What Is the Optimal Initial Treatment for Chronic Lymphocytic Leukemia?

December 1, 2007

For decades, initial therapy for chronic lymphocytic leukemia (CLL) consisted of alkylators such as chlorambucil (Leukeran). The introduction of nucleoside analogs such as fludarabine and monoclonal antibodies such as rituximab (Rituxan) markedly changed the initial therapy of CLL, particularly in the United States. Fludarabine and combination regimens such as fludarabine/cyclophosphamide (FC) have achieved higher complete response (CR) rates and progression-free survival (PFS) than chlorambucil in previously untreated CLL, but long-term overall survival has not improved, due to concurrent improvement in salvage therapy of relapsed CLL patients. Upfront chemoimmunotherapy regimens such as fludarabine/rituximab (FR) and fludarabine/cyclophosphamide/rituximab (FCR) have similarly improved CR rates and PFS in previously untreated CLL patients, but it is unclear whether overall survival is improved. Advances in cytogenetic analysis and other biologic prognostic factors have greatly enhanced clinicians' ability to risk-stratify newly diagnosed CLL patients, and knowledge of such prognostic factors is necessary to properly interpret results of clinical treatment studies. The choice of initial therapy for an individual patient should depend upon the patient's age and medical condition, cytogenetic and other prognostic factors, and whether the goal of therapy is maximization of CR and PFS or palliation of symptoms with minimal toxicity.

For decades, initial therapy for chronic lymphocytic leukemia (CLL) consisted of alkylators such as chlorambucil (Leukeran). The introduction of nucleoside analogs such as fludarabine and monoclonal antibodies such as rituximab (Rituxan) markedly changed the initial therapy of CLL, particularly in the United States. Fludarabine and combination regimens such as fludarabine/cyclophosphamide (FC) have achieved higher complete response (CR) rates and progression-free survival (PFS) than chlorambucil in previously untreated CLL, but long-term overall survival has not improved, due to concurrent improvement in salvage therapy of relapsed CLL patients. Upfront chemoimmunotherapy regimens such as fludarabine/rituximab (FR) and fludarabine/cyclophosphamide/rituximab (FCR) have similarly improved CR rates and PFS in previously untreated CLL patients, but it is unclear whether overall survival is improved. Advances in cytogenetic analysis and other biologic prognostic factors have greatly enhanced clinicians' ability to risk-stratify newly diagnosed CLL patients, and knowledge of such prognostic factors is necessary to properly interpret results of clinical treatment studies. The choice of initial therapy for an individual patient should depend upon the patient's age and medical condition, cytogenetic and other prognostic factors, and whether the goal of therapy is maximization of CR and PFS or palliation of symptoms with minimal toxicity.

The past decade has seen significant advances in our understanding of the effects of cytogenetic abnormalities and other biologic factors on the natural history of chronic lymphocytic leukemia (CLL). Deletion of 17p13 and 11q22-corresponding to loss of the p53 and ataxia telengiectasia mutated (ATM) tumor-suppressor genes, respectively-is associated with the need for earlier therapy and a poor long-term prognosis.[1,2] The mutational status of the immunoglobulin heavy chain variable region (IgVH) also predicts time to treatment and long-term survival.[3-6] Patients whose CLL exhibits unmutated (germline) IgVH have a markedly inferior prognosis to that of patients with mutated IgVH. Expression of CD38 and zeta-associated protein (ZAP)-70 correlates with unmutated IgVH, the need for earlier therapy, and inferior long-term survival.[3,5-9]

These invaluable prognostic tools help clinicians predict the biologic behavior of a patient's CLL over time. Risk-stratification provides critical information on the percentage of high-risk patients in a clinical trial and is essential for proper interpretation of the results of clinical treatment studies in CLL. However, the use of these prognostic factors in selecting the optimal initial therapy for the individual CLL patient is less clear. While the impact of adverse cytogenetic abnormalities on response to therapy has been documented,[1,10] the effect of IgVH mutational status, CD38, and ZAP-70 on response to treatment is less clear. This review will pay particular attention to the efficacy of the various upfront treatment options in patients with poor-risk features such as del(17p13) and del(11q22).

