Haemopoietic Stem Cell Transplantation for Diamond Blackfan Anaemia Leads to Early and Sustained Engraftment with Good Long-Term Outcomes, but Has an Increased Risk of Gut Toxicity and Lung GvHD

Haemopoietic stem cell transplantation (HSCT) is able to achieve normal haemopoiesis in patients with Diamond Blackfan anaemia. However, historically the results of alternative donors have been poor limiting its application. Little is known about the spectrum of toxicities encountered and whether it is different from other transfusion dependent anaemias using similar conditioning regimens. Furthermore, there has not been molecular data of engraftment to ascertain the intensity of available protocols. From 2006 to 2015 thirteen consecutive patients received a HSCT with either a busulfan/cyclophosphamide or a fludarabine/thiotepa/treosulfan conditioning. In addition, four other patients cared for in our centre had the HSCT elsewhere for practical reasons. Serotherapy with either alemtuzumab or ATG (Thymoglobulin) was included in all transplants. GvHD prophylaxis was provided with ciclosporin and MMF or methotrexate. The median age was 8 years (4 - 19). The donors were 10/10 matched siblings in ten patients, 10/10 unrelated donors in two patients and one 5/6 unrelated cord. The source of stem cells was BM in 9 patients, mixed cord blood and BM in 3 related patients, and unrelated cord blood in one patient. The median cell dose was 3.56 x 10⁸ TNC/kg (range 1.91 - 8.83) and 7.11 x 10⁶ CD34+/kg (range 5.39 - 10.37) for the patients receiving bone marrow only; 1.73 x 10⁸ TNC/kg (range 0.7 - 2.7) for BM and 3.94 x 10⁷ TNC/kg (range 2.54 - 5.4) and 0.93 x 10⁶ CD34+/kg (range 0.43 - 1.4) for cord blood for the patients receiving a combination of cord blood and bone marrow, and 9.61 x 10⁷ TNC/kg and 3.7 x 10⁶ for the unrelated cord. The median survival was 31.1 months (1.7-122.5). All patients were evaluated with liver biopsy pre-transplantation and defibrotide prophylaxis given if Ishak stage ≥ 3.

All patients engrafted and achieved evidence of donor haemopoiesis on day +28, and none suffered secondary graft failure. There was one death (7.7%), on day +53 due to idiopathic pneumonia syndrome in a busulfan containing regimen. Acute GvHD ≥ grade 2 occurred in 4 patients (30.8%). Chronic limited GvHD occurred in 1 patient (7.7%) and extensive in 3 patients (23.1%). Chronic GvHD resolved in all patients by 18 months. VOD occurred in 2 patients and responded to standard measures and defibrotide treatment. The median neutrophil engraftment was 17 days (range 11 to 27). The median platelet engraftment >20 x10⁹/L was 33 days (range 19 to 24) and >50 x10⁹/L was 36 days (range 19 to 94). The median time to cessation of immunosuppression was 171 days (99-356). Analyzing the entire cohort of 17 patients, it was unusual in comparison with transplants for haemoglobinopathies that 2 patients had acute and 3 chronic GvHD of the lungs, and that six had serious gut toxicity unrelated to GvHD requiring prolonged used of total parenteral nutrition and often hemorrhagic.

Chimerism studies on day +28 demonstrated 100% in whole blood (WB) and 100% in T cells (T) >95% [n=12]; day +90: 100% WB and 66.7% T >95%, and 33.3% T >50-89% [n=11]; and day +365: 100% WB and 100% T >95% [n=10].

In conclusion, related and unrelated transplantation with modern conditioning regimens leads to early and sustained engraftment with low rate of graft failure and mortality. However, there is an increased risk of serious gut toxicity and lung GvHD that in view of the low rate of mixed chimerism, may be decreased by reducing the intensity of conditioning.