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Risk of subsequent neoplasms following allo-HSCT with different conditioning regimens

The impact of the dose and fractionation of total body irradiation (TBI) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) on subsequent malignant neoplasms was investigated by Scott Baker from the Fred Hutchinson Cancer Research Center, Seattle, WA, USA, and colleagues. The results of this study were published on 16 April 2019 in Blood1 and included 4,500 one-year allo-HSCT survivors with hematological malignancies.

With the increased use of allo-HSCT and the reduction in the incidence of graft-versus-host disease ─ one of the most common HSCT complications ─ patients are surviving longer and are being cured of their primary disease. Nevertheless, an increase in the incidence of post-transplant subsequent malignant neoplasms (SMNs) has been observed.3,2 In this study, the authors sought to investigate whether HSCT conditioning regimens of various intensities impact on the occurrence of SMNs.

Study design & baseline characteristics
  • N = 4,905 patients who underwent allo-HSCT for hematological malignancies (lymphoma, leukemia, myelodysplastic syndrome; n = 4500) or non-malignant disorders (n = 405) and who survived at least one year after allo-HSCT without developing SMNs
  • Median age at time of allo-HSCT (range): 34.5 (0.3−9) years
  • Median follow-up length (range): 12.5 (1.00−11) years
  • Myeloablative regimens used for allo-HSCT conditioning:
    • Single-fraction TBI (sf-TBI): 600−1000 cGy, single fraction
    • Fractionated TBI (f-TBI): 600−1200 cGy or 1200−1400 cGy multiple fractions
    • High-dose f-TBI: 1440−1750 cGy, multiple fractions
    • Chemotherapy-only: majority received busulfan-based conditioning with cyclophosphamide
  • Non-myeloablative regimens used for allo-HSCT conditioning:
    • Low dose TBI (ld-TBI): 200 cGy single fraction and 450 cGy single or double fraction, and fludarabine
  • GvHD prophylaxis according to conditioning regimen intensity:
    • Myeloablative regimens:
    • Non-myeloablative regimens: mycophenolate mofetil and a calcineurin inhibitor (cyclosporine or tacrolimus)
  • As of the data cut-off date (July 2014), amongst living survivors:
    • Patients who had follow-up contact within 2 years: 74%
    • Patients who had follow-up contact within 3 years: 84%
    • Out of contact for > 5 years: 11%
  • Malignancies were considered as SMN if:
    • Histological classification was different from initial diagnosis that led to allo-HSCT
    • Histological classification differed from that of any prior malignancy diagnosed before allo-HSCT
    • Post-transplant lymphoproliferative diseases occurring within the first year after allo-HSCT were excluded
    • Squamous cell carcinoma (SCC) of the skin and basal cell carcinoma were included but will be published separately
    • Non-skin SCC were included in this analysis

Key findings

  • Patients who developed at least one SMN (total cohort): 11% (n = 499)
  • Median time of SMN occurrence after allo-HSCT (range; total cohort): 10.3 (1.0−7) years
    • Patients who developed > 1 SMN after allo-HSCT: n = 81 (69 had 2 SMNs, 9 had 3 SMNs and 3 had 4 SMNs) in the following sites:
      • Skin (melanoma, n = 16)
      • Breast (n = 13)
      • Renal/urinary bladder (n = 8)
      • Oral cavity (n = 7)
      • Gastrointestinal sites (n = 6)
      • Others (n = 31)
    • 30-year cumulative SMN incidence after allo-HSCT (total cohort): 22.0% (95% CI, 19.8−1)
    • Cumulative SMN incidence at 20 years post allo-HSCT by patient age:

Patient age at allo-HSCT

Cumulative SMN incidence at 20 years post allo-HSCT

< 20 years old

8.1% (95% CI, 6.1−10.1)

20−50 years old

13.5% (95% CI, 11.8−15.2)

> 50 years old

23.6% (95% CI, 18.4−28.8)

Cox proportional hazard modelling

Patient age at allo-HSCT         Risk of SMN                    P value            95% CI

≤ 20 years old

2.28-fold higher risk than those aged > 50 years

0.003

1.31−3.96

  • Identified risk factors for developing SMNs:

Cox proportional hazard modelling

Risk factor                  Risk of SMN                    P value           95% CI         HR

White race

Higher risk of SMN compared to other races

0.04

1.04−2.94

1.75

Patient age at allo-HSCT ≤ 20 years old

2.28-fold higher risk than those aged > 50 years

0.003

1.31−3.96

-

Stem cell source:

Cord blood

PBSC

 

Higher risk of SMN compared to bone marrow

 

0.01

0.003

 

1.29−7.09

1.16−2.07

 

3.02

1.55

Acute GvHD

Higher overall risk of SMN

0.05

1.00−1.88

1.37

Patient sex

Non-significant

-

-

Diagnosis (malignant vs non-malignant)

Non-significant

Patients receiving sf-TBI (600−1000 cGy)

Highest risk of SMN from the TBI-based regimens

< 0.0001

1.92−5.26

3.18

Patients receiving f-TBI (1440−1750 cGy)

Next highest risk of SMN from the TBI-based regimens

< 0.0001

1.49−3.06

2.14

Patients receiving intermediate f-TBI (600−1200 cGy)

Higher risk of SMN compared to patients given chemotherapy-only

0.0004

1.26−2.21

1.67

Patients receiving intermediate f-TBI (1320−1400 cGy)

Higher risk of SMN compared to patients given chemotherapy-only

0.02

1.09−2.21

1.55

Patients receiving ld-TBI (200−450 cGy)

Non-significant risk of SMN compared to patients given chemotherapy-only

0.42

0.8− 1.72

1.17

  • Standardized incidence ratios (SIR):
    • The risk of developing an SMN even in patients who received chemotherapy-only conditioning regimen was almost 2-fold higher than in the general population (SIR = 1.9; 95% CI, 1.6−3) and nearly the same for patients receiving ld-TBI (SIR = 2.0; 95% CI, 1.6−2.6). But the risk has higher for all other TBI-based cohorts:
      • sf-TBI (SIR = 7.8; 95% CI, 5.5−2)
      • high-dose f-TBI (SIR = 5.7; 95% CI, 4.5−7.3)
      • f-TBI (600−1200 cGy; SIR = 3.3; 95% CI, 2.8−3.8)
      • f-TBI (1320−1400 cGy; SIR = 3.1; 95% CI, 2.4−4.0)
Conclusions

The study showed that there is a higher risk of developing SMNs for patients exposed to high-dose unfractionated or very high-dose fractionated TBI. Even in patients who had received low-dose TBI, SMN risk was similar to those who received chemotherapy alone, and was still 2-fold higher than the general population. This further indicated that even the lowest intensity conditioning regimens increase the risk of SMNs in patients receiving allo-HSCT.

References
  1. Baker K.S. et al. Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood. 2019 Apr 16. pii: blood.2018874115. DOI: 10.1182/blood.2018874115 [Epub ahead of print]
  2. Baker K.S. et al. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003;21(7):1352-1358
  3. Curtis R.E. et al. Solid cancers after bone marrow transplantation. N Engl J Med. 1997;336(13):897-904
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