Patient demographics and baseline characteristics
Among the 83 patients included in this study, 49% had PMF, and 51% had MF secondary to another MPN. Their median age was 62 years (range 55–68) and the majority of the patients were male (n = 53,64%). The JAK2 V617F mutation was detected in 65% (n = 54) of patients. Prior to an alloHCT, 61% (n = 51) had received treatment with ruxolitinib. The median spleen size was 20 cm (range 16–23 cm). > 90% of patients had ≥ MF2 bone marrow fibrosis. Patient characteristics are shown in detail in Table 1.
Hematopoietic Cell Transplantation.
The median HCT CI score was 2 (range 0–7). Graft source for alloHCT was matched unrelated donor (MUD) in 54%, followed by matched related donor (MRD) in 23%, mis-matched unrelated (MMUD) in 12%, and haplo-identical donor in 11%. Mobilized peripheral blood stem cells were used as a graft source in 97.6% of donors. Fludarabine-melphalan was the most common conditioning regimen used (83%). Tacrolimus/sirolimus GVHD prophylaxis was used in more than half of the patients (57.8%, n = 48). The median CD34 + and CD3 cells were infused at a median 6x106 cells/kg (range: 2.49–12.96) and 2.21x106cells/kg (range: 0.25–4.90) respectively. The median time for neutrophil engraftment was 20.0 days. The median time for platelet engraftment was 37.0 days. Details of HCT are depicted in Table 1.
Table 1. Patient and HCT characteristics
|
Total (N = 83)
|
Age at HCT, years
|
|
Median
|
62
|
Interquartile range
|
55, 68
|
Range
|
(17–75)
|
Recipient sex
|
|
Male
|
53 (63.9%)
|
Female
|
30 (36.1%)
|
Karnofsky performance status %
|
|
Missing
|
3 (3.6%)
|
70
|
6 (7.2%)
|
80
|
31 (37.3%)
|
90
|
35 (42.2%)
|
100
|
8 (9.6%)
|
80–100
|
74 (89.2%)
|
<80
|
6 (7.2%)
|
Unknown
|
3 (3.6%)
|
HCT Comorbidity Index
|
|
Median
|
2
|
Interquartile range
|
0, 3
|
Range
|
(0–7)
|
0
|
21 (25.3%)
|
1–2
|
24 (28.9%)
|
≥
|
34 (41%)
|
Unknown
|
4 (4.8%)
|
Primary MF
|
|
Yes
|
41 (49.4%)
|
No
|
42 (50.6%)
|
JAK2 mutation
|
|
Yes
|
54 (65.1%)
|
No
|
29 (34.9%)
|
Degree of marrow fibrosis
|
|
Missing
|
2 (2.4%)
|
1+
|
6 (7.2%)
|
2+
|
33 (39.8%)
|
3+
|
42 (50.6%)
|
Ruxolitinib therapy
|
|
Yes
|
50 (60.2%)
|
No
|
33 (39.8%)
|
Pre HCT EF
|
|
N
|
81
|
Median
|
61
|
Interquartile range
|
60, 65
|
Range
|
(45–69)
|
Pre HCT PASP (mmhg)
|
|
N
|
79
|
Median
|
28
|
Interquartile range
|
20, 34
|
Range
|
(3–74)
|
Pre HCT Spleen Size (cm)
|
|
N
|
75
|
Median
|
20
|
Interquartile range
|
16, 23
|
Range
|
(10–34)
|
Year of HCT
|
|
2015
|
17 (20.5%)
|
2016
|
12 (14.5%)
|
2017
|
14 (16.9%)
|
2018
|
15 (18.1%)
|
2019
|
21 (25.3%)
|
2020
|
4 (4.8%)
