Infectious Complications ICs Associated with Alemtuzumab Treatment

1
Infectious Complications (ICs) Associated with
Alemtuzumab Treatment
Shahzad Siddique, MD Nathan Fowler, MD
Ekatherine Asatiani, MD Philip Cohen, MD Craig
M. Kessler, MD Bruce D. Cheson, MD
Lombardi Comprehensive Cancer Center and
Department of Medicine Georgetown University
Hospital, Washington, DC
Abstract
Results
Introduction We report our single institutional
experience of ICs associated with alemtuzumab
treatment. Methods Patients (pts) who received
alemtuzumab were identified by review of the GUH
pharmacy database. All ICs occurring from
initiation of alemtuzumab until death or end of
follow up as of January 3, 2007 were reviewed and
categorized as opportunistic (OI) or
non-opportunistic (NOIs). Pts who received
hematopoietic stem cell or solid organ
transplantation subsequent to alemtuzumab (n33)
or who could not tolerate test doses of
alemtuzumab (n1) were excluded from
analysis. Results Data were reviewed for 16 pts
treated with alemtuzumab from February 2003 to
September 2006. Median age was 60 years (range
40-78) with 4 females and 12 males. Fifteen pts
had chronic lymphocytic leukemia (CLL), and 1 had
acute lymphoblastic leukemia (ALL). Alemtuzumab
was administered subcutaneously, 30 mg three
times a week. A median of 29 doses (range 7-45)
were given. Pneumocystis jirovecii (PCP) and
herpesvirus (HSV) prophylaxis was given to 15
(93) pts. Cytomegalovirus (CMV) surveillance
was performed for all. Thirteen OIs were
diagnosed in 9 (56) pts including asymptomatic
CMV viremia (n5), PCP (n2, one pt did not
receive PCP prophylaxis), invasive pulmonary
aspergillosis (n2), disseminated histoplasmosis
(n1), localized HSV (n1), disseminated herpes
zoster (n1), and cerebral acanthamoebiasis
(n1). Thirty NOIs were noted in fourteen pts
including bacterial pneumonia, sinusitis,
endocarditis and pseudo-membranous colitis.
Mortality secondary to ICs was 31. Conclusion
ICs secondary to alemtuzumab are more frequent
and diverse than previously reported in clinical
trials.

• 16 patients were treated with alemtuzumab from
  February 2003 to September 2006.
• Alemtuzumab was administered 30 mg SQ TIW, with
  a median of 29 doses given.
• The median follow-up after starting alemtuzumab
  treatment was 462 days.
• The patient population consisted of 12 males and
  4 females. Fifteen patients had chronic
  lymphocytic leukemia (CLL), and one patient had
  acute lymphoblastic leumekia (ALL).
• The patients with CLL had an average of 2.4 prior
  treatments with a range of 1 to 6.
• Among the patients with CLL, the response rate
  was 60, with one complete response, eight
  partial responses, and six patients with
  progression of disease.
• Pneumocystis jirovecii (PCP) and herpesvirus
  (HSV) prophylaxis was given to 15 patients (93),
  and cytomegalovirus (CMV) surveillance was
  performed on all patients.
• Thirteen opportunistic infections (OI) were
  diagnosed in nine patients (56) and include
  asymptomatic CMV viremia (n5), PCP (n2),
  invasive pulmonary aspergillosis (n2),
  disseminated histoplasmosis (n1), localized HSV
  (n1), disseminated herpes zoster (n1), and
  cerebral acanthamebiasis (n1).
• Thirty NOIs were noted in fourteen patients
  (87) and include pneumonia, sinusitis,
  endocarditis, and pseudo-membranous colitis.
• Mortality due to infections complications was 31.

Introduction

• Alemtuzumab is a humanized IgG1 class monoclonal
  antibody which activates ADCC as well as
  complement against the cell surface antigen CD52.
  
