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Allogeneic hematopoietic cell transplantation provides effective salvage despite refractory disease or failed prior autologous transplant in angioimmunoblastic T-cell lymphoma: a CIBMTR analysis

  • Narendranath Epperla
  • Kwang W. Ahn
  • Carlos Litovich
  • Sairah Ahmed
  • Minoo Battiwalla
  • Jonathon B. Cohen
  • Parastoo Dahi
  • Nosha Farhadfar
  • Umar Farooq
  • Cesar O. Freytes
  • Nilanjan Ghosh
  • Bradley Haverkos
  • Alex Herrera
  • Mark Hertzberg
  • Gerhard Hildebrandt
  • David Inwards
  • Mohamed A. Kharfan-Dabaja
  • Farhad Khimani
  • Hillard Lazarus
  • Aleksandr Lazaryan
  • Lazaros Lekakis
  • Hemant Murthy
  • Sunita Nathan
  • Taiga Nishihori
  • Attaphol Pawarode
  • Tim Prestidge
  • Praveen Ramakrishnan
  • Andrew R. Rezvani
  • Rizwan Romee
  • Nirav N. Shah
  • Ana Sureda
  • Timothy S. Fenske
  • Mehdi Hamadani
Open Access
Research

Abstract

Background

There is a paucity of data on the role of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with angioimmunoblastic T-cell lymphoma (AITL). Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT.

Methods

We evaluated 249 adult AITL patients who received their first allo-HCT during 2000–2016.

Results

The median patient age was 56 years (range = 21–77). Majority of the patients were Caucasians (86%), with a male predominance (60%). Graft-versus-host disease (GVHD) prophylaxis was predominantly calcineurin inhibitor-based approaches while the most common graft source was peripheral blood (97%). Median follow-up of survivors was 49 months (range = 4–170 months). The cumulative incidence of grade 2–4 and grade 3–4 acute GVHD at day 180 were 36% (95% CI = 30–42) and 12 (95% CI = 8–17), respectively. The cumulative incidence of chronic GVHD at 1 year was 49% (95%CI 43–56). The 1-year non-relapse mortality (NRM) was 19% (95% CI = 14–24), while the 4-year relapse/progression, progression-free survival (PFS), and overall survival (OS) were 21% (95% CI = 16–27), 49% (95% CI = 42–56), and 56% (95% CI = 49–63), respectively. On multivariate analysis, chemoresistant status at the time of allo-HCT was associated with a significantly higher risk for therapy failure (inverse of PFS) (RR = 1.73 95% CI = 1.08–2.77), while KPS < 90% was associated with a significantly higher risk of mortality (inverse of OS) (RR = 3.46 95% CI = 1.75–6.87).

Conclusion

Our analysis shows that allo-HCT provides durable disease control even in AITL patients who failed a prior auto-HCT and in those subjects with refractory disease at the time of allografting.

Keywords

Angioimmunoblastic T-cell lymphoma Allogeneic transplantation GVL effects 

Abbreviations

AITL

Angioimmunoblastic T-cell lymphoma

Allo-HCT

Allogeneic hematopoietic cell transplantation

CNI

Calcineurin inhibitor

CR

Complete remission

CRF

Comprehensive Report Form

GRFS

GVHD free, relapse-free survival

GVHD

Graft-versus-host disease

NRM

Non-relapse mortality

OS

Overall survival

PFS

Progression-free survival

PR

Partial remission

RR

Relative risk

TED

Transplant essential data

Background

Angioimmunoblastic T-cell lymphoma (AITL) represents a distinct clinicopathologic entity among the mature T- and NK-cell neoplasms, accounting for approximately 1–2% of all non-Hodgkin lymphomas (NHLs) [1, 2]. AITL patients typically present with advanced stage disease, diffuse lymphadenopathy, hepatosplenomegaly, systemic symptoms, and hypergammaglobulinemia [3]. The clinical course is aggressive and the disease generally carries a poor prognosis even when treated with intensive induction regimens [3]. Standard first-line therapy mostly consists of anthracycline-based regimens with or without etoposide, based on the age [2, 4, 5, 6]. With this approach, overall survival (OS) is a little over 30% at 5 years [7]. In an attempt to improve the outcomes, autologous hematopoietic cell transplantation (auto-HCT) consolidation has been applied in this patient population [8, 9, 10]. While durable disease control can be observed typically in patients in first complete remission (CR), the outcomes of AITL subjects in partial remission (PR), and in those with refractory disease or treated with ≥ 2 prior therapy lines, following auto-HCT are less encouraging [10].

