SAN DIEGO—Fludarabine-refractory chronic lymphocytic leukemia (CLL) has a poor prognosis, with a median survival time of 10 months. Intravenous alemtuzumab has been shown to extend survival in patients with fludarabine-refractory CLL to a median of 16 months.
The results of the CLL2h study of the German CLL Study Group presented here at the American Society of Hematology Annual Meeting suggest that subcutaneous alemtuzumab offers an equally safe and effective alternative to IV alemtuzumab in fludarabine-refractory patients.
In addition, SC alemtuzumab can be given in an outpatient setting and is more convenient for both patients and physicians.
Another study presented at the ASH meeting, a Phase III trial, suggests that front-line therapy with IV alemtuzumab has acceptable toxicity compared with chlorambucil for patients with progressive B-cell CLL. Efficacy data are not yet available.
Since treatment with alemtuzumab is associated with cytomegalovirus (CMV) reactivation, speakers agreed that screening for CMV is advisable. Treatment with an antiviral agent such as ganciclovir has been found effective in resolving this infection.
Speakers also commented that alemtuzumab is more effective in clearing minimal residual disease, the reason for most relapses, from peripheral blood rather than from lymph nodes and is probably useful in patients with bulky disease.
In high-risk, fludarabine-refractory CLL patients, SC alemtuzumab had efficacy comparable to IV administration of this agent and was equally active in patients at high genetic risk (11q and 17 p deletions, unmutated VH genes) as in the overall population, reported Stephan Stilgenbauer, MD, of the Department of Internal Medicine of the University of Ulm, who presented the results.
Treatment was initiated with IV alemtuzumab, and when 30 mg was tolerated, patients were switched to SC alemtuzumab at 30 mg three times a week for four to 12 weeks.
Dr. Stilgenbauer noted that IV alemtuzumab was used initially in the study to prevent painful local cutaneous reactions that could occur with the SC formulation. Once the investigators determined that the SC route was safe, they initiated treatment with SC alemtuzumab in the second cohort of the study.
The interim analysis he presented was based on the first 50 consecutive patients, who had a median age of 63 (range of 35 to 79).
Seventy-four percent were Rai Stage III/IV, and the median number of prior lines of therapy was four (range of 1 to 9). Unmutated VH status (a negative predictive factor) was observed in 73% of patients, and high-risk genomic mutations (i.e., deletions of 17p, 11q, 12q, and 13q) were observed in the majority of patients.
The median dose of alemtuzumab was 838 mg. SC treatment was given as the outpatient treatment. Dose interruptions were needed 46 times in 29 patients for neutropenia or infection; and alemtuzumab was stopped early in 26 patients due to lack of response, infection, or neutropenia.
Screening for CMV reactivation revealed six cases, five of whom responded promptly to oral valganciclovir.
During SC treatment, nonhematologic toxicity was mostly mild to moderate. Sixty-six percent of patients had Grade 3 or 4 neutropenia, 34% had Grade 3 or 4 thrombocytopenia, and 24% had Grade 3 or 4 infections.
At a median follow-up of 12.2 months, 18 deaths were reported. The response rates were as follows: complete response, 4%; partial response, 33%; stable disease, 44%; and progressive disease, 18%.
The median overall survival at the time of the ASH report was 17.4 months, and median progression-free survival was 10.8 months, which compares favorably with the results of the pivotal trial of IV alemtuzumab reported by a team led by Michael Keating, MD, of the University of Texas M. D. Anderson Cancer Center.
“Achieving a complete response impacts survival, but patients who have stable disease still benefit from alemtuzumab to some extent,” Dr. Stilgenbauer said.
Similar responses and progression-free survival rates were observed in patients with poor-prognostic genetic subtypes in CLL (i.e., deletions of 17p, 11q, and unmutated VH genes) as in the overall study population.
“The amount of alemtuzumab mattered,” he said. “Doses of more than 900 mg, if tolerated, were associated with improved overall survival compared with lower doses.”
Although other studies suggest that 18 weeks is an optimal duration of treatment with alemtuzumab, this study used a 12-week treatment period to make it comparable to the 12-week pivotal alemtuzumab trial.
Dr. Stilgenbauer said that SC alemtuzumab, a more convenient alternative to IV, appears to have similar efficacy and an improved side-effects profile compared with IV alemtuzumab. Ongoing studies are exploring different schedules of administration for SC alemtuzumab.
During a question-and-answer session, he said that the major reason for disease progression was bulky lymphadenopathy and suggested that caution should be exercised when considering the use of alemtuzumab in patients with swollen nodes.
