Introduction
Data collection
Definitions and statistical endpoints
Statistical analysis
Results
Patient and transplant characteristics
Characteristic | value |
---|---|
Follow-up, years, median (IQR) | 11.4 (9.0–14.9) |
Patient age at allogeneic hematopoietic stem cell transplantation, years, median (IQR) | 55.9 (45.8–61.4) |
Gender, n (%) | |
Male | 148 (55.6%) |
Female | 118 (44.4%) |
Primary diagnosis, n (%) | |
De novo, primary acute myeloid leukemia | 178 (66.9%) |
Secondary acute myeloid leukemia | 88 (33.1%) |
Karnofsky performance score | |
< 80 | 43 (16.2%) |
≥ 80 | 223 (83.8%) |
Hematopoietic cell transplantation-comorbidity index (HCT-CI), n (%) | |
0 | 71 (26.7%) |
1–2 | 88 (33.1%) |
≥ 3 | 107 (40.2%) |
2017 ELN genetic risk stratification, n (%) | |
Favorable | 41 (15.4%) |
Intermediate | 112 (42.1%) |
Adverse | 113 (42.5%) |
Disease status at 1st allo-HSCT, n (%) | |
First complete remission, CR1 | 103 (38.7%) |
CR2, first partial remission, PR1 | 77 (28.9%) |
> CR2, refractory, active AML | 86 (32.3%) |
Donor type, n (%) | |
Matched sibling donor | 86 (32.3%) |
Matched unrelated donor | 124 (46.6%) |
Mismatched unrelated donor | 51 (19.2%) |
Haploidentical, mismatched related donor | 5 (1.9%) |
Stem cell source, n (%) | |
Peripheral blood | 244 (91.7%) |
Bone marrow | 22 (8.3%) |
Donor age, years, median (IQR) | 40.0 (31.0–48.0) |
Female donors to male recipients, n (%) | |
Yes | 38 (14.3%) |
No | 228 (85.7%) |
Donor/recipient CMV serostatus, n (%) | |
Negative/negative | 94 (35.3%) |
Negative/positive | 57 (21.4%) |
Positive/positive | 78 (29.3%) |
Positive/negative | 37 (13.9%) |
Graft-versus-host disease prophylaxis, n (%) | |
Cyclosporine, MTX | 174 (65.4%) |
Cyclosporine, MMF | 83 (31.2%) |
Post-transplant cyclophosphamide, tacrolimus, MMF | 9 (3.4%) |
Antithymocyte globulin (ATG), n (%) | |
Yes | 201 (75.6%) |
No | 65 (24.4%) |
Regimens | n (%) |
---|---|
FBM (Fludarabine, BCNU, Melphalan) Fludarabine 5 × 30 mg/m2 on five consecutive days (d-8 to d-4), BCNU 2 × 150 mg/m2 (d-6, d-5), Melphalan 110 mg/m2 on d-3 (age ≥ 55 years) or Melphalan 140 mg/m2 on d-3 (age < 55 years) | 144 (54.1%) |
FTM (Fludarabine, Thiopeta, Melphalan) Fludarabine 5 × 30 mg/m2 (d-7 to d-3), Thiopeta 5 mg/kg (d-6), Melphalan 110 mg/m2 on d-3 (age ≥ 55 years) or Melphalan 140 mg/m2 on d-3 (age < 55 years) | 31 (11.6%) |
FLAMSA-RIC Treosulfan, Fludarabine FLAMSA regimen (d-12 to d-9): Fludarabine 4 × 30 mg/m2, HD-Ara-C 4 × 2000 mg/m2, Amsacrine 4 × 100 mg/m2. RIC-regimen after 3 days of rest (d-3 to d-5): Fludarabine 3 × 30 mg/m2, Treosulfan 3 × 14 g/m2 (d-5 to d-3), ATG 10 mg/kg for MRD or 20 mg/kg for MUD, MMRD, MMUD from d -4 to d -2, pDLTs at day + 120 or 30 days after discontinuation of immunosuppression, 1–5 × 106 CD3+ cells/kg | 20 (7.5%) |
FM (Fludarabine, Melphalan) Fludarabine 5 × 30 mg/m2 (d-8 to d-4), Melphalan 140 mg/m2 (d-4) | 18 (6.8%) |
Fludarabine, Treosulfan Fludarabine 5 × 30 mg/m2 on five consecutive days (d-6 to d-2), Treosulfan 3 × 10 g/m2 on three consecutive days (d-4 to d-2) | 15 (5.6%) |
