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Non-myeloablative allo-HSCT for patients with hematological malignancies: A 20-year summary of clinical changes

Aug 13, 2020
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Over the last 20 years, non-myeloablative conditioning regimens have been widely used for allogeneic hematopoietic stem cell transplantation (allo-HSCT). There have been many advances in clinical practice to reduce morbidity and mortality during this time. Recently, Jason Cooper and colleagues published a study in Haematologica, investigating whether these updates have actually led to improved outcomes following allo-HSCT over the years.1

Methods

A total of 1,720 patients who were transplanted between 1997 and 2017 were retrospectively included in this study. Three transplantation periods were examined: 1997–2003, 2004–2009, and 2010–2017. The conditioning regimens used are listed in Table 1, and patient characteristics are shown in Table 2.

The graft cell source was peripheral blood stem cells mobilized with granulocyte colony-stimulating factor. High-resolution allelic typing was performed to match donors and recipients at HLA-A, -B, -C, -DRB1, and -DQB1. Only 104 unrelated donor–patient pairs were mismatched at the level of one HLA Class I allele. For disease assessment, bone marrow aspirates were taken on Days 28 and 84, as well as 1 year after allo-HSCT.

Table 1. Conditioning regimens and graft-versus-host disease prophylaxis used in the three transplantation eras1

CI, calcineurin inhibitor; Gy, gray; GvHD, graft-versus-host disease; MMF, mycophenolate mofetil; TBI, total body irradiation

 

1997−2003

(n = 562)

2004−2009

(n = 594)

2010−2017

(n = 564)

Conditioning regimen (%)

TBI 2 Gy

33

17

9

TBI 2 Gy + fludarabine

77

76

50

TBI 3 Gy + fludarabine

6

31

TBI 4-4.5 Gy + fludarabine

1

3

TBI 2 Gy + clofarabine

7

GvHD prophylaxis (%)

CI + MMF

100

89

80

CI + MMF + sirolimus

11

20

Key findings

Study population changes

Table 2. Patient characteristics for the three transplantation eras of interest1

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMV, cytomegalovirus; D, donor; FH, Fred Hutchinson Cancer Research Center; GCSF, granulocyte colony-stimulating factor; HCT, hematopoietic cell transplantation; HCT-CI, HCT comorbidity index; HL, Hodgkin lymphoma; MDS, myelodysplastic syndrome; MM, multiple myeloma; MPN, myeloproliferative neoplasms; NHL, non-Hodgkin lymphoma; WM, Waldenström’s macroglobulinemia

* Disease group classified by Kahl’s criteria

Bold font indicates statistical significance

 

1997−2003

(n = 562)

2004−2009

(n = 594)

2010−2017

(n = 564)

p value

Center/treatment (%)

Non-FH on-protocol

51

35

23

< 0.0001

FH on-protocol

47

55

59

 

FH off-protocol

2

10

18

 

Diagnosis (%)

ALL

3

5

8

< 0.0001

AML

16

31

30

 

CLL

11

11

13

 

CML

7

2

1

 

HL

6

5

3

 

MDS/MPN

15

12

16

 

MM

22

16

10

 

NHL

18

17

19

 

WM

1

1

< 1

 

Donor (%)

Related

66

42

35

< 0.0001

Unrelated

34

58

65

 

Disease risk group* (%)

 

 

 

 

Low

23

22

30

0.002

Standard

48

50

49

 

High

29

28

21

 

Age, years (%)

≤ 49

31

22

18

< 0.0001

50−59

42

35

26

 

≥ 60

27

43

56

 

HCT-CI (%)

0

21

15

10

< 0.0001

1,2

23

23

27

 

3

13

22

20

 

≥ 4

12

21

25

 

Missing

31

19

18

 

Prior HCT (%)

 

 

 

 

No

76

70

77

0.008

Yes

24

30

23

 

The findings in Table 2 show that, with increasing time, a significantly greater proportion of patients underwent HSCT on protocol at the Fred Hutchinson Cancer Research Center (p < 0.001). In addition, these results demonstrate that the average age of the patients treated increased in the two most recent eras compared to 1997−2003, with the proportion of patients ≥ 60 years increasing from 27% to 56% in 2010−2017. Changes in the donor type are also notable, with a greater percentage of unrelated donors being used more recently.

The percentage of patients diagnosed with AML nearly doubled, increasing from 16% to 30% between the first and last era examined, whereas for multiple myeloma and chronic myelogenous leukemia, the percentages dropped. There was a significant decrease in the percentage of patients with high-risk disease and a reciprocal increase in patients with low-risk disease moving from 1997 to 2017.

Only a small proportion of patients had prior HSCT, but there were changes in the types of transplantation used over time. The number of autologous HSCTs decreased from 107 in 1997−2003 to only one in 2010−2017. However, the number of unsuccessful transplants (either allogeneic or autologous) increased. The proportion of patients with a hematopoietic cell transplantation comorbidity index > 3 increased in the two most recent eras.