When to Initiate Treatment

The National Cancer Institute (NCI) Working Group on CLL established guidelines for initiating treatment in 1996.[11] These indications included autoimmue and nonautoimmune cytopenias, bulky or symptomatic lymphadenopathy or organomegaly, disease-related B-symptoms or fatigue, and rapid lymphocyte doubling time. However, CLL is often diagnosed by routine complete blood count examination, and most patients are asymptomatic with a normal hemoglobin and platelet count at diagnosis. Such asymptomatic patients should be followed expectantly and should receive treatment only upon disease progression.

Several studies in asymptomatic patients failed to show a benefit in overall survival (OS) with early chlorambucil (Leukeran) therapy.[12] However, chemoimmunotherapy regimens combining monoclonal antibody therapy with purine analogs achieve much higher complete response (CR) rates than chlorambucil.[13-15] Thus, early treatment needs to be reconsidered, particularly in patients with high-risk biologic or genetic markers predicting a poor long-term prognosis.

Ongoing efforts by the German CLL Study Group (GCLLSG) and several US cooperative groups will address whether early intervention with chemoimmunotherapy can improve long-term survival in high-risk CLL. High-risk, previously untreated CLL patients in the United States who do not meet NCI 1996 treatment criteria but wish to be considered for early therapy should be referred to the Intergroup study randomizing such patients to observation or early chemoimmunotherapy.

Cytotoxic Chemotherapy

Alkylating Agents

Alkylating agents served as initial therapy for CLL for decades, and chlorambucil is still given as first-line therapy, particularly for older patients and patients who cannot tolerate purine analogs.[16] Chlorambucil is typically given as a single pulse dose of 40 mg/m2 orally every 28 days. The use of concurrent steroids did not improve long-term survival; thus, chlorambucil is typically administered as a single agent.

While continuous daily dosing attained superior results, higher doses resulted in increased myelosuppression and frequent dose reductions, particularly in older or frailer patients. Thus, less-intensive pulse dosing should generally be used. Its primary advantages are a well established toxicity profile and low cost, whereas its disadvantages are a low CR rate, even in previously untreated patients, and the risk of myelodysplasia with extended use.

Fludarabine

The introduction of purine analogs in the 1980s dramatically altered the treatment of CLL.[17-21] Fludarabine was approved for alkylator-refractory CLL, but several large, prospective, randomized studies demonstrating improved response rates and progression-free survival (PFS) established fludarabine as standard initial therapy for CLL in the United States.[22-24] These studies are summarized in Table 1.

A multicenter European study randomized 196 evaluable patients to fludarabine or the alkylator-based regimen CAP (cyclophosphamide, doxorubicin [Adriamycin], prednisone). The overall response (OR) rate favored fludarabine (60% vs 44%) in both relapsed (n = 96, 48% vs 27%) and previously untreated (n = 100, 71% vs 60%) patients, although the difference in the untreated group was not statistically significant. Fludarabine achieved a longer median duration of response and a tendency toward improved OS in previously untreated patients.[22]

A randomized, multicenter study confirmed these findings in 509 previously untreated CLL patients. Patients were randomized to receive fludarabine at 25 mg/m2 IV daily for 5 days every 28 days, chlorambucil at 40 mg/m2 orally every 28 days, or fludarabine at 20 mg/m2 IV daily for 5 days and chlorambucil at 20 mg/m2 orally every 28 days, for up to 12 cycles. Patients who failed to respond or relapsed were allowed to cross over to the other arm. The combination arm was closed due to excessive toxicity. Fludarabine achieved superior CR, OR, median duration of remission, and median PFS (20%, 63%, 25 months, 20 months) than chlorambucil (4%, 37%, 14 months, 14 months). However, due to the crossover design, no statistically significant OS difference (66 vs 56 months) was observed.[23]

A multicenter French study randomized 938 patients with previously untreated Binet stage B or C CLL to fludarabine, CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone), or CAP. While fludarabine achieved better response rates than CAP, OS was identical (67–70 months) in all three groups.[24]

Most recently, the GCLLSG randomized 180 patients over age 65 to standard IV fludarabine for up to 6 cycles or chlorambucil at 0.4 to 0.8 mg/kg orally on days 1 and 15 every 28 days for up to 12 cycles. Patients in the fludarabine arm experienced more hematologic toxicity (63% vs 39%) but had a similar infection rate (5%) and better quality of life than patients treated with chlorambucil. Fludarabine induced higher CR rates (13% vs 0%) and OR rates (85% vs 68%), but there was no difference in PFS or OS. Thus, while single-agent fludarabine achieves superior response rates and PFS than alkylator-based regimens, OS is unchanged, due to the ability to salvage alkylator failures (Table 1).

