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Keywords:

  • chronic lymphocytic leukemia;
  • high risk;
  • early stage;
  • alemtuzumab;
  • rituximab

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Patients with chronic lymphocytic leukemia (CLL) usually are treated only for progressive disease. However, the discovery of biologic predictors of a high risk of disease progression, together with the development of newer, more targeted therapies, could change this paradigm. In this phase 2 study, the authors tested the safety and efficacy of early treatment for patients with high-risk CLL using alemtuzumab and rituximab.

METHODS.

Patients were eligible for treatment if they were 1) previously untreated, 2) had no National Cancer Institute-Working Group 1996 criteria for treatment, and 3) had at least 1 marker of high-risk disease 17p13−, 11q22−, or a combination of unmutated IgVH and CD38+/ZAP70+). Treatment consisted of subcutaneous alemtuzumab (initial dose escalation followed by 30 mg on Monday, Wednesday, and Friday for 4 weeks) and intravenous rituximab (375 mg/m2 per week ×4 doses). All patients received Pneumocystis pneumonia and herpes virus prophylaxis and were monitored for cytomegalovirus reactivation.

RESULTS.

Twenty-seven of 30 patients (90%) responded to therapy with 11 (37%) complete responses (CRs). Five patients (17%) patients who had a CR had no detectable minimal residual disease. The median response duration was 14.4 months, and only 9 patients required retreatment for progressive disease at the time of the current report (median follow-up, 17.6 months). Study patients had a significantly longer time from diagnosis to first treatment for CLL according to conventional indications than a comparison cohort with similar biologic risk profiles.

CONCLUSIONS.

The therapy regimen used was safe and effective for early treatment of patients with high-risk CLL. Further studies will be required to determine whether this early treatment strategy decreases morbidity and mortality for high-risk CLL. Cancer 2008. © 2008 American Cancer Society.

Chronic lymphocytic leukemia (CLL) is not yet curable with standard therapies, and most patients will die from the disease or its complications.1, 2 Survival from diagnosis ranges from months to many decades with a median of about 10 years.2, 3 The diagnosis of CLL is now most often made early in the course of the disease with the routine use of flow cytometry, and biologic parameters can be used to predict prognosis for these patients. Thus, patients with earlier stage, high-risk CLL may be candidates for interventions designed to decrease the morbidity and mortality of their disease.

The best characterized novel prognostic parameters are specific chromosomal defects that are detected by using interphase fluorescent in situ hybridization (FISH), immunoglobulin mutation sequence analysis (mutation status of IgVH] gene), and expression of the intracellular protein ZAP-70 and the membrane protein CD38. FISH analysis can detect deletions of 17q13 (17p13−), which result in loss of the P53 gene and are associated with a shorter time to initial treatment, poor response to treatment, and very poor survival.4 FISH also can detect deletions of 11q22 (11q22−), which result in the loss of the ataxia telangiectasia mutated gene ATM and are associated with a poor prognosis.4 Unmutated (UM) IgVH (<2% difference from germline sequence),5, 6 ZAP-70 expression (≥20% positive cells),7 and CD38 (≥30% expression)5 also are associated with a poorer prognosis in CLL. In addition, CLL patients with UM IgVH and CD38 have a worse prognosis than CLL patients with UM IgVH and cells that do not express CD38.8 Although the use of these molecular prognostic markers is relatively new, sufficient progress has been made to apply this knowledge to treatment decisions in clinical trials for CLL.

Universal therapy for all patients with early- to intermediate-stage (Rai9) CLL at diagnosis currently is not considered beneficial, and the standard of care is to treat only patients with progressive or advanced-stage disease.10, 11 Delaying therapy protects patients with earlier stage, indolent disease from toxicity. However, this ‘watch-and-wait’ approach also may delay therapy unnecessarily for patients who have inherently aggressive disease. In this subset of patients with a kinetically more active form of CLL, earlier treatment when the disease burden is low theoretically could decrease the risk of clonal evolution, which probably is an important factor in disease progression and resistance to treatment.12, 13 In addition, newer and potentially less toxic therapies, such as lymphocyte-targeted monoclonal antibodies (MoAbs), are known as most effective before the development of bulky adenopathy and splenomegaly.14 Therefore, in the current study, we tested the efficacy and safety of a regimen that combined alemtuzumab (CAMPATH 1H; Genzyme, Cambridge, Mass) and rituximab (Rituxan; Genentech, San Francisco, Calif) in patients with earlier stage, high-risk CLL based on the biologic characteristics of their disease.

