At time of allogeneic SCT, the majority of patients (55%, 44/80) were not in remission. The median percentage of bone marrow blasts at start of conditioning was 22.6% (CI (15% - 30%)) in these patients and 12 of those patients harboured the following mutations: FLT3-ITD (3), FLT3-ITD and NPM1 (2), FLT3-ITD, FLT3-TKD and MLL (1), FLT3-TKD and MLL (1), IDH1, U2AF1 and MPL (1), MLL (1) and NPM1 (1). In contrast, 16 of the patients in CR harboured the following aberrations: FLT3-ITD (5), FLT3-ITD and NPM1 (6), FLT-TKD (1), NRAS and U2AF1 (1), RUNX1 (1), RUNX-RUNX1T1 and FIP1L1-PDGFRA (1), RUNX-RUNX1T1 and FLT3-ITD (1). Median follow-up time was 3.2 years (range 13 days – 9.8 years) after SCT.
Relapse-free survival (RFS)
One-, two- and three-year RFS was 47.5%, 40.7% and 37.3% (see Figure 1). For matched-unrelated donor (MUD) transplantations, these figures were 46.9%, 38.0% and 35.4% and for matched-related donor (MRD) transplantations, 52.4%, 47.1% and 39.3%, respectively. For mismatched unrelated donor (MMUD) transplantations, RFS was 40.0% at one year and remained at this level throughout follow-up. There was no significant difference between the groups (p = 0.76).
Patients transplanted in CR had a one-, two and three-year RFS of 48.6%, 37.5% and 34.1%. The figures for those transplanted in non-CR were 46.5%, 41.5% and 38.0% (p = 0.907).
Patients receiving a transplant at or over the age of 50 had a higher one-, two- and three-year RFS (49.1%, 43.1% and 40.2%) compared with patients younger than 50 years old (44.4%, 37.0% and 33.3%; p = 0.969) (see supplemental table S1).
One-, two- and three-year RFS rates for the AML subgroup analysis were 43.3%, 38.1% and 33.5%.
Overall survival (OS)
One, two- and three-year OS was 59.3%, 49.3% and 45.4% (see Figure 1). For MRD transplantations, these figures were 70.0%, 48.1% and 40.1% and for MUD transplantations, these figures were 56.8%, 49.9% and 46.7% (p = 0.95). The one-year OS for those receiving a MMUD was 48.0%.
For patients transplanted in CR, the one-, two- and three-year OS was 65.6%, 53.3% and 45.1% and for those transplanted not in CR 54.3%, 46.2% and 46.21% (p = 0.996), respectively (see supplemental table S2). The one-, two- and three-year OS for patients aged under 50 was 58.1%, 54.2% and 44.4% and for patients aged 50 and over 60.3%, 47.4% and 44.5% (p= 0.785), respectively.
The one-, two- and three-year OS of the patients with AML was 56.5%, 48.9% and 43.5%.
Non-relapse mortality and cumulative incidence of relapse
Eighteen patients were neutropenic before the start of conditioning and eight received conditioning despite radiological evidence of fungal pneumonia. Eighteen patients died without disease relapse. The causes of death of those patients who died before day +28 were: sinusoidal obstruction syndrome (1), sepsis (2) or pneumonia (1). The causes of death for the remaining fourteen patients were: sepsis/infection (7), acute respiratory distress syndrome (2), intracerebral bleed (1), post-transplant lymphoproliferative disorder (1), grade IV liver GvHD (1) or unknown (2).
Cumulative incidences of NRM were 10.0% (95% CI (5%, 18%)) at 100 days, 18.8% (95% CI (11%, 28%)) at 1 year and 20.1% (95% CI (12%, 30%)) at 2 years (see Figure 2). The one-, two- and three-year cumulative incidences of relapse were 34.0% (95% CI (24%, 44%)), 40.2% (95% CI (28%, 53%)) and 41.0% (95% CI (30%, 52%)), respectively (see Figure 3). The subgroup analyses for NRM and the cumulative incidence of relapse are depicted in table 2 and 3.
Engraftment, graft failure and chimerism
CTCAE grade IV neutropenia, leukocytopenia and thrombocytopenia occurred in all patients. Three patients died in the pre-engraftment phase. One patient achieved neutrophil engraftment, but died before platelet engraftment was achieved. The rest achieved engraftment of neutrophils and platelets.
The day 28 cumulative incidence of engraftment for neutrophils was 85.0% (95% CI (75%, 91%)). By day +37 all patients had achieved successful neutrophil engraftment. The day 28 cumulative incidence of platelet engraftment was 82.5% (95% CI (72%, 89%)). By day +100, this had increased to 85.0% (95% CI (75%, 91%)).
The median time to neutrophil engraftment was 20 days (range 9–37 days), to platelet engraftment 20 days (range 11–174 days). No primary or secondary failure of engraftment was documented. There were nine cases of poor graft function with regards to neutrophil engraftment and twelve cases with regard to platelet engraftment.
The cumulative incidence of complete donor-type chimerism was 84.0% (95% CI (74%, 90%), 66 subjects) on day +28. By day +100, 80.0% of patients were found to have complete donor-type chimerism (55 subjects). By day +180 this figure fell to 68.0% (41 subjects). The course of chimerism mirrored the incidence of relapse.
Acute and chronic graft versus host disease
Day 100 cumulative incidences of grade I-IV, II-IV and III-IV acute GVHD were 38.0% (95% CI (27%, 48%)), 22.0% (95% CI (13%, 33%)) and 6.0% (95% CI (2%, 14%)). Two patients developed grade IV aGvHD of the liver. The cumulative incidence of mild to severe cGVHD at 2 years was 15.0% (95% CI (8%, 24%)). There were three cases of severe cGvHD.
Toxicities and adverse events
Every patient experienced the expected chemotherapy related myelosuppression and required the transfusion of blood products following or prior to transplantation as a direct consequence of the conditioning chemotherapy. In some cases, myelosuppression was also caused by the underlying malignant condition or previous bridging or salvage therapy given prior to the start of conditioning. A detailed breakdown of recorded toxicities is depicted in table 4.
The diagnosis of sinusoidal obstruction syndrome (SOS) (grade 3) was suspected in two patients who suffered from progressive AML or from CML in transition to accelerated phase. A third patient suffering from progressive AML and renal insufficiency, who has received stem cells from a MMUD, likely died due to SOS (grade 5). The patients received SCT at the age of 44, 55, and 52 years from a matched-related donor, except for the younger AML patient, who had a MMUD. The HCT-CI was 3, 0 and, 0, respectively . All three patients received the same fludarabine containing conditioning therapy as well as the same GvHD prophylaxis and none of them had received gemtuzumab ozogamicin, which is known to increase the risk of SOS .
Further adverse events included haemorrhagic colitis (1), neutropenic colitis (1), post-transplant lymphoproliferative disease (1), pericardial effusion with hemodynamic relevance (2), non-ST-segment elevation myocardial infarction (NSTEMI) (1), pulmonary embolism (1) and cardiac decompensation (2). Two patients developed a secondary malignancy. The first developed gallbladder cancer three years following a MMUD transplantation for AML. The second developed a ductal carcinoma in situ just over two and a half years following a MUD transplantation for CML.