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Keywords:

  • alemtuzumab;
  • lymphoproliferative disorders;
  • chronic lymphocytic leukemia (CLL);
  • prolymphocytic leukemia (PLL);
  • toxicity;
  • infections

Abstract

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

BACKGROUND

Pilot studies showed that alemtuzumab is active in lymphoproliferative disorders. The authors conducted a Phase II trial to evaluate the efficacy and safety of alemtuzumab in advanced or refractory chronic lymphoproliferative disorders.

METHODS

Seventy-eight patients were enrolled. The most common diagnoses were chronic lymphocytic leukemia (n = 42 patients) and T-cell prolymphocytic leukemia (n = 18 patients). Before entering the study, the patients had received multiple therapies (median, three therapies) and the median time from diagnosis was 7 years. Alemtuzumab was given intravenously at doses of 3 mg, 10 mg, and 30 mg on 3 consecutive days, after which 30 mg was administered 3 times a week. Patients were treated for 4–12 weeks depending on disease response. All patients received prophylactic trimethoprim/sulfamethoxazole and valacyclovir.

RESULTS

The overall response rate was 35%, the complete response (CR) rate was 13%, and the partial response (PR) rate was 22%. The median duration of response was 18 months for patients achieving a CR and 7 months for patients achieving a PR. The median duration of survival was 25 months for patients who had a response and 12 months for the entire population. Normalization of the lymphocyte count was observed in 84% of patients and resolution of bone marrow involvement was observed in 49% of patients. The most common infusion-related adverse events were fever, rigors, skin rash, nausea, and dyspnea. These were most common during the first week of therapy. Hematologic toxicity was comprised of long-lasting lymphocytopenia and transient neutropenia and thrombocytopenia. Thirty-six patients (46%) experienced at least one episode of fever or infection.

CONCLUSIONS

Alemtuzumab has a high response rate in patients with chronic lymphoproliferative disorders. Cancer 2003;98:773–8. © 2003 American Cancer Society.

DOI 10.1002/cncr.11551

Alemtuzumab is a humanized monoclonal antibody (MoAb) directed against CD52.1 CD52 is present at a high density on the cell surface of normal and malignant B and T lymphocytes.2 The binding of alemtuzumab to CD52 induces cell death. The specific mechanism of action is unknown, but complement activation, antibody-dependent cellular cytotoxicity, and, possibly, induction of apoptosis are involved in cell killing.3 Tumor cells from patients with chronic lymphocytic leukemia (CLL) and other chronic lymphoproliferative disorders express CD52, albeit with varying intensity.4

The prognosis was poor for patients with CLL who did not respond to fludarabine treatment. Their median duration of survival was only 10 months.5 Patients with CLL that is refractory to alkylating agents may respond to fludarabine or fludarabine-based combinations, but responses usually do not last long and resistance frequently develops. There is also no established treatment for uncommon lymphoproliferative disorders such as prolymphocytic leukemia (PLL), splenic lymphoma with villous lymphocytes, and large granular lymphocytosis (LGL).

At the time this trial was designed, alemtuzumab had been shown to be active in lymphoproliferative disorders in early pilot studies.6–8 In 1996, Osterborg et al.9 reported activity in nine patients with CLL who had not received previous treatment. In 1997, they published the responses of a small Phase II trial of 29 patients with CLL who had received previous chemotherapy.10 In 1997, Pawson et al.11 described the activity of alemtuzumab in 15 patients with PLL. We conducted a Phase II trial to evaluate the efficacy and safety of alemtuzumab in patients with hematologic malignancies that express CD52. The alemtuzumab trial began after conventional treatment had failed or if there was no established frontline therapy.