Combining Fludarabine and Alkylator Therapy

Studies of the combination of fludarabine and cyclophosphamide (FC) in relapsed CLL have demonstrated promising clinical activity and acceptable toxicity.[20,21] Based on these results, the GCLLSG randomized 375 previously untreated CLL patients (age ≤ 65 years) to standard fludarabine or FC (fludarabine at 30 mg/m2 IV and cyclophosphamide at 250 mg/m2 IV daily for 3 days) every 28 days for 6 cycles.[25] The OR rate (94% vs 83%), CR rate (24% vs 7%), median PFS (48 vs 20 months), and treatment-free survival (37 vs 25 months) favored FC, but no difference in OS was observed. FC was superior to fludarabine in IgVH unmutated patients (median PFS = 52 vs 20 months) and del(11q22) patients (median PFS = 36 vs 16 months). However, patients with del(17p13) did poorly regardless of treatment arm, with a median PFS and OS of 11 and 16 months, respectively.[26] Thus, FC mitigated the poor prognosis associated with unmutated IgVH status and del(11q22), but not of del(17p13).

The US Eastern Cooperative Oncology Group (EGOG) randomized 278 patients to single-agent fludarabine or FC.[27] FC consisted of fludarabine at 20 mg/m2 IV on days 1 through 5 and cyclophosphamide at 600 mg/m2 IV on day 1 every 28 days for up to 6 cycles. FC achieved a superior OR (74% vs 59%), CR (23% vs 5%), and median PFS (32 vs 19 months), but no OS advantage was seen. Information on genetic and molecular prognostic factors was available on 235 patients. CR and OR were not affected by cytogenetics, IgVH mutational status, CD38, ZAP-70, or p53 mutational status. There was no statistically significant difference in median PFS between IgVH-mutated (29.6 months) and -unmutated patients (20.8 months), and FC was superior to fludarabine in both groups. However, the presence of del(17p13) or del(11q22) negatively affected PFS, with hazard ratios (HRs) of 3.43 and 1.90, respectively. This study suggested that cytogenetics, but not IgVH mutational or ZAP-70 status, predicts the clinical outcome of fludarabine-based therapy.[28]

Finally, the UK CLL4 study randomized 777 patients to oral chlorambucil, fludarabine, or FC.[29] Patients randomized to FC enjoyed a superior OR, CR, and 5-year PFS (94%, 38%, 36%, respectively), compared to patients who received chlorambucil (72%, 7%, 10%) or fludarabine (80%, 15%, 10%). FC was superior in all age groups, including patients over 70 years old. However, patients with del(17p13) had markedly inferior CR/nodular partial response (nPR) and OR rates compared to patients without loss of 17p13, whether therapy was fludarabine (22% and 44% vs 38% and 79%) or FC (25% and 38% vs 65% and 97%).

Thus, FC achieves superior response rates and PFS compared to single-agent fludarabine (Table 1). However, no OS advantage for upfront FC has been observed to date. Furthermore, patients with del(17p13), which occurs in 5% of CLL patients at diagnosis, do poorly even with FC. Therefore, clinical research to identify effective initial therapy regimens in this cytogenetic group remains a priority.

Chemoimmunotherapy

Single-Agent Rituximab for Previously Untreated CLL

The monoclonal anti-CD20 antibody rituximab (Rituxan) has limited activity when given weekly as a single agent in CLL (OR = 13%) but is more effective when given as initial therapy. The OR rate was 51% (CR = 4%) in 44 previously untreated patients with CLL or small lymphocytic lymphoma (SLL) who received four weekly doses of rituximab (375 mg/m2). Additional 4-week courses of rituximab given every 6 months for up to 4 cycles to 28 patients with stable or responsive disease modestly increased OR (58%) and CR (9%). Median PFS was 19 months, similar to that achieved by single-agent fludarabine in the upfront setting.[30]