|
Donor Type
|
|
MRD
|
19 (22.9%)
|
MUD
|
45 (54.2%)
|
MMUD
|
10 (12%)
|
Haplo
|
9 (10.8%)
|
Donor sex
|
|
Male
|
60 (72.3%)
|
Female
|
23 (27.7%)
|
Female donor to male recipient
|
|
Yes
|
13 (15.7%)
|
No
|
70 (84.3%)
|
Donor age
|
|
Median
|
36
|
Interquartile range
|
27, 47
|
Range
|
(18–69)
|
Graft Source
|
|
Bone Marrow
|
2 (2.4%)
|
Peripheral Blood Stem Cells
|
81 (97.6%)
|
ABO blood group compatibility
|
|
ABO compatible
|
48 (57.8%)
|
Minor mismatch (donor is O)
|
13 (15.7%)
|
Major mismatch (Recipient is O)
|
15 (18.1%)
|
Bidirectional (None are O)
|
7 (8.4%)
|
Donor/Recipient CMV serostatus
|
|
D-/R-
|
14 (16.9%)
|
D-/R+
|
29 (34.9%)
|
D+/R-
|
8 (9.6%)
|
D+/R+
|
32 (38.6%)
|
Conditioning regimen
|
|
BUSULFAN/CTX
|
4 (4.8%)
|
FLUDARABINE/BUSULFAN
|
1 (1.2%)
|
FLUDARABINE/CTX/TBI
|
1 (1.2%)
|
FLUDARABINE/MELPHALAN
|
67 (80.7%)
|
FLUDARABINE/MELPHALAN/Ruxolitinib/
|
2 (2.4%)
|
FLUDARABINE/MELPHALAN/TBI
|
7 (8.4%)
|
FTBI/FLUDARABINE
|
1 (1.2%)
|
Conditioning Regimen Intensity
|
|
Myeloblative
|
5 (6%)
|
Non-myeloablative/Reduced Intensity
|
78 (94%)
|
GVHD prophylaxis
|
|
CTX/TACROLIMUS/CELLCEPT
|
14 (16.9%)
|
TACROLIMUS/MTX
|
5 (6%)
|
TACROLIMUS/MTX/BORTEZOMIB
|
1 (1.2%)
|
TACROLIMUS/SIROLIMUS
|
48 (57.8%)
|
TACROLIMUS/SIROLIMUS/MTX
|
3 (3.6%)
|
TACROLIMUS/SIROLIMUS/OTHER
|
1 (1.2%)
|
TACROLIMUS/SIROLIMUS/Ruxolitinib
|
11 (13.3%)
|
Pulmonary Engraftment Syndrome
Twenty-five patients (30%) had pulmonary infiltrates between days 10 and 20 of HCT. Radiologic findings included ground glass opacities, areas of consolidation or pulmonary nodules. Among them, eighteen patients (72%) met the criteria for pulmonary ES. Eight patients (44%) required an ICU admission. Fifteen (83%) patients had hypoxemia that required supplemental oxygen, and six (40%) of these patients required intubation with mechanical ventilation. Of the remaining patients with hypoxemia, two patients (13%) required high flow oxygen and seven (47%) required 2-6L of oxygen via nasal cannula. The most common engraftment symptoms included fever (33%), diarrhea (33%), and rash (22%). Half (n = 9) of the patients with PES required systemic steroid therapy.
Risk factors for pulmonary engraftment syndrome
The association of pre-HCT pulmonary parameters with PES is shown in Table 2. Demographic factors and transplant characteristics did not reveal any risk factors for PES (Table 3). Pre-HCT CT scan chest was reported as normal in 87% of patients. Among the 18 patients who experienced PES, 9 had nodules (≤ 5mm) on pre HCT CT imaging. Representative CT images for 2 patients with PES are shown in Fig. 1.
