Secondary Graft Failure in Allogeneic Stem Cell Transplantation for Myelofibrosis - a Single Institution Experience

Myelofibrosis (MF), either primary (PMF) or post polycythemia vera (PV) or essential thrombocythemia (ET) affects older patients. JAK2 inhibitors can ameliorate symptoms but allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option.  In recent years, reduced intensity conditioning (RIC) has become the preferred transplant modality for MF. Higher rates of graft failure (GF) have been noted in patients with MF undergoing allogeneic HSCT as compared to other diseases.  Whether due to an abnormal marrow microenvironment, organomegaly or an expanded clonal stem cell pool, GF leads to dismal outcomes.

Between 2008 and 2014, 42 patients, median age 58 (range 40-68, 22 with PMF (5/22 transformed to AML), 20 with post-PV/-ET (8/20 transformed to AML)] underwent RIC peripheral blood stem cell (PBSC) transplantation. RIC included Flu/Bu (5 patients), Flu/Bu/rATG (4 patients), Flu/Mel (20 patients) and Flu/Mel/rATG (11 patients). GVHD prophylaxis was administered as FK/MTX (38 patients), CSA/MTX (1 patients) and CSA/MMF (3 patients). Sixteen were related donors, and 26 unrelated; 36 donors were 10/10 and 6 were 9/10 HLA matched. A JAK2 inhibitor was administered to 19 patients prior to HSCT. Mean and median OS were 24 and 13 months (range 1-79).  Seventeen patients survived more than 2 years, and 7 are alive >5 years from second transplant.  Neutrophil engraftment, median 13 days (range 10-40); platelet engraftment, median 20 days (range 11-87) with 10 patients failing to engraft platelets. For acute GVHD, 25 patients developed grade II-IV, and 8 patients developed chronic GVHD.  Six patients (14%) developed GF (4 primary, 2 secondary).

Table 1 – Characteristics of Patients with Graft Failure

Pt	Diagnosis	1st graft	Conditioning 1st graft	Graft failure	Chimerism CD3%/CD33%	2nd graft	Same than 1st graft	Conditioning 2nd graft	Poor graft function	Chimerism CD3%/CD33 %	Outcome from 2nd graft
1	Post-ET MF	VUD 10/10	Flu/Mel	2ry	10/98	VUD 10/10	no	Flu/Cy/TBI200	no	100/100	Died, GVHD
2	Post-PV MF	MMRD 9/10	Flu/Mel	1ry	N/A	VUD 9/10	yes	Flu/Cy/TBI200	no	100/100	Alive 58 mo
3	PMF	VUD 10/10	Flu/Mel/rATG	1ry	N/A	VUD 10/10	yes	Flu/TBI200	yes	100/100	Died GVHD
4	PMF transformed to AML	VUD  9/10	Flu/Bu/rATG	1ry	N/A	VUD 10/10	no	Flu/Mel/Thio	no	100/100	Alive 9 mo
5	Post-PV MF	VUD 10/10	Flu/Mel	2ry	76/0	N/A	N/A	N/A	no	N/A	Died, pneumonia
6	PMF	VUD 9/10 (DQ)	Flu/Bu/rATG	2ry	0/100	N/A	N/A	N/A	yes	N/A	Alive 3 mo

RIC-HSCT for MF still counts with significant hurdles including primary and secondary GF. Use of unrelated, mismatched donors, RIC conditioning, and in vivo T-cell depletion are potential risk factors for GF.   Highly immunosuppressive non-myeloablative conditioning combining fludarabine and low dose TBI promotes a successful engraftment and can be used to salvage these patients.

Re-transplantation following graft failure is feasible.  Further studies regarding optimal conditioning regimens are needed.