Allogeneic HCT (allo-HCT) may result in a lower risk of relapse in part due to a graft-versus-lymphoma effect mediated by the alloreactive donor cells [11, 12, 13]. Several retrospective studies [11, 14, 15, 16] have reported excellent disease control with low rates of relapse and a 1-year non-relapse mortality (NRM) ranging from 8 to 25% with allo-HCT in AITL patients. However, these analyses were done mainly in peripheral T-cell lymphoma (PTCL) patients with AITL as a subgroup or reported only a small number of patients with AITL (range N = 9–45 patients; Additional file 1: Table S1). We report here a registry analysis, evaluating the outcomes of patients with AITL undergoing allo-HCT.

Methods

Data sources

The Center for International Blood and Marrow Transplant Research (CIBMTR) is a working group of more than 500 transplantation centers worldwide that contribute detailed data on HCT to a statistical center at the Medical College of Wisconsin (MCW). Participating centers are required to report all transplantations consecutively and compliance is monitored by on-site audits. Computerized checks for discrepancies, physicians’ review of submitted data, and on-site audits of participating centers ensure data quality. Observational studies conducted by the CIBMTR are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. The MCW and National Marrow Donor Program, Institutional Review Boards approved this study.

The CIBMTR collects data at two levels: transplant essential data (TED) and comprehensive report form (CRF) data. TED data includes disease type, age, gender, pre-HCT disease stage and chemotherapy-responsiveness, date of diagnosis, graft type, conditioning regimen, post-transplant disease progression and survival, development of a new malignancy, and cause of death. All CIBMTR centers contribute to TED data. More detailed disease and pre- and post-transplant clinical information is collected on a subset of registered patients selected for CRF data by a weighted randomization scheme. TED- and CRF-level data are collected pre-transplant, 100-days, and 6 months post-HCT and annually thereafter or until death. Data for the current analysis were retrieved from CIBMTR (TED and CRF) report forms.

Patients

Included in this analysis are adult (≥ 18 years) patients with AITL, undergoing their first allo-HCT between 2000 and 2016. Eligible donors included either HLA-identical sibling donors or unrelated donors (URD) matched at the allele-level at HLA-A, -B, -C, and -DRB1 and graft sources included peripheral blood and bone marrow. Graft-versus-host disease (GVHD) prophylaxis included both calcineurin inhibitor (CNI) and non-CNI-based regimens. Recipients of alternative donor transplantation were excluded due to small numbers (haploidentical allografts, n = 8; mismatched unrelated donor, n = 22; cord blood grafts, n = 21).

Definitions and study endpoints

The intensity of conditioning regimens was defined using consensus criteria [17]. Disease response at the time of HCT was determined using the International Working Group criteria in use during the era of this analysis [18].

The primary endpoint was OS; death from any cause was considered an event and surviving patients were censored at last contact. Secondary endpoints included cumulative incidence of acute GVHD, chronic GVHD, GVHD free, relapse-free survival (GRFS), NRM, progression/relapse, and progression-free survival (PFS). NRM was defined as death without evidence of lymphoma progression/relapse; relapse was considered a competing risk. Progression/relapse was defined as progressive lymphoma after HCT or lymphoma recurrence after a CR; NRM was considered a competing risk. For PFS, a patient was considered treatment failure at the time of progression/relapse or death from any cause. Patients alive without evidence of disease relapse or progression were censored at last follow-up. Acute GVHD [19] and chronic GVHD [20] were graded using standard criteria. Neutrophil recovery was defined as the first of three successive days with absolute neutrophil count (ANC) ≥ 500/μL after post-transplantation nadir. Platelet recovery was defined as achieving platelet counts ≥ 20,000/μL for at least 3 days, unsupported by transfusion. For neutrophil and platelet recovery, death without the event was considered a competing risk. The causes of death are reported in accordance to the methodology described previously [21].

