days every 3 to 4 weeks, this nucleoside analog produced responses in 20% to 50% of patients, with 5% to 15% of patients achieving CR and an additional 5% to 20% achieving a "nodular partial response (PR)," ie, a CR but with the presence of lymphoid nodules in the bone marrow (Table 3). In previously untreated patients, the response rate was 63% to 80%, with 8% to 35% of patients achieving a CR.

The addition of prednisone or chlorambucil to fludarabine therapy did not improve the response rate and is associated with an increased incidence of opportunistic infections and other toxicities. A large randomized study comparing fludarabine, CAP, and CHOP demonstrated an increased response rate with fludarabine but no difference in survival. Randomized trials of fludarabine vs chlorambucil in previously untreated younger patients showed improvements in response rate (overall and CR), duration of response, and disease progression–free survival with fludarabine but no survival advantage.

Cladribine(Drug information on cladribine) (2-chlorodeoxyadenosine, 2-CdA) is also active in CLL when given at doses of 0.1 mg/kg/day (or 4 mg/m²/day) for 7 days. At therapeutic doses, this agent appears to be associated with more myelosuppression, particularly thrombocytopenia, than fludarabine.

The GCLLSG has presented a prospective randomized trial of fludarabine (F), cyclophosphamide (C), and rituximab(Drug information on rituximab) (Rituxan) (R) (FCR) vs FC for previously untreated patients with CLL. Overall response, complete response, and progression-free survival rates were improved with FCR. With additional follow-up, this is the first randomized trial to demonstrate a benefit in overall survival with the addition of rituximab to FC (FCR arm, 87%; FC arm, 82%; P = .01).

The third purine analog active against CLL is pentostatin (Nipent). Previously, toxicity limited its use as an antineoplastic agent. More recently, the recognition that safe use of this drug requires concomitant hydration and attention to renal function (it is both toxic to and cleared by the kidneys) has renewed interest in clinical evaluation with this agent. The group at Memorial Sloan-Kettering Cancer Center studied pentostatin combined with cyclophosphamide and demonstrated responses in > 70% of previously treated patients (including those whose disease is refractory to fludarabine) with acceptable toxicity.

Combination chemotherapy

To improve the frequency of response achieved with single-agent purine nucleoside analogs, a variety of combination regimens have been developed. Initial studies of fludarabine and cyclophosphamide (FC), pentostatin and cyclophosphamide (PC), cladribine and cyclophosphamide (CC), as well as fludarabine and rituximab (Rituxan, FR) suggested an increased frequency of overall response and CR rates but at the price of added myelotoxicity and infectious complications. Three prospective clinical trials for chemotherapy-naive patients with CLL have randomized patients to receive monotherapy with fludarabine or combination therapy with FC. All three studies reported an increased frequency of overall response and CR rates and a longer progression-free survival with FC combination therapy than with monotherapy. These studies included ECOG 2997, BMRC CLL 4 trial, and GCSG CLL 4 trials. Despite improvement in overall response, CR, and progression-free survival rates, none of these studies demonstrated a survival advantage for patients receiving combination therapy.

TABLE 4Comparison of sequential F→C→R, FCR, and FCR lite

Because of the success of two-drug combinations, several groups started exploring triple-drug therapy in CLL. Three published trials have evaluated the combination of fludarabine, cyclophosphamide, and rituximab as up-front treatment of CLL. These three studies used variations in dose and schedule, but all achieved excellent results in a cohort of primarily younger, healthier patients (Table 4). Despite the encouraging results in younger patients, these combinations are not recommended for most older patients (over age 65–70) with CLL.

Because of the concern about toxicity with these regimens, some groups looked at an alternative purine analog to maintain efficacy in a more tolerable regimen. Building on the positive results of combination pentostatin, cyclophosphamide, and rituximab (PCR) in previously treated patients, Kay et al reported on the use of this regimen in patients with untreated CLL. Responses occurred in 91% of patients, with 63% achieving a CR or a nodular response. More important, a subset analysis demonstrated that PCR treatment was equally effective in patients over the age of 70 and in younger individuals.