Table 2
Association of disease and HCT factors with occurrence of PES
| PES | |
| | N | Yes | No | Fisher's exact test p value | Adjusted OR (95%CI)* | P value* |
Age at HCT (years) | < 65 | 44 | 9(20.5%) | 35(79.5%) | 0.80 | Reference | 1.00 |
| ≥ 65 | 39 | 9(23.1%) | 30(76.9%) | | 0.88(0.24,3.05) | |
Sex | M | 53 | 11(20.8%) | 42(79.2%) | 0.79 | Reference | 1.00 |
| F | 30 | 7(23.3%) | 23(76.7%) | | 1.07(0.29,3.74) | |
KPS, % | 90–100 | 43 | 10(23.3%) | 33(76.7%) | 0.79 | Reference | 1.00 |
| ≤ 80 | 37 | 7(18.9%) | 30(81.1%) | | 0.86(0.23,3.04) | |
HCT Comorbidity Index | 0 | 21 | 4(19.0%) | 17(81.0%) | 0.62 | Reference | 0.74 |
| 1–2 | 25 | 7(28.0%) | 18(72.0%) | | 1.67(0.28,11.02) | |
| ≥ 3 | 34 | 6(17.6%) | 28(82.4%) | | 0.98(0.19,5.71) | |
Donor | Matched | 64 | 13(20.3%) | 51(79.7%) | 0.54 | Reference | 0.74 |
| MMUD or Haplo | 19 | 5(26.3%) | 14(73.7%) | | 1.28(0.28,5.23) | |
Female to Male HCT | No | 70 | 16(22.9%) | 54(77.1%) | 0.72 | Reference | 0.71 |
| Yes | 13 | 2(15.4%) | 11(84.6%) | | 0.53(0.05,3.00) | |
Primary MF | Yes | 41 | 8(19.5%) | 33(80.5%) | 0.79 | Reference | 0.79 |
| No | 42 | 10(23.8%) | 32(76.2%) | | 1.18(0.34,4.17) | |
JAK2 mutation | Yes | 54 | 14(25.9%) | 40(74.1%) | 0.27 | Reference | 0.16 |
| No | 29 | 4(13.8%) | 25(86.2%) | | 0.39(0.08,1.50) | |
Degree of fibrosis (MF grade) | 1 + or 2+ | 39 | 9(23.1%) | 30(76.9%) | 1.00 | Reference | 1.00 |
| 3+ | 42 | 9(21.4%) | 33(78.6%) | | 0.88(0.24,3.24) | |
Ruxolitinib use | Yes | 50 | 14(28.0%) | 36(72.0%) | 0.11 | Reference | 0.099 |
| No | 33 | 4(12.1%) | 29(87.9%) | | 0.35(0.07,1.34) | |
Pre HCT EF | ≤ 60 | 40 | 11(27.5%) | 29(72.5%) | 0.30 | Reference | 0.77 |
| > 60 | 41 | 7(17.1%) | 34(82.9%) | | 0.74(0.20,2.70) | |
Pre BMT PASP (mmHg) | ≤ 28 | 43 | 4(9.3%) | 39(90.7%) | 0.011 | Reference | 0.011 |
| > 28 | 36 | 12(33.3%) | 24(66.7%) | | 4.78(1.26,22.69) | |
| < 35 | 61 | 9(14.8%) | 52(85.2%) | 0.042 | Reference | 0.042 |
| ≥ 35 | 18 | 7(38.9%) | 11(61.1%) | | 3.68(1.13,12.00) | |
Pre HCT Spleen Size (cm) | < 20 | 39 | 6(15.4%) | 33(84.6%) | 0.26 | Reference | 0.23 |
| ≥ 20 | 36 | 10(27.8%) | 26(72.2%) | | 2.21(0.54,9.82) | |
Pre HCT CT chest finding | Normal | 72 | 17(23.6%) | 55(76.4%) | 0.44 | Reference | 0.42 |
| Abnormal | 11 | 1(9.1%) | 10(90.9%) | | 0.29(0.01,2.52) | |
Pre HCT FEV1 | ≥ 80% | 63 | 11(17.5%) | 52(82.5%) | 0.28 | Reference | 0.25 |
| < 80% | 15 | 5(33.3%) | 10(66.7%) | | 2.60(0.50,13.32) | |
Pre HCT FEV1/FVC | ≥ 70% | 60 | 13(21.7%) | 47(78.3%) | 0.75 | Reference | 1.00 |
| < 70% | 18 | 3(16.7%) | 15(83.3%) | | 0.84(0.08,5.40) | |
Pre HCT DLCO | ≥ 80% | 21 | 5(23.8%) | 16(76.2%) | 0.76 | Reference | 0.74 |
| < 80% | 56 | 11(19.6%) | 45(80.4%) | | 0.79(0.18,4.10) | |
