A Pilot Study of Alemtuzumab (Campath[R]) in Patients With Myelodysplastic Syndrome
Study Details
Study Description
Brief Summary
This study will evaluate the safety and effectiveness of a genetically engineered antibody, alemtuzumab (Campath[R]) on patients with myelodysplastic syndrome. MDS is made up of malignant stem cell disorders that can mean low levels of red blood cells-that is, anemia-and low counts of white blood cells and platelets. Patients with MDS are at risk for infection, spontaneous bleeding, and possible progression to leukemia, a cancer of bone marrow. Although bone marrow can produce some blood cells, patients with MDS experience a decrease in production of blood cells. Alemtuzumab recognizes specific types of white cells called lymphocytes and destroys them. This study will examine not only the usefulness of the medication but also the side effects in patients with MDS.
Patients ages 18 to 72 who have MDS that requires transfusions and who do not have HIV or a life expectancy of less than 6 months may be eligible for this study. Screening tests include a complete physical examination and medical history. There will be a collection of about 8 tablespoons of blood for analysis of blood counts as well as liver, kidney, and thyroid function; a pregnancy test; an electrocardiogram (EKG) to measure electrical activity of the heartbeat; an echocardiogram (ECHO), which uses sound waves to evaluate heart function; wearing of a Holter monitor for 24 hours while the electrical activity of the heart is recorded; and a bone marrow biopsy. Patients should not receive any vaccines when taking alemtuzumab or for at least 12 months after the last dose. In addition, patients should not take the herbal supplements Echinacea purpurea or Usnea 2 weeks before beginning the study and during it.
For the study, all patients will receive a test dose of 1 mg of alemtuzumab infused into a vein during the course of 1 hour. If the dose is tolerated, the medication will be given at 10 mg doses into the vein for 10 days, as an infusion of 2 hours. Blood samples of 2 tablespoons will be taken daily, and vital signs will be measured daily. The ECHO and 24-hour Holter monitoring will be repeated after patients receive the last dose of the medication. Because suppression of the immune system results from a decrease in white cells that fight infections, patients will take medications to protect them against infections and to treat them if infections occur. If needed, patients will receive blood transfusions for their MDS. Side effects of alemtuzumab involve a temporarily significant lowering of the number of red blood cells, white cells, and platelets. Side effects of the infusion can be rigidity, or stiffness, and fever, as well as risks of infections resulting from the decrease of white blood cells. Blood counts and reactions to all procedures will be carefully monitored throughout the study. After patients receive the last dose of alemtuzumab, they will have follow-up by their referring doctor or at NIH. They must be able to return to NIH after 1 month, 3 months, 6 months, and annually for 5 years after the study. At follow-up visits, there will be blood tests to reevaluate blood counts and test for the presence of viruses. Blood tests will be done weekly for the first 3 months after patients have completed taking alemtuzumab, every other week until 6 months, and then annually for 5 years. There will also be a repeat ECHO at the 3-month visit, and a repeat bone marrow biopsy at the 5-month and 12-month follow-up visits, and as needed after that.
This study may or may not have a direct benefit for participants. For some, the antibody may improve blood counts and decrease the need for transfusions. Knowledge gained in the study may help people in the future.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Many bone marrow failure syndromes in humans are now recognized to result from immunological mechanisms. These diseases include aplastic anemia, pure red cell aplasia, and some types of myelodysplasia. Patients with these conditions, who may suffer variable degrees of anemia, leukopenia, and thrombocytopenia, alone or in combination, have been shown to respond to a wide variety of immunosuppressive agents, ranging from corticosteroids to cyclosporine (CsA) and horse antithymocyte globulin (h-ATG). However, non-response and relapse continues to be a problem. Why some patients do not respond initially or others respond and then relapse is unclear. Autoreactive T cells may be resistant to the effect of h-ATG/CsA (non-responders), while in others, residual autoreactive T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). Therefore, novel, less toxic immunosuppressive regimens that increase response rates and hematologic recovery and decrease relapse rates are needed.
One such novel therapy, alemtuzumab (Campath[R]) is a humanized IgG1 monoclonal antibody directed against the CD52 protein, which is highly expressed on all lymphoid cells and monocytes. Alemtuzumab (Campath[R]), produces profound and persistent lymphopenia, affecting predominantly the CD4+ T cell subset. This property has made it attractive in the treatment of a wide range of diseases including rheumatoid arthritis, multiple sclerosis, ocular inflammatory disease, lymphoid malignancies, organ allograft rejection, and in conditioning regimens in stem cell transplantation to prevent graft failure and graft-versus-host disease.
We therefore propose a non-randomized, off label, pilot, Phase I/II study of alemtuzumab (Campath) in MDS patients who are likely to respond to immunosuppression.