The M.D. Anderson Cancer Center (MDACC) administered eight weekly doses of rituximab (375 mg/m2) to 31 untreated, early-stage, asymptomatic CLL patients (21 evaluable) with beta2-microglobulin ≥ 2.0 mg/dL who otherwise did not require therapy. Toxicity was minimal except for infusion toxicity, and OR was 90% (CR = 19%, nPR = 19%).[31] While the activity of single-agent rituximab as initial therapy for poor-risk patients is unknown, thrice-weekly rituximab failed to achieve a single response in relapsed CLL patients with del(17p13), suggesting that single-agent rituximab may be similarly inactive as upfront therapy in high-risk CLL patients.[32]

Fludarabine and Rituximab

 

Cytotoxic chemotherapy
• Alkylating agents
• Fludarabine
• Alkylator + fludarabine

Chemoimmunotherapy
• Single-agent rituximab
• Fludarabine + rituximab
• Fludarabine/rituximab/
cyclophosphamide
• Fludarabine/rituximab/
cyclophosphamide/alemtuzumab
• Fludarabine + anthracycline
• Pentostatin/cyclophosphamide/
rituximab
• Single-agent alemtuzumab
• Fludarabine induction + alemtuzumab consolidation

Although rituximab demonstrated clinical activity as a single agent in CLL, the low CR rates indicated that combining rituximab with cytotoxic drugs is necessary if rituxmab is to have an impact on long-term survival in CLL. The Cancer and Leukemia Group B (CALGB) 9712 study randomized 104 previously untreated CLL patients to sequential or concurrent FR therapy.[13] Patients received fludarabine at 25 mg/m2 on days 1 through 5 every 28 days for 6 cycles, with or without concurrent rituximab at 375 mg/m2 on day 1 of cycles 1 through 6 and day 4 of cycle 1. All patients received rituximab at 375 mg/m2 weekly for four doses beginning 2 months after completion of fludarabine. Superior CR (47% vs 28%) and OR (90% vs 77%) rates were observed in the concurrent FR arm. While patients with high-risk disease-defined as having unmutated IgVH, del(11q22) or del(17p13)-were as likely to achieve CR as patients without high-risk features, they relapsed faster and had an inferior median progression-free survival (PFS = 32 vs 43 months).[33]

A retrospective comparison to 179 previously untreated patients who received single-agent fludarabine in the CALGB 9011 study showed that patients who received FR attained superior OR (84% vs 63%), CR (38% vs 20%), 2-year PFS (67% vs 45%), and 2-year OS (93% vs 81%).[34] These results were confirmed by a multicenter European phase II study in which 31 evaluable CLL patients received fludarabine at 25 mg/m2 on days 1 through 5 every 4 weeks for 6 cycles and rituximab at 375 mg/m2 on day 1 of cycles 3 through 6. The OR rate was similar in previously treated (91%) and untreated patients (85%), and the CR rate was actually higher in relapsed patients (45%) than in previously untreated patients (25%).[35]

Fludarabine, Cyclophosphamide, and Rituximab

The chemoimmunotherapy regimen that has demonstrated the best phase II results as initial therapy of CLL is the combination of fludarabine, cyclophosphamide, and rituximab (FCR). Fludarabine at 25 mg/m2 and cyclophosphamide at 250 mg/m2 on days 2 through 4 of cycle 1 and days 1 through 3 of cycles 2 through 6, plus rituximab at 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, were given every 28 days for 6 cycles to 300 previously untreated CLL patients. The OR rate was 94%, with a 72% CR rate, 4-year relapse free survival (RFS) rate of 77%, and 4-year OS rate of 83%.[14] The ability to achieve ≤ 1% residual CLL by two-color flow cytometry significantly affected RFS and OS. Only 5 (4%) of 138 patients whose post-FCR bone marrow flow cytometry had ≤ 1% residual CLL developed relapse, in contrast to 17 (27%) of 62 patients with > 1% residual CLL. The impact of poor prognostic factors on response to FCR was not reported.