The combination of alemtuzumab and rituximab was used because these MoAbs have different molecular targets, could have different mechanisms of action, and are reported to have complementary activity in tissue sites involved with CLL. Alemtuzumab is specific for the CD52 antigen, which is expressed at high levels by CLL cells,15 and is effective as initial16, 17 and salvage18, 19 therapy for CLL. In CLL, alemtuzumab is very effective at clearing circulating leukemic cells and has appreciable activity against malignant lymphocytes in the bone marrow (BM), but it is less effective against leukemic cells in the lymph nodes.16, 19 Alemtuzumab is effective therapy for many patients with 17p13− or P53 mutation who are resistant to purine analogues.20 Although clinical trials have demonstrated only limited single-agent activity for rituximab in CLL,21 chemoimmunotherapy combinations of purine analogues and rituximab are highly effective for the treatment of CLL.22–24 In CLL, rituximab tends to be more effective at decreasing lymphadenopathy and splenomegaly than alemtuzumab, but it is less effective in clearing tumor cells from the BM.14, 25 These data suggesting that the combination of alemtuzumab and rituximab could be an effective therapy for CLL are supported by a study of patients with relapsed or refractory chronic B-cell lymphoid malignancies who had a response rate of 52% with 8% complete responses (CR).14 In the current study, we report on the treatment of 30 patients with early- to intermediate-stage, high-risk CLL who did not meet the conventional criteria for therapy. This study is an initial step to determine whether a short course alemtuzumab and rituximab therapy can achieve a clinically relevant delay in the need for conventional therapy in patients with earlier stage high-risk CLL.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Selection

The study was approved by the Mayo Clinic Institutional Review Board, and all patients were enrolled with written informed consent. Sequential patients who were seen in the Division of Hematology at Mayo Clinic, Rochester from January 2005 to June 2007 were evaluated for eligibility. Patients were eligible for the study if they had CLL diagnosed by flow cytometric analysis of peripheral blood, early to intermediate clinical stage disease (Rai 0-II),9 did not fulfill criteria for treatment of their disease as defined by the National Cancer Institute-Working Group criteria of 1996 (NCI-WG96),11 and had molecular markers predictive of a high risk of disease progression. The diagnosis of CLL required an absolute lymphocyte count >5 × 109/L, monoclonal B lymphocytes with a CLL immunophenotype,11, 26 and FISH analysis with an IgH probe to exclude mantle cell lymphoma. Risk of disease progression was determined using interphase FISH analysis of peripheral blood,27 IgVH mutation analysis,28 and expression of CD3828 and ZAP-70,29 as described previously. Patients were considered to be at high risk of disease progression if they had at least 1 of the following: 1) 17p13− by FISH analysis, 2) 11q22− by FISH analysis, and 3) UM IgVH (<2% sequence variation from germline) and ZAP-70 expression (≥20% cells positive on flow cytometry) and/or CD38 expression (≥30% cells positive on flow cytometry).

All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function (serum creatinine ≤1.5 times the upper limit of normal [UNL], total bilirubin ≤3 times the UNL, and serum aspartate aminotransferase ≤3 times the UNL). Exclusion criteria included any previous treatment for CLL, evidence of active autoimmune disease, and any another active, primary malignancy that required treatment or that limited expected survival to ≤2 years.

Therapy

The duration of treatment was 31 days. Patients received subcutaneous alemtuzumab with dose escalation (3 mg, 10 mg, 30 mg) over the first 3 days (Wednesday through Friday) and then received 30 mg per day on Monday, Wednesday, and Friday for the next 4 weeks. Rituximab therapy was started on Day 8 (375 mg/m2 intravenously at a standard infusion rate) and then was repeated weekly for a total of 4 doses. This regimen design ensured that the first dose of rituximab was given after the circulating lymphocyte count had been decreased by alemtuzumab therapy to decrease the risk of a ‘first-dose’ reaction. The first 3 doses of alemtuzumab and all doses of rituximab were premedicated with acetaminophen and diphenhydramine. Patients received allopurinol (300 mg per day) for the first 14 days of therapy. All patients received prophylaxis for Pneumocystis pneumonia and herpes simplex and varicella zoster viruses during treatment and then for an additional 6 months. Patients were monitored for cytomegalovirus (CMV) reactivation by polymerase chain reaction analysis for viral DNA weekly during treatment and then monthly for 6 months.

