Fludarabine, Cyclophosphamide, and Antithymocyte Globulin for a ...

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MRD. Cy-140, ATG. CMV, rectal carcinoma Alive, > 463 days. Langston et al. [3]. 2. M. 22. MRD. Cy-140, ATG. aGVHD*. Died, 44 days after SCT Langston et al.
Biology of Blood and Marrow Transplantation 13:366-368 (2007) 䊚 2007 American Society for Blood and Marrow Transplantation 1083-8791/07/1303-0001$32.00/0 doi:10.1016/j.bbmt.2006.11.015

LETTER

TO THE

EDITOR

Fludarabine, Cyclophosphamide, and Antithymocyte Globulin for a Patient with Dyskeratosis Congenita and Severe Bone Marrow Failure Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome characterized by a classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia [1]. Two-thirds of deaths in patients with DC are attributed to bone marrow (BM) failure [2]. Conventional hematopoietic stem cell transplantation (SCT) is associated with an unexpectedly high frequency of early and late complications [3-6]. Although reduced-intensity conditioning (RIC) has been safely used in this setting, with durable engraftment and lower toxicity, there is no consensus regarding the optimal conditioning regimen for this disorder [3,7-11]. The European Group for Blood and Marrow Transplantation (EBMT) has developed an RIC regimen for patients with severe aplastic anemia (SAA) who are not eligible for conventional conditioning before SCT [12]. Here we report the second case in which such a regimen was used before SCT in a patient with DC and SAA [8]. We also review the relevant literature on SCT and DC. The patient was a 5-year-old girl, the fourth child of a consanguineous couple. Pregnancy, delivery, growth, and development were all normal. The couple’s second child, also a girl, had clinical features of DC and died of BM failure. The patient developed seizures at age 1 month, but these were well controlled by phenytoin. The nails of her hands and feet were dystrophic at age 2 years, and 2 years later reticular pigmentation of the skin and intermittent oral leukoplakia appeared. In June 2004, at age 5 years, the patient’s parents came in for consultation because of her easy bruising. Laboratory tests revealed a hemoglobin level of 7.8 g/dL, hematocrit of 22%, a white blood cell count of 2100/mm3 (neutrophils 609/mm3), and a platelet count of 16,000/mm3. BM aspiration and biopsy were compatible with SAA. The karyotype was normal, and the diepoxybutane test was negative. Given the patient’s history of seizures, computed tomography (CT) scan of the head was obtained before BM transplantation (BMT) and was found to be normal. In December 2004, the patient underwent BMT, 366

with her healthy HLA-identical 17-year-old sister as the donor. The EBMT RIC regimen was used [12] after approval by the institutional board and signed informed consent from the parents. The following drugs and doses were given on days ⫺6 to ⫺3: fludarabine (Flu) 30 mg/m2, cyclophosphamide (Cy) 300 mg/m2 (40 mg/kg) and antithymocyte globulin (ATG) 3.75 mg/kg (Thymoglobulin; Genzyme, Cambridge, MA). Unmanipulated BM was infused on day 0. Graft-versus-host disease (GVHD) prophylaxis consisted of mycophenolate mofetil (MMF) 15 mg/kg/day and cyclosporine A (CsA) 5 mg/kg/day, starting on day ⫺2, for 6 and 12 months, respectively. The graft contained 2.06 ⫻ 108 mononuclear cells/kg. Engraftment occurred on day ⫹9 (984 neutrophils/mm3). The posttransplantation course was uneventful, with no signs of GVHD. On posttransplantation days 30, 180, and 360, variable number of tandem repeats analysis on peripheral blood showed 100% donor chimerism of neutrophils and mononuclear cells. The patient was well 17 months after the transplantation, with normal growth and development. The only treatment option for DC patients with SAA has been allogeneic SCT; however, conventional myeloablative conditioning regimens are associated with frequent and severe adverse events (eg, interstitial pneumonia, lung fibrosis, veno-occlusive disease, secondary tumors) [3-6]. The optimal conditioning regimen for these patients remains to be determined. The chromosomal instability and inherited extreme short telomerase found in patients with DC is a possible explanation for their increased susceptibility to posttransplantation complications [13]. The EBMT RIC regimen offers a high engraftment rate and low toxicity in patients undergoing SCT for acquired and constitutional SAA [12]. The case reported here suggests that such a regimen also may be used safely in patients with DC. The low-intensity dose is possibly less toxic to the abnormal telomerase activity and telomerase shortening observed in patients with DC [1,4]. In this case, GVHD was successfully prevented by combining MMF and CsA. Moreover, the high dose

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Letter to the Editor

Table 1. RIC for Patients in SAA with DC

Date

Patient

Sex

Age (years)