Primary endpoints will be changes in peripheral blood counts (platelets, absolute neutrophil count, reticulocyte count, hemoglobin). Secondary endpoints (in transfusion-dependent patients) include improvement in the transfusion requirements (measured as decrease in the number of transfusion administered on as needed basis), duration of response, late effects of treatment, relapse and survival.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Alemtuzumab Patients received a 1-mg test dose of alemtuzumab, and the following day, alemtuzumab was administered at 10 mg/dose intravenously for 10 days |
Drug: Alemtuzumab (Campath)
|
Outcome Measures
Primary Outcome Measures
- Response to Treatment - Hematologic Improvement or Complete Response [3 months]
Response to treatment at 3 months after the first dose of alemtuzumab. The parameters for hematologic improvement (HI) and complete response (CR) were defined according to the International Working Group (IWG) criteria. The IWG criteria for HI define specific responses of cytopenias in the 3 hematopoietic lineages: erythroid (HI-E), platelet (HI-P), and neutrophil (HI-N).7 The HIs are measured in patients with pretreatment abnormal values: hemoglobin level less than 110 g/L (11 g/dL) or RBC-transfusion dependence, platelet count less than 100 × 109/L or platelet-transfusion dependence, absolute neutrophil count (ANC) less than 1.0 × 109/L. The parameters for CR include less than 5% marrow blasts without evidence of dysplasia and normalization of peripheral blood counts, including a hemoglobin level of 110 g/L (11 g/dL) or more (in patients not receiving erythropoietin or transfusions), a neutrophil count of 1.5 × 109/L or more, and a platelet count of 100 × 109/L.
Eligibility Criteria
Criteria
- INCLUSION CRITERIA:
-
MDS with WHO classification of RA, RARS, RCMD-RS, RCUD, and RCMD and RAEB-1 (all subtypes of MDS with the exception of RAEB 2, CMML, and MDS/MPN overlap)
-
Anemia requiring transfusion support with at least one unit of packed red blood cells per month for greater than or equal to 2 months
OR
Anemia (hemoglobin less than 9 or a reticulocyte count less than 60,000)
OR
thrombocytopenia (platelet count less than 50000/ul)
OR
neutropenia (absolute neutrophil count less than 500/ul).
-
Off all other treatments for MDS (except filgrastim (G-CSF), erythropoietin, and transfusion support and related medications) for at least four weeks. Filgrastim (G-CSF) can be used before, during and after the protocol treatment for patients with documented neutropenia (less than 500/Ul) as long as they meet the criteria for anemia and/or thrombocytopenia as stated above.
-
Ages 18-72 (inclusive)
EXCLUSION CRITERIA:
-
Chronic myelomonocytic leukemia (CMML), MDS/MPN overlap, WHO RAEB-2
-
Secondary MDS
-
Failure to respond to prior therapy with ATG or ATG/CsA
-
Prior therapy with combination chemotherapy
-
Transformation to acute leukemia (FAB sub-group RAEB-T, i.e., greater than 20% blasts in marrow aspirate)
-
Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within 2 weeks of enrollment.
-
Active infection not adequately responding to appropriate therapy
-
HIV positive patients
-
Active malignant disease (excluding non-melanoma skin carcinoma)
-
Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to tolerate protocol therapy or that death within 7-10 days is likely.
-
Life expectancy less than 6 months
-
Low predicted probability of response
-
Previous hypersensitivity to alemtuzumab (Campath[R]) or its components
-
Current pregnancy, or unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential
-
Not able to understand the investigational nature of the study or give informed consent
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Chris Hourigan, BMBCh, National Heart, Lung, and Blood Institute (NHLBI)
Study Documents (Full-Text)
More Information
Publications
- Biesma DH, van den Tweel JG, Verdonck LF. Immunosuppressive therapy for hypoplastic myelodysplastic syndrome. Cancer. 1997 Apr 15;79(8):1548-51.
- Nydegger UE. Suppressive and substitutive immunotherapy: an essay with a review of recent literature. Immunol Lett. 1985;9(4):185-90. Review.
- Tichelli A, Gratwohl A, Wuersch A, Nissen C, Speck B. Antilymphocyte globulin for myelodysplastic syndrome. Br J Haematol. 1988 Jan;68(1):139-40.