Asked to comment on the study, John G. Gribben, MD, DSc, of Cancer Research UK, Professor of Oncology at Barts and the London School of Medicine, said, “Once patients are refractory, alemtuzumab is the only therapy we have that is effective. In the US, it is approved as an IV drug, but European studies suggest that it is easier and safer to use subcutaneously. Although it is more convenient, it has not been shown that the doses of both formulations are equivalent.”
SC alemtuzumab is more convenient and can overcome infusion-related reactions with IV alemtuzumab, he said, so it is good news that it appears to be equally safe and efficacious.
Front-Line Therapy with Alemtuzumab
In a related study presented at the ASH meeting, preliminary safety results of the Phase III, open-label, international randomized CAM307 trial suggest that front-line treatment with alemtuzumab has an acceptable safety profile compared with chlorambucil in patients with progressive CLL, reported Peter Hillmen, MD, of Leeds General Infirmary of Wakefield, UK.
Chlorambucil is approved front-line therapy, while alemtuzumab is approved for patients previously treated with alkylating agents and following failure on fludarabine. Efficacy results of the study will not be available until later in 2005.
The major serious adverse event that can occur with alemtuzumab is CMV infection reactivation. An optimized CMV screening strategy allowed successful treatment with alemtuzumab in the majority of patients who experienced a symptomatic CMV infection reactivation, Dr. Hillmen said.
“There were no remarkable increased toxicities in the alemtuzumab arm. Events were predictable, and CMV reactivation was manageable.”
The study population included 297 patients with B-CLL Stage I-IV disease and evidence of progression. Patients were randomized in a 1:1 ratio to receive IV alemtuzumab at 30 mg three times a week for a maximum of 12 weeks vs oral chlorambucil at 40 mg/m2 once every 28 days to a maximum of 12 cycles.
The preliminary safety data reported by Dr. Hillmen were based on investigator reporting. Most adverse events occurred during the first month of treatment and declined from that point on.
Infusion-related symptoms developed in up to 65% of patients, but were mostly mild to moderate. Grade 3 and 4 neutropenia was seen in 9% of the alemtuzumab arm and 2% of the chlorambucil arm; 2.5% developed febrile neutropenia in both arms.
Grade 3 and 4 anemia was seen in 2.5% of alemtuzumab patients and 4% of chlorambucil patients. Nausea and vomiting were well controlled in both arms.
CMV reactivation accounted for the biggest difference in serious adverse events between the two arms of the study: 25 patients in the alemtuzumab group and 0 in the chlorambucil group. In 19 of 25 cases, mild to moderate fever was the only symptom.
Prompt treatment with ganciclovir was effective, and most patients were able to complete alemtuzumab therapy per protocol.
Potential for Front-Line Use
Concerns have been raised in the community setting about the safety of alemtuzumab, Professor Gribben noted. “It has a bad rap. This study compared IV alemtuzumab with chlorambucil, the safest drug in CLL, in the front-line setting and showed that if antiviral prophylaxis is used, it is safe as upfront therapy.”
Alemtuzumab is approved in the refractory setting, and he said, as with most drugs, it is likely to be effective if used earlier in the course of disease. In the past, patients with CLL were treated with a palliative intent, using the least toxic drugs first.
“Now, with more effective agents, we are beginning to think about curative approaches. It is a new era, and we have response rates in CLL that approach rates in other diseases that we consider curable, like Hodgkin's lymphoma and childhood acute leukemia,” Professor Gribben said.
“It makes sense to use our more effective drugs upfront, but it will require long-term follow-up to determine whether cure is possible.”
ACS Cancer Statistics & the AHA
The American Heart Association and the American Cancer Society made a joint news statement in January after the ACS's release of its annual cancer statistics drew criticism from the AHA for creating confusion about the leading cause of death in the US. The original ACS statement had said that cancer was the No. 1 killer among all those under age 85, leading the AHA to note that the ACS had compared cancer deaths only with deaths from heart disease, not from all cardiovascular diseases.
Heart disease remains the No. 1 killer for the entire population as a whole (both men and women), while cancer has surpassed heart disease as the No. 1 killer in all Americans under age 85.
After the ACS released its 2005 cancer statistics report, some media reports stated only that the very oldest Americans continue to die of heart disease more often than cancer, when heart disease remains the No. 1 killer in some specific age groups, such as men ages 40 to 59 and older adults age 75 to 84. In addition, cardiovascular diseases continue to be the No. 1 killer overall as well as across most age groups.
Both organizations expressed concern that confusion around which disease is the No. 1 killer will take the spotlight off what is really important, and both said neither organization wants to be No. 1.