Outcomes of long-term survivors after hematopoietic stem cell transplantation

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Despite advances in the field of targeted therapies, hematopoietic stem cell transplantation (HSCT) is still an important curative option for a number of hematological and non-hematological disorders.¹ Over the last years, changes such as the use of cord blood (CB) cells or haploidentical donors as stem cell sources, conditioning regimens, and graft-versus-host disease prophylaxis have increased the accessibility to HSCT,¹ augmenting the number of global annual HSCT.²

In a paper, published in Biology of Blood and Marrow Transplantation, David Kliman and colleagues reported the outcome of long-term survivors who underwent HSCT from 2002–2011. Data were obtained from the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) and compared with survivors transplanted between 1992–2001 and with the age-matched general population.³

Study design³

• Of 12,664 recorded transplants between 2002–2011, 2-year disease-free post-HSCT survivors who underwent allogeneic (allo) or autologous (auto) HSCT for specific diseases were included in the study analysis:
  • Allo-HSCT (n = 1562)
    • Acute lymphoblastic leukemia
    • AML
    • Chronic myeloid leukemia (CML)
    • Myelodysplastic syndromes (MDS)
    • Non-Hodgkin lymphoma (NHL)
  • AutoHSCT (n = 3822)
    • Hodgkin lymphoma
    • Multiple myeloma (MM)
    • NHL
  • Median follow up was 5.6 years

Results³

Outcomes after allo-HSCT

Compared with 2-year allo-HSCT survivors from 1992─2001, the 2002─2011 cohort presented different characteristics, reported in Table 1.

Table 1. Patient and transplant characteristics of 2-year allo-HSCT survivors by time period³

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; CB, cord blood; CML, chronic myeloid leukemia; MDS, myelodysplastic syndromes; NHL, non-Hodgkin lymphoma; PB, peripheral blood
Characteristic	1992─2001 N = 1038	2002─2011 N = 1562	p value
Median age (years)	33 (0.4–68)	38 (0.3–71.5)	< 0.001
Hematopoietic cell source BM PB CB Other	716 (69%) 295 (28%) 19 (2%) 8 (1%)	330 (21%) 1,071 (69%) 160 (10%) 1 (0%)	< 0.001
Conditioning intensity Myeloablative Reduced intensity	1,006 (97%) 32 (3%)	1,151 (74%) 411 (26%)	< 0.001
Indication for transplant ALL AML CML MDS NHL	242 (23%) 326 (31%) 334 (32%) 51 (5%) 85 (8%)	400 (26%) 755 (48%) 124 (8%) 127 (8%) 156 (10%)	< 0.001
Donor relation HLA-identical sibling Haploidentical Other related Syngeneic Unrelated	753 (73%) 3 (0.3%) 81 (8%) 11 (1%) 190 (18%)	810 (52%) 11 (1%) 35 (2%) 18 (1%) 688 (44%)	< 0.001

Despite the different characteristics, such as transplant age (with an increase from 11% to 21% in patients transplanted at ages 50─59, and from 1% to 7% in patients transplanted over 60 years), cell source, and donors, the 10-year OS was similar between the two cohorts: 78.4% vs 80.3% in the 1992─2001 vs the 2002─2011 cohort, respectively. Favorable factors associated with OS were age < 16 years and transplantation for CML, whereas adverse factors were represented by peripheral blood (PB) stem cell source, transplantation for MDS, male recipient, poor risk disease, and age > 45 years. Hazard ratio (HR), 95% confidence interval (CI), and p values for each variable are reported in Table 2.

Table 2. Risk factors for OS in 2-year allo-HSCT survivors³

CI, confidence interval; CML, chronic myeloid leukemia; HR, hazard ratio; MDS, myelodysplastic syndromes
Variable	HR	95% CI	p value
Age < 16 years	0.58	0.43─0.79	0.001
Transplantation for CML	0.69	0.54─0.90	0.005
PB stem cell source	1.25	1.02─1.54	0.03
Transplantation for MDS	1.44	1.02─2.04	0.04
Male recipient	1.44	1.19─1.74	< 0.001
Poor risk disease	1.57	1.30─1.90	< 0.001
Age > 45 years	1.63	1.30─1.90	< 0.001

• Relative survival was similar to the age-matched population, with survival ratios ranging from 96% to 99%, but still significantly lower than the general population
• By 10-year posttransplant
  • cumulative incidences of chronic GvHD: 30%
  • relapse: 11%
  • death due to relapse: 7%
  • NRM incidence: 14%
  • deaths due to new malignancy: 7%

Outcomes after auto-HSCT

The characteristics of the 2-year auto-HSCT survivors from the 2002─2011 cohort were compared with the 1992─2001 cohort and are reported in Table 3. An increase in median age at transplant (with a greater proportion of patients, 37% vs 16%, transplanted over 60 years in the 2002─2011 cohort vs the 1992─2001 cohort) and a decrease in the use of BM as stem cell source were observed.

Table 3. Patient and transplant characteristics of 2-year auto-HSCT survivors by time period³

BM, bone marrow; HL, Hodgkin lymphoma; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; PB peripheral blood
Characteristic	1992─2001 N = 1630	2002─2011 N = 3822	p value
Median age, years (range)	49 (6─75)	56 (4.4─79)	< 0.001
Hematopoietic cell source BM PB BM & PB	118 (7%) 1,452 (89%) 60 (4%)	17 (0%) 3,787 (99%) 78 (0%)	< 0.001
Indication for transplant HL MM NHL	236 (14%) 600 (37%) 794 (49%)	379 (10%) 1,981 (52%) 1,462 (38%)	< 0.001

Despite these differences, by 10-year post auto-HSCT,

• for lymphoma
  • OS: 61.8% vs7% (p = 0.2) in the 2002─2011 vs the 1992─2001 cohort, respectively
  • cumulative incidences of relapse: 23%
  • death due to relapse: 15%
  • NRM: 23%
• for MM
  • OS: 42.5% vs2% (p = 0.5) in the 2002─2011 vs the 1992─2001 cohort, respectively
  • cumulative incidences of death: 37%
  • NRM: 21%

Adverse risk factors for OS were

• male recipient, HR 1.15 (95% CI, 1.04─26; p = 0.005)
• transplant for myeloma, HR 1.75 (95% CI, 1.59─94; p < 0.001)
• age > 45 years, HR 1.97 (95% CI, 1.73─25; p < 0.001)

The relative survival ratio was close to the age-matched population but still significantly lower (89–96%), with a better relative survival for patients with lymphoma (91–97%) compared with MM (88–96%).

Conclusion³

• Two-year allo-HSCT and auto-HSCT recent survivors are older and more likely to receive PB stem cells than survivors from the 1992─2001 cohort, but this analysis showed that advancing age (for both allo-HSCT and auto-HSCT) and the use of PB as stem cell source (for allo-HSCT) were an adverse risk factor for OS
• Despite this, OS is similar between the 2002─2011 and the 1992─2001 cohort, and relative survival is similar to the general population but still reduced
• Auto-HSCT for MM has increased but the OS of 42.5% was lower than for patients with lymphoma
• Late mortality, after allo-HSCT, was primarily due to NRM but for auto-HSCT, relapse or disease progression were the major causes of death
• Risk factors, except for the selection of cell source, are not modifiable but might be used to identify high-risk patients requiring additional follow-up after HSCT
• All together, these results, specific to the Australian and New Zealand population, demonstrate that the outcomes of the 2-year HSCT survivors are similar over time, and a tailored risk-specific monitoring for late effects is essential to improve long-term survival