* Based on exact logistic regression adjusting for Pre HCT pulmonary pressure |
Table 3
Association of patient and HCT characteristics with OS and NRM
| Overall Survival | NRM |
| | N | 1 Yr (95%CI)* | HR (95%CI)* | P* | Adjusted HR (95%CI)† | P† | 100 day (95%CI)* | HR (95%CI)* | P* | Adjusted HR (95%CI) † | P† |
Age at HCT, years | < 65 | 44 | 0.656(0.494,0.776) | Reference | 0.82 | Reference | 0.56 | 0.114(0.041,0.227) | Reference | 0.71 | Reference | 0.67 |
| ≥ 65 | 39 | 0.615(0.445,0.747) | 1.08(0.55,2.11) | | 1.22(0.62,2.40) | | 0.205(0.095,0.344) | 1.13(0.51,2.51) | | 1.19(0.53,2.66) | |
Sex | M | 53 | 0.657(0.512,0.769) | Reference | 0.65 | Reference | 0.64 | 0.132(0.057,0.238) | Reference | 0.81 | Reference | 0.84 |
| F | 30 | 0.600(0.405,0.750) | 1.16(0.59,2.29) | | 1.18(0.58,2.41) | | 0.200(0.079,0.360) | 1.16(0.51,2.61) | | 1.09(0.47,2.51) | |
KPS, % | 90–100 | 43 | 0.647(0.484,0.771) | Reference | 0.90 | Reference | 0.83 | 0.186(0.086,0.315) | Reference | 0.31 | Reference | 0.25 |
| ≤ 80 | 37 | 0.649(0.473,0.779) | 0.96(0.48,1.90) | | 0.93(0.47,1.85) | | 0.108(0.034,0.233) | 0.63(0.27,1.48) | | 0.60(0.25,1.44) | |
HCT Comorbidity Index | 0 | 21 | 0.571(0.338,0.749) | Reference | 0.15 | Reference | 0.81 | 0.238(0.083,0.437) | Reference | 0.53 | Reference | 0.67 |
| 1–2 | 25 | 0.513(0.304,0.689) | 0.89(0.40,2.01) | | 1.13(0.46,2.79) | | 0.120(0.029,0.280) | 0.67(0.25,1.79) | | 0.72(0.26,1.99) | |
| ≥ 3 | 34 | 0.765(0.584,0.875) | 0.48(0.21,1.13) | | 0.84(0.33,2.11) | | 0.147(0.053,0.287) | 0.60(0.23,1.56) | | 0.65(0.25,1.71) | |
Donor | Matched | 64 | 0.686(0.556,0.784) | Reference | 0.065 | Reference | 0.022 | 0.125(0.058,0.219) | Reference | 0.25 | Reference | 0.27 |
| MMUD or Haplo | 19 | 0.474(0.244,0.673) | 1.92(0.94,3.93) | | 2.41(1.13,5.11) | | 0.263(0.092,0.474) | 1.66(0.68,4.05) | | 1.66(0.68,4.05) | |
Female to Male HCT | No | 70 | 0.627(0.503,0.729) | Reference | 0.94 | Reference | 0.81 | 0.157(0.083,0.252) | Reference | 0.77 | Reference | 0.82 |
| Yes | 13 | 0.692(0.373,0.872) | 0.96(0.37,2.48) | | 1.12(0.43,2.92) | | 0.154(0.022,0.399) | 1.15(0.41,3.27) | | 1.13(0.40,3.20) | |
Primary MF | Yes | 41 | 0.707(0.543,0.822) | Reference | 0.34 | Reference | 0.75 | 0.171(0.074,0.301) | Reference | 0.51 | Reference | 0.44 |
| No | 42 | 0.568(0.405,0.702) | 1.37(0.70,2.67) | | 1.12(0.56,2.23) | | 0.143(0.057,0.266) | 1.34(0.60,2.99) | | 1.38(0.61,3.10) | |
JAK2 mutation | Yes | 54 | 0.630(0.487,0.743) | Reference | 0.99 | Reference | 0.66 | 0.167(0.081,0.278) | Reference | 0.52 | Reference | 0.57 |
| No | 29 | 0.651(0.448,0.795) | 1.00(0.50,1.98) | | 1.18(0.56,2.50) | | 0.138(0.042,0.289) | 0.78(0.34,1.78) | | 0.79(0.34,1.81) | |
