Treatment of severe aplastic
anemia using high-dose cyclophosphamide alone in China
Zhixiong Li,1,2 Songmei Yin,1 Shuangfeng
Xie,1 Liping Ma,1 Danian Nie,1
Lizuo Xsu1
1Division of Hematology, Sun Yat-Sen Memorial Hospital,
Sun Yat-Sen University of Medical Sciences, Guangzhou, PR. China.
2Heinrich-Pette-Institute, University of
Hamburg, Hamburg, Germany.
Correspondence: Z. Li, Heinrich-Pette-Institute, University of
Hamburg, Hamburg, Germany. E-mail: li@hpi.uni-hamburg.de
Two young patients with acquired severe aplastic anemia (SAA )
and lacking an HLA-identical sibling were treated with one course
of high-dose Cyclophosphamide (Cy) (160mg/kg). One patient, who
received this approach immediately after confirmation of the
diagnosis, got complete hematopoietic recovery at day 220 after
therapy, and is still in complete remission after 8 months
fellow-up. Another patient, who didnot respond to prior therapy,
died 2 weeks after treatment. This result supports previous
studies which indicated high effectiveness of high dose
cyclophosphamide in SAA patients without prior therapy. Patients
with acquired severe aplastic anemia (SAA) can be successfully
treated by allogeneic bone marrow transplantation (BMT) and
immunosuppressive therapy (i.e. antithymocyte globulin/ATG,
antilymphocyte globulin/ALG, Cyclosporine A/CSA). However, the
majority of patients with SAA are not candidates for BMT because
of lacking an HLA-identical sibling, and immunosuppressive therapy
is limited by the fact that up to 50% of successfully treated
patients either relapse or develop late clonal
diseases.1,2 Recently Brodsky et al.2,3
reported that durable complete remissions in SAA can be achieved
by high-dose Cyclophosphamide (Cy) without allogeneic BMT. Here we
present our preliminary result of two patients treated with this
approach.Two male patients, aged 19 and 18 years, lacking an
HLA-identical sibling, were treated in May 1999 and July 1999 on a
normal ward without LAFR in Sun yat-Sen Memorial Hospital,
respectively. SAA was diagnosed by standard criteria.2
After confirmation of the diagnosis, patient 1 received
immediately one course of cyclophosphamide (Asta, Germany) at
40mg/kg/d intravenously on days 1 through 4. Mesna (total dose:
120% of Cy) was given during Cy therapy for preventing hemorrhagic
cystitis. GM-CSF (dose: 5µg/kg) and Epo (4,000U/week) were
administered on day 40 after high-dose Cy therapy for 2 weeks and
8 weeks, respectively. The time to 500 neutrophils, last red cell
transfusion and last platelet transfusion was day 45, day 56 and
day 65, respectively. A normal myelogram was achieved at day 94.
An ANC of 1,5 x 109/lL, hemoglobin level>130 g/L and
platelet count>125 x109/L were reached at day 150,
170 and 220, respectively. Therefore a complete remission was
achieved in this patient at day 220 after Cy therapy. High-dose Cy
was well-tolerated in this patient despite developing febrile
neutropenia requiring combination of antibiotics. The patient is
still in complete remission after 8 months fellow-up. Patient 2
has received a combination of androgen and CSA for 5 months before
treatment of high-dose Cy. Appendectomy was performed one month
before Cy therapy because of a perforated acute appendicitis. At
the beginning of Cy therapy, he had still fever, chest X-ray and
computer tomography revealed minimal invasive pulmonary infection,
but blood, bowel and urine cultures were negative. His blood
counts were as following: ANC: 0,4 x 109/lL, platelet
count: 10 x109/L and reticulocytes: 1%. Under treating
with intensive combination of antibiotics and antifungal agents,
high-dose Cy (160mg/kg) was administered using the same protocol
as patient #1. After Cy-therapy, no significant change was shown
by chest x-xay, but blood cultures made one day before his death
demonstrated candidemia. The patient didn´t respond to
therapy and died 2 weeks after treatment from an intracerebral
hemorrhage. In addition, neither of the two patients developed
hemorrhagic cystitis.
Our preliminary results are in agreement with the reports of Brodsky et al. which indicated that high-dose Cy without BMT is a promising approach in patients with SAA, when used as front-line therapy. Whether high-dose Cy can replace the standard combination of ATG/ALG and CSA as a immunosuppressive therapy of choice in SAA will be answered by ongoing randomized studies aimed this question. As high-dose Cy can produce cure rates above 70% in SAA patients without any prior therapy, and is not restricted by age or donor availability,2,3 one may expect that the majority of patients with SAA, who don´t have an HLA-identiacl family donor, could be successfully treated by this approach, and therefore mismatched or unrelated allogenic BMT might not be necessary for this group of patients any more. This needs certainly further careful inverstigation. But if this would be in the case, it would result in reducution of treatment costs up to 50% and maybe hopefully improve outcome of patients with SAA, particularly in developing countries, where the incidence of SAA is much higher than in the west, and BMT approach is usually limited by high expenses and donor availability.