Statistical analysis

Probabilities of PFS and OS were calculated using the Kaplan–Meier estimates. Cumulative incidence of NRM, lymphoma progression/relapse, and GVHD were calculated to accommodate for competing risks. Associations among patient-, disease-, and transplantation-related variables and outcomes of interest were evaluated using Cox proportional hazards regression. A stepwise model-building approach was used to identify covariates that influenced outcomes. Covariates with a p < 0.05 were considered statistically significant. The proportional hazards assumption for Cox regression was tested by adding a time-dependent covariate for each risk factor and each outcome. If a variable violated the proportional hazards assumption, it was added as a time-varying covariate. Interactions between the main effect and significant covariates were examined and none were found. Results are expressed as relative risks (RR). The center effect was examined using the random effect score test [22] for OS, PFS, relapse, and NRM. The variables considered in multivariate analysis are shown in Additional file 1: Table S2 of the supplemental appendix. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).

Results

Baseline characteristics

A total of 249 patients met the inclusion criteria and were included in this analysis. The baseline patient-, disease-, and transplantation-related characteristics are shown in Table 1. The median patient age was 56 years (range = 21–77 years). Most of the patients were Caucasians (86%), with a male (60%) predominance. The majority had a chemosensitive disease at the time of allo-HCT (79%) and received a non-myeloablative/reduced intensity conditioning regimen (73%). Most common type of GVHD prophylaxis included CNI ± methotrexate-based regimens. The graft source used for allo-HCT was predominantly peripheral blood (97%). Pre-transplant (allo-HCT) donor/recipient cytomegalovirus status was available in 200 patients (81%) and the details are provided in Table 1. There was no center effect noted on the outcomes. Median follow-up of survivors was 49 months (range, 4–170 months).
Table 1

Baseline patient characteristics of patients with AITL receiving first allo-HCT reported to the CIBMTR from 2000 to 2016

Variable

N = 249 (%)

Median age at HCT, years (range)

56 (21–77)

Male gender

150 (60)

Race

 Caucasian

214 (86)

 African American

5 (2)

 Othersa

17 (7)

 Missing

13 (5)

Karnofsky performance score ≥ 90

119 (48)

 < 90

113 (45)

 Missing

17 (7)

HCT-CI

 0

46 (18)

 1–2

53 (21)

 ≥ 3

84 (34)

 Not available before 2007

55 (22)

 Missing

11 (4)

Interval from diagnosis to HCT, months

 Median (range)

14 (3–118)

Median lines of therapy before HCT (range)

3 (1–5)

Remission status at HCT

 Complete remission

108 (43)

 Partial remission

90 (36)

 Chemorefractory

38 (15)

 Untreated/unknown

13 (5)

History of prior autologous HCT

98 (39)

TBI in conditioning

83 (34)

ATG/alemtuzumab in conditioningb

59 (24)

Conditioning intensityc

 Myeloablative conditioning

66 (27)

 Non-myeloablative/RIC

183 (73)

Graft source

 Bone marrow

8 (3)

 Peripheral blood

241 (97)

Donor type

 HLA-identical sibling

140 (56)

 Unrelated donor 8/8

109 (44)

Donor/recipient CMV status

 Both negative

72 (29)

 Both positive

59 (24)

 Either donor/recipient +

69 (28)

 Missing

49 (19)

Graft-versus-host disease prophylaxis

 Calcineurin inhibitor + MTX ± othersd (except MMF)

119 (48)

 Calcineurin inhibitor + MMF ± othersd

76 (31)

 Calcineurin inhibitor + others (except MMF)

40 (16)

 Othersd

10 (4)

 Missing

4 (2)

Year of HCT

 2000–2006

47 (19)

 2007–2011

82 (33)

 2012–2016

120 (48)

Median follow-up of survivors (range), months

49 (4–170)

ATG antithymocyte globulin, CMV cytomegalovirus, HCT hematopoietic cell transplantation, HCT-CI HCT-Comorbidity index, MMF mycophenolate mofetil, MTX methotrexate, TBI total body irradiation, RIC reduced intensity conditioning

aOthers: 13 Asian; 3 Hispanic or Latino; 1 race unspecified, non-Hispanic

bATG/alemtuzumab—49 ATG alone; 10 alemtuzumab alone

cFor details, refer to Additional file 1: Table S4

dFor details, refer to Additional file 1: Table S5

Hematopoietic recovery

On univariate analysis, the cumulative incidence of neutrophil engraftment at 1-year was 97% (95% CI 94–99). The 1-year cumulative incidence of platelet recovery (Table 2) was 91% (95% CI 87–94).
Table 2

Univariate Analysis

Outcomes

N Eval

Prob (95% CI)

Neutrophil engraftment

236

 