Degree of marrow fibrosis | 1 + or 2+ | 39 | 0.615(0.445,0.747) | Reference | 0.34 | Reference | 0.30 | 0.205(0.095,0.344) | Reference | 0.35 | Reference | 0.45 |
| 3+ | 42 | 0.687(0.522,0.805) | 0.72(0.36,1.43) | | 0.68(0.33,1.41) | | 0.119(0.043,0.237) | 0.65(0.28,1.52) | | 0.71(0.29,1.72) | |
Ruxolitinib therapy | Yes | 50 | 0.640(0.491,0.756) | Reference | 0.78 | Reference | 0.46 | 0.160(0.074,0.275) | Reference | 0.68 | Reference | 0.64 |
| No | 33 | 0.632(0.442,0.772) | 1.10(0.56,2.14) | | 1.32(0.63,2.77) | | 0.152(0.054,0.295) | 1.21(0.55,2.66) | | 1.21(0.55,2.67) | |
Pre HCT EF | ≤ 60 | 40 | 0.721(0.553,0.835) | Reference | 0.87 | Reference | 0.65 | 0.125(0.045,0.248) | Reference | 0.50 | Reference | 0.55 |
| > 60 | 41 | 0.585(0.420,0.718) | 1.06(0.53,2.09) | | 0.84(0.41,1.74) | | 0.195(0.090,0.329) | 1.32(0.57,3.05) | | 1.30(0.56,2.99) | |
Pre HCT PASP(mmHg) | ≤ 28 | 43 | 0.674(0.513,0.793) | Reference | 0.46 | Reference | 0.10 | 0.140(0.056,0.261) | Reference | 0.81 | Reference | 0.83 |
| > 28 | 36 | 0.636(0.457,0.770) | 1.28(0.64,2.57) | | 1.88(0.88,4.00) | | 0.194(0.084,0.338) | 1.14(0.50,2.61) | | 1.09(0.48,2.47) | |
| < 35 | 61 | 0.719(0.587,0.815) | Reference | 0.007 | Reference | < 0.001 | 0.115(0.050,0.209) | Reference | 0.031 | Reference | 0.040 |
| ≥ 35 | 18 | 0.444(0.216,0.651) | 2.58(1.24,5.40) | | 4.68(1.93,11.37) | | 0.333(0.131,0.552) | 2.55(1.07,6.08) | | 2.42(1.04,5.62) | |
Pre HCT Spleen Size (cm) | < 20 | 39 | 0.872(0.719,0.945) | Reference | < 0.001 | Reference | < 0.001 | 0.103(0.032,0.222) | Reference | 0.083 | Reference | 0.094 |
| ≥ 20 | 36 | 0.444(0.280,0.596) | 3.70(1.67,8.22) | | 4.14(1.83,9.36) | | 0.194(0.084,0.338) | 2.18(0.88,5.39) | | 2.17(0.88,5.38) | |
Pre HCT CT chest finding | Normal | 72 | 0.651(0.528,0.749) | Reference | 0.42 | Reference | 0.19 | 0.139(0.071,0.229) | Reference | 0.47 | Reference | 0.60 |
| Abnormal | 11 | 0.545(0.229,0.780) | 1.42(0.59,3.44) | | 1.84(0.75,4.55) | | 0.273(0.058,0.552) | 1.47(0.50,4.33) | | 1.36(0.44,4.22) | |
Pre HCT FEV1 | ≥ 80% | 63 | 0.635(0.504,0.740) | Reference | 0.66 | Reference | 0.96 | 0.175(0.093,0.278) | Reference | 0.17 | Reference | 0.21 |
| < 80% | 15 | 0.660(0.365,0.843) | 0.82(0.34,1.99) | | 1.03(0.41,2.54) | | 0.067(0.004,0.270) | 0.38(0.09,1.60) | | 0.39(0.09,1.68) | |
Pre HCT FEV1/FVC | ≥ 70% | 60 | 0.631(0.496,0.740) | Reference | 0.45 | Reference | 0.80 | 0.150(0.073,0.252) | Reference | 0.67 | Reference | 0.97 |
| < 70% | 18 | 0.667(0.404,0.834) | 0.72(0.30,1.73) | | 0.88(0.35,2.27) | | 0.167(0.039,0.372) | 0.78(0.26,2.29) | | 0.98(0.32,3.03) | |
Pre HCT DLCO | ≥ 80% | 21 | 0.714(0.472,0.860) | Reference | 0.24 | Reference | 0.064 | 0.048(0.003,0.202) | Reference | 0.37 | Reference | 0.39 |