Fludarabine, Cyclophosphamide, Rituximab, and Alemtuzumab

MDACC investigators added the anti-CD52 antibody alemtuzumab (Campath) to FCR, to determine whether efficacy could be improved. This CFAR regimen consists of fludarabine at 25 mg/m2 on days 2 through 4, cyclophosphamide at 250 mg/m2 on days 2 through 4, rituximab at 375 mg/m2 (cycle 1) or 500 mg/m2 (cycles 2–6) on day 2, and alemtuzumab at 30 mg IV on days 1, 3, and 5 every 28 days for up to 6 cycles.[36] Patients receive pegfilgrastim (Neulasta), as well as prophylaxis for Pneumocystis carinii pneumonia and cytomegalovirus.

A phase II study in 78 relapsed CLL patients attained an OR of 65% (CR = 24%); median PFS was 27 months for the 19 CR patients and 10 months for the 32 PR patients. Hematologic and infectious toxicity was acceptable, although cytomegalovirus reactivation was common without valganciclovir (Valcyte) prophylaxis. Given these promising results, the MDACC is currently conducting a phase II study of CFAR in previously untreated patients.

Fludarabine With an Anthracycline

The Spanish multicenter study group Grupo de Estudios de Linfomas de Catalua y Baleares (GELCAB) administered fludarabine, cyclophosphamide, and mitoxantrone (FCM) to 64 patients with previously untreated CLL.[37] The OR rate was 88% (CR = 47%, nPR = 22%), and 24% of patients were negative for minimal residual disease (MRD); 55% of patients remained in remission at 3 years.

Thirteen previously untreated CLL patients received FCM and rituximab, followed by autologous stem-cell transplantation.[38] Patients received fludarabine at 25 mg/m2 on days 1 through 3, cyclophosphamide at 200 mg/m2 on days 1 through 3, and mitoxantrone at 10 mg/m2 on day 1 every 4 weeks for 4 to 6 cycles, followed by rituximab at 375 mg/m2 weekly for four doses. OR was 100% (CR = 77%), and four patients (31%) became MRD-negative. The ability of this regimen to induce complete hematologic and molecular remissions is intriguing, but the durability of these responses remains to be seen.

Pentostatin, Cyclophosphamide, and Rituximab

While FR and FCR achieved excellent results in this setting, the median age of patients in these studies was 63 and 58 years, respectively, in contrast to a median age of 72 at first therapy in the Surveillance, Epidemiology and End Results (SEER) database.

On the other hand, a phase II study of pentostatin, cyclophosphamide, and rituximab (PCR) in 64 previously untreated CLL patients included 18 aged ≥ 70 years. The results indicated that older patients tolerate and respond to PCR.[15,39] Median age was 62.5 years, and 71% of patients had unmutated IgVH. Patients received pentostatin (Nipent) at 2 mg/m2 on day 1, cyclophosphamide at 600 mg/m2 on day 1, and rituximab at 375 mg/m2 on day 1 (100 mg/m2 on day 1 and 375 mg/m2 on days 3 and 5 of cycle 1) every 21 days for up to 6 cycles. Granulocyte colony-stimulating factor (filgrastim, Neupogen) was given beginning on day 3. PCR was well tolerated. OR, CR, and nPR rates were 91%, 41%, and 22%, respectively. Median PFS was 33 months. The ability to achieve CR/nPR was independent of high-risk genetic or biologic factors, with the exception that all three patients with del(17p13) failed to achieve CR or nPR.

Patients aged ≥ 70 and < 70 tolerated PCR equally well, although older patients were more likely to require a dose delay > 1 week (28% vs 7%, P = .03).[39] Grade 3/4 hematologic (61% vs 48%), infectious (6% vs 11%), and nonhematologic toxicities (22% vs 28%) were similar in both age groups. There was no difference in OR (83% vs 93%), CR (39% vs 41%), and event-free survival (P = .98) between older and younger patients.

Thus, PCR is a therapeutic option for previously untreated CLL patients ≥ 70 years old, who constitute more than half of patients requiring initial CLL therapy. Prophylactic antibiotics and filgrastim should be used, as in this study. Table 2 summarizes the major clinical studies of chemoimmunotherapy regimens that have included rituximab.