MATERIALS AND METHODS

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

Seventy-eight patients with chronic lymphoproliferative disorders were enrolled in the current study between May 1999 and March 2001. Informed consent was obtained from all patients. Inclusion criteria were an age of 16 years of age or older, CD52 expression on greater than 20% of malignant cells, and a less than 20% predicted probability of response to conventional therapy. Patients with any subtype of leukemia for which there is no established frontline therapy and patients with PLL in whom at least one previous regimen had failed were also included. Other eligibility criteria included a World Health Organization performance status of 0–2 and creatinine and conjugated bilirubin levels less than twice the upper limit of normal, unless secondary to direct infiltration. Exclusion criteria were a history of anaphylaxis after exposure to rat or mouse-derived CDR-grafted humanized MoAbs, a period of less than 3 weeks since previous chemotherapy, pregnancy or lactation, and any severe concurrent diseases or mental disorders.

All but one patient had received prior treatment with a median of three previous regimens. The majority of the patients had long history of disease with a median time from diagnosis of 7 years. The most common diagnoses were CLL (n = 42 patients) and T-cell PLL (n = 18 patients; Table 1). Fifty-five percent of the patients with CLL were refractory to alkylating agents, 55% were refractory to fludarabine, and 40% were refractory to both alkylating agents and fludarabine (Table 2).

Table 1. Disease Characteristics of 78 Patients
CharacteristicsNo. of patients
Diagnosis 
 B-cell chronic lymphocytic leukemia42
 B-cell prolymphocytic leukemia3
 T-cell prolymphocytic leukemia18
 Cutaneous t-cell lymphoma6
 T-cell lymphoma3
 T-cell large granular lymphocytosis2
 Mantle cell lymphoma3
 Hairy cell leukemia1
Age (yrs) 
 Median (range): 61 (29–83) 
Time since diagnosis (yrs) 
 Median (range): 7 (0–24) 
No. of previous therapies 
 Median (range): 3 (0–9) 
Table 2. Characteristics of 42 Patients with Chronic Lymphocytic Leukemia at the Initiation of Alemtuzumab Therapy
CharacteristicsNo. of patients
No. of previous therapies 
 Median (range): 3 (1–9) 
 Fludarabine refractory23
 Alkylator refractory23
 Fludarabine and alkylator refractory17
Rai stage 
 I-II10
 III-IV32
β-2-microglobulin (mg/dL) 
 Median (range): 5.3 (2–59.4) 
Age (yrs) 
 Median (range): 61 (35–75) 
Time since diagnosis (yrs) 
 Median (range): 7 (1–24) 

Treatment Plan and Evaluation

Alemtuzumab was given intravenously at doses of 3 mg, 10 mg, and 30 mg on 3 consecutive days during the first week, after which 30 mg was administered 3 times a week, each dose being separated by at least 1 day. Patients were treated for a minimum of 4 weeks and a maximum of 12 weeks, depending on their response to treatment and the toxic side effects. Diphenhydramine (50 mg) and acetaminophen (650 mg) were administered 30 minutes before each alemtuzumab infusion. Corticosteroids were not used routinely. Prophylaxis with oral trimethoprim/sulfamethoxazole (160/800 mg twice a day, 3 times a week) and valacyclovir (500 mg daily) was initiated on Day 8 and continued for at least 2 months after the discontinuation of alemtuzumab treatment.

Disease staging before treatment included bone marrow aspiration and biopsy and immunophenotypic evaluation when appropriate. A complete blood count, medical history, and a physical examination were performed once a week. At the end of 4 weeks of treatment, all relevant sites of disease, such as blood, bone marrow, lymph nodes, liver, spleen, and other involved sites, were evaluated for response. Response criteria were defined according to National Cancer Institute (NCI) Working Group criteria for response in CLL.12 Response in patients with non-Hodgkin lymphoma was evaluated according to published guidelines.13 Side effects were graded according to NCI Common Toxicity Criteria. After completion of alemtuzumab therapy, patients with a complete response (CR), partial response (PR), or nodular PR were assessed monthly for 6 months. Performance status, blood counts, and infections were recorded, as were any major medical events that were related to alemtuzumab treatment. After 6 months, assessments were performed at 3-month intervals until further treatment or death.

RESULTS

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

Response

The overall response (OR) rate in 78 patients was 35% (n = 27 patients), the CR rate was 13% (n = 10 patients), and the PR rate was 22% (n = 17 patients; Table 3).