Monoclonal antibody–targeted therapy

Monoclonal antibodies have been used in patients with CLL to exploit antibody-mediated cytotoxicity. Alemtuzumab(Drug information on alemtuzumab) (Campath) has been approved by the US Food and Drug Administration (FDA) for the treatment of refractory CLL. In a pivotal trial in patients with fludarabine-refractory disease, alemtuzumab resulted in an overall response rate of 33%.

Two other monoclonal antibodies that may have potent activity in CLL are ofatumumab (Arzerra) and GA101 (RO5072759).

Ofatumumab is an anti-CD20 antibody that differs from rituximab in that it binds to the "small loop epitope" of CD20. Recent studies of ofatumumab in patients with CLL who were refractory to fludarabine or alemtuzumab (or were inappropriate candidates for alemtuzumab because of bulky adenopathy) demonstrated an impressive response frequency (51% and 44% overall response rates, respectively). This trial led to the approval of ofatumumab by the FDA for selected patients with CLL. Ofatumumab was recently combined with fludarabine and cyclophosphamide and showed high activity in patients with previously untreated CLL. In 61 patients assessable for response (31 at the 500-mg dose level), overall response and complete response rates were 77% and 32%, respectively. At the 1,000-mg dose level, overall response and complete response rates were 73% and 50%.

R05072759 is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials. In a phase I study in relapsed and refractory CLL, of 13 evaluable patients, 62% had a response, and the response duration ranged from 3.5 to 8 months.

Rituximab also has been investigated and is active both as a single agent and in combination with chemotherapy. Because rituximab has demonstrated improvement in survival when given with chemotherapy, it is being used in most treatment regimens for patients with CLL.

The combination of alemtuzumab and rituximab has been evaluated in patients with relapsed or refractory lymphoid malignancies. Alemtuzumab was given twice weekly at 30 mg IV for 4 weeks. Rituximab (375 mg/m²) was given concurrently weekly for the 4 weeks. Responses were reported for 48 patients: 32 with CLL, 9 with CLL/PLL (prolymphocytic leukemia), 1 with PLL, 4 with mantle cell lymphoma, and 2 with Richter's transformation. The overall response rate was 52%; CR was noted in 8%, nodular PR in 4%, and PR in 40% of treated patients. Toxicities included infusion-related reactions. Infections occurred in 52% of patients, with cytomegalovirus reactivation occurring in 27% of patients. Overall, this was a well-tolerated combination for relapsed patients with CLL. Recently, early results of a randomized study of FCR vs FCR-alemtuzumab were reported in 165 patients. There was excessive toxicity in the alemtuzumab arm leading to premature cessation of the study.

Lumiliximab is an anti-CD23 monoclonal antibody. A phase I study in patients with relapsed or refractory CLL demonstrated an acceptable toxicity profile but revealed no responses. Recently, the results of a phase I/II dose-escalation study of lumiliximab added to FCR in previously untreated CLL patients were reported. Two different doses of lumiliximab were combined with FCR for 6 cycles, and the overall response rate was 65%, with 52% of patients achieving a CR.

Other agents

In March 2008, the FDA approved bendamustine (Treanda) for CLL. In a randomized, multicenter study of 319 treatment-naive patients with CLL, those treated with bendamustine had a significantly higher overall response than those treated with chlorambucil (68% vs 31%; P < .0001). In the bendamustine group, 8% had a CR, compared with less than 1% of the chlorambucil group. In addition, patients who received bendamustine had a longer progression-free survival than those who received chlorambucil (21.6 months vs 3 months, P < .0001). Reportedly, the most common adverse events in the trial were myelosuppression, fever, nausea, and vomiting.

Recently, bendamustine plus rituximab was evaluated as initial therapy for patients with CLL. In a group of 117 patients (median age, 64 years), the overall response rate was 91%, with 33% achieving a CR. First-line use of this combination continues to be investigated in patients with advanced CLL.

In a phase I study, a pharmacokinetically derived hybrid schedule of flavopiridol showed promising activity in CLL, even in patients with high-risk features. Recently, the results of a phase II study of this hybrid schedule in relapsed and refractory CLL were published. A total of 64 patients (median age, 60 years; median prior therapies, four) were enrolled. In all, 53% of patients achieved a PR or CR, and the median progression-free-survival time among responders was 10 to 12 months across all cytogenetic risk groups.