 1-year

 

97 (94–99)%

 2-year

 

97 (94–99)%

Platelet recovery

218

 

 1-year

 

91 (87–94)%

 2-year

 

91 (87–95)%

Acute GVHD (II-IV)

239

 

 180-day

 

36 (30–42)%

Acute GVHD (III-IV)

229

 

 180-day

 

12 (8–17)%

Chronic GVHD

230

 

 1-year

 

49 (43–56)%

 2-year

 

58 (51–64)%

Extensive cGVHD

230

 

 1-year

 

39 (33–46)%

 2-year

 

46 (39–53)%

GRFS

230

 

 1-year

 

35 (29–41)%

 2-year

 

27 (21–33)%

NRM

249

 

 1-year

 

19 (14–24)%

 2-year

 

25 (20–31)%

 4-year

 

30 (24–36)%

Progression/relapse

249

 

 1-year

 

15 (11–20)%

 2-year

 

19 (15–25)%

 4-year

 

21 (16–27)%

PFS

249

 

 1-year

 

66 (60–72)%

 2-year

 

56 (49–62)%

 4-year

 

47 (41–54)%

Overall survival

249

 

 1-year

 

73 (68–79)%

 2-year

 

63 (56–69)%

 4-year

 

56 (49–63)%

GVHD graft-versus-host disease, Prob probability, CI confidence interval, N number, NRM non-relapse mortality, PFS progression-free survival, GRFS GVHD free, relapse-free survival

Probabilities of acute GVHD, chronic GVHD, treatment-related mortality and progression/relapse were calculated using the cumulative incidence estimate. Progression-free survival and overall survival was calculated using the Kaplan-Meier product limit estimate

Univariate analysis of alternative donor sources is shown in Additional file 1 Table S6

Acute and chronic GVHD

On univariate analysis, the cumulative incidence of grade II–IV acute GVHD was 36% (95% CI 30–42) and grades III–IV acute GVHD was 12% (95% CI 8–17) at day 180 (Table 2). None of the tested covariates (Additional file 1: Table S2) affected the risk of the development of acute GVHD.

On univariate analysis, the cumulative incidence of chronic GVHD at 1-year (Table 2) was 49% (95% CI 43–56), while the cumulative incidence of extensive chronic GVHD at 1 year (Table 2) was 39% (95% CI 33–46). Multivariate analysis (Table 3) showed that patients who received anti-thymocyte globulin (ATG) or alemtuzumab had a significantly lower risk of chronic GVHD (RR = 0.58, 95% CI 0.36–0.93, p = 0.02) relative to those who did not receive ATG/alemtuzumab.
Table 3

Multivariate analysis results

 

Number

RR

95% CI lower limit

95% CI upper limit

P-value

Overall p value

Chronic GVHD

 ATG/alemtuzumab

  No

174

1

   

0.02

  Yes

55

0.58

0.36

0.93

0.02

 

Progression/Relapse

 No significant covariates

Non-relapse mortality

 No significant covariates

Progression-free survival

 Disease status

  CR

108

1

   

0.03

  PR

90

1.13

0.76

1.66

0.54

 

  Chemoresistant

38

1.73

1.08

2.77

0.02

 

  Missing/Untreated

13

0.43

0.15

1.20

0.11

 

Overall survival

 Karnofsky performance score (≤ 6 months)a

  ≥ 90%

119

1

   

0.002

  < 90%

113

3.46

1.74

6.87

0.0004

 

  Missing

17

1.95

0.54

6.98

0.31

 

 Karnofsky performance score (> 6 months)a

  ≥ 90%

106

1

   

0.28

  < 90%

80

0.66

0.39

1.12

0.12

 

  Missing

14

0.73

0.29

1.86

0.51

 

GVHD graft-versus-host disease, CI confidence interval, ATG anti-thymocyte globulin, CR complete remission, PR partial remission, RR relative risk

Variables tested in the Multivariate analysis are listed in Additional file 1 Table S2

a6-months was chosen as cut-off based on the maximum likelihood value in the Cox model

p-value <0.05 is considered significant

Transplantation outcomes

On univariate analysis, the cumulative incidence of 1-year GRFS (Table 2) was 35% (95% CI 29–41).

