TO THE EDITOR:

The recent point and counterpoint articles by Peggs1  and Moskowitz2  discuss the evolving role of allogeneic hematopoietic cell transplantation (HCT) for Hodgkin lymphoma (HL) after failure of autologous HCT in the era of highly active novel agents including brentuximab vedotin (BV) and the immune checkpoint inhibitors. Although a subset of HL patients may achieve durable remissions with BV after failure of autologous HCT, the majority of patients will relapse, and median progression-free survival (PFS) for patients who do not achieve a complete response (CR) with BV is only 6 to 7 months.3  Furthermore, recent trial results have led to adoption of BV in earlier treatment paradigms, including maintenance following autologous HCT per the AETHERA trial,4  and frontline therapy per the ECHELON-1 trial.5  The efficacy of BV at relapse in these settings is unknown. The immune checkpoint inhibitors, nivolumab and pembrolizumab, are approved by the US Food and Drug Administration after failure of autologous HCT and BV and are associated with high response rates, but longer follow-up is required to determine the durability of these responses.6,7  In a recent update of the CheckMate 205 trial, patients who progressed after nivolumab had poor outcomes with 1-year overall survival (OS) of 59%.8 

In our experience, nonmyeloablative allogeneic HCT using total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is an effective treatment strategy for HL after failure of autologous HCT with a very low risk of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) and excellent long-term OS. From 2003 to 2016, we performed allogeneic HCT using TLI-ATG conditioning for 33 HL patients who had failure of autologous HCT, including 14 patients who had received prior BV (Table 1). All patients provided informed consent in the accordance with the Declaration of Helsinki and were enrolled in transplant protocols approved by the Stanford University institutional review board. All patients were transplanted before the US Food and Drug Administration approval of the immune checkpoint inhibitors for relapsed or refractory HL. Median age at the time of transplantation was 28 years (range, 22-51 years). Fourteen patients had HLA-matched related, 10 had HLA-matched unrelated, and 9 had HLA-mismatched unrelated donors. Fourteen patients had a CR at the time of allogeneic HCT, 16 had a partial response, and 3 had SD or PD. Four patients received additional radiotherapy during TLI as a boost to sites of residual disease prior to transplantation.

Table 1.