Single-Agent Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody that targets CD52, which is expressed on all CLL cells and indolent B–non-Hodgkin's lymphoma cells.[40-43] However, the ubiquitous expression of CD52 on normal lymphocytes and monocytes predicted the infusion, hematologic, and infectious complications of alemtuzumab. Several clinical studies established a role for alemtuzumab in the treatment of relapsed CLL.[44-47] These studies established a dose of 30 mg IV three times per week for 4 to 12 weeks, and stepped-up dosing was necessary to diminish infusion toxicity and make drug administration tolerable and feasible.

Alemtuzumab has a unique ability to eradicate MRD and improve long-term survival. Of 91 relapsed CLL patients who received up to 16 weeks of IV alemtuzumab (median = 9 weeks), 18 achieved a flow-negative bone marrow.[48] Median treatment-free survival was significantly longer (not reached) in MRD-negative patients than in those with an MRD-positive CR (20 months) or MRD-positive PR (13 months). Five-year OS was 84% for MRD-negative patients.

Alemtuzumab is one of the few agents active in CLL patients with high-risk features such as del(17p13). A total of 6 (40%) of 15 patients with del(17p13) and 3 (27%) of 11 patients with del(11q22) responded to three-times-weekly IV alemtuzumab.[32] In the GCLLSG CLL2H study of subcutaneous alemtuzumab, 7 (54%) of 13 patients with del(17p13), 5 (38%) of 13 patients with del(11q22), and 14 (52%) of 27 patients with unmutated IgVH responded to therapy, compared to 16 (36%) of 44 patients in the entire study.[49] However, infusion, hematologic, and infectious toxicities have been observed with both intravenous and subcutaneous alemtuzumab in relapsed CLL.

Alemtuzumab as Initial Therapy of CLL-Investigators have examined the use of alemtuzumab as initial therapy for CLL, with hopes of reducing the hematologic and infectious complications seen in heavily treated relapsed patients. In a phase II study, investigators gave subcutaneous alemtuzumab, 30 mg three times weekly for up to 18 weeks, to 41 previously untreated CLL patients. Except for transient grade 1/2 fever, first-dose reactions were minimal. OR was 81%, and 87% of the 38 patients who received at least 2 weeks of therapy responded.[50] Alemtuzumab effectively cleared peripheral blood (CR = 95%), bone marrow (CR + nPR = 66%) and nodal disease (OR = 87%, CR = 29%). Some patients who achieved CR in the marrow required 18 weeks of therapy to do so, suggesting that prolonged administration was necessary to clear disease. Median time to treatment failure had not been reached at the time of the study report (18+ months).

Based on these promising results, the CAM307 study prospectively randomized 297 previously untreated CLL patients to chlorambucil, 40 mg/m2 orally every 4 weeks for 12 cycles, or alemtuzumab, 30 mg IV three times weekly for up to 12 weeks.[51] Patients on the alemtuzumab arm received prophylaxis for P carinii pneumonia and varicella-zoster virus. Alemtuzumab therapy was well tolerated, with patients receiving a median of 11.7 weeks of therapy, but 52% of patients developed cytomegalovirus reactivation. In contrast, patients in the chlorambucil arm received a median of only 24.4 weeks of therapy.

Alemtuzumab achieved superior OR (83% vs 55%), CR (22% vs 2%), PFS (HR = 0.58), and time to alternative therapy (23.3 vs 14.7 months). Median PFS of del(11q22) patients (n = 54) was identical (8.5 months) in both treatment arms. Median PFS of del(17p13) patients (n = 21) was superior in the alemtuzumab arm (10.7 vs 2.2 months) but still remained disappointing. The results of this study are in the process of being published.

Fludarabine Induction Followed by Alemtuzumab Consolidation

Several studies showed that alemtuzumab consolidation therapy can improve response and eradicate MRD after fludarabine-based induction therapy. Investigators at MDACC gave alemtuzumab, 10 or 30 mg IV three times weekly for 4 weeks, to 58 patients with residual CLL after their last therapy.[52] The OR rate was 53%, and 65% of patients receiving the 30-mg dose responded, compared to 39% of patients given 10 mg. Of 29 patients, 11 (38%) achieved an MRD-negative marrow. Time to progression was significantly longer in patients who became MRD-negative.