The 1-year NRM rate (Table 2) was 19% (95% CI 14–24) (Fig. 1a). On multivariate analysis, there were no significant covariates affecting the risk of NRM. The cumulative incidence of progression/relapse at 4 years (Table 2) was 21% (95% CI 16–27) (Fig. 1b). On multivariate analysis (Table 3), none of the covariates (Additional file 1: Table S1, including chronic GVHD assessed as a time-dependent variable) significantly affected the relapse risk.
Fig. 1

Outcomes of patients receiving first allo-HCT for AITL. a Cumulative incidence of non-relapse mortality. b Cumulative incidence of lymphoma progression/relapse. c Progression-free survival. d Overall survival

The 4-year PFS and OS (Table 2) were 47% (95% CI 41–54) (Fig. 1c) and 56% (95% CI 49–63) (Fig. 1d), respectively. On multivariate analysis (Table 3), chemoresistant status at the time of allo-HCT significantly increased the risk for therapy failure (inverse of PFS) (RR = 1.73 95% CI = 1.08–2.77, p = 0.02), while KPS < 90% was associated with a significantly higher risk of mortality (inverse of OS) in the first 6-months post allo-HCT (RR = 3.46 95% CI = 1.74–6.87, p = 0.0004).

Causes of death

At last follow-up, 45% (n = 112) of allo-HCT recipients had died (Additional file 1: Table S3). The most common cause of death was organ failure, 20% (n = 22) followed by recurrent/progressive disease, 19% (n = 21). GVHD was the cause of death in 17% (n = 19) and infectious complications accounted for death in 15% (n = 17) of patients. The other causes of death are listed in Additional file 1: Table S3.

Impact of prior autograft and disease status

Among the 249 patients who received first allo-HCT, 98 patients (39%) had received a prior auto-HCT. Univariate analysis looking at the impact of prior auto-HCT (no prior auto-HCT vs prior auto-HCT) on the outcomes showed no significant difference in the 1-year NRM (17% [95% CI 11–23] vs 22% [95% CI 14–30], p = 0.33), 4-year progression/relapse (24% [95% CI 17–31] vs 17% [95% CI 10–25], p = 0.21), PFS (50% [95% CI 42–59] vs 47% [95% CI 36–57], p = 0.60), or OS (57% [95% CI 49–65] vs 54% [95% CI 44–65], p = 0.70) (Table 4, Fig. 2).
Table 4

Comparative analysis of AITL patients who received prior auto-HCT vs no prior auto-HCT

Outcomes

No prior auto-HCT (N = 151)

Prior auto-HCT (N = 98)

p value

N

Prob (95% CI)

N

Prob (95% CI)

NRM

151

 

98

 

0.25

1-year

 

17 (11–23)%

 

22 (14–30)%

0.33

2-year

 

21 (15–28)%

 

31 (22–41)%

0.08

3-year

 

22 (16–29)%

 

33 (23–43)%

0.07

4-year

 

26 (19–34)%

 

36 (26–47)%

0.11

Progression/relapse

151

 

98

 

0.69

1-year

 

16 (11–22)%

 

15 (8–22)%

0.77

2-year

 

22 (15–29)%

 

16 (9–24)%

0.23

3-year

 

23 (16–30)%

 

17 (10–25)%

0.28

4-year

 

24 (17–31)%

 

17 (10–25)%

0.21

PFS

151

 

98

 

0.45

1-year

 

68 (60–75)%

 

64 (54–73)%

0.56

2-year

 

57 (49–65)%

 

53 (43–63)%

0.53

3-year

 

55 (47–64)%

 

50 (40–61)%

0.43

4-year

 

50 (42–59)%

 

47 (36–57)%

0.60

Overall survival

151

 

98

 

0.81

1-year

 

73 (65–80)%

 

74 (65–82)%

0.81

2-year

 

65 (57–72)%

 

59 (49–69)%

0.43

3-year

 

61 (53–69)%

 

58 (47–68)%

0.63

4-year

 

57 (49–65)%

 

54 (44–65)%

0.70

Prob probability, CI confidence interval, N number, NRM non-relapse mortality, PFS progression-free survival, HCT hematopoietic cell transplantation

Fig. 2

Outcomes of AITL patients based on the receipt of prior auto-HCT vs no prior auto-HCT. a Cumulative incidence of non-relapse mortality. b Cumulative incidence of lymphoma progression/relapse. c Progression-free survival. d Overall survival