Response Evaluation

Patients were evaluated for the effects of treatment by physical examination and blood testing weekly during treatment, then monthly for 6 months, and then at 9 months and 12 months after the completion of therapy. Response to treatment was measured 2 months after the completion of therapy by physical examination, complete blood count, and a BM aspirate and biopsy. Minimal residual disease (MRD) was measured in peripheral blood weekly during treatment, then monthly for 6 months, and at 9 months and 12 months after the completion of therapy. The MRD analysis was performed by flow cytometry on the patient's blood. Lymphocytes were distinguished from other mononuclear peripheral blood cells by forward- and side-scatter parameters (lymphocyte gate). This population of cells was then examined using 3-color flow cytometry for cells that coexpressed CD19 and CD5 and had dim or absent expression of CD79b. The method was capable of detecting 1:104 CLL lymphocytes but was less sensitive than the more complex 4-color MRD assays that were developed after the study was initiated.30 Cytopenia caused by the treatment protocol was monitored weekly during treatment, then monthly for 6 months, and at 9 months and 12 months after the completion of treatment. The percentages of T cells (CD4-positive and CD8-positive) and natural killer (NK) cells (CD16-positive) in the lymphocyte gate were measured by flow cytometry, and absolute T-cell and NK-cell counts were then calculated by using the absolute lymphocyte count.

The primary objective of this study was to evaluate response to treatment 2 months after the completion of therapy. All patients initially were evaluated for response using the NCI-WG96 criteria.11 In patients who achieved a CR or a nodular partial response (nPR), the BM biopsy was evaluated with immunohistochemical staining for evidence of residual CLL B cells. BM biopsies were stained with T-cell specific (CD3) and B-cell associated (PAX5, CD79a) antibodies to determine whether the residual lymphocytes were predominantly T cells or B cells. In specimens with residual lymphocytes that were predominantly B cells, antibodies against κ and λ light chains and antibodies to CD5 and CD23 were used to distinguish monoclonal B cells from benign lymphocytes. Then, patients who had evidence of residual disease were reclassified as having a partial response (PR), and those with no residual disease were reclassified as having a true CR.

The time from CLL diagnosis to initial treatment required by NCI-WG96 criteria was calculated for study patients and a comparison cohort. Patients in the comparison group, which was obtained from the Mayo Clinic CLL Database, had stage 0 through II CLL, FISH analysis within 3 years of diagnosis, and fulfilled the eligibility criteria for high-risk disease used in the clinical trial, but they had not been not enrolled in this clinical trial for logistic or other nonmedical reasons.

Statistical Analysis

This study was a 2-stage phase 2 trial (Fleming design). A success was defined as a response (NCI-WG96 CR, nPR, or PR) at the evaluation 2 months after completion of therapy. The null hypothesis was that the true response rate for this regimen is ≤50% versus the alternative hypothesis that the true response rate is ≥75%. The study had 92% power, with a 9% Type I error rate, to detect an effective treatment if the true success rate was ≥75% versus ≤50%. Patients were considered evaluable for response if they were eligible and received treatment. A minimum of 11 and a maximum of 30 evaluable patients were required to evaluate the decision criteria. The first-stage analysis was performed after the first 11 patients were evaluable for response. If ≤5 successes were observed, then the study would be terminated; and, if ≥6 successes were observed, then the study would continue. At final analysis, if ≤18 successes were observed, then the regimen would be considered insufficiently active; however, if ≥19 successes were observed, then we would consider this evidence that this regimen is promising and warrants further study. Assuming that the number of responses was distributed binomially, a 95% confidence interval (CI) for the true response rate was calculated according to the approach of Duffy and Santner.

The duration of response and the time to progression (TTP) were evaluated. Responses were measured from the end of treatment. The duration of response was defined as the time from the date study therapy was completed until the date of disease progression. The TTP was defined as the time from registration until the date of disease progression. The distributions of time-to-event endpoints were estimated using the Kaplan-Meier method, and patients who were event free were censored on the date of last follow-up.