A GCLLSG study randomizing patients with persistent CLL after fludarabine or FC to observation (n = 10) or alemtuzumab at 30 mg IV three times weekly for up to 12 weeks (n = 11) was discontinued early due to toxicity in the alemtuzumab arm; 6 of 11 patients developed grade 4 hematologic toxicity, and 7 patients developed grade 3/4 infections, including 4 cases of cytomegalovirus.[53] However, 5 of 6 patients achieved MRD-negative bone marrow after alemtuzumab. With a median follow-up of 48 months, median PFS favored alemtuzumab therapy (not reached vs 20.6 months), and only 3 of 11 patients in the alemtuzumab arm relapsed.[54]

In the CALGB 19901 study, researchers administered standard IV fludarabine for 6 cycles, followed by subcutaneous alemtuzumab at 30 mg three times weekly for 6 weeks in previously untreated CLL patients.[55] The OR after fludarabine was only 36% (CR = 4%), and 18 of 28 patients (24 evaluable) with stable or responsive disease received alemtuzumab consolidation. Overall, 12 of 18 patients responded, and 4 of 8 patients converted from PR to CR. The final OR was 50% (CR = 18%). Treatment was well tolerated, and cytomegalovirus was reactivated in only 3 of 18 patients.

Several studies continue to assess the use of alemtuzumab consolidation after fludarabine-based induction therapy. The CALGB 10101 study is currently examining a phase II regimen of concurrent FR for 6 cycles, followed by SC alemtuzumab for 6 weeks as consolidation therapy. The GCLLSG FLL2i and UK CLL8 studies are evaluating the optimal dose and schedule of alemtuzumab consolidation after initial fludarabine-based therapy.

Conclusions

• Treatment should be individualized, based on age, performance status, and cytogenetics.

• For older patients with comorbidities or palliative objective: Chlorambucil

• For older patients desiring aggressive therapy: PCR (pentostatin, cyclophosphamide, rituximab)

• For younger patients, generally: FC (fludarabine, cyclophosphamide), FR (fludarabine, rituximab), or FCR (fludarabine, cyclophosphamide, rituximab), possibly with alemtuzumab consolidation

• For younger patients with high-risk cytogenetic profile: Possibly nonmyeloablative allogeneic stem-cell transplant after first-line therapy

The development of a chemoimmunotherapy regimen such as FCR has resulted in OR and CR rates in excess of 90% and 70%, respectively, and improved PFS. However, no studies have yet demonstrated an OS advantage for such regimens, due to improved therapies for patients with relapsed CLL. Recent data indicate that patients who relapse after aggressive chemoimmunotherapy regimens such as FCR respond poorly to salvage therapy, suggesting that long-term survival may not necessarily be improved by such combination regimens.

Patients in the community are generally older and in poorer medical condition than patients who are enrolled on clinical studies of initial CLL therapy at academic centers. Furthermore, the goal of therapy may be much different in older patients with multiple comorbid medical conditions who are most concerned about palliation of symptoms, compared with younger patients who are in excellent health and wish to maximize their likelihood of survival 15 or 20 years later. Finally, the increasing ability to risk-stratify CLL patients according to cytogenetic and biologic prognostic factors allows clinicians to identify patients who may need more aggressive regimens.

Thus, there is no “best” initial therapy for CLL, and a treatment plan should be selected for an individual patient after consideration of the above points. Chlorambucil is still a reasonable option in elderly patients with multiple comorbid illnesses who may be poor candidates for fludarabine therapy or in whom the primary goal of therapy is palliation. Alternatively, PCR is a viable option for older patients in whom more aggressive therapy is desired.

Younger patients, particularly those who possess high-risk cytogenetic features such as del(17p13), should be considered for FC or a chemoimmunotherapy regimen such as FR or FCR. While FCR has demonstrated the best phase II results, no randomized data have yet shown that FCR is superior to FC or FR. However, phase III studies to answer this question are ongoing. Achievement of MRD-negative marrow should be a therapeutic goal in younger, poor-risk patients, given that eradication of MRD correlates with improved survival. Studies to optimize the timing and dosing of alemtuzumab to eradicate MRD after induction therapy continue to address this question.

Finally, patients with del(17p13), while constituting only 5% of newly diagnosed CLL patients, remain a therapeutic challenge. Such patients should at least be referred for consideration of nonmyeloablative allogeneic stem-cell transplantation after first treatment.

References:

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