Among the 198 patients with chemosensitive disease at the time of allo-HCT, 33 patients (17%) were in CR1, while 75 patients (38%) were in CR > 1 and 90 patients (45%) were in PR. Univariate analysis looking at the effect of remission status at allo-HCT, CR1 vs CR > 1 vs PR vs refractory (Table 5), showed a 4-year PFS of 58% vs 45% vs 47% vs 38%, respectively, and a 4-year OS of 70% vs 54% vs 50% vs 52%, respectively. Among patients with chemorefractory AITL, the 1-year NRM was 24%, while the 4-year progression/relapse, PFS, and OS in patients with refractory AITL were 32%, 38%, and 52%, respectively. Figure 3 shows the disease outcomes for AITL patients based on the remission status at allo-HCT (CR vs PR vs chemoresistant).
Table 5

Comparative analysis of AITL patients based on the remission status at the time of allo-HCT

 

CR1 (N = 33)

CR > 1 (N = 75)

PR (N = 90)

Refractory (N = 38)

Outcomes

N

Prob (95% CI)

N

Prob (95% CI)

N

Prob (95% CI)

N

Prob (95% CI)

NRM

33

 

75

 

90

 

38

 

1-year

 

6 (1–17)%

 

20 (12–30)%

 

20 (13–29)%

 

24 (12–38)%

2-year

 

13 (4–26)%

 

29 (19–40)%

 

25 (17–35)%

 

30 (16–45)%

3-year

 

17 (6–32)%

 

31 (21–43)%

 

25 (17–35)%

 

30 (16–45)%

4-year

 

17 (6–32)%

 

36 (25–49)%

 

33 (22–44)%

 

30 (16–45)%

Progression/ relapse

33

 

75

 

90

 

38

 

1-year

 

15 (5–29)%

 

13 (7–22)%

 

14 (7–21)%

 

29 (16–44)%

2-year

 

25 (12–41)%

 

16 (9–26)%

 

19 (11–28)%

 

29 (16–44)%

3-year

 

25 (12–41)%

 

18 (10–28)%

 

19 (11–28)%

 

32 (18–48)%

4-year

 

25 (12–41)%

 

18 (10–28)%

 

21 (12–30)%

 

32 (18–48)%

PFS

33

 

75

 

90

 

38

 

1-year

 

79 (63–91)%

 

67 (56–77)%

 

66 (56–76)%

 

47 (32–63)%

2-year

 

62 (45–78)%

 

54 (43–66)%

 

56 (45–66)%

 

41 (26–57)%

3-year

 

58 (41–75)%

 

50 (38–62)%

 

56 (45–66)%

 

38 (23–54)%

4-year

 

58 (41–75)%

 

45 (33–58)%

 

47 (36–58)%

 

38 (23–54)%

Overall survival

33

 

75

 

90

 

38

 

1-year

 

88 (75–97)%

 

73 (63–83)%

 

71 (61–80)%

 

63 (47–78)%

2-year

 

78 (62–90)%

 

62 (51–73)%

 

59 (48–69)%

 

52 (36–67)%

3-year

 

70 (52–85)%

 

58 (46–70)%

 

57 (47–68)%

 

52 (36–67)%

4-year

 

70 (52–85)%

 

54 (41–66)%

 

50 (39–62)%

 

52 (36–67)%

CR complete response, PR partial response, Prob probability, CI confidence interval, N number, NRM non-relapse mortality, PFS progression-free survival

Fig. 3

Outcomes of AITL patients based on the disease status at allo-HCT. a Cumulative incidence of non-relapse mortality. b Cumulative incidence of lymphoma progression/relapse. c Progression-free survival. d Overall survival

Discussion

Prospective studies evaluating the outcomes of allo-HCT exclusively in AITL have not been performed given an overall rarity of this PTCL subtype. Here, we performed a registry analysis of AITL patients receiving first allo-HCT and made several important observations. First, allo-HCT provided durable disease control in patients with AITL as evidenced by 4-year PFS of 47%. Second, the risk of relapse tended to plateau at 2-year post allo-HCT. Lastly, allo-HCT provided durable disease control even in patients with a failed prior auto-HCT and those subjects with refractory disease at the time of allografting.