Fisher exact tests and Wilcoxon rank-sum tests were used to determine whether prognostic factors (age, clinical Rai stage, and risk group using novel prognostic parameters) were similar between patients who received the study regimen and the comparison cohort. The time to treatment (TTT) was defined as the time from the date of CLL diagnosis to the date of initial treatment required by NCI-WG96 criteria. Differences between groups were evaluated using standard Kaplan-Meier methods and log-rank statistics. A multivariate Cox model was used to determine whether receiving the study regimen was a significant prognostic factor for TTT.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Between January 2005 and June 2007, 30 eligible patients were accrued to this study at Mayo Clinic, Rochester. Patient characteristics are summarized in Table 1.

Table 1. Patient Characteristics at the Time of Registration
CharacteristicNo. (%) of Patients
  • −Indicates deletion; UM, unmutated; IgVH, immunoglobulin heavy-chain variable gene; +, addition; ZAP-70, zeta chain-associated protein kinase 70 kDa; FISH, fluorescence in situ hybridization; ALC, absolute lymphocyte count; HGB, hemoglobin; PLT, platelets; ECOG, Eastern Cooperative Oncology Group.

  • *

    Risk group is hierarchical (17p−>11q−>UM+ and ZAP-70+ with or without CD38+).

  • FISH is stated as the highest risk abnormality in each patient (17p13−>11q22−>12+>nil>13q−).

Total30 (100)
Age, y 
 Median61.0
 Range29.0-77
Age group, y 
 <7022 (73.3)
 ≥708 (26.7)
Sex 
 Women10 (33.3)
 Men20 (66.7)
Clinical Rai stage 
 07 (23.3)
 I21 (70)
 II2 (6.7)
Risk group* 
 17p−9 (30)
 11q−8 (26.7)
UM IgVH+ ZAP-70+ ± CD38+13 (43.3)
FISH, mean % positive nuclei [range] 
 17p−, 9 Patients62 [15-94]
 11q−, 8 Patients61.5 [22-90]
 Nil, 7 Patients 
 12+, 3 Patients58 [5-84]
 13q−, 3 Patients61 [9-80]
IgVH status 
 Mutated, ≥2%5 (16.7)
 Unmutated, <2%25 (83.3)
ZAP-70 
 Negative (<20%)7 (23.3)
 Positive (≥20%)23 (76.7)
CD38 
 Negative, <30%18 (60)
 Positive, ≥30%12 (40)
Pretreatment blood count 
 ALC, ×109/L 
  Median25.3
  Range4.8-124.7
 HGB, g/dL 
  Median14.2
  Range12-17.7
 PLT, ×109/L 
  Median178.5
  Range100-312
Time from diagnosis to treatment, mo 
 Median7.8
 Range0.7-73.1
ECOG performance score 
 027 (90)
 13 (10)

Toxicity

All patients received the scheduled doses of treatment with no treatment delays. Most patients had asymptomatic skin erythema at their alemtuzumab injection sites for the first 2 or 3 days of treatment. Only 1 patient had a symptomatic ‘first-dose’ reaction to rituximab (grade 2), which responded to standard supportive care. CMV reactivation occurred in 3 patients (10%) at 13 days, 21 days, and 43 days after starting therapy. One patient required hospitalization for symptomatic CMV infection and was treated with intravenous foscarnet therapy for ganciclovir resistance infection, which resulted in a full recovery. One patient with minor symptoms and 1 asymptomatic patient responded well to oral valganciclovir. Two patients had fever and rashes caused by trimethoprim/sulfamethoxazole, and 1 of those patients required hospitalization for evaluation until the cause of fever was recognized. There were 3 other nonhematologic grade 3 toxicities attributable to therapy (an increased alanine aminotransferase level, which resolved spontaneously; a skin infection, which was responsive to oral antibiotics; and diarrhea, which responded to supportive care).

The most common adverse effect was cytopenia. Neutropenia (Fig. 1) was common but was severe (grade 3-4) in only 5 patients, and there were no neutropenic infections. There was no grade 3/4 anemia or thrombocytopenia. All cytopenias resolved without intervention during or within 1 month of the completion of therapy. Monocytopenia occurred in all patients in this study with a median nadir of 0.08 × 109/L (range, 0-0.29 × 109/L) (Fig. 1). Patients had the expected, profound decreases in their absolute lymphocyte counts with a median nadir count of 0.03 × 109/L (range, 0-0.1 × 109/L). The recovery of T-cell counts after the completion of therapy was slow with median levels below normal at 6 months for CD8-positive cells and beyond 12 months for CD4-positive cells (Fig. 2). In contrast, NK cells recovered faster with a median level in the normal range by 2 months after the completion of therapy (Fig. 3).