FLAMSA-RIC Busulfan, Cyclophosphamide FLAMSA regimen (d-12 to d-9): Fludarabine 4 × 30 mg/m2, HD-Ara-C 4 × 2000 mg/m2, Amsacrine 4 × 100 mg/m2. RIC-regimen: Busulfan 4 × 0.8 mg/kg on four consecutive days (d-6 to d-4), Cyclophosphamide (2 × 60 mg/kg for MUD, MMRD and MMUD or 2 × 40 mg/kg for MRD, d-3 to d-2), ATG 10 mg/kg for MRD or 20 mg/kg for MUD, MMRD, MMUD from d-4 to d-2, pDLTs at day + 120 or 30 days after discontinuation of immunosuppression, 1–5 × 106 CD3+ cells/kg | 8 (3.0%) |
Other | 30 (11.3%) |
Acute and chronic graft-versus-host disease
Characteristic | value |
---|---|
Combination of grade II-IV acute and chronic GVHD*, (n = 266) | |
No acute GVHD, no chronic GVHD | 92 (34.6%) |
Acute GVHD, no chronic GVHD | 75 (28.2%) |
Acute GVHD and chronic GVHD | 49 (18.4%) |
Chronic GVHD, no acute GVHD | 50 (18.8%) |
Number of organs affected by chronic GVHD*, median (IQR), (n = 99) | 3 (2–4) |
Maximum grade of chronic GVHD*, (n = 99) | |
Mild | 10 (10.1%) |
Moderate | 42 (42.4%) |
Severe | 47 (47.5%) |
Organs affected by chronic GVHD*, (n = 99) | |
Skin | 77 (77.8%) |
Oral mucosa | 67 (67.7%) |
Eyes | 59 (59.6%) |
Liver | 29 (29.3%) |
Lung | 21 (21.2%) |
Gastrointestinal tract | 16 (16.2%) |
Fascia | 16 (16.2%) |
Genitals | 9 (9.1%) |
Joints | 7 (7.1%) |
Central nervous system | 4 (4.0%) |
Days of systemic immunosuppressive therapy of chronic GVHD, (n = 93) | |
Median (IQR) | 729.0 (337.5–1715.0) |
Mean (95% CI) | 1151.2 (95% CI [922.2, 1380.2]) |
Secondary solid malignancies including precancerous lesions
Pat.no | Secondary solid malignancies (SSMs), precancerous lesions, atypical nevi | Conditioning regimens | Years from HSCT to SSMs | Age at HSCT | Sex | Grade II–IV acute GVHD | Chronic GVHD requiring systemic immunosuppression, sites of involvement, days of systemic immunosuppression (IS) of cGVHD | Smoker (yes/no) | Death due to SSMs, time from diagnosis of SSMs to death due to SSMs |
---|---|---|---|---|---|---|---|---|---|
Invasive squamous cell carcinomas, SCCs (n = 19) in 16 patients | |||||||||
26 | Squamous cell carcinoma, soft palate, G2, pT1 pN0 cM0 L0 V0 Pn0 R0 | FBM | 2.21 | 59.8 | Male | No | Yes, skin, eyes, liver, oral mucosa, 328 days | Yes | No |
352 | Cutaneous squamous cell carcinoma, face | FBM | 12.54 | 55.2 | Male | Yes | Yes, skin, oral mucosa, gastrointestinal, 5252 days | No | No |
86 | Squamous cell carcinoma, tongue, G2, pT2 pN0 L0 V0 cM0 R1 | FBM | 4.39 | 48.1 | Female | No | Yes, oral mucosa, liver, skin, fascia, eyes, 1298 days | No | No |
415 | Squamous cell carcinoma, cervical carcinoma, pT1b pN1 cM0, HPV pos | Treosulfan, Fludarabine | 12.27 | 43.4 | Female | Yes | No | No | No |
75 | Cutaneous squamous cell carcinoma, face | FBM | 11.96 | 68.2 | Male | Yes | Yes, skin, 677 days | No | No |
272 | Laryngeal cancer, squamous cell, pT1b pN0 cM0, HPV neg | FM | 10.89 | 43.9 | Male | No | No | Yes | No |
282 | Squamous cell carcinoma, tongue, G3, pT1 pN1 R0 | Treosulfan, Fludarabine | 3.89 | 69.1 | Male | Yes | Yes, eyes, gastrointestinal, oral mucosa, 1863 days | Yes | Yes, 1.65 years |
256 | Cutaneous squamous cell carcinoma, scalp | FBM | 3.15 | 61.4 | Male | Yes | Yes, skin, lung, eyes, 2744 days | No | No |