| < 80% | 56 | 0.624(0.484,0.736) | 1.68(0.69,4.08) | | 2.36(0.95,5.87) | | 0.196(0.104,0.310) | 1.66(0.58,4.73) | | 1.59(0.55,4.58) | |
PES | No | 65 | 0.677(0.549,0.776) | Reference | 0.062 | Reference | 0.074 | 0.138(0.068,0.234) | Reference | 0.26 | Reference | 0.26 |
| Yes | 18 | 0.500(0.259,0.701) | 1.94(0.95,3.96) | | 1.93(0.94,3.97) | | 0.222(0.065,0.436) | 1.65(0.70,3.89) | | 1.63(0.70,3.83) | |
* based on univariate analysis, log-rank test for OS, and Gray’s test for NRM |
† Based on multivariable Cox regression model for OS adjusting for donor type and pre BMT spleen size, and Fine and Gray regression model for NRM adjusting for donor type. |
Pulmonary hypertension is a well-recognized complication of MF. Pulmonary artery systolic pressure measurement was available in 79 patients. In this cohort, the median pulmonary artery systolic pressure (PASP) for the cohort was 28 mmHg (range 3–74 mm Hg). Pulmonary artery hypertension (defined as PASP ≥ 35 mmHg) was observed in 61 patients (77%) in this cohort. PAH was associated with increased risk of PES with an odds ratio 3.68 (95% CI 1.13,12; P = 0.04)
An abnormal pulmonary function test (PFT), defined as FEV1 < 80%, FEV1/FVC < 70%, and DLCO < 80 were found in 19%, 23% and 72% patients during pre-HCT testing, respectively. No association was seen between PFT abnormalities prior to transplant and the occurrence of PES was observed. (FEV1 p = 0.25 [95% CI 2.60 0.50-13.32], FEV1/FVC p = 1.00, [95% CI 0.84 0.08–5.40], DLCO p = 0.74 [95% CI 0.18–4.10]).
Spleen size was not associated with the occurrence of PES (p = 0.23, 95% CI 2.21 0.54–9.82). Neutrophil engraftment was noted to be earlier in those with PES (median 17 days vs 20 days) but this was not statistically significant (p = 0.20).
Overall Survival (OS) and Non-Relapse Mortality (NRM)
The 12-month OS and 2-yr OS were 65% and 63%, respectively. The day 100 mortality was 16% and 2-year NRM was 24%. (Fig. 2) Patients who experienced PES had no difference in overall survival (OS) and non-relapse mortality (NRM) in comparison to those who did not have PES (HR;1.93, 95% CI 0.94–3.97, P 0.074 and HR 1.63; 95% CI 0.70–3.83, P 0.26, respectively).
Median ICU stay for patients with PES was 18 days. Patients with median PASP > 35 and pre-HCT spleen size > 20 cm had worse OS in multivariate analysis (HR 2.58, 95% CI 1.24–5.40, P < 0.001, and HR 4.14, 95% CI 1.83–9.36, p < 0.001), while pre-HCT median PASP of greater or equal with 35 mmHg was associate with worse NRM (HR 2.42, 95% CI 1.04–5.62, p 0.040)
Patient, donor, and transplant characteristics and their association with OS and NRM are listed in Table 3.