Should busulfan-containing regimen be avoided for young female patients undergoing hematopoietic stem cell transplantation?

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In a recent issue of Biology of Blood and Marrow Transplantation, Matias et al.1 reported a successful pregnancy after allogeneic BMT for CML using a conditioning regimen consisting of BU and CY. This is the second case of successful pregnancy after this conditioning regimen in the literature, although there have been many such reports after a conditioning regimen using CY and TBI.2 Ovarian recovery was observed in 10–15% of patients who received the CY–TBI regimen, whereas it was observed only in 1% of patients who received the BU–CY regimen.2 Considering the high variability of absorption of oral BU, ovarian recovery and successful pregnancy might be because of a low bioavailability of BU in these patients.

The ovarian toxicity of BU appeared to be much stronger than that of CY, as most patients showed ovarian recovery after a conditioning regimen with high-dose CY alone for patients with aplastic anemia.2 Therefore, ovarian function can be preserved by reducing the ovarian toxicity by TBI in the CY–TBI regimen. We have investigated ovarian shielding to preserve ovarian function in young female patients undergoing hematopoietic stem cell transplantation using the CY–TBI regimen.3, 4 The recovery of menstruation cycle associated with a normalization of serum follicle-stimulating hormone level was observed in six of the eight patients at 15 months (median) (range, 6–24 months) after transplantation. One of them had an uncomplicated normal term birth with a healthy male baby (birth weight 2500 g) at 5 years after transplantation. Another patient got pregnant 1.5 years after transplantation (ongoing pregnancy). The incidence of relapse of malignancy may not increase if this procedure is performed in patients in remission, as the total radiation dose to the ovary was approximately 3 Gy in this protocol, higher than the TBI dose (2 Gy) in the non-myeloablative regimen of the Seattle group that produced similar progression-free survival and progression rate compared with myeloablative conditioning.5

The ovarian shielding was started in the University of Tokyo Hospital with a stationary vertical radiation source setting. Patients moved horizontally in a mobile box as described earlier.3, 4 However, such a facility is available only in limited centers. Therefore, we investigated the ovarian shielding in the Saitama Medical Center, with a direct lateral source and long source axis distance (400 cm) setting. Patients were treated in a lateral position alternately facing and turning their back to the beam. Position of the ovaries was checked with computed tomography and marked onto the patient's skin. A pair of columnar metal blocks (eight centimeters in height and five centimeters in diameter) attached on an acrylic board was placed in front of the patient's body as demonstrated in Figure 1. Ovarian shielding was done in all six fractions. The actual dose to the ovaries measured by the dosimeters was 2.4 Gy that was equivalent to the dose in the University of Tokyo setting. By this method, ovarian shielding can be performed in virtually all transplant centers.

Figure 1
figure1

Ovarian shielding with a direct lateral source and long source axis distance (400 cm).

Several randomized controlled trials have been performed to compare the BU–CY and CY-TBI regimens in BMT from a HLA-matched sibling donor. A meta-analysis of these trials revealed a non-inferiority of the CY–TBI regimen in terms of overall survival and disease-free survival.6 Another report showed a trend toward better survival after allogeneic transplantation for AML using the CY–TBI regimen than the BU–CY regimen.7 Furthermore, a long-term observation of one of these trials showed that the incidence of persistent alopecia was higher after the BU–CY regimen.8 A retrospective study of Japan Marrow Donor Program suggested that the CY–TBI regimen was superior to the BU–CY regimen in engraftment rate and overall survival after BMT from an unrelated donor.9 The incidence of ovarian recovery was higher after the CY–TBI regimen than the BU–CY regimen, even in the absence of ovarian shielding.2 Also, patients who will receive the CY–TBI regimen can choose whether they will undergo ovarian shielding or not. Taking all these facts into consideration, we believe that the BU–CY regimen should be avoided as far as possible in young female patients undergoing hematopoietic stem cell transplantation, although BU, especially in its intravenous form, is an attractive agent for high-dose chemotherapy before hematopoietic stem cell transplantation in the other settings because of its strong anti-tumor effect and low gastrointestinal toxicity.

References

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    Nakagawa K, Kanda Y, Yamashita H, Hosoi Y, Oshima K, Ohtomo K et al. Preservation of ovarian function by ovarian shielding when undergoing total body irradiation for hematopoietic stem cell transplantation: a report of two successful cases. Bone Marrow Transplant 2006; 37: 583–587.

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    Nakagawa K, Kanda Y, Yamashita H, Nakagawa S, Sasano N, Ohtomo K et al. Ovarian shielding allows ovarian recovery and normal birth in female hematopoietic stem cell transplantation recipients undergoing total body irradiation. Bone Marrow Transplant (in press); e-pub ahead of print 11 August 2008, PMID 18695667.

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    Socie G, Clift RA, Blaise D, Devergie A, Ringden O, Martin PJ et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Blood 2001; 98: 3569–3574.

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    Ringden O, Remberger M, Ruutu T, Nikoskelainen J, Volin L, Vindelov L et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia nordic bone marrow transplantation group. Blood 1999; 93: 2196–2201.

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    Kanda Y, Sakamaki H, Sao H, Okamoto S, Kodera Y, Tanosaki R et al. Effect of conditioning regimen on the outcome of bone marrow transplantation from an unrelated donor. Biol Blood Marrow Transplant 2005; 11: 881–889.

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Correspondence to Y Kanda.

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