Auto-HCT has been previously studied as a consolidation modality for patients with AITL in first CR and beyond. While auto-HCT can provide durable disease control in AITL subjects in CR1, the outcomes of patients not in CR, or those with heavily pretreated disease are not optimal [10]. In addition, despite low transplant-related mortality, the risk of relapse following autografting remains high (1- and 2-year relapse risk is 40% and 51%, respectively) [10]. In contrast, allo-HCT provides excellent survival outcomes for patients with AITL with a lower risk of relapse. Additional file 1: Table S1 summarizes the retrospective studies (n ≥ 9) that have looked at the role of allo-HCT in AITL [11, 14, 15, 16]. The current study is the largest registry validation of these results showing durable responses in patients with AITL following allo-HCT. Though previous studies included patients with prior auto-HCT failure and chemorefractory state, the data are limited by very small patient numbers (for example, the previously published study with a large number of AITL patients [n = 45] included 15 patients with prior auto-HCT failure and 18 patients with chemorefractory disease at allo-HCT) [14] limiting the ability to draw meaningful conclusions. Considering the fact that ASBMT Clinical Practice Recommendation Panel [23] endorses the use of auto-HCT in AITL patients in CR1/PR1, and the high rates of disease relapse in patients receiving high-dose therapy, addressing the role of a subsequent allo-HCT is a clinically important question. In the current analysis, we did not observe any statistically significant differences in outcomes for patients who had prior auto-HCT vs no prior auto-HCT. Our results support the curative potential of allo-HCT in high-risk AITL patients who have failed a prior auto-HCT.

Limited data are published on the role of allo-HCT in refractory AITL. Registry data from the European Society for Blood and Marrow Transplantation (EBMT) identified chemorefractory disease as a predictor of inferior outcomes but included only 18 refractory AITL patients [14]. In the current analysis, the 4-year PFS and OS of chemorefractory patients was 38% and 52% respectively, which supports the use of allografting in this ultra-high-risk subset of patients (who otherwise are fit to undergo allo-HCT). In our study, we did not find a relationship between chronic GVHD and relapse rate in contrast to the previously reported data [14]. The retrospective nature of the registry data does not permit us to analyze the optimal timing of allo-HCT. While the outcomes of CR1 patients in the current study were favorable (4-year PFS and OS 58% and 70%), prior studies have also suggested very encouraging outcomes of AITL patients undergoing auto-HCT in CR1 [10, 24].

AITL is a challenging diagnosis with roughly only 80% concordance even among expert pathologists with access to archival tissue [3, 7]. One of the limitations of the current study is the lack of central pathology review of archival tissue for all patients. The current study included cases as diagnosed by the pathologists at the respective institutions. Of note, disease histology is one of the critical fields CIBMTR examines during its onsite transplant center audits (where diagnosis reported to CIBMTR is audited relative to the pathology records available at the reporting center). In recent CIBMTR studies involving rare T-cell histologies, > 95% concordance was seen between center-reported diagnosis and central review of pathology reports [25, 26]. We acknowledge that this analysis is not a substitute of central review of archival tissue by expert pathologists. At the same time, it is important to note that the majority of prospective clinical trials enrolling AITL subjects accept the patients based on the pathology reports at the participating sites, without a mandatory central review of archival tissue. In addition, the CIBMTR registry does not capture post-relapse salvage therapy, thereby limiting the ability to assess the post allo-HCT relapse survival.

Conclusions

With a better understanding of the biology and development of prognostic tools, there has been a major effort to study novel drug combinations and immunotherapy agents (including checkpoint inhibitors and chimeric antigen receptor T-cell [CAR-T] therapy) in patients with NHL. Brentuximab vedotin (anti-CD30 antibody-drug conjugate) is being studied in combination with chemotherapy in the frontline setting in PTCL patients (ECHELON 2 trial, NCT 01777152). The final results are eagerly awaited to assess the impact of CD30-directed therapies in the subset of AITL patients. While the data on CAR-T cell therapy for B-cell NHL (mainly diffuse large B-cell lymphoma) in the relapsed/refractory setting is impressive [27], similar constructs in T-cell NHL have not been translated to the bedside. Our results suggest that allo-HCT offers the potential for cure in AITL patients including those with otherwise chemo-refractory disease. In the foreseeable future, allo-HCT is likely to remain an important therapeutic option for AITL patients.

Notes

Acknowledgments

CIBMTR Support List

The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children’s Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick’s Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA), or any other agency of the U.S. Government.

*Corporate Members.

Morgan Geronime for administrative Support.

Funding

Not applicable.

Availability of data and materials

Please contact author for data requests.