Table 3. Disease Response
HistologiesResponse (%)
No. of patientsCRPROR
  • CR: complete response; PR: partial response; OR: overall response.

  • a

    Six patients were refractory to fludarabine treatment.

B-cell chronic lymphocytic leukemia42211a13
T-cell prolymphocytic leukemia188210
B-cell prolymphocytic leukemia3 22
Cutaneous T-cell lymphoma6 22
Others9   
Total7810 (13)17 (22)27 (35)

Thirteen of the 42 patients with CLL (31%) had a response. Of these 13 patients, 2 (5%) had a CR, 10 (24%) had a PR, and 1 (2%) had a nodular PR. Two CRs and 5 PRs (an OR rate of 37%) were observed among the 19 patients with CLL that was sensitive to fludarabine at the time of initiation of treatment with alemtuzumab. Six PRs (an OR rate of 26%) were observed among the 23 patients with CLL that was refractory to fludarabine.

Of the 18 patients with T-cell PLL, the OR rate was 55% (n = 10 patients), the CR rate was 44% (n = 8 patients), and the PR rate was 11% (n = 2 patients).

Of the three patients with B-cell PLL, two had a PR and of the six patients with cutaneous T-cell lymphoma (CTCL), two had a PR.

Normalization of the lymphocyte count was observed in 84% of the patients, resolution of bone marrow involvement was observed in 49% of the patients, and improvement of greater than 50% in hepatomegaly, splenomegaly, and lymphadenopathy was observed in 59%, 56%, and 39% of patients, respectively (Fig. 1). The median duration of response was 18 months for patients achieving a CR and 7 months for patients achieving a PR. Five patients, all with T-cell PLL, are still in CR at 9 months, 10 months, 11 months, 12 months, and 15 months, respectively. One patient with CLL is in PR at 11 months.

thumbnail image

Figure 1. Proportion of patients who responded to alemtuzumab according to sites of disease.

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The majority of the patients received 4 weeks of treatment, 12 patients (15%) received 8 weeks of treatment, and 10 patients (13%) received 12 weeks of treatment. As of December 31, 2002, 29 (37%) patients were alive. The median survival period was 25 months for the patients who had a response, compared with 12 months for the entire patient population (Fig. 2).

thumbnail image

Figure 2. Overall survival of patients who achieved a response compared with all patients who received alemtuzumab.

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Toxicity

The most common infusion-related adverse events were fever in 85% of the patients (Grade 3 in 1%), rigors in 73% of the patients, skin rash in 42% of the patients, nausea in 35% of the patients, dyspnea in 31% of the patients (Grade 3 in 8% and Grade 4 in 3%), hypotension in 18% of the patients (Grade 3 in 1%), and headache in 7% of the patients (Grade 3 in 1%; Table 4). Infusion-related adverse events decreased with time. During the first week of treatment, Grade 3 and Grade 4 nonhematologic toxic side effects were recorded in eight and one patient, respectively. During the second week and beyond, only two patients had Grade 3 nonhematologic toxic side effects (skin rash in one and dyspnea in the other).

Table 4. Adverse Events
CharacteristicsNo. of patients (%)NCI grade
1234
  1. NCI: National Cancer Institute.

Nonhematologic     
 Fever66 (85)33321
 Rigors57 (73)6501
 Rash33 (42)627
 Nausea27 (35)1611
 Dyspnea24 (31)51043
 Hypotension18 (23)5121
 Headache 7 (9)511
Hematologic     
 Anemia 5 (6)32
 Thrombocytopenia63 (81)10212210
 Neutropenia41 (53)3111512

Cardiovascular toxicity was observed in three patients with T-cell malignancies. One patient with T-cell LGL developed chest pain during the first infusion of alemtuzumab at the 3-mg dose and again during the second infusion (10-mg dose). The patient had no evidence of ischemic heart disease. Treatment with alemtuzumab was discontinued. A second patient with CTCL with lung involvement developed congestive heart failure after the third dose of alemtuzumab. This patient required transient ventilatory support, treatment with alemtuzumab was discontinued, and the patient responded to medical management (an echocardiographic evaluation obtained 48 hours after the last infusion of alemtuzumab showed a depressed systolic ejection fraction to 20–29%, an echocardiographic evaluation 3 months prior showed a normal systolic ejection fraction, and no follow-up studies were obtained). A third patient with CTCL developed worsening peripheral edema 2 months after treatment with alemtuzumab began. An echocardiographic evaluation revealed a severely depressed systolic ejection fraction of less then 20%. Previous echocardiographic evaluation was available for this patient. The patient improved with medical management and a repeated cardiac evaluation obtained 2 months later showed a normal systolic ejection fraction.