Endpoints by transplant era

The key endpoints for outcome association for each allo-HSCT era used in this study were overall survival (OS), progression free survival (PFS), and non-relapse mortality (NRM).

Table 3 shows outcome associations per transplantation era. Significant improvements were found when the earliest time period (1997−2003) was compared with the two most recent eras for OS, PFS, and NRM.

In 2010−2017, OS, PFS, relapse rate, and the rates of Grade 2−4 acute (a)GvHD were significantly improved in comparison with 2004−2009.

The time period during which allo-HSCT was performed was also significantly associated with the rates of Grade 2−4 aGvHD, Grade 3−4 aGvHD, and chronic GvHD, all of which improved in the two most recent eras.

Table 3. Association of key endpoints with transplant era

CI, confidence interval; GvHD, graft-versus-host disease; HR, hazard ratio; NRM, non-relapse mortality; OS, overall survival; PFS, progression free survival

 

Adjusted (n = 1,668)

 

19972003
HR (95% CI)

20042009
HR (95% CI)

p value

20102017
HR (95% CI)

p value

OS

1.0

0.72 (0.6−0.9)

0.001

0.60 (0.5−0.7)

< 0.001

PFS

1.0

0.78 (0.7−0.9)

0.002

0.63 (0.5−0.8)

< 0.001

NRM

1.0

0.58 (0.5−0.7)

< 0.001

0.52 (0.4−0.7)

< 0.001

Relapse/ progression

1.0

0.93 (0.8−1.1)

0.52

0.71 (0.6−0.9)

0.006

Acute GvHD Grade 2−4

1.0

0.81 (0.7−1.0)

0.03

0.64 (0.5−0.8)

< 0.001

Acute GvHD Grade 3−4

1.0

0.67 (0.5−1.0)

0.03

0.54 (0.4−0.8)

0.004

Chronic GvHD

1.0

0.59 (0.5−0.7)

< 0.001

0.57 (0.5−0.7)

< 0.001

The addition of sirolimus to mycophenolate mofetil and calcineurin inhibitor (MMF + CI) significantly decreased the rates of Grade 2−4 and 3−4 aGvHD (p < 0.0001 and p = 0.05, respectively) when compared to MMF + CI alone.

Relapse and disease progression

A total of 351 patients with AML in first or second complete response were analyzed, but no significant changes in the rate of relapse were found over time. Of these patients, measurable residual disease was detected in 11% during 2004−2009 and in 23% during 2010−2017. No relevant data were available prior to these time points.

Adverse events by era of HSCT

Table 4 shows the association of liver or kidney injury and infections with each transplantation era. The two most recent time periods show significantly decreased risk of having liver or kidney complications, gram-negative bacteremia, or invasive fungal infection.

Cytomegalovirus (CMV) infection was also evaluated in patients that were seropositive at the time of transplant. There was no significant change in the incidence of CMV reactivation, however there was a significant decrease in the incidence of CMV disease in 2010−2017.

Table 4. Association of adverse events with transplantation era1

CI, confidence interval; HR, hazard ratio; OR, odds ratio

Bold font indicates statistical significance

 

Adjusted

Organ toxicity (n = 1,548)

OR (95% CI)

p value

Bilirubin > 4 mg/dL

 

 

1997–2003

1.00

 

2004–2009

0.28 (0.18–0.42)

< 0.0001

2010–2017

0.22 (0.14–0.35)

< 0.0001

Bilirubin > 10 mg/dL

 

 

1997–2003

1.00

 

2004–2009

0.18 (0.08–0.43)

0.0001

2010–2017

0.21 (0.09–0.50)

0.0005

Creatinine > 2 × baseline

 

 

1997–2003

1.00

0.002

2004–2009

0.63 (0.47–0.84)

0.03

2010–2017

0.71 (0.52–0.97)

 

Infections (n = 1,502)

HR (95% CI)

p value

Gram-negative bacteremia

 

 

1997–2003

1.00

 

2004–2009

0.82 (0.70–0.97)

0.2

2010–2017

0.68 (0.56–0.82)

< 0.0001

Invasive fungal infection

 

 

1997–2003

1.00

 

2004−2009

0.75 (0.63–0.89)

0.0008

2010–2017

0.63 (0.52–0.76)

< 0.0001

Conclusion

Over the past two decades, the median age of patients, impact of comorbidity at the time of transplant, and use of unrelated donors have all increased, indicating the increasing availability of allo-HSCT with time for patients with hematological malignancies. The results of this study also show that patient outcomes (namely PFS and OS) significantly improved over the last 20 years, with accompanying lower risk of NRM and Grade 2−4 aGvHD/chronic GvHD. These results are encouraging for the referral of elderly or medically unfit patients for allo-HSCT.

  1. Cooper JP, Storer BE, Granot N, et al. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2020;105(6). DOI: 3324/haematol.2020.248187

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