Immunomodulatory drugs

Lenalidomide (Revlimid) has recently been investigated and shown to be active in patients with relapsed or refractory CLL. It is reported to modulate an immune effector cell response through activation of the T and natural killer cells and to directly induce apoptosis in tumor cells. Initial studies by Chanan-Khan et al in patients with relapsed or refractory CLL demonstrated an overall response rate of 47% (CR in 9%) in patients with relapsed or refractory CLL. Lenalidomide was administered orally at 25 mg on days 1 through 21 of a 28-day cycle. Myelosuppression led to a dose reduction to 10 mg.

Ferrajoli et al also evaluated lenalidomide in patients with relapsed or refractory CLL utilizing a low-dose daily schedule starting at 10 mg on a 28-day cycle (with a 5-mg incremental increase to a maximum of 25 mg daily if no significant toxicities were observed). Most patients were treated with 5 or 10 mg daily. Reponses were obtained in 14 of 44 evaluable patients (3 CRs, 1 with no response, and 10 PRs). Eleven patients had disease improvement without fulfilling the criteria for PR and were able to continue on treatment. Notable toxicities with this agent include myelosuppression, tumor lysis syndrome, and tumor flare.

Lenalidomide has also been evaluated in patients with previously untreated CLL. Chen et al evaluated the drug in 25 patients with CLL starting at 2.5 mg (on days 1–21) with a dose escalation of 5 mg with each cycle. All patients achieved stable disease or better, including 11 PRs and 6 cases of stable disease. Ferrajoli et al also reported the use of low-dose lenalidomide as initial treatment of "elderly" patients with CLL (median age, 72 years). All patients received continuous lenalidomide, starting at 5 mg for the first 56 days. Thereafter, the drug could be titrated up by 5-mg increments every 28 days to a maximum of 25 mg. An overall response of 65% was achieved with the median number of cycles (27 cycles), and more than half of the patients still remain on therapy. The median dose was 5 mg.

Ferrajoli et al combined lenalidomide with rituximab for relapsed and refractory CLL patients. They achieved an overall response rate of 68%, with responses seen across all prognostic groups, including patients with 17p deletion. Not only did the combination appear to be more active than did single-agent lenalidomide, but by acting as a "debulking" agent, rituximab reduced the toxicity associated with lenalidomide therapy (ie, flare reactions, tumor lysis).

Novel Agents

A variety of new targeted agents are being explored. The Bruton tyrosine kinase (BTK) is a Tec family kinase that is required for B-cell activation mediated by BCR signalling. Bruton's tyrosine kinase inhibitor PCI-32765 appears to be an active agent that in CLL cells may promote apoptosis, inhibit ERK1/AKT phosphorylation, NFKB DNA binding, CpG mediated proliferation, and inhibit CLL migration and adhesion. Byrd et al evaluated a small cohort of patients who received this oral agent and the overall response in treatment-naive patients was 67% and in relapsed/refractory patients 48%.

The phosphatidylinositol 3-kinase (PI3K) pathway appears to also be important in BCR signalling. There are several inhibitors being evaluated. One inhibitor, CAL-101, which is a delta-specific PI3K inhibitor, has been evaluated in a phase I study in heavily pretreated patients with CLL who received a median of 8 cycles of CAL-101. In a report presented at the 2011 meeting of ASCO, CAL-101 reduced lymphadenopathy by 50% or more in 80% of patients, and the overall intention-to-treat rate by IWCLL 2008 criteria was 26%. At the time of study presentation, median duration of response and PFS had not been reached (> 11 months), with 46% of patients continuing on treatment.

Achieving minimal residual disease-free status

The current formal criteria to assess response are based on physical examination, blood counts, and microscopic evaluation of bone marrow (Table 3). Minimal residual disease (MRD) can be evaluated by more sensitive methods such as polymerase chain reaction (PCR) for the IgV_H gene or four-color flow cytometry. In a study of 91 previously treated patients who received alemtuzumab (30 mg thrice weekly for up to 16 weeks), 36% achieved CR, and the overall response rate was 54%. Of the 91 patients, 18 achieved MRD-free status by flow-cytometry evaluation of their bone marrow. Survival was significantly longer for patients who achieved MRD-free status. Overall survival for the 18 patients with MRD-free remission was 84% at 5 years.

