Bone Marrow Transplantation for Severe Aplastic Anemia Secondary to Temozolomide

Abstract

Radiotherapy (RT) and concomitant/adjuvant therapy with temozolomide (Temodar) is a common treatment regimen for children and adults with glioma. Although temozolomide is generally well tolerated with temporary myelosuppression as the primary dose-limiting toxicity, irreversible bone-marrow aplasia after treatment with temozolomide has been reported. We report the case of an adolescent patient with a high-grade glioma who, after > 2 years of event-free survival, underwent successful bone marrow transplantation for treatment of temozolomide-induced severe aplastic anemia (SAA).

Introduction

Radiotherapy (RT) and concomitant/adjuvant therapy with temozolomide (Temodar) has become the standard treatment for glioblastoma (World Health Organization Grade 4) in adults after this regimen demonstrated improved progression-free and overall survival compared to RT alone.[1] Additionaly, temozolomide has been used in the treatment of adults with low-grade glioma[2,3] and children with both high-[4,5] and low-grade glioma.[6,7] Although temozolomide is generally well tolerated with temporary myelosuppression as the primary dose-limiting toxicity, irreversible bone-marrow aplasia after treatment with temozolomide has been reported.[8–11] With permission from our institutional review board, we report the case of an adolescent patient with a high-grade glioma who, after > 2 years of event-free survival, underwent bone marrow transplantation for treatment of temozolomide-induced severe aplastic anemia (SAA).

Case History

A previously healthy 16 year-old girl presented in April 2004 with a left fronto-parietal intraparenchymal hemorrhage that was presumed to be from an arteriovenous malformation. After a second hemorrhage in July 2004, she underwent a brain biopsy and was subsequently referred to our institution because of concern for an underlying malignant tumor. A debulking surgery was performed and histopathological examination of the tumor revealed areas of necrosis and scattered mitotic figures among a population of uniform small cells with a high nuclear:cytoplasmic ratio and focal astrocytic, epithelioid, or rhadboid differentiation. An unusual feature of the tumor's architecture was its circumscribed nature, as it showed little tendency to invade adjacent cerebral tissues. Many tumor cells expressed glial fibrillary acidic protein, but there was no immunoreactivity for epithelial membrane antigen, synaptophysin or smooth muscle actin. Minimal tumor cells (<1%) expressed convincing immunoreactivity for neurofilament proteins. All tumor cells expressed the SMARCB1 (INI1) gene product. Interphase FISH showed no PTEN loss or EGFR amplification, although polysomy of chromosome 7 was detected. Despite the unusual appearance, based on the astrocytic phenotype and high-grade features, the patient was diagnosed with glioblastoma.

She was enrolled in August 2004 on the Children's Oncology Group (COG) protocol CNS126, a phase II study utilizing cranial irradiation with concurrent temozolomide at a dose of 90mg/m² per day. Patient became pancytopenic on day 24 of therapy and temozolomide was discontinued. She completed radiation therapy to a total dose of 59.4 Gy.

Ultimately, the patient became red blood cell and platelet transfusion dependent with an absolute neutrophil count (ANC) of zero. Bone marrow aspirate at this time revealed a markedly hypocellular marrow (<1% cellularity) with trilineage hypoplasia and stromal degenerative changes, but no dysplasia, infection, or neoplasm (Fig. 1a). She was diagnosed with SAA and received filgrastim therapy from December 2004 to March 2005. Although the ANC responded well with levels consistently >0.5 × 10⁹/L, she remained transfusion dependent with weekly requirement of packed red blood cell transfusions to keep her hemoglobin >8g/dL and twice weekly platelet transfusions to maintain her counts >20 × 10⁹/L due to frequent epistaxis. Following discontinuation of filgrastim severe neutropenia re-occurred and the patient experienced frequent diarrheal illness and recurrent anal fissures. A bone marrow aspirate in September 2005 revealed a cellularity of <5% with small patches of myelopoiesis and erythropoiesis, markedly decreased megakaryocytes, and no morphologic evidence of microorganisms or malignancy. Cytogenetic analysis was not completed as no metaphases were available for analysis. Subsequent chromosome breakage analysis (DEB-induced) was within normal range and paroxysmal nocturnal hemoglobinuria screen was negative. She was restarted on a colony-stimulating factor. Unfortunately, sargramostim did not reveal additional benefit and caused significant local bruising and burning, so that after 2 months of treatment, filgrastim was again utilized. Our patient was diagnosed with significant iron overload (serum ferritin >5000ng/ml and liver iron concentration of 30mg/gm) in March 2006 and oral chelation therapy was initiated. Despite stable residual tumor on surveillance neuroimaging, the patient's quality of life markedly deteriorated given the degree of transfusion dependence and its associated side-effects.

figure 1.

In June 2006, 26 months after her sentinel bleed and 23 months after diagnosis of glioblastoma, she began intensive immunosuppressive therapy (IST) for SAA with anti-thymoglobulin (ATG), cyclosporine, and corticosteroids. Unfortunately, she did not have an adequate response to IST and bone marrow transplantation (BMT) was considered as potentially curative therapy for SAA. After careful deliberation and consideration of the patient's extended progression-free survival and her significant desire to improve her quality of life, the patient underwent an 8/8 HLA-matched unrelated donor BMT in March 2007. The preparative regimen consisted of cyclophosphamide, 8Gy total lymphocyte irradiation, and ATG. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Despite initial chimerism studies by variable number of tandem repeats (VNTR) being 100% donor (T-cell chimerism = 98%), her graft function remained quite poor. In early August 2007, she received additional immunosuppression (ATG) followed by a stem cell boost from the original donor. Cyclosporine was initiated again for GVHD prophylaxis. Her graft function continues to improve (Fig. 1b). Currently, 13 months after BMT and 45 months after diagnosis of glioblastoma, the patient is 100% donor by VNTR analysis, has reduced transfusion requirements (only platelet transfusions every 1–2 weeks to maintain her counts >20 × 10⁹/L), no longer requires IST, is without GVHD, and is infection free. Importantly, she has experienced significant improvement in her quality of life as she now resides at home, interacts more often with her friends, and envisions enrolling in her local community college this fall.

Conclusion

Temozolomide, an oral methylating agent, is frequently used in the treatment of patients with gliomas. Although generally well tolerated, several patients have developed temozolomide-induced aplastic anemia. Given the use of temozolomide in patients with a more favorable tumor histology, this report of a long-term survivor of glioblastoma and SAA who experienced significantly improved quality of life after receiving a matched unrelated donor BMT is noteworthy.