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Figure 1. The effects of treatment on peripheral blood absolute neutrophil counts (ANC) (upper data points, black) and absolute monocyte counts (AMC) (lower data points, gray) were determined in the routine clinical laboratory. This graph shows the median and 25th to 75th quartiles for each time point. The median nadir ANC was 1.68 × 109/L (range, 0.15-3.65 × 109/L), and the median nadir AMC was 0.08 × 109/L (range, 0-0.29 × 109/L). PreTx indicates pretreatment; D, day; MTH, month.

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Figure 2. The effects of treatment on CD4-positive (black data points) and CD8-positive (gray data points) T-lymphocyte subsets counts were calculated from the absolute lymphocyte count and flow cytometric analysis for expression of CD3, CD4, and CD8. The median nadir count for CD4-positive T cells was 0.0001 × 109/L (range, 0-0.0034 × 109/L) and for CD8-positive T cells was 0.0003 × 109/L (range, 0-0.032 × 109/L). PreTx indicates pretreatment; D, day; MTH, month.

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Figure 3. The effect of treatment on natural killer (NK) lymphocyte counts was calculated by using the absolute lymphocyte count and flow cytometric analysis of cells within the lymphocyte gate for expression of CD16. The median nadir count for NK cells was 0.0004 × 109/L (range, 0-0.0078 × 109/L). PreTx indicates pretreatment; D, day; MTH, month.

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Treatment Response

All 30 patients were evaluable, and there were 27 responses (11 CRs, 10 nPRs, 6 PRs) according to the NCI-WG96 criteria for an overall response rate of 90% (95% CI, 77%-97%) and a CR rate of 37% (95% CI, 20%-56%). Resolution of lymphocytosis after the initiation of treatment was rapid with a median nadir B-cell count of 0.01 × 109/L (range, 0-2.8 × 109/L) (Fig. 4). When patients with an nPR or CR were evaluated for residual CLL in the BM by immunohistochemical examination, 6 patients had no detectable disease. Thus, there were 6 true CRs and 21 PRs according to our modified criteria for clinical response. Only 6 of 11 patients who achieved a CR by the NCI-WG96 criteria achieved blood MRD-negative status by flow cytometry (determined from 2 negative assays that were obtained at least 1 month apart after the completion of therapy). In contrast, 5 of 6 patients who achieved a CR with a negative immunohistochemical BM analysis had MRD-negative status determined by flow cytometry.

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Figure 4. The number of circulating chronic lymphocytic leukemia (CLL) B lymphocytes (circulating CLL cells) was calculated after the initiation of treatment by using the absolute lymphocyte count and the percentage of cells on flow cytometry in the lymphocyte gate defined on forward and side scatter that expressed CD19. PreTx indicates pretreatment; D, day; MTH, month.

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Nineteen patients had disease progression, and 1 patient died of complications from allogeneic stem cell transplantation. The median follow-up for patients who remained alive was 17.6 months (range, 4.7-33.6 months). The median duration of response in the 27 responders was 14.4 months (95% CI, 9.3-22.5 months) (Fig. 5). The median TTP for all patients was 12.5 months (95% CI, 7.2-19.3 months). Of the 5 patients who achieved a CR with negative immunohistochemical analysis and MRD tests, 4 patients were progression-free after a median of 30.2 months (range, 15.3-32.3 months), and 1 patient had progressive disease at 23 months but has not required subsequent treatment. An analysis of the percentage of nuclei with FISH-detectable chromosomal abnormalities in patients with progressive disease (Table 2) produced no evidence of the selection of aggressive clones by treatment. There were no patients who had evidence of clonal evolution among those with progressive CLL.

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Figure 5. The median duration of response to therapy for the 27 responders was 14.4 months (95% confidence interval, 9.3-22.5 months).

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Table 2. Initial and Subsequent Fluorescence In Situ Hybridization Analysis on Blood in Patients With Progressive Disease
FISH Category (Hierarchical)*% Peripheral Blood Cell Nuclei
Baseline2 Months After Completion of Treatment12 Months After Completion of Treatment
  1. FISH indicates fluorescence in situ hybridization; −, deletion; +, addition.