Another study demonstrated the utility of an MRD-negative state. Lamanna et al found that patients who achieved an MRD-negative complete response had a superior response duration when compared with those who were in CR but MRD-positive (P = .007).

Stem cell transplantation

Both allogeneic and autologous stem-cell transplantations (SCTs) have been tested in patients with CLL.

Allogeneic SCT is a viable option for younger patients with CLL, particularly if they have not responded to alkylating agents and/or nucleoside analogs and are in an advanced stage of disease. The series reported to date, including a majority of patients with advanced refractory disease, has documented a CR rate in excess of 70%. The response is sustained in most patients, although reported follow-up is typically short. SCT using nonablative conditioning regimens has produced encouraging results and should be considered in the setting of a clinical trial, particularly for patients > 60 years.

Since the median age of patients with CLL is usually higher than the age considered acceptable for allogeneic SCT, autologous transplants using purged marrow have also been investigated. In general, results have been disappointing, with the best results seen in patients with responsive disease and low tumor burdens—a group that might have fared well without a transplant.

Splenectomy

Splenectomy may be beneficial for cytopenias caused by hypersplenism (particularly in patients without significant lymphadenopathy) or for palliation when splenomegaly is symptomatic and refractory to chemotherapy. Cytopenias frequently respond to splenectomy. Perioperative mortality varies widely and is largely related to the experience of the surgeon in performing splenectomy in these patients. In experienced hands, splenectomy can be performed with minimal mortality, even in patients with end-stage disease.

Complications

Infections

Patients with CLL are prone to multiple infections, and infectious complications are a leading cause of death in patients with CLL. Hypogammaglobulinemia plays a central role in the predisposition of patients to this problem, and prophylactic IV administration of immunoglobulin preparations may reduce the incidence of infections. Cytotoxic therapy further weakens the immune system and may increase the risk of opportunistic infections.

Autoimmune cytopenias

These frequently complicate CLL and may be precipitated or aggravated by therapy (eg, fludarabine) for CLL. Autoimmune hemolytic anemia can be treated successfully with prednisone in the majority of patients. Combinations of cyclophosphamide with rituximab are beneficial in cases refractory to prednisone, splenectomy, or cyclosporine. Similar approaches may be useful for autoimmune thrombocytopenia. In a study from The University of Texas MD Anderson Cancer Center, 31 patients with CLL and autoimmune anemia or thrombocytopenia received cyclosporine (300 mg/day). Sixty-three percent of patients responded, with a median duration of response of 10 months. No grade 3/4 toxicity was seen.

Pure red cell aplasia and the less commonly amegakaryocytic thrombocytopenia are infrequent complications of CLL, which are mediated by immune mechanisms. Therapy with cyclosporine (3 to 6 mg/kg/day) is frequently effective.

Transformation

Diffuse large B-cell lymphoma

CLL transforms into DLBCL in 3% to 10% of patients and rarely to other entities, such as Hodgkin lymphoma. This phenomenon, known as Richter's transformation, has an aggressive presentation with fever and other B symptoms and progressive lymphadenopathy. Extranodal involvement occurs in approximately 40% of patients. Paraproteinemia, hypercalcemia, and a sharp rise in serum LDH levels can be frequently seen.

The prognosis of patients whose disease progresses to DLBCL is variable and depends in part on the degree of prior treatment used for the underlying CLL. In treatment-naive patients with DLBCL, standard therapy with R-CHOP may offer long-term control of the transformed component. In patients who have had significant prior therapy, the disease is often refractory, and combination chemotherapy including SCT is frequently ineffective.

PLL

More rarely, CLL can transform into PLL, characterized by a > 55% increase in prolymphocytes. The transformation is frequently accompanied by progression of splenomegaly, cytopenias, and refractoriness to therapy.

Other diseases Anecdotal cases of CLL evolving into acute lymphocytic leukemia, myeloma, low-grade lymphoma, and Hodgkin lymphoma have been reported. The rarity of these reports makes a true causal connection less likely.