SCT Donor

1996

1 2 3

M M M

33 22 18

MRD MRD MRD

Cy-140, ATG Cy-140, ATG Cy-80, Bus-0.8

4

F

21

MRD

Cy-80, Bus-0.8

2002

5

M

8

MRD

2003

6 7 8 9 10 11

F M F M M F

10 3 8 15 5 5

MRD MUD MUD MUD MRD MRD

Cy-40, Flu-120, and ATG Flu-30, TBI-2 Gy Flu-30, Cy-60, ATG Flu-30, Cy-60, ATG Flu-30, Cy-60, ATG Cy-60, ATG Cy-40, Flu-120, ATG

1999

2005 2005 2006

Conditioning

Complications

Outcome post-HSCT

Reference

CMV, rectal carcinoma aGVHD* GVHD vs DC-related skin changes GVHD vs DC-related skin changes None

Alive, > 463 days Died, 44 days after SCT Alive, > 6 years

Alive, 4 years

Langston et al. [3] Langston et al. [3] Ghavamzadeh et al. [7] Ghavamzadeh et al. [7] Nobili et al. [8]

None None None Diffuse capilaritis None None

Alive, 2 years Alive, > 15 months Alive, > 17 months Died, 48 days Alive, 6 months Alive, 17 months

Güngör et al. [9] Dror et al. [10] Dror et al. [10] Brazzola et al. [20] Ayas et al. [11] Present report

Alive, > 5 years

F indicates female; M, male; MRD, matched related donor; MUD, matched unrelated donor; CMV, cytomegalovirus. *Cause of death.

of ATG given pretransplantation (a total dose of 15 mg/kg) has been shown to be effective in preventing acute GVHD [14,15]. The same conditioning regimen was used successfully in an 8-year-old boy with DC who underwent cord blood transplantation for SAA [8], with no early or late complications seen during 3 years of follow-up. GVHD prophylaxis consisted of CsA alone. Including the present case, 30 patients with DC have now undergone SCT [1,3-11,16-22]. Nine of these patients received RIC [3,7-11,20], of whom 2 died (22%) [3,20]. In contrast, the mortality rate in the patients who underwent conventional transplantation was 71% (15 of 21 patients who received conventional myeloablative SCT died) [1,3-5,16-22]. Most of the deaths were related to the SCT procedure. The 2 patients who died after RIC had received higher doses of Cy (140 mg/kg and 60 mg/kg) than our patient (40 mg/kg) [3,20]. Six patients, including our patient, have received Flu-based regimens [8-10,20]; the only death was of a patient who had received a higher dose of Cy and UD marrow, which per se carries a higher risk. Compared with the RIC protocol followed here, previous RIC regimens have used considerably higher Cy doses [3], or a lower CsA dose but with another alkylating agent as an adjunct, such as busulfan [7], or total body irradiation (TBI) (Table 1) [9]. Although pulmonary complications have been reported in DC patients with or without SCT, it is advisable to avoid conditioning agents known to be associated with pulmonary toxicity, such as busulfan and irradiation [4]. Dror et al. [10] used a similar conditioning regimen for 2 patients with DC and severe marrow failure who underwent SCT with matched UDs. The regimen consisted of Flu 30 mg/m2/day from days ⫺10 to ⫺5, Cy 60 mg/kg/day on days ⫺6 and ⫺5, and equine thymocyte globulin 40 mg/kg/day from days ⫺4 to

⫺1. Durable engraftment was achieved, and no early or late severe adverse effects occurred. However, this same regimen was later administered to a boy with DC who also underwent UD BMT and died of an early complication (diffuse capillaritis). That regimen included a higher dose of Cy (60 mg/kg vs 40 mg/kg in the present conditioning regimen). This illustrates that, despite early encouraging reports of some RIC regimens, the ideal approach to patients with DC has not yet been identified, and modified SCT is warranted. The transplantation regimen used here was well tolerated in our patient and in the previously reported case [8], both of which involved matched donors. This regimen has also been safely used in patients with acquired SAA who underwent SCT from mismatched donors and UDs. The value of this regimen in patients with DC who have alternative donors remains to be determined. Given the encouraging results, the high mortality of the conventional regimen, and the lack of consensus regarding the ideal conditioning regimen in patients in SAA with DC, we believe that this protocol should be explored further [23].

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Letter to the Editor

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Fabiana Ostronoff, MD Mauricio Ostronoff, MD Rodolfo Calixto, MD Rodrigo Florêncio, MD Mariana C. Domingues, MD Ana Patricia Souto Maior, research nurse Alexandre Sucupira, pharmacist Clemente Tagliari, MD Hematology and Bone Marrow Transplantation Unit Real Hospital Português Recife, Brazil