256 | Cutaneous squamous cell carcinoma, face | FBM | 3.3 | 61.4 | Male | Yes | Yes, skin, lung, eyes, 2744 days | No | No |
104 | Squamous cell carcinoma, vulva, HPV pos | Thio, Treo, Flud | 6.94 | 57.2 | Female | Yes | Yes, skin, oral mucosa, eyes, liver, 254 days | No | No |
142 | Cutaneous squamous cell carcinoma, face | FBM | 10.1 | 67.3 | Male | Yes | Yes, eyes, oral mucosa, lung, 1561 days | No | No |
142 | Cutaneous squamous cell carcinoma, ear | FBM | 10.1 | 67.3 | Male | Yes | Yes, eyes, oral mucosa, lung, 1561 days | Yes | No |
142 | Cutaneous squamous cell carcinoma, face | FBM | 13.1 | 67.3 | Male | Yes | Yes, eyes, oral mucosa, lung, 1561 days | Yes | No |
157 | Squamous cell cancer, lung, UICC IIIB | FBM | 7.90 | 64.5 | Female | No | Yes, skin, eyes, oral mucosa, genitalia, unknown end of IS | Yes | Yes, 0.79 years |
31 | Esophageal cancer, squamous cell, ypT3 ypN2 L0 V0 R0 | FBM | 3.2 | 54.4 | Male | Yes | Yes, oral mucosa, eyes, skin, 1355 days | No | Yes, 0.53 years |
66 | Squamous cell carcinoma, lung, G3, pT2a pN0 (0/21) cM0 L0 V0 R0 | FTM | 5.8 | 56.4 | Male | No | No | No | No |
238 | Squamous cell carcinoma, tongue, G2, pT1 pN0 cM0 Pn0 R0 L0 | FTM | 8.0 | 40.8 | Female | No | Yes, skin, oral mucosa, eyes, lung, joints, 2105 days | yes | No |
17 | Cutaneous squamous cell carcinoma, face | FBM | 1.94 | 56.1 | Male | Yes | Yes, oral mucosa, eyes, lung, 876 days | No | No |
63 | Cutaneous squamous cell carcinoma, face | FBM | 1.95 | 63.8 | Male | Yes | Yes, oral mucosa, eyes, joints, lung, 927 days | No | No |
Non-squamous cell carcinomas, non-SCCs (n = 23) in 16 patients | |||||||||
75 | Fibrosarcoma, cheek | FBM | 4.19 | 68.2 | Male | Yes | Yes, skin, 677 days | No | No |
75 | Merkel cell carcinoma, lip, pT2 pN1 cM0 | FBM | 11.4 | 68.2 | Male | Yes | Yes, skin, 677 days | No | No |
104 | Malignant melanoma of the skin, back, pT1a pN0 cM0 | Thio, Treo, Flud | 1.77 | 57.2 | Female | Yes | Yes, skin, oral mucosa, eyes, liver, 254 days | No | No |
272 | Cutaneous basal cell carcinoma, back | FM | 9.92 | 43.9 | Male | No | No | Yes | No |
256 | Cutaneous basal cell carcinoma, face | FBM | 3.31 | 61.4 | Male | Yes | Yes, skin, lung, eyes, 2744 days | No | No |
212 | Glioblastoma multiforma | FLAMSA-RIC, Bu, Cy | 7.21 | 54.5 | Female | No | Yes, oral mucosa, eyes, skin, 1714 days | No | Yes, 1.45 years |
263 | Gastroesophageal cancer, adenocarcinoma | FLAMSA-RIC, Treo, Flud | 2.02 | 49.2 | Female | No | Yes, skin, oral mucosa, 167 days | No | Yes, 0.70 years |
397 | Cutaneous basal cell carcinoma, nasal bridge | FBM | 3.05 | 65.8 | Male | Yes | Yes, oral mucosa, liver, lung, skin, eyes, 1716 days | No | No |
309 | Cutaneous basal cell carcinoma, nose | FLAMSA-RIC, Treo | 3.46 | 61.4 | Male | No | No | No | No |
309 | Cutaneous basal cell carcinoma, nose | FLAMSA-RIC, Treo | 4.6 | 61.4 | Male | No | No | No | No |
22 | Cutaneous basal cell carcinoma, face | FBM | 5.98 | 60.6 | Male | No | No | No | No |
403 | Follicular thyroid cancer, pT2 pN0 cM0 L0 V1 R0 | FTM | 4.51 | 30.6 | Female | Yes | No | No | No |
66 | Conjunctival malignant melanoma, pT1a pN0 cM0 L0 V0 R1 | FTM | 5.74 | 56.4 | Male | No | No | No | No |