Hematologic toxic effects consisted of persistent lymphocytopenia, which occurred in all patients, and transient neutropenia and thrombocytopenia. Approximately 53% of patients developed neutropenia (Grade 3 in 19% and Grade 4 in 15%) and 81% of patients developed thrombocytopenia (Grade 3 in 28% and Grade 4 in 13%). Anemia developed in only 6% of patients and was only Grade 1 or 2 (Table 4). One patient with Grade 4 thrombocytopenia due to progressive CLL at study entry died of intracranial hemorrhage after the second dose of alemtuzumab.

Infections

Thirty-six patients (46%) experienced at least 1 episode of infection or fever of unknown origin (FUO). Thirty of 42 patients with CLL (71%) experienced at least 1 episode of infection or FUO. The most common viral infection was cytomegalovirus (CMV) reactivation, which was documented by positive CMV antigenemia assay (CMVpp65)14 in 14 patients and by positive nasal wash in 1 patient (20%). The CMV reactivation resulted in febrile syndrome without evidence of invasive CMV disease such as pneumonitis, colitis, and retinitis. The second most common viral infection was caused by herpes viruses, which was reported in three patients (two with localized herpes simplex infection and one with disseminated varicella-zoster infection after exposure to a child with chicken pox). Hemo-adsorbing virus was detected in the sputum of three patients and documented as parainfluenza in one. All viral infections occurred during the first month of treatment. Pneumocystis carinii pneumonia was documented in 1 patient 35 days from the initiation of treatment. This patient had not been compliant in taking prophylactic trimetroprim/sulfamethoxazole. Twenty episodes of FUO were reported in 19 patients (24%), 11 during the first month of treatment and 8 during the second month. Eleven episodes of pneumonia were documented in 10 patients (13%), 1 patient had concomitant Staphylococcus bacteremia, and another had probable invasive aspergillosis. The remaining nine episodes were pneumonias of unknown pathogen. One case was observed during the first month, two during the second month, three during the third month, one during the fourth month, and one during the fifth month. Two patients died of progressive pneumonia. Seventeen episodes of bacteremia occurred in 11 patients (14%). Bloodstream isolates included coagulase-negative Staphylococcus species in six, Staphylococcus aureus in two, and Stenotrophomonas maltophilia in two. In addition, unspecified Gram-positive cocci, vancomycin-resistant Enterococcus, Escherichia coli, Acinetobacter species, Corynebacterium species, Stomatococcus species, Micrococcus species were found in one isolate each. Two patients died of septicemia: one patient with CLL undergoing peritoneal dyalisis developed peritonitis and S. aureus bacteremia 36 days after beginning alemtuzumab; another patient developed E. coli bacteremia 49 days after beginning alemtuzumab treatment. Aspergillus species were isolated from the sputum of two patients. Sinus zygomycosis infection was documented in one patient. Finally, acid-fast bacilli was detected in a skin biopsy performed for two patients with CLL and skin lesions (Mycobacterium avium complex in one and nonspecified atypical mycobacteriae in the other).

