Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Congenital Amegakaryocytic Thrombocytopenia, a PDWP/EBMT Study

Background: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome, which is characterized by a severe thrombocytopenia at birth without predictive stigmata and by a risk for progression into aplastic anemia and myeloid malignancy. CAMT is caused by a mutation of the thrombopoietin (THPO) receptor, c-Mpl. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only potentially curative treatment option. The outcomes of transplanted patient for CAMT have not been well described.

Design/Method We conducted an EBMT (European Society for Blood and Marrow Transplantation) registry-based retrospective study in patients diagnosed with CAMT receiving an allogeneic HSCT.

Results 66 patients with CAMT could be included which were transplanted between 1998 and 2020. Median age at diagnosis was 1.3 years (0.1-2.8). The mutation was identified in 18 patients and absent in 7 patients. For the remaining patients, the genetic testing was not performed. The median age at transplant was 3.2 years (0.3-13). The median year of transplant is 2013. Bone marrow (BM) was the main stem cell source (59%) followed by peripheral blood (PB) (27%) and cord blood (CB (12%)) with 1 BM+CB from the same donor. The predominant donor type was HLA-matched (65% with matched-sibling donor (MSD) 34.8%, unrelated donor (UD) 10/10 22.7%, matched other relative 4.5% and umbilical cord blood (UCB) 6/6 3%)), followed by UD < 10/10 (15.1%), then the UCB< 6/6 (9%) then haploidentical (7.5%) and UD missing HLA (3%). The most frequently used conditioning regimen included busulphan and cyclophosphamide in 30% of cases, followed by the busulfan-fludarabine (14%) and treosulfan-fluradarabine-thiotepa (14%). Considering death and second transplant as competing event, platelet recovery (>= 20 000/mm³) occurred in 69.8% (95% confidence interval [CI] 56.6-79.7%) at day 60 and 71.4% (95% [CI] 58.2-81.1%) at day 180. Grade II-IV acute graft-versus-host disease (GvHD) was 20% (95% CI 11.3-30.5%), grade III-IV was 3.1% (95% CI 0.6-9.6%), and the 6-year cumulative incidence (CI) of chronic GvHD was 14.3% (95% CI 6.9-24.3%). The 6y-CI was 17.2% (95% [CI] 9.1-27.5%). Six-year overall survival (OS) was 85.6% (95% [CI] 74-92.3%) with a transplant related mortality of 8.0% (95% [CI] 2.9-16.6%). 6y-GVHD/-graft failure-free survival was 65.7% (95% [CI] 52.6-76%). OS was significantly lower after CB transplantation (6y OS: 37.5% with 95% [CI] 8.7-64.4%) than after BM (6y OS: 95% [CI] 81.5-98.7%) or PB (6y OS: 88.9% 95% [CI] 62.4-97.1%) transplantation (p<0.001).

Conclusion: This study demonstrates that HSCT, the only available potentially curative option, has an acceptable 6-year overall survival and an acceptable rate of chronic GvHD. While the number of patients in such a rare disease does not allow to perform multivariable analyses, we can confirm that OS is better with the use of BM as the main stem cell source compared to the CB.

Merli:JAZZ Pharmaceuticals: Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Díaz-de-Heredia:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: meeting and travel expenses ; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: meeting and travel expenses ; Biotest: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: meeting and travel expenses ; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: meeting and travel expenses . Bader:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Research Funding; Neovii: Research Funding; Riemser: Research Funding, Speakers Bureau; Medac: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Miltenyi: Speakers Bureau. Locatelli:JAZZ PHARMACEUTICALS: Speakers Bureau; TAKEDA: Speakers Bureau; GILEAD: Speakers Bureau; MEDAC: Speakers Bureau; SOBI: Speakers Bureau; BLUEBIRD BIO: Speakers Bureau; NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Membership on an entity's Board of Directors or advisory committees; MILTENYI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NEOVII: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Membership on an entity's Board of Directors or advisory committees. Dalle:Novartis: Honoraria; Vertex: Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; Orchard: Honoraria; Medac: Honoraria; Teva: Current equity holder in private company.