Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative option for patients (pts) with myelofibrosis (MF). Patients with MF transformed to Acute Myeloid Leukemia (AML) have a very short life expectancy without transplantation (< 4 months). Umbilical cord blood transplantation (UCBT) from unrelated donor is a valid alternative to conventional allogeneic HSCT for pts with hematologic malignancies who do not have an HLA matched donor. Delayed engraftment and graft failure are the limitations of this procedure and represent a major issue for MF.
We analyzed 42 adults (28 males and 14 females) who underwent a single (n=15) or double (n=27) HLA mismatched UCBT between 2005 and 2012 in 26 EBMT centers reported to Eurocord. At diagnosis, 21 had primary MF (PMF), 5 polycythemia vera (PV), and 16 essential thrombocytemia (ET). Twelve patients transformed to acute myeloid leukemia (AML) before UCBT. Among pts with pre-transplant information available, 13/25 had severe marrow fibrosis; 8/16 had a high Lille score at diagnosis and 13/27 had JAK2 V617F mutation; 13/35 underwent splenectomy and 16/30 had an abnormal karyotype. The median time from diagnosis to transplant was 80 months (range 5-316), while in the subgroup of pts with transformation to AML, it was 119 months (range 5-246). Five pts had a prior transplant (1 autologous, 3 allogeneic and 1 had 2 consecutive allogeneic transplants). The median age at UCBT was 54 years (range 28-69). Conditioning regimens were reduced intensity (RIC) (n= 29) or myeloablative (MAC) (n=13). The most common conditioning in both MAC (n=5) and RIC (n=16) was Cyclophosphamide and Fludarabine associated with total body irradiation (TBI). Overall, 27 pts received TBI with a dose of 12-14 Gy in MAC (n=6) and 2-4 Gy in RIC (n=21); 20 pts received anti-thymoglobulin (ATG) in the conditioning regimen. The median infused total nucleated and CD34+ cells were 3,4x107/Kg (range 0,3-6,8) and 1,3x105/Kg (range 0,04-3,8),respectively.
Median follow-up for survivors was 25 months (range 6 -72). The cumulative incidence (CI) of neutrophil engraftment was 64% (28 pts) with a median time of 29 days, and among the 12 pts transformed to AML, 10 engrafted in a median time of 30 days, while 18 of 30 pts without transformation engrafted in a median time of 28 days. Of the 14 pts who did not reach neutrophil engraftment, 7 had no hematological recovery, 6 of them died after a median of 3 months and 1 pt is alive at 14 months post UCBT. The remaining 7 pts had an autologous reconstitution, and 4 of them are alive with progressive disease at a median time of 42 months. Pts who received RIC conditioning had better engraftment (79% versus 36%, p=0.02).
Twelve pts developed acute GvHD of grades II-IV; 7 pts had limited chronic GvHD with a median time of onset of 144 days.
Overall, 17 pts relapsed (6 had transformed into AML before transplantation) at a median time of 5 months. The CI of relapse at 2 years was 29%±2%. The CI of transplant-related mortality at 1 year was 33%±2%. Causes of death were relapse (n=9), post-transplant lymphoproliferative disease (n=3), GvHD (n=3), multiorgan failure (n=1), bacterial infection (n=3), acute respiratory distress syndrome (n=2), infection of unknown origin (n=3), cardiac toxicity (n=1) and fungal infection (n=1). OS at 2 years was 44±8%: 80%, 21% and 52% for pts transplanted respectively for MF secondary to PV, ET and PMF (p=0.07). No difference in OS was seen in the subgroup of pts with JAK2 mutation. OS was 51% versus 29% for pts receiving double or single UCBT (p=0.15), and it was 37% for AML-transformed pts. Pts who did not receive ATG, had an OS of 59% versus 24% for those who received ATG (p=0.01). Among pts who underwent RIC (n=29), 13 had a TBI based conditioning without ATG, and 7 are alive. Failure-engraftment free survival at 2 years was 29±7%, better in pts receiving double UCBT as compared with single (40% versus 8% , p=0,01), and in pts receiving TBI (43% versus 7%, p=0,03).
Graft failure was a major concern for these pts. Despite a limited number of patients, our results indicate that life expectancy can be increased with UCBT particularly for patients with advanced stage MF. Furthermore, the use of RIC TBI based regimen without ATG and double CB might improve outcomes.
Gluckman:Cord use: Honoraria; gamida: Honoraria.
Asterisk with author names denotes non-ASH members.