DISCUSSION

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

In the current study, 78 patients with advanced or refractory lymphoproliferative disorders were treated with alemtuzumab at a single institution. An OR rate of 35% was observed in this previously and heavily treated population. Patients with T-cell PLL had the highest OR rate (55%). An OR rate of 31% was observed in previously treated patients with CLL and an encouraging PR rate of 26% was observed among the 26 patients with CLL that was refractory to fludarabine treatment. The activity observed in the current study confirms similar results reported in multicenter trials conducted in the U. S. and Europe. Keating et al.15 reported a similar efficacy in 93 patients with CLL in whom fludarabine treatment had failed. In their study, the CR rate was 2% and the PR rate was 31%.15 Rai et al.16 reported an OR rate of 33% in patients with CLL who had received previous fludarabine treatment. Similar to the results obtained for the group of patients with fludarabine-refractory CLL in the current study, all responses in the study by Rai et al. were PRs only.16 Osterborg et al.10 reported an OR rate of 42% in 29 patients with CLL. All patients had been treated previously, but only 3 of the 29 patients had received previous fludarabine treatment.10

The marked sensitivity of T-cell PLL to alemtuzumab observed in the current study (an OR rate of 55%) is similar to the results obtained in a Phase II multicenter European study that included 39 patients with T-cell PLL. In that study,17 37 patients had not received previous treatment. The OR rate was 76% and the CR rate was 60%.17 In a retrospective review of 76 patients with T-cell PLL who had received previous treatment, 51% responded to alemtuzumab and 40% achieved a CR.18

The current study included six patients with CTCL. Two of these patients achieved a PR, suggesting activity of alemtuzumab in this disease. This finding confirms the observation of Lundin et al.19, 20 in low-grade lymphomas with skin involvement.

The toxic effects observed in the current study included infusion-related events, with typical first-dose reactions that resolved during subsequent treatment. The infusion-related toxicity was reduced by administering pretreatment therapy with antihistamines and acetaminophen and by slowing the rate of infusion.

Hematologic toxicity was common. Grade 3 and 4 thrombocytopenia and neutropenia were observed in 42% and 35% of the patients, respectively. Thrombocytopenia occurred during the first 2 weeks of treatment and returned to baseline or improved by the third week. Neutropenia was more common during the third week of treatment and resolved spontaneously. Many patients in whom cytopenias developed had low platelet and neutrophil counts when they entered the study and it was often difficult to distinguish between disease-related and treatment-related cytopenias.

Cardiovascular toxicity occurred in three patients. Significant impairment in ejection fraction was observed in 2 patients 3 days and 2 months, respectively, after alemtuzumab treatment was initiated. This toxicity was unexpected and it has not been reported in other studies with alemtuzumab, including a study of 22 patients with advanced mycosis fungoides.20

A significant number of infections and episodes of fever were observed. The incidence of infections was significantly higher in patients with CLL, reflecting the greater degree of cumulative immunosuppression present in these patients. Bacterial infections were the more common documented infection. Prophylactic treatment with trimethoprim-sulfamethoxazole was successful in preventing P. carinii pneumonia and only one episode of disseminated herpes virus infection was reported. CMV reactivation was observed in 20% of the patients in the current study. Of the 14 patients with CMV infection, 12 had CLL and the infections responded to intravenous gancyclovir or foscarnet. Reactivation of CMV infection is becoming a recognized event in the setting of alemtuzumab therapy.15, 16, 21 Clinical trials evaluating the usefulness of prophylactic treatment with agents active against CMV such as valgancyclovir are warranted. Based on our experience, patients treated with alemtuzumab who develop febrile syndromes need to be evaluated for CMV reactivation. Patients with refractory lymphoproliferative disorders have a high propensity for infections as a result of the primary disease as well as previous treatment with immunosuppressive agents. Perkins et al.22 reported a high rate of serious infections in patients with fludarabine-refractory chronic lymphoproliferative disorders treated with noninvestigational supportive therapies. Keating et al.5 observed a high rate of infections among 147 patients with fludarabine-refractory CLL who received first salvage therapy. In the current study, the 20% incidence of CMV reactivation and the occurrence of invasive mold and cutaneous atypical mycobacterial infections may be related to the lympholytic effect of alemtuzumab.

The results of our experience with alemtuzumab in 78 patients with refractory lymphoproliferative disorders indicates that this agent induces a significant number of sustained responses in a population of heavily treated patients. Infectious complications, despite prophylactic treatment, are common. Future studies of alemtuzumab in combination with chemotherapy, MoAbs, or novel agents are indicated.23

REFERENCES

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