Authors’ contributions

Collection and assembly of data: NE, CL, and MH. Data analysis: KWA, NE, MH, and CL. Data interpretation: All authors. Manuscript writing: First draft prepared by NE and MH. All authors helped revise the manuscript. Final approval of manuscript: All authors.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Supplementary material

13045_2018_696_MOESM1_ESM.docx (46 kb)
Additional file 1: Table S1. Outcomes of patients with AITL who underwent allogeneic HCT. Table S2. Variables tested in Cox proportional hazards regression models. Table S3. Causes of Death. Table S4. Conditioning Intensity. Table S5. Details of GVHD prophylaxis regimens. Table S6. Univariate outcomes of AITL patients receiving alternative donor sources. (DOCX 29 kb)

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Narendranath Epperla
    • 1
  • Kwang W. Ahn
    • 2
  • Carlos Litovich
    • 2
  • Sairah Ahmed
    • 3
  • Minoo Battiwalla
    • 4
  • Jonathon B. Cohen
    • 5
  • Parastoo Dahi
    • 6
  • Nosha Farhadfar
    • 7
  • Umar Farooq
    • 8
  • Cesar O. Freytes
    • 9
  • Nilanjan Ghosh
    • 10
  • Bradley Haverkos
    • 11
  • Alex Herrera
    • 12
  • Mark Hertzberg
    • 13
  • Gerhard Hildebrandt
    • 14
  • David Inwards
    • 15
  • Mohamed A. Kharfan-Dabaja
    • 16
  • Farhad Khimani
    • 17
  • Hillard Lazarus
    • 18
    • 19
  • Aleksandr Lazaryan
    • 17
  • Lazaros Lekakis
    • 18
    • 19
  • Hemant Murthy
    • 20
  • Sunita Nathan
    • 21
  • Taiga Nishihori
    • 17
  • Attaphol Pawarode
    • 22
  • Tim Prestidge
    • 23
  • Praveen Ramakrishnan
    • 24
  • Andrew R. Rezvani
    • 25
  • Rizwan Romee
    • 26
  • Nirav N. Shah
    • 27
  • Ana Sureda
    • 28
  • Timothy S. Fenske
    • 27
  • Mehdi Hamadani
    • 2
    • 27
  1. 1.Division of Hematology, Department of MedicineThe James Cancer Hospital and Solove Research Institute, The Ohio State UniversityColumbusUSA
  2. 2.Center for International Blood and Marrow Transplant Research, Department of MedicineMedical College of WisconsinMilwaukeeUSA
  3. 3.M.D. Anderson Cancer CenterHoustonUSA
  4. 4.Sarah Cannon BMT ProgramNashvilleUSA
  5. 5.Winship Cancer Institute, Emory University School of MedicineAtlantaUSA
  6. 6.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  7. 7.Shands Healthcare and University of FloridaGainesvilleUSA
  8. 8.University of Iowa Hospitals and ClinicsIowa CityUSA
  9. 9.Texas Transplant InstituteSan AntonioUSA
  10. 10.Levine Cancer InstituteCharlotteUSA
  11. 11.University of Colorado HospitalAuroraUSA
  12. 12.City of Hope National Medical CenterDuarteUSA
  13. 13.Prince of Wales HospitalRandwickAustralia
  14. 14.University of Kentucky Chandler Medical CenterLexingtonUSA
  15. 15.Mayo Clinic RochesterRochesterUSA
  16. 16.Mayo ClinicJacksonvilleUSA
  17. 17.H. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  18. 18.Case Western Reserve UniversityClevelandUSA
  19. 19.Univeristy of MiamiMiamiUSA
  20. 20.Division of Hematology/OncologyUniversity Florida College of MedicineTampaUSA
  21. 21.Rush University Medical CenterChicagoUSA
  22. 22.The University of MichiganAnn ArborUSA
  23. 23.Starship Children’s Health, Level 7 Blood and Cancer Center Park RoadAucklandNew Zealand
  24. 24.UT Southwestern Medical Center – BMT ProgramPhiladelphiaUSA
  25. 25.Stanford Health CareStanfordUSA
  26. 26.Dana Farber Cancer Institute - AdultsBostonUSA
  27. 27.Division of Hematology and Oncology, Department of MedicineMedical College of WisconsinMilwaukeeUSA
  28. 28.Institut Català d’Oncologia - Hospital Duran I ReynalsAvda. Granvfa 199-203BarcelonaSpain

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