- 050206
- 05-H-0206
- NCT00123721
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Out of 40 enrolled subjects, only 31 subjects were evaluable. |
| Arm/Group Title | Alemtuzumab |
|---|---|
| Arm/Group Description | Patients received a 1-mg test dose of alemtuzumab, and the following day, alemtuzumab was administered at 10 mg/dose intravenously for 10 days |
| Period Title: Overall Study | |
| STARTED | 31 |
| COMPLETED | 31 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Alemtuzumab |
|---|---|
| Arm/Group Description | Patients received a 1-mg test dose of alemtuzumab, and the following day, alemtuzumab was administered at 10 mg/dose intravenously for 10 days |
| Overall Participants | 31 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
57
|
| Sex: Female, Male (Count of Participants) | |
| Female |
9
29%
|
| Male |
22
71%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| White |
24
77.4%
|
| African American |
2
6.5%
|
| Asian |
2
6.5%
|
| Hispanic |
3
9.7%
|
Outcome Measures
| Title | Response to Treatment - Hematologic Improvement or Complete Response |
|---|---|
| Description | Response to treatment at 3 months after the first dose of alemtuzumab. The parameters for hematologic improvement (HI) and complete response (CR) were defined according to the International Working Group (IWG) criteria. The IWG criteria for HI define specific responses of cytopenias in the 3 hematopoietic lineages: erythroid (HI-E), platelet (HI-P), and neutrophil (HI-N).7 The HIs are measured in patients with pretreatment abnormal values: hemoglobin level less than 110 g/L (11 g/dL) or RBC-transfusion dependence, platelet count less than 100 × 109/L or platelet-transfusion dependence, absolute neutrophil count (ANC) less than 1.0 × 109/L. The parameters for CR include less than 5% marrow blasts without evidence of dysplasia and normalization of peripheral blood counts, including a hemoglobin level of 110 g/L (11 g/dL) or more (in patients not receiving erythropoietin or transfusions), a neutrophil count of 1.5 × 109/L or more, and a platelet count of 100 × 109/L. |
| Time Frame | 3 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Alemtuzumab |
|---|---|
| Arm/Group Description | Patients received a 1-mg test dose of alemtuzumab, and the following day, alemtuzumab was administered at 10 mg/dose intravenously for 10 days |
| Measure Participants | 31 |
| Count of Participants [Participants] |
21
67.7%
|
Adverse Events
| Time Frame | 2 years | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Alemtuzumab | |
| Arm/Group Description | Patients received a 1-mg test dose of alemtuzumab, and the following day, alemtuzumab was administered at 10 mg/dose intravenously for 10 days | |
All Cause Mortality |
||
| Alemtuzumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/31 (0%) | |
Serious Adverse Events |
||
| Alemtuzumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 15/31 (48.4%) | |
| Blood and lymphatic system disorders | ||
| Autoimmune thrombocytopenia | 1/31 (3.2%) | |
| Infections and infestations | ||
| Bacterial pneumonia | 1/31 (3.2%) | |
| Cellulitis | 1/31 (3.2%) | |
| Clostridium difficile diarrhea | 2/31 (6.5%) | |
| Neutropenic fever | 3/31 (9.7%) | |
| Non-neutropenic fever | 2/31 (6.5%) | |
| Shingles | 1/31 (3.2%) | |
| Sinusitis | 1/31 (3.2%) | |
| URI symptoms | 1/31 (3.2%) | |
| Injury, poisoning and procedural complications | ||
| Hypotension | 1/31 (3.2%) | |
| Skin and subcutaneous tissue disorders | ||
| Molluscum contagiosum skin lesion | 1/31 (3.2%) | |
Other (Not Including Serious) Adverse Events |
||
| Alemtuzumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 31/31 (100%) | |
| Blood and lymphatic system disorders | ||
| Hand swelling | 1/31 (3.2%) | |
| Cardiac disorders | ||
| Hypertension | 1/31 (3.2%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 1/31 (3.2%) | |
| Nausea | 1/31 (3.2%) | |
| General disorders | ||
| Asthenia | 2/31 (6.5%) | |
| Fatigue | 1/31 (3.2%) | |
| Stiffness | 1/31 (3.2%) | |
| Headache | 2/31 (6.5%) | |
| Infections and infestations | ||
| Orchitis | 1/31 (3.2%) | |
| Pilonidal cyst | 1/31 (3.2%) | |
| Upper respiratory tract | 9/31 (29%) | |
| Mycobacterium chelonae | 1/31 (3.2%) | |
| Injury, poisoning and procedural complications | ||
| Infusion reaction | 23/31 (74.2%) | |
| Metabolism and nutrition disorders | ||
| Decreased phosphate | 1/31 (3.2%) | |
| Elevated AST, ALT | 8/31 (25.8%) | |
| Elevated LDH | 1/31 (3.2%) | |
| Elevated creatinine | 1/31 (3.2%) | |
| Musculoskeletal and connective tissue disorders | ||
| Muscle cramps | 3/31 (9.7%) | |
| Nervous system disorders | ||
| Dizziness | 1/31 (3.2%) | |
| Neuropathic | 1/31 (3.2%) | |
| Renal and urinary disorders | ||
| Darkened urine | 1/31 (3.2%) | |
| Skin and subcutaneous tissue disorders | ||
| Facial flushing | 1/31 (3.2%) | |
| Pruritus | 1/31 (3.2%) | |
| Rash | 2/31 (6.5%) | |
| Urticaria | 3/31 (9.7%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Chris Hourigan MD |
|---|---|
| Organization | NHLBI, NIH |
| Phone | 301-451-0257 |
| hourigancs@mail.nih.gov |
- 050206
- 05-H-0206
- NCT00123721