66 | Adenocarcinoma, lung, pT1b pN2 (8/33) cM0 L1 V0, UICC IIIA | FTM | 6.8 | 56.4 | Male | No | No | No | No |
21 | Cutaneous basal cell carcinoma, face | Treosulfan, Fludarabine | 11.33 | 68.0 | Female | Yes | Yes, liver, 796 days | No | No |
21 | Cutaneous basal cell carcinoma, face | Treosulfan, Fludarabine | 11.7 | 68.0 | Female | Yes | Yes, liver, 796 days | No | No |
114 | Cutaneous basal cell carcinoma, face | FBM | 11.53 | 35.0 | Female | Yes | Yes, skin, fascia, eyes, genitalia, liver, gastrointestinal, 685 days | No | No |
114 | Cutaneous basal cell carcinoma, face | FBM | 11.53 | 35.0 | Female | Yes | Yes, skin, fascia, eyes, genitalia, liver, gastrointestinal, 685 days | No | No |
236 | Cutaneous basal cell carcinoma, face | FBM | 2.10 | 53.5 | Male | No | No | No | No |
372 | Malignant melanoma, arm, pT4b N3 M1b L1 V0 R0 | FBM | 1.40 | 54.5 | Male | Yes | Yes, skin, 403 days | No | No |
436 | Cutaneous basal cell carcinoma, cheek | FBM | 1.40 | 64.2 | Male | Yes | Yes, liver, 103 days | No | No |
436 | Cutaneous basal cell carcinoma, face | FBM | 1.40 | 64.2 | Male | Yes | Yes, liver, 103 days | No | No |
436 | Cutaneous basal cell carcinoma, face | FBM | 1.40 | 64.2 | Male | Yes | Yes, liver, 103 days | No | No |
Precancerous lesions, histologically proven atypical nevi (n = 15) in 11 patients | |||||||||
7 | Atypical nevi, back | FBM | 3.1 | 64.8 | Male | No | No | No | No |
40 | Actinic keratosis, ear | FTM | 2.6 | 44.2 | Male | No | No | No | No |
62 | Atypical nevi, back | FBM | 1.3 | 62.1 | Female | Yes | No | No | No |
126 | Cutaneous carcinoma in situ, arm | FM | 14.1 | 64.0 | Male | No | Yes, skin, 5173 days | No | No |
126 | Cutaneous carcinoma in situ, arm | FM | 15.5 | 64.0 | Male | No | Yes, skin, 5173 days | No | No |
172 | Vulvar intraepithelial neoplasia, VIN III | FLAMSA-RIC, Treo | 3.8 | 43.4 | Female | No | Yes, skin, oral mucosa, eyes, fascia, 388 days | No | No |
208 | Atypical nevi, shoulder | FTM | 2.6 | 56.8 | Male | Yes | Yes, skin, 495 days | No | No |
238 | Cutaneous carcinoma in situ, perineal | FTM | 5.7 | 40.8 | Female | No | Yes, skin, oral mucosa, eyes, lung, joints, 2105 days | Yes | No |
260 | Atypical nevi, hand | FBM | 2.9 | 48.7 | Female | Yes | No | No | No |
397 | Cutaneous carcinoma in situ, face | FBM | 8.5 | 65.8 | Male | Yes | Yes, oral mucosa, liver, lung, skin, eyes, 1716 days | No | No |
397 | Cutaneous carcinoma in situ, face | FBM | 8.5 | 65.8 | Male | Yes | Yes, oral mucosa, liver, lung, skin, eyes, 1716 days | No | No |
397 | Cutaneous carcinoma in situ, face | FBM | 8.5 | 65.8 | Male | Yes | Yes, oral mucosa, liver, lung, skin, eyes, 1716 days | No | No |
422 | Intraepithelial neoplasia, colon | FBM | 11.1 | 55.2 | Female | No | No | No | No |
429 | Cutaneous carcinoma in situ, hand | Treosulfan, Fludarabine | 2.4 | 61.6 | Female | No | No | No | No |
429 | Cutaneous carcinoma in situ, hand | Treosulfan, Fludarabine | 2.4 | 61.6 | Female | No | No | No | No |
Secondary squamous cell carcinomas
Secondary non-squamous cell carcinomas
Precancerous lesions and atypical nevi
Multivariate analysis of secondary solid malignancies and pre-transplantation variables
