Cyclophosphamide Plus Cyclosporine in Treatment-Naive Severe Aplastic Anemia

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Brief Title

Cyclophosphamide Plus Cyclosporine in Treatment-Naive Severe Aplastic Anemia

Official Title

Cyclophosphamide Plus Cyclosporine in Treatment-Naive Severe Aplastic Anemia

Brief Summary


        -  Severe aplastic anemia (SAA) can lead to problems with bone marrow health and result in
           low blood cell counts, which require frequent transfusions. Standard treatment for SAA
           involves injections of antithymocyte globulin (ATG) plus cyclosporine (CsA). This
           regimen has been shown to improve the blood counts in about two-thirds of patients.
           However, the ATG/CsA regimen has the following limitations: (a) the disease can come
           back (relapse) in about one-third of patients who improve initially; and (b) in about
           10% to 15% of cases, certain types of bone marrow cancer (such as myelodysplasia and
           leukemia) can develop (called evolution). Experience with other drugs in SAA such as
           cyclophosphamide suggests that similar response rates to ATG/CsA can be achieved with a
           lower risk of relapse and clonal evolution. However, cyclophosphamide was found to have
           significant side effects in SAA when investigated over 10 years ago due to increase risk
           of fungal infections.

        -  Better antibiotic drugs against fungus have been developed and are widely used to treat
           patients who have low white blood cell counts and are at risk of developing infections.
           In SAA patients in particular, these newer antibiotics have had a large impact in
           preventing and treating fungus infections. Researchers are revisiting the use of
           cyclophosphamide in SAA treatment, and plan to give a lower dose of CsA in combination
           with the immune-suppressing drug cyclophosphamide, as well as antibiotics to protect
           against infections, as a possible treatment for the disease.


      - To determine the safety and effectiveness of the combination of cyclophosphamide and
      cyclosporine in treating severe aplastic anemia that has not been treated with
      immunosuppressive therapy.

Detailed Description

      Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized
      by pancytopenia and a hypocellular bone marrow. Allogeneic hematopoietic stem cell
      transplantation (HSCT) offers the opportunity for cure in 70 percent of patients, but most
      patients are not suitable candidates for this treatment modality due to advanced age,
      comorbidities or lack of a histocompatible donor. For these patients, comparable long-term
      survival is attainable with immunosuppressive treatment (IST) with anti-thymocyte globulin
      (ATG) and cyclosporine (CsA). However, approximately 1/3 of patients do not show blood count
      improvement after ATG/CsA and are considered to have refractory disease. Furthermore,
      analysis of our own extensive clinical data suggests that poor blood count responses to a
      single course of ATG (non-robust responders), even when transfusion-independence is achieved,
      predicts a markedly worse prognosis compared to those who achieve a robust hematologic
      improvement (protocol 90-H-0146).

      The current limitations of IST in SAA are: 1) the majority of the responses observed
      following initial h-ATG/CsA are partial with only a few patients achieving normal blood
      counts; 2) 1/3 of patients are refractory to initial h-ATG/CsA; 3) hematologic relapses occur
      in 35 percent of responders following initial response to h-ATG/CsA; 4) among relapsed
      patients chronic use of CsA is not infrequent which often leads to toxicities from the long
      term exposure to this drug (especially in older patients); 5) and clonal evolution is still
      observed in 10-15 percent of patients. Efforts to improve initial IST in treatment-naive
      patients with the addition of mycophenolate mofetil and sirolimus to standard h-ATG/CsA or
      use of lymphocytotoxic agents such as r-ATG/CsA or alemtuzumab have not yielded the expected
      better outcomes when compared to standard h-ATG/CsA (protocols 00-H-0032, 03-H-0193, and
      06-H-0034). Because the majority of SAA patients in the US and worldwide are treated with IST
      due to lack of an human leukocyte antigen (HLA)-matched donor or inaccessibility to
      transplant, novel regimens are needed to overcome the current limitations of IST in SAA.
      Towards the goal of addressing these limitations we are proposing a regimen of
      cyclophosphamide (Cy) plus low dose CsA.

      Cy has been proposed by the investigators at Johns Hopkins as an alternative IST regimen to
      h-ATG/CsA. In a pilot study, high dose Cy (200 mg/kg) yielded similar results to that
      observed for h-ATG/CsA. In a randomized study, at National Institute of Heart, Lung, and
      BIood (NHLBI), comparing high dose Cy (200 mg/kg) and h-ATG/CsA in treatment-na(SqrRoot) ve
      patients (protocol 97-H-0117), excess toxicity and deaths from invasive fungal infections
      were observed in the Cy arm which led to the discontinuation of this regimen. Recently
      reported long-term results from Johns Hopkins of 44 treatment-naive patients who received
      high dose Cy (200 mg/kg) as sole therapy for SAA showed that a greater number of complete
      responses were observed with few instances of relapse and clonal evolution noted with Cy when
      compared to h-ATG/CsA (historical comparison). In an accompanying editorial, the incidence of
      invasive fungal infections in this cohort were highlighted. Of note, antifungal prophylaxis
      against Aspergillus sp, the deadliest culprit when neutropenia is severe and prolonged, was
      not employed in the Hopkins high dose Cy protocol. In the Chinese experience, data presented
      in a recent meeting in Japan showed that lower doses of Cy (120 mg/kg) plus CsA achieved
      similar results reported by the Hopkins investigators with reduced toxicity. These data
      suggest that Cy has activity in SAA and could be a viable alternative to standard h-ATG/CsA
      if the immediate toxicities associated to prolonged neutropenia could be overcome.

