Trial Information

Cyclophosphamide Plus Cyclosporine in Treatment-Na ve Severe Aplastic Anemia

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-na ve
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 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 NHLBI comparing high dose Cy (200 mg/kg)
and h-ATG/CsA in treatment-na 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-na
ve 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-thirdof 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 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.