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Heterogeneity in CAMT-MPL
Table 4. Hematopoietic stem cell transplantation in congenital amegakaryocytic thrombocytopenia.
Age at 1st HSCT [y]
# of pts with available info
38
Median: 3.55 y, range: 0.6 – 11 y <1 year
1-5 years
>5 years
HLA matched related donor haploident related donor matched unrelated donor mismatched unrelated donor
BM PBSC CB
N %
5 13 23 61
10 26
19 56 3 9 11 32 1 3
10 48 7 33 5 19
Pos outcome (%)
4/4 (100) 15/17 (88)
7/9 (78)
12/12 (100) 4/4 (100) 5/8 (63) 1*/1 (100)
8/10 (80) 6/7 (86) 3/4(75)
information about neg. outcome
CAMT039: TRD (no details, BM, MUD)
CAMT015: death after GvHD-induced bronchiolitis
obliterans (BM, MUD)
CAMT007: death after graft rejection and sepsis (PBSC, MUD)
CAMT157: death after GvHD grade 4 (lung, skin) and sepsis (CB)
HSC donor
HSC source
34
22
The table summarizes the available information regarding age of hematopoietic stem cell transplantation (HSCT),donor and source of hematopoietic stem cell (HSC) and out- come. Information about outcome was not available for all transplantations. BM: bone marrow; CB: cord blood, PBSC: peripheral blood stem cells; pts: patients; TRD: transplan- tation related death;*: CB, 1 mismatch. GvHD: graft-versus-host disease; MUD: matched unrelated donor.
Chromosomal anomalies, leukemic development
Cytogenetic data were inconspicuous for most of the patients with available data (n= 23 of 27, 85%). An abnor- mal karyotype has been detected in 4 patients: t2;11 (5%) in CAMT009,14 a not further specified additional marker chromosome (94%) in CAMT01314 and monosomy 7 in CAMT04330 (50%) and CAMT067 (13-30%). The latter has been diagnosed with MDS. All underwent hematopoietic stem cell transplantation (HSCT) because of aplastic anemia. In none of the patients a development of overt leukemia has been reported in the period of record.
Non-hematological abnormalities
The rate of non-hematological abnormalities in our CAMT-MPL patients was markedly higher than report- ed: 50% of the patients with available data (25 of 50) had non-hematological abnormalities appearing as structural abnormalities or other abnormal clinical find- ings (Table 3). Most of the reported anomalies were related to the head region: brain anomalies (n=7), ocular and orbital anomalies (n=10), especially strabismus (n= 9), nystagmus (n=4) and facial abnormalities (n=4). Mental or psychomotor retardation was observed in seven patients, mostly correlated with brain anomalies. Intracranial bleedings are documented for five of seven patientswithmentalorpsychomotorretardation,forsix of seven with brain anomalies, and for six of ten with ocular anomalies (Table 3). Interestingly, we found some anomalies which are typical for other IBMFS and which misled the first diagnosis: eczema (n=2), hypopigmenta- tion (n=1), high palate and/or small uvula (n=2). No skeletal, cardiac or urogenital abnormalities were observed. There was no correlation between type or localization of MPL mutations and non-hematological abnormalities.
Treatment
Thirty-seven of 45 documented cases of our patient group received platelet transfusions, most of them tran- siently in a period immediately after diagnosis of severe thrombocytopenia and/or during the aplastic stage of the disease. During the advanced stage of the pancytopenia the patients often received erythrocyte transfusions (16 of 45). Neutropenia and associated infections were treated with antibiotics; two of the patients were treated with recombinant granulocyte colony-stimulating factor.
Half of the patients (25 of 50) have been initially treated with immunoglobulins (23 of 50) or corticosteroids (15 of 50). Interestingly, three patients responded with a tran- sient increase in platelet counts, which initially misled the diagnosis but none showed a persistent response.
The only available curative treatment for CAMT-MPL is HSCT. Thirty-eight of 51 patients in our group were treated with HSCT, for another ten HSCT was planned for the near future. For 26 of 30 patients with information about the post-transplant course a positive outcome was documented (87%). The available information about age of transplantation, donor, stem cell source and outcome is summarized in Table 4.
Three patients were unsuccessfully treated with recom- binant IL-11 (oprelvekin). Two of them showed a slight and transient increase in platelet counts, followed by a prolonged phase of severe thrombocytopenia, which could be explained by an exhaustion of residual megakaryopoiesis by stimulation of cytoplasmic matura- tion.
Congenital amegakaryocytic thrombocytopenia with only one affected MPL allele
In six patients with clinical diagnosis of CAMT we found only a single mutated allele (Online Supplementary Table S3), as judged by reproducible balanced distribution
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