Alemtuzumab and Low-Dose Cyclosporine in Treating Patients With Severe Aplastic Anemia or Acquired Marrow Failure

Alemtuzumab and Low-Dose Cyclosporine-A as Alternative Immunosuppressive Treatment for Severe Aplastic Anemia (SAA) and Single-Lineage Aplastic Patients

RATIONALE: Immunosuppressive therapies, such as alemtuzumab and cyclosporine, may improve bone marrow function and increase blood cell counts. Giving alemtuzumab together with cyclosporine may be an effective treatment for severe aplastic anemia or acquired marrow failure.

PURPOSE: This phase II trial is studying the side effects of giving alemtuzumab together with cyclosporine and to see how well it works in treating patients with severe aplastic anemia or acquired marrow failure.

Study Overview

• Status: Unknown
• Conditions: Nonmalignant Neoplasm
• Intervention / Treatment: Biological: alemtuzumab; Drug: cyclosporine

Detailed Description

OBJECTIVES:

Primary

• Determine the safety of alemtuzumab and low-dose cyclosporine, as defined by occurrence of adverse effects, in patients with severe aplastic anemia or single lineage acquired marrow failure.
• Determine the efficacy of this regimen, in terms of overall survival, hematological response (partial and complete response, including time to response) and failure-free survival (failure is defined as no response, chronic treatment-maintained response, or relapse), in these patients.

Secondary

• Evaluate the incidence of adverse effects after treatment.
• Evaluate the long-term safety of alemtuzumab treatment.
• Determine the time to achieve a complete hematological response.
• Determine the proportion of patients maintaining hematological response free of any treatment.
• Determine the incidence of relapse in responding patients.
• Determine the incidence of severe infections.
• Determine the requirement for IV antibiotics and antifungal therapy.
• Determine the requirement for red cell and platelet transfusion.
• Determine the incidence of CMV reactivation.
• Determine the kinetics of immune reconstitution.
• Determine the incidence of paroxysmal nocturnal hemoglobinuria clone (lymphoid or myeloid) development.
• Determine the incidence of clonal evolution (i.e., karyotypic abnormalities or secondary myelodysplasia/leukemia).

OUTLINE: Patients receive alemtuzumab subcutaneously on days 1-5*. Patients also receive oral cyclosporine beginning on day 7 and continuing for ≥ 180 days, followed by a taper according to clinical condition.

NOTE: *Patients with single lineage aquired marrow failure receive alemtuzumab on days 1-4.

After completion of study therapy, patients will be followed up every 3 months for up to 2 years.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Naples, Italy, 80131
    • Recruiting
    • Federico II University Medical School
    • Contact: Bruno Rotoli, MD; Phone Number: 39-081-746-2068; Email: rotoli@unina.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

  • Severe or very severe aplastic anemia, as defined by the following criteria:

    • Meets ≥ 2 of the following criteria:

      • Absolute neutrophil count < 0.5 x 10^9/L (severe) or < 0.2 x 10^9/L (very severe)
      • Platelet count < 20 x 10^9/L
      • Reticulocyte count < 20 x 10^9/L
    • Hypocellular bone marrow (< 30% cellularity) without evidence of fibrosis or malignant cells
  • Single lineage acquired marrow failure (e.g., pure red cell aplasia, agranulocytosis, amegakaryocytic thrombocytopenia)
• Paroxysmal nocturnal hemoglobinuria clone allowed

• Failed first-line therapy with antithymocyte globulin (ATG) and cyclosporine OR not eligible for ATG-based studies

  • Failure is defined as lack of hematological response, requirement for chronic immunosuppressive treatment to sustain response, or relapse
• Not eligible for a low-risk stem cell transplantation
• No evidence of risky myelodysplastic syndromes (i.e., IPSS 3-4), as defined by the presence of marrow blast excess or karyotypic abnormalities, or other primitive marrow disease
• No history of constitutional aplastic anemia (e.g., Fanconi anemia or dyskeratosis congenita)

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Not pregnant or nursing
• No active malignant tumor within the past 5 years
• Transaminases ≤ 3 times upper limit of normal (ULN)
• Albumin ≥ 1.5 g/L
• Creatinine ≤ 3 times ULN
• No CMV viremia, as defined by positive PCR or pp65 test
• No cardiac failure (i.e., ejection fraction < 35%)
• No other concurrent life-threatening disease (including HIV infection)

PRIOR CONCURRENT THERAPY:

• No prior allogeneic stem cell transplantation
• At least 2 weeks since prior cyclosporine or filgrastim (G-CSF)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall survival
Safety, as defined by occurrence of adverse effects
Hematologic response (partial and complete response, including time to response)
Failure-free survival (failure is defined as no response, chronic treatment-maintained response, or relapse)

Secondary Outcome Measures

Outcome Measure
Incidence of adverse effects after treatment
Long-term safety of alemtuzumab treatment
Time to achieve a complete hematological response
Proportion of patients maintaining hematological response free of any treatment
Incidence of relapse in responding patients
Incidence of severe infections
Requirement for IV antibiotics and antifungal therapy
Requirement for red cell and platelet transfusion
Incidence of CMV reactivation
Kinetics of immune reconstitution
Incidence of paroxysmal nocturnal hemoglobinuria (PNH) clone (lymphoid or myeloid) development
Incidence of clonal evolution (i.e., karyotypic abnormalities or secondary myelodysplasia/leukemia)

Collaborators and Investigators

• Sponsor: Federico II University
• Investigators: Principal Investigator: Bruno Rotoli, MD, Federico II University

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion: December 7, 2022
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: May 7, 2009
• First Submitted That Met QC Criteria: May 7, 2009
• First Posted (Estimate): May 8, 2009

Study Record Updates

• Last Update Posted (Estimate): August 12, 2013
• Last Update Submitted That Met QC Criteria: August 9, 2013
• Last Verified: May 1, 2009

More Information

Terms related to this study

• Keywords: aplastic anemia
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Bone Marrow Failure Disorders; Anemia; Anemia, Aplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Cyclosporine; Cyclosporins; Alemtuzumab
• Other Study ID Numbers: UNMS-ALESAA; CDR0000639649 (Registry Identifier: PDQ (Physician Data Query)); EU-20927; EUDRACT-2008-001151-22

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No