  2. Hierarchy indicates use of highest risk abnormality (17p13−>11q22−>12+>13q14−).

17p−   
 58034.5
 3915.5 
 900 
 620 
 8400
 6875.5 
 940 
11q−390 
 8808
 69840.5
 2210 
12+73021.5
 5330.5 
 7710 
13q−6108.5
 97 
 80423.5

Nine patients received subsequent therapy for progressive CLL, and some required more than 1 treatment regimen. The initial retreatment regimens were alemtuzumab and rituximab therapy using the same schedule (n = 1 patient); cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR) (n = 2 patients); pentostatin, cyclophosphamide, and rituximab (PCR) (n = 4 patients); fludarabine, cyclophosphamide, and rituximab (FCR) (n = 1 patient); and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) (n = 1 patient). For patients who received subsequent therapies, the median time from completion of protocol therapy with alemtuzumab and rituximab to the date of initiation of subsequent therapy was 8.5 months (range, 2.4-32.9 months). The responses to the first retreatment regimen were: alemtuzumab and rituximab, clinical complete response (CCR) (n = 1 patient); CFAR, PR (n = 1 patient) and progressive disease (n = 1 patient); PCR, CR (n = 1 patient), PR (n = 2 patients), and progressive disease (n = 1 patient); FCR, CCR (n = 1 patient); and R-CVP, CCR (n = 1 patient). It is noteworthy that 2 of these patients received further subsequent retreatment with alemtuzumab and rituximab and achieved responses (PR) that were at least as good as their initial responses to this regimen.

The time from diagnosis to first therapy for progressive CLL (according to NCI-WG96 criteria) was compared between the study patients and the comparison cohort. Patients in the comparison group were similar in age, clinical stage, and risk group (17p13−, 11q22−, UM IgVH, and CD38+ and/or ZAP-70+) (Table 3). The median time from the date of CLL diagnosis to the date of initial treatment, as required by NCI-WG96 criteria, was significantly longer in patients who received with alemtuzumab and rituximab (4.4 years; 95% CI, 3.1-6.7 years) than in the comparison group (1.9 years; 95% CI, 1.5-2.7 years; P = .001) (Fig. 6). In a multivariate Cox model, treatment with alemtuzumab and rituximab was a significant predictor of time from diagnosis to initial treatment required by NCI-WG96 criteria after adjusting for age, stage, and risk group (P = .001) (Table 4).

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Figure 6. The time from diagnosis of chronic lymphocytic leukemia (CLL) to first treatment for progressive disease (using the National Cancer Institute-Working Group 1996 criteria) was plotted for patients who were treated on this study and for a comparison cohort from the Mayo Clinic CLL database with the same high-risk features for progressive CLL who did not receive early therapy. The time to first treatment for progressive disease was significantly longer in patients who received alemtuzumab and rituximab therapy.

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Table 3. Characteristics of Treated and Comparison Groups
CharacteristicNo. (%) of Patients
Cases, n=30Comparison Group, n=117P*
  • −Indicates deletion; UM, unmutated; ZAP-70, zeta chain-associated protein kinase 70 kDa; +, addition.

  • *

    Wilcoxon rank-sum or Fisher exact P value.

  • Hierarchy indicates risk stratification with use of the single highest risk prognostic factor (17p13−>11q22−> immunoglobulin heavy-chain variable gene IgVH UM and ZAP-70+/CD38+).

Age at diagnosis, y  .15
 Median6163 
 Range28-7642-89 
Clinical Rai stage at diagnosis  .58
 017 (57)55 (47) 
 I11 (37)48 (41) 
 II2 (7)15 (12) 
Risk group, hierarchical  .24
 17p−9 (30)19 (16) 
 11q−8 (27)39 (33) 
 UM and ZAP-70+ and/or CD38+13 (43)59 (50) 
Table 4. Results of Multivariate Analysis of Treated and Comparison Groups (n=147)
GroupHR (95% CI)P
  1. HR indicates hazard ratio; CI, confidence interval.