Fine and Gray subdistribution hazard model for | ||||||
---|---|---|---|---|---|---|
Squamous cell carcinomas competing death | Non-squamous cell carcinomas competing death | |||||
HR | 95% CI | P-value | HR | 95% CI | P-value | |
Patient age | 1.04 | 0.98, 1.10 | 0.21 | 1.01 | 0.96, 1.06 | 0.73 |
Donor type | ||||||
Matched sibling donor (reference) | ||||||
Matched unrelated donor | 4.65 | 0.90, 24.1 | 0.067 | 2.24 | 0.18, 27.7 | 0.53 |
Mismatched unrelated, haploidentical, mismatched related donor | 2.19 | 0.98, 4.90 | 0.055 | 0.96 | 0.26, 3.50 | 0.95 |
Donor/recipient CMV status | ||||||
Negative/negative (reference) | ||||||
Negative/positive | 1.77 | 0.52, 6.05 | 0.36 | 1.27 | 0.25, 6.32 | 0.77 |
Positive/positive | 0.78 | 0.17, 3.66 | 0.75 | 2.72 | 0.65, 11.4 | 0.17 |
Positive/negative | 0.49 | 0.06, 3.80 | 0.50 | 1.55 | 0.25, 9.75 | 0.64 |
Patient sex | ||||||
Male (reference) | ||||||
Female | 0.68 | 0.21, 2.26 | 0.53 | 0.55 | 0.16, 1.92 | 0.35 |
ATG (Antithymocyte globulin) | ||||||
No (reference) | ||||||
Yes | 0.09 | 0.02, 0.40 | 0.002 | 1.45 | 0.10, 21.1 | 0.78 |
Stem cell source | ||||||
Peripheral blood (reference) | ||||||
Bone marrow | 0.30 | 0.02, 5.45 | 0.42 | 0.93 | 0.04, 22.9 | 0.96 |
Female donor to male recipient | ||||||
No (reference) | ||||||
Yes | 1.72 | 0.38, 7.68 | 0.48 | 1.60 | 0.25, 10.2 | 0.62 |
Donor age | 1.02 | 0.97, 1.07 | 0.49 | 0.99 | 0.95, 1.04 | 0.81 |
Graft-versus-host prophylaxis | ||||||
Cyclosporin A, MTX (reference) | ||||||
Cyclosporin A, MMF | 0.55 | 0.16, 1.86 | 0.33 | 0.30 | 0.07, 1.34 | 0.12 |
Post-transplant cyclophosphamide, tacrolimus, MMF | 0.66 | 0.07, 6.18 | 0.71 | 12.1 | 1.83, 79.4 | 0.010 |
Conditioning regimens | ||||||
Melphalan based, RIC (reference) | ||||||
Other RIC | 0.64 | 0.16, 2.46 | 0.51 | 1.37 | 0.43, 4.37 | 0.59 |
Cause-specific hazard ratios for development of secondary solid malignancies
Variables | Cause-specific hazard regression for | |||||
---|---|---|---|---|---|---|
Squamous cell carcinomas | Non-squamous cell carcinomas | |||||
HR | 95% CI | P-value | HR | 95% CI | P-value | |
Model 1 | ||||||
Grade II–IV acute GVHD | 3.18 | 1.13, 8.93 | 0.028 | 2.35 | 0.86, 6.39 | 0.094 |
Patient age | 1.05 | 1.00, 1.11 | 0.070 | 1.04 | 0.99, 1.09 | 0.2 |
Model 2 | ||||||
Grade II–IV acute GVHD | 2.83 | 1.01, 7.93 | 0.047 | 2.43 | 0.89, 6.69 | 0.084 |
Patient age | 1.08 | 1.01, 1.14 | 0.017 | 1.03 | 0.98, 1.09 | 0.2 |
ATG | 0.25 | 0.09, 0.71 | 0.010 | 1.42 | 0.39, 5.15 | 0.6 |
Variables | Cause-specific hazard regression for | |||||
---|---|---|---|---|---|---|
Squamous cell carcinomas | Non-squamous cell carcinomas | |||||
HR | 95% CI | P-value | HR | 95% CI | P-value | |
Model 1 | ||||||
Chronic GVHD requiring systemic immunosuppression | 4.75 | 1.35, 16.8 | 0.015 | 1.31 | 0.49, 3.53 | 0.6 |
Patient age | 1.06 | 1.01, 1.12 | 0.022 | 1.04 | 0.99, 1.10 | 0.090 |
Model 2 | ||||||
Chronic GVHD requiring systemic immunosuppression | 3.56 | 0.96, 13.1 | 0.057 | 1.37 | 0.50, 3.76 | 0.5 |
Patient age | 1.07 | 1.01, 1.14 | 0.016 | 1.04 | 0.99, 1.10 | 0.10 |
ATG | 0.34 | 0.12, 0.96 | 0.042 | 1.34 | 0.37, 4.85 | 0.7 |