      In recent years we have observed a marked improvement in survival in our SAA patients
      especially among those who are non-responders to IST where pancytopenia remain persistent for
      months. A detailed analysis (shown in Section 2.4 Scientific and Clinical Justification of
      Protocol) showed that better antifungal supportive care in recent years contributed to a
      reduction of infection-related mortality in the months following IST among non-responders,
      who remain persistently neutropenic. This observation suggests that nowadays patients can be
      better supported through periods of neutropenia due to improved antifungal supportive care
      with agents that are better tolerated (compared to deoxycholate amphotericin B), retain a
      broad-spectrum of activity (especially against Aspergillus sp), and can be administered
      orally as an outpatient.

      The fact that about one-third of initial refractory patients respond to retreatment and that
      late complications (relapse and clonal evolution) occur in about 40-50 percent of cases
      suggest that initial IST with h-ATG/CsA has important limitations. Therefore, we propose to
      investigate Cy + CsA as initial therapy in SAA. Our intention is not to recapitulate the high
      dose Cy regimen initially proposed by Hopkins (200 mg/kg) but instead, investigate lower
      doses proposed by the Chinese (120 mg/kg) in addition to low dose CsA (target therapeutic
      level 100 200 microg/L). The ability to better support patients during periods of neutropenia
      with better antifungals should allow for the immediate toxicity to be overcome and assess the
      activity of Cy in SAA.

      The main objective of this study is to assess the safety and efficacy of Cy 120 mg/kg + low
      dose CsA (100 200 microg/L) in treatment-naive SAA. The primary endpoint will be hematologic
      response, defined as no longer meeting criteria for SAA, at 6 months. Secondary endpoints are
      relapse, robustness of hematologic recovery at 6 months, response at 3 months and 12 months,
      survival, clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and
      acute leukemia. The primary endpoint will be changes in absolute neutrophil count, platelet
      count, and reticulocyte count at 6 months. Secondary endpoints will include time to relapse,
      changes in cytogenetics, and time to death.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Blood Counts and Adverse Event Profile After 6 Months of Treatment.


Aplastic Anemia



Study Arms / Comparison Groups

 SAA hematologic response
Description:  Treatment-naive severe aplastic anemia patients will receive a low dose of cyclophosphamide (120mg/kg) and low dose cyclosporine ( target therapeutic level of 100-200 micrograms per liter). Cyclophosphamide will be given once daily for 4 doses. Cyclosporine will be started after cyclophosphamide completion, cyclosporine will be given twice daily. The dosing will be modified to attain the therapeutic level.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

August 2010

Completion Date

September 2014

Primary Completion Date

September 2014

Eligibility Criteria


        Severe aplastic anemia characterized by:

        Bone marrow cellularity less than 30 percent (excluding lymphocytes)


        At least two of the following:

        Absolute neutrophil count less than 500/ microL

        Platelet count less than 20,000/ microL

        Absolute reticulocyte count less than 60,000/ microL

        Age greater than or equal to 2 years old

        Weight greater than or equal to 12 kg


        Diagnosis of Fanconi anemia

        Cardiac ejection fraction less than 30 percent (evaluated by ECHO)

        Evidence of a clonal hematologic bone marrow disorder on cytogenetics. Patients with the
        presence of trisomy 8, loss of Y or del(20q) will not be excluded in the absence of
        dysplastic changes in the marrow. Patients with very severe neutropenia (ANC less than 200
        /microL) will not be excluded initially if cytogenetics are not available or pending. If
        evidence of a clonal disorder is later identified, the patient will go off study.

        Prior immunosuppressive therapy with high dose Cy or ATG

        Infection not adequately controlled with appropriate therapy

        Serologic evidence of HIV infection

        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 30 days is likely

        Subjects with cancer who are not considered cured, are on active chemotherapeutic treatment
        or who take drugs with hematological effects

        Current pregnancy or unwillingness to take oral contraceptives or refrain from pregnancy if
        of childbearing potential

        Not able to understand the investigational nature of the study or to give informed consent.




2 Years - N/A

Accepts Healthy Volunteers



Danielle M Townsley, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party

Principal Investigator

Study Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Danielle M Townsley, M.D., Principal Investigator, National Heart, Lung, and Blood Institute (NHLBI)

Verification Date

April 2017