Received study regimen0.28 (0.13-0.60).001
Risk group  
 17p−2.98 (1.53-5.80).001
 11q−1.38 (0.73-2.58).32
Age ≥70 y0.69 (0.34-1.42).32
Rai stage I or II vs 02.84 (1.58-5.11).0005

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

We report the first study in CLL to our knowledge in which patients were selected for early treatment of their disease based on molecular prognostic markers. Early treatment with the lymphocyte-directed MoAbs alemtuzumab and rituximab was effective and well tolerated. However, this treatment is noncurative, and its utility in the management of high-risk, earlier stage CLL will need further study.

The ability to accurately diagnose CLL in an early stage and the discovery of biologic markers that accurately predict poor prognosis allows for the selection of patients with high-risk CLL who have low disease burden for experimental therapy. We used stringent criteria to define high-risk disease based on previous studies4–6 that suggested the median time from diagnosis to treatment based on the NCI-WG96 criteria for enrolled patients would be ≈2 years. To test the accuracy of this prediction, we analyzed patients from a comparison group from our database (n = 117 patients) who were not enrolled in this clinical trial. These patients had a median TTT of 1.9 years (95% CI, 1.5-2.7 years), which validated our selection criteria.

Recent developments have greatly expanded the therapeutic repertoire for patients with CLL and provide lower toxicity treatment options. The major toxicities of the MoAb used in this study are the ‘first-dose’ reactions and immunosuppression. In this study, there was only 1 ‘first-dose’ reaction that required additional therapy, which reflects the lower disease burden, the use of subcutaneous alemtuzumab, and the reduction in CLL cell counts before the first administration of rituximab. In this study, there were no serious long-term complications and no deaths from infectious complications. The CMV morbidity could have been decreased by monitoring and early treatment for CMV reactivation. Two patients had unanticipated and severe new allergies to prophylactic trimethoprim/sulfamethoxazole during the initial posttreatment period, suggesting an aberrant response by the regenerating immune system. Cytopenia is an expected complication of MoAb treatment. All patients in the study had profound monocytopenia with slow recovery of these counts. In contrast, neutropenia was transient and had no observed clinical consequences. These data on toxicity suggest that this MoAb regimen can be used safely in patients with CLL provided there is careful monitoring for complications and a rapid response to adverse effects.

A potential concern about the use of early treatment in patients with CLL is the development of resistance to drug therapy because of the selection of resistant clones. Patients with progressive disease showed no evidence of increased resistance to treatment, and FISH analysis of their CLL cells did not suggest clonal selection or clonal evolution. These data suggest that the treatment regimen tested does not limit future treatment options for these patients.

This phase 2 study was designed to evaluate the safety and efficacy of the MoAb therapy and provided the data required to plan a phase 3 randomized trial comparing earlier treatment to standard treatment. The significantly increased time from diagnosis of CLL to treatment for progressive disease using NCI-WG96 criteria among study patients relative to that in a comparison cohort is important clinically and suggests that a randomized phase 3 study is justified.

The 5 patients who achieved MRD-negative remissions had the best response durations, suggesting that the extent of response predicts its duration in patients with high-risk disease. In contrast, patients who did not achieve an MRD-negative remission had a relatively short duration of response. These patients potentially could benefit from longer treatment, but this likely also would increase the risk of toxicity. Toxicity could be minimized if treatment was individualized using response assessed by clinical measurements, MRD assays, and computed tomography scans. In addition, the efficacy of the alemtuzumab and rituximab regimen could be improved by the addition of other drugs with potentially additive or synergistic effects based on a better understanding of the mechanisms of action of the MoAb and the mechanism of resistance to MoAb in CLL cells.

We conclude that alemtuzumab and rituximab therapy for high-risk patients with earlier clinical stage CLL is a promising new option that will require further evaluation and development. We intend to study the regimen in combination with other agents, including purine analogues and newer drugs, for the treatment of high-risk, earlier stage, progressive, and relapsed/refractory CLL. The data from our initial study, combined with a better understanding of the mechanism of action of alemtuzumab and rituximab, could result in the development of more effective and less toxic therapies for patients with CLL.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Call TG,Phyliky RL,Noel P, et al. Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis. Mayo Clin Proc. 1994; 69: 323328.
  • 2
    Zent CS,Ding W,Schwager SM, et al. The prognostic significance of cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Br J Haematol. 2008; 141: 615621.
  • 3
    Dighiero G,Binet J-L. When and how to treat chronic lymphocytic leukemia. N Engl J Med. 2000; 343: 17991801.
  • 4
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