Patient characteristics and posttransplant outcomes

Patient no.Age/sexPrior BVPre-HCT disease statusDonorAcute GVHD gradeChronic GVHDRelapsedSalvage therapy after relapseStatus at last follow-upFollow-up days post-HCT
27/M No CR MRD None None No — Alive in CR 1559 
36/F No CR MUD None None No — Alive in CR 2163 
24/F No CR MUD Mild No — Alive in CR 2188 
48/F No CR MUD None None No — Alive in CR 1433 
44/M Yes CR MUD None None No — Alive in CR 768 
24/F No CR MUD None No — Dead in CR 535 
34/M No PR MMUD Mild No — Alive in CR 2540 
25/F No PR MRD None No — Alive in CR 1468 
37/F Yes PR MUD Mild No — Alive in CR 1603 
10 22/F Yes PR MMUD None Mild No — Alive in CR 1125 
11 42/F Yes PR MRD None None No — Alive in CR 663 
12 27/F Yes PR MMUD None No — Alive in CR 313 
13 42/F Yes PR MRD None Mild No — Alive in CR 1435 
14 26/M Yes PR MMUD None Moderate No — Alive in CR 801 
15 22/M No SD MRD None None No — Alive in CR 2262 
16 21/F No SD MMUD Moderate No — Alive in CR 1387 
17 27/M Yes PD MUD None Mild No — Alive in CR 1506 
18 46/F No CR MRD None None Day +523 C-MOPP, DLI Alive in CR 2852 
19 43/M Yes CR MMUD None Day +749 Bendamustine, DLI Alive in CR 2513 
20 26/F No CR MUD None Moderate Day +96 RT (local relapse) Alive in CR 2901 
21 30/M Yes CR MRD Mild Day +791 RT (local relapse) Alive in CR 1449 
22 23/M No CR MUD None None Day +1242 BV Alive with PD 2560 
23 51/M Yes CR MMUD None Day +355 BV, bendamustine Alive with PD 753 
24 39/M No CR MMUD None Day +742 BV Dead with PD 843 
25 26/F Yes CR MRD None Mild Day +201 BV Dead with PD 420 
26 25/M No PR MRD None None Day +490 BV Alive in CR 1747 
27 32/F No PR MMUD None None Day +144 Nivolumab Alive in CR 1109 
28 37/F Yes PR MRD Moderate Day +321 Bendamustine Alive with PR 500 
29 28/F No PR MRD None Moderate Day +320 Gemcitabine, DLI Alive with PR 3605 
30 37/M No PR MRD None Moderate Day +284 DLI Dead with PD 779 
31 26/M No PR MRD Mild Day +406 ESHAP, DLI, BV Dead with PD 1658 
32 29/M No PR MRD None None Day +216 BV Dead with PD 1179 
33 24/M Yes PR MUD None None Day +306 Lenalidomide, RT Dead with PD 587 
Patient no.Age/sexPrior BVPre-HCT disease statusDonorAcute GVHD gradeChronic GVHDRelapsedSalvage therapy after relapseStatus at last follow-upFollow-up days post-HCT
27/M No CR MRD None None No — Alive in CR 1559 
36/F No CR MUD None None No — Alive in CR 2163 
24/F No CR MUD Mild No — Alive in CR 2188 
48/F No CR MUD None None No — Alive in CR 1433 
44/M Yes CR MUD None None No — Alive in CR 768 
24/F No CR MUD None No — Dead in CR 535 
34/M No PR MMUD Mild No — Alive in CR 2540 
25/F No PR MRD None No — Alive in CR 1468 
37/F Yes PR MUD Mild No — Alive in CR 1603 
10 22/F Yes PR MMUD None Mild No — Alive in CR 1125 
11 42/F Yes PR MRD None None No — Alive in CR 663 
12 27/F Yes PR MMUD None No — Alive in CR 313 
13 42/F Yes PR MRD None Mild No — Alive in CR 1435 
14 26/M Yes PR MMUD None Moderate No — Alive in CR 801 
15 22/M No SD MRD None None No — Alive in CR 2262 
16 21/F No SD MMUD Moderate No — Alive in CR 1387 
17 27/M Yes PD MUD None Mild No — Alive in CR 1506 
18 46/F No CR MRD None None Day +523 C-MOPP, DLI Alive in CR 2852 
19 43/M Yes CR MMUD None Day +749 Bendamustine, DLI Alive in CR 2513 
20 26/F No CR MUD None Moderate Day +96 RT (local relapse) Alive in CR 2901 
21 30/M Yes CR MRD Mild Day +791 RT (local relapse) Alive in CR 1449 
22 23/M No CR MUD None None Day +1242 BV Alive with PD 2560 
23 51/M Yes CR MMUD None Day +355 BV, bendamustine Alive with PD 753 
24 39/M No CR MMUD None Day +742 BV Dead with PD 843 
25 26/F Yes CR MRD None Mild Day +201 BV Dead with PD 420 
26 25/M No PR MRD None None Day +490 BV Alive in CR 1747 
27 32/F No PR MMUD None None Day +144 Nivolumab Alive in CR 1109 
28 37/F Yes PR MRD Moderate Day +321 Bendamustine Alive with PR 500 
29 28/F No PR MRD None Moderate Day +320 Gemcitabine, DLI Alive with PR 3605 
30 37/M No PR MRD None Moderate Day +284 DLI Dead with PD 779 
31 26/M No PR MRD Mild Day +406 ESHAP, DLI, BV Dead with PD 1658 
32 29/M No PR MRD None None Day +216 BV Dead with PD 1179 
33 24/M Yes PR MUD None None Day +306 Lenalidomide, RT Dead with PD 587 

BV, brentuximab vedotin; C-MOPP, cyclophosphamide, vincristine, procarbazine, prednisone; DLI, donor lymphocyte infusion; ESHAP, etoposide, methylprednisolone, cytarabine, cisplatin; F, female; M, male; MRD, matched related donor; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; PD, progressive disease; PR, partial response; RT, radiotherapy; SD, stable disease.

At a median follow-up of 4 years, the 4-year OS was 79% (8-year OS was 71%), and the 4-year PFS was 45% (Figure 1). Of the 16 patients who relapsed after allogeneic HCT, 6 were able to achieve a durable CR after treatment with additional chemotherapy, radiotherapy, and/or donor lymphocyte infusion, including 1 patient who received posttransplant nivolumab. The latter patient developed pneumonitis that resolved with corticosteroids but did not develop acute GVHD after treatment with nivolumab. At the last follow-up, 22 patients (67%) were alive in CR, 4 were alive with disease, and 7 were deceased. NRM was 0% at 1 year, with only 1 death from infection occurring 1.5 years posttransplant. The cumulative incidences of acute GVHD grade 2‐4 and grade 3‐4 at day +100 were 6% and 3%, respectively, and were consistently low regardless of donor type. The cumulative incidence of chronic GVHD (mild to moderate) was 27% at 1 year and 34% at 2 years. Durable remissions were seen even among patients with residual disease at the time of transplantation (Figure 2).

Figure 1.

Outcomes after allogeneic transplantation with TLI-ATG conditioning. Kaplan-Meier and cumulative incidence curves show outcomes for 33 patients with Hodgkin lymphoma who underwent nonmyeloablative allogeneic transplantation with TLI-ATG conditioning after failure of autologous transplantation. (A) OS. (B) PFS. (C) Nonrelapse mortality. (D) Acute GVHD grade 2-4. (E) Acute GVHD grade 3-4. (F) Chronic GVHD.

Figure 1.

Outcomes after allogeneic transplantation with TLI-ATG conditioning. Kaplan-Meier and cