Infantile osteopetrosis (OP), a rare, inherited, life-threatening disease that causes significant morbidity and mortality, is characterized by insufficient osteoclast activity causing defective bone resorption and a marked increase in bone mass. Affected children present with failure to thrive, macrocephaly, hydrocephaly, cranial nerve deficits leading to blindness or deafness, micrognathia, small thorax, hepatosplenomegaly and hypocalcemia. Up to 75% of patients develop anemia and/or thrombocytopenia.1, 2 A number of different genes responsible for the defective function of mature osteoclasts (TCIRG1, CLCN7, OSTM1, CAII and PLEKHM1) or their failure to differentiate (RANK and RANKL) have been recognized so far, and other genetic defects are still not identified.3 The single curative treatment is allogeneic hematopoietic SCT (HSCT), which causes engraftment of macrophage-derived donor source osteoclasts, resulting in remodeling of bone and restoration of normal hematopoiesis.4
A 5-month-old male child, born to consanguineous parents, presented with failure to thrive, snoring and cough. The extended family history was positive for unexplained child mortality. Physical examination revealed frontal bossing, a bell-shaped thorax and hepatosplenomegaly. Neurological examination demonstrated nystagmus, divergent eyes, a sluggish pupillary reaction to light, a normal optic disc in the right eye and optic disc pallor on the left. Mild thrombocytopenia (150 × 109/L) and anemia (Hb 8.7 g/dL) were found. On X-ray, increased bone density was noted (Figure 1a). Genetic work-up confirmed the diagnosis of infantile OP with mutation in the TCIRG1/OC116 gene (heterozygous nucleotide exchange (CGG to TTG) in exon 3 leading to exchange of amino acid 56 Arginine to Tryptophan). An extended donor search did not reveal a matched related or unrelated donor.
Pretransplant conditioning consisted of fludarabine 180 mg/kg, busulfex 16 mg/kg, thiotepa 10 mg/kg and Campath 1H 1.2 mg/kg. Peripheral stem cells were collected from his haploidentical mother after priming with G-CSF and positive CD34+ selection with a yield of 44 × 106 CD34+ and 1.3 × 105 CD3+. The child was transplanted with 1/4 of this amount and the rest of the treated cells were frozen in three aliquots.
Neutrophils engrafted (ANC >0.5 × 109/L) on day +25 and platelets (>20 × 109/L) on day +37. The post transplant course was complicated by several septic episodes (Streptococcus group B, Stenotrophomonas), which were successfully treated with appropriate antibiotics. He developed a recognized complication of HSCT in OP: prolonged hypercalcemia and hyperphosphatemia that responded well to treatment with forced diuresis, calcitonin and phosphorus binders. Two months after HSCT, a gradual decrease in donor chimerism was observed. Six months after the transplantation only 3/200 female cells were seen on FISH examination of his BM, although no clinical deterioration was seen. The treating physicians, together with the child's family, decided to proceed to a second SCT, which was performed 7 months after the first. Treosulfan 42 g/m2, CY 120 mg/kg and rabbit ATG 5 mg/kg were used for conditioning. He received 10 × 106 CD34+ and 0.3 × 105 CD3+ thawed cells from first collection with 95% viability. He engrafted on day +12 for neutrophils and on day +14 for platelets. The second HSCT was complicated by Pseudomonas aeruginosa sepsis, bilateral otitis media and mastoiditis treated by mastoidectomy, bilateral ventilation tube insertion, antibiotics and granulocyte transfusions. Nine months after the second transplantation, the child is well with 100% donor type hematopoiesis and no evidence of GVHD. His X-rays show bone remodeling (Figure 1b).
Transplantation in OP is usually urgent because one of the major goals is to try to save vision and hearing. Thus, the transplanting physician has to make a quick and precise decision regarding HSCT from alternative sources.
Transplantations in patients with OP are characterized by a high rate of life-threatening complications in the peri-transplant period, such as hepatic veno-occlusive disease (VOD) and severe pulmonary hypertension.5, 6
An additional problem in HSCT for OP is the inability to achieve sustained donor engraftment. In one study, engraftment was seen in only 30–40% of patients when a source other than a matched-related donor was utilized.7 This obstacle poses the dilemma of whether to use myeloablative conditioning with its increased risk of transplant-related mortality or to use a less-intensive preparative regimen with the risk of loss of long-term donor chimerism. Umbilical cord blood transplantation for treatment of OP using a reduced intensity regimen has not been found to be adequate in achieving stable engraftment and results in a high rate of morbidity and mortality.8 Taking all these considerations into account, we decided to use haploidentical stem cells as a graft source. Historically, the outcome of haploidentical HSCT for treatment of OP has been disappointingly poor, with a survival rate of approximately 25%, although since 1994 there has been a trend for better results.9 A single-center study reported significant improvement in survival with five out of seven cured patients.9
Our approach demonstrates that the first conditioning regimen with fludarabine, busulfex, thiotepa and Campath 1H was sufficient to provide transient chimerism and bone remodeling (as evidenced by hypercalcemia), and prevent progressive loss of vision, but was not enough for sustained long-term chimerism. The second haploidentical HSCT was facilitated by temporary osteoclast activity, with the creation of a BM niche for successful stem cell engraftment as was previously shown in cases of a second transplantation with umbilical cord.8 We would like to emphasize the difficult course of the second HSCT, which was complicated by life-threatening episodes requiring multi-disciplinary supportive care. On the other hand, there were no signs of VOD. This may support existing data of significantly lower VOD rates when Treosulfan-based protocols are used.10 Another important issue is the use of previously collected positive selected frozen CD 34+ cells, which demonstrated high viability and expansion potential both in vitro and in vivo. This approach may help prevent additional discomfort for the donor associated with stem cell collection.
In summary, our case demonstrates the feasibility of a second haploidentical transplantation as treatment for OP. This provides an optional graft source for patients who are lacking a matched donor, and warrants further exploration of the conditioning regimen used.
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The authors declare no conflict of interest.
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Stepensky, P., Schulz, A., Lahr, G. et al. Successful second haploidentical SCT in osteopetrosis. Bone Marrow Transplant 46, 1021–1022 (2011) doi:10.1038/bmt.2010.223
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