• The CD52 antigen is found on virtually all
  lymphocytes at varying levels of differentiation
  as well as in macrophages, monocytes, and
  eosinophils.1 It is not seen on hematopoietic
  stem cells, erythrocytes, or platelets.2
• Expression is high in T-prolymphocytic leukemia
  (PLL) and B-cell chronic lymphocytic leukemia
  (CLL), and the level of expression may correlate
  with response to treatment.3-4
• Alemtuzumab was FDA approved in 2001 for the
  treatment of Fludarabine refractory CLL, and
  clinical trials have also demonstrated efficacy
  in the treatment of non-Hodgkins lymphoma and
  PLL.5-7
• Alemtuzumab causes a profound and often prolonged
  period of immunosupression characterized by
  depletion of B- and T- lymphocytes, natural
  killer cells, and monocytes.8 Levels of CD4
  and CD8 lymphocytes have been shown to be below
  25 of baseline at months following therapy, and
  may remain suppressed beyond two years.9
• The risk of infection is further potentiated from
  immunosuppression that occurs secondary to a
  patients underlying hematologic disorder as well
  as previous chemotherapy and radiation regimens.
  
• Although the risk of serious ICs were reported in
  27 of patients treated in the pivotal trail,
  subsequent reports are concerning for higher
  rates of infection.10
• In order to further define the risk and type of
  infections encountered, we report the infectious
  complications encountered at our institution
  following alemtuzumab use.

Conclusions
Methods
Despite the use of herpesvirus and Pneumocyctis
prophylaxis, serious infectious complications
were noted in patients receiving alemtuzumab for
hematologic malignancies. Infectious
complications were more diverse and frequent than
reported in previous clinical trials.

• Single center, retrospective, non-randomized
  study.
• Patients that were treated at Lombardi Cancer
  Center, Georgetown University Hospital, between
  February 2003 and September 2006 were identified
  by review of the pharmacy database.
• A complete review of the patients paper chart
  and electronic medical record was performed.
• A database was constructed which included the
  patients age, sex, underlying diagnosis, the
  infectious prophylaxis used, the total dose and
  duration of therapy of alemtuzumab, and all prior
  treatments.
• All infectious complications, including the
  organism, treatment, and clinical outcome that
  occurred during or following alemtuzumab
  administration were documented.
• Patients that received alemtuzumab as part of a
  conditioning regimen in preparation for a
  hematopoietic cell transplant or prior to solid
  organ transplantation were excluded from
  analysis.

References

• 1. Mavromatis B, Cheson BD. Monoclonal antibody
  therapy of chronic lymphocytic leukemia. JCO.
  Vol 21 (9) 1874-1881. 2003.
• 2. James L. et al. A structure of the
  therapeutic antibody CAMPATH-1H fab in complex
  with a synthetic peptide antigen. J Molec
  Bio. Vol 292 (5) 1161-1166. 1999.
• 3. Rossmann E. et al. Variability in B-cell
  antigen expression implications for the
  treatment of B-cell lymphomas and leukemias with
  monoclonal antibodies. Hemat. J. Vol 2 300-
  306. 2001.
• 4. Ginalbi, L. et al. Levels of expression of
  CD52 in normal and leukemic B and T cells
  Correlation with in vivo therapeutic responses to
  Campath-1H. Leuk. Res. Vol 22 (2) 185-191. 1998.
• 5. FDA approval of application (BLA) 103948
  (Alemtuzumab). Avail at http//www.fda.gov/cder/f
  oi/label/2006/103948s5065lbl.pdf. Accessed Aug.
  13, 2007.
• 6. Enblad, G. et al. A pilot study of
  alemtuzumab (anti-CD52 monoclonal antibody)
  therapy for patients with relapsed or
  chemotherapy-refractory peripheral T-cell
  lymphomas. Blood. Vol 103(8) 2920 2924. 2004.
• 7. Faderl, S. et al Experience with alemtuzumab
  plus rituximab in patients with relapsed and
  refractory lymphoid malignancies. Blood. Vol
  101(9) 3413-3415. 2003.
• 8. Thursky, K. et al Spectrum of infection, risk
  and recommendations for prophylaxis and screening
  among patients with lymphoproliferative disorders
  treated with Alemtuzumab. Brit. J. of Hemat. Vol
  132 3-12. 2005.
• Lundin, J. et al. Cellular immune reconstitution
  after subcutaneous alemtuzumab (anti-CD52
  monoclonal antibody, CAMPATH-1H) treatment as
  first-line therapy for B-cell chronic lymphocytic
  leukemia. Leukemia. Vol 18 484
• 490. 2004.
• 10. Keating M. et al. Therapeutic role of
  alemtuzumab (Campath-11H) in patients who have
  failed fludarabine results of a large
  internatinal study. Blood. Vol 99(10) 3554-3561.
  2002.