Allogeneic hematopoietic SCT and mechanical heart valve: feasibility of reduced toxicity myeloablative conditioning

Nowadays, heart valve replacement by mechanical heart valve (MHV) is considered as a standard practice procedure, but it remains to be associated with significant morbidity and potential mortality.1 Major complications include valve thrombosis/dysfunction and bleeding related to the mandatory long-term anticoagulation therapy.2 Both potential complications may be exacerbated in patients treated for hematological malignancies because disease itself, because of infections and also because of the treatments used.3 Regarding allo-SCT, MHV is considered as an exclusion criterion by most of the physicians and, to our knowledge, there is no report of allo-SCT for patients with MHV. Furthermore, heart valve disease including MHV is included in most of the current comorbidity scales developed to determine the acceptable nonrelapse mortality risk for each patient. In Sorror's4 transplantation-specific comorbidity index (HCT-CI), heart valve disease had a rating of 3. Indeed, a HCT-CI score of 3 or more predicts nonrelapse mortality and OS rates of 41 and 34%, respectively. However, recent reports addressing the topic of mitral replacement by MHV showed good long-term survival of 40.8% at 25 years,5 and advances in the control of nonrelapse mortality risk by less-toxic conditioning regimens6, 7 allow reconsideration of MHV as a systematic contraindication for allo-SCT. We report here the case of a woman with mitral MHV, who had been transplanted for a hypoplastic myelodysplastic syndrome.

A 56-year-old woman developed left atrium sarcoma in the year 2006, which was treated by cardiac surgery, mechanical mitral valve replacement and secondary chemotherapy (ifosphamide and doxorubicin). She obtained a durable CR, but 2 years later, she was hospitalized for progressive pancytopenia with transfusion dependence for plts and red cells. A BM biopsy showed a hypoplastic BM with myelodysplastic features and no excess of blasts. Cytogenetic analysis showed a monosomy 7 and a translocation (3;21). The international prognostic scoring system score was 1.5 and WHO classification-based prognostic scoring system score was 3 indicating a high risk of leukemic transformation. The patient had a matched sibling donor, and a frontline allogeneic PBSC transplantation was decided despite a HCT-CI score of 6. Pretransplant cardiac evaluation found a left ventricular ejection fraction of 60% without any valvular dysfunction. For conditioning, we used a myeloablative regimen: fludarabine (40 mg/m2, 4 days), i.v. BU (130 mg/m2, 3 days) and antithymoglobulin (2.5 mg/kg, 2 days). The GVHD was prevented by i.v. CsA at 3 mg/kg, starting at day −3. Continuous i.v. heparin (200 U/kg/day) was given for thrombosis prophylaxis and plts was transfused if the plt count was below 20 g/l. A total of eight plt packs were used during aplasia. Engraftment was fast with ANC >1 g/l at day 23 and plt >20 g/l at day 26. Full donor chimerism was confirmed at day 48. There was no major bleeding, no cardiac failure or MHV dysfunction. The s.c. low-MW heparin (Tinzaparine, 175 UI/kg) was used for prevention of thrombosis after discharge. Early BM evaluation showed a CR, including the disappearance of chromosomal abnormalities. The patient experienced a mild cutaneous chronic GVHD. Unfortunately, she relapsed 4 months after transplantation with the same clinical presentation and died from non-documented pneumonia before any other treatment could be administered.

This report illustrates that allogeneic transplantation could be manageable in patients with MHV. The use of conditioning based on i.v. BU administration delivers an intensive regimen with significant anti-leukemic potential and reduced toxicity.6 Moreover, the use of PBSC graft hastens plt engraftment.8 Data from reduced intensity conditioning regimen9 showed that 70% of patients have a plt count over 100 g/l at day 100 that may allow to re-introduce long-term anticoagulation with coumadin derivatives quite early. However, acute GVHD and a low plt count before conditioning are negative predictive factors for long-term plt recovery and should be integrated in the decision model for reintroducing these drugs. The use of i.v. or s.c. heparin with adapted transfusion levels allows the easy management of the bleeding/thrombosis balance in the initial period. In the present case, the patient died rapidly from progressive disease, and the choice of allo-SCT may be discussed as the optimal strategy on both efficacy and toxicity aspects. Induction chemotherapy may be discussed as the international prognostic scoring system score was 1.5, but unfavorable cytogenetics predicted poor results and the expected long-lasting thrombocytopenia seemed hardly manageable. The alternative strategy should have been the use of demethylating agents such as azacitidine. Response rate reached 50–60% in patients harboring monosomy 7;10 a sustained hematological improvement occurred in most of the patients, with major plt improvement in 33% of cases and a median response duration of 13.6 months. Even if the plt response may be fast for some patients, in most of the cases response is delayed for up to 6 months, especially in patients with severe thrombocytopenia. In the AZA001 study, 74% of the patients experienced grade III to IV thrombocytopenia and bleeding remained one of the main cause of treatment-related death. Moreover, most of the patients treated with frontline azacitidine relapsed within 2 years, and this is an important issue when an identical sibling is available and time to transplant is limited. Finally, treatment with azacitidine as a preparative regimen for transplantation could have been used. Nevertheless, thrombocytopenia and bleeding occurred in the first cycles and the effects on post transplant disease control remained hypothetical. In conclusion, we report here the first case of patient with MHV treated by allo-SCT. The use of PBSC graft, reduced toxicity conditioning and adapted transfusion/thrombosis prevention strategies allowed to limit the risk of major complications. Reporting of additional cases and further evaluation in collaboration with cardiologists are warranted to evaluate the optimal standard of care for these patients.

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Acknowledgements

TP thanks Dr G Maxant of the Cardiovascular Surgery Department, CHU Montpellier for research support.

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Prébet, T., Devillier, R., Fürst, S. et al. Allogeneic hematopoietic SCT and mechanical heart valve: feasibility of reduced toxicity myeloablative conditioning. Bone Marrow Transplant 45, 1574–1575 (2010). https://doi.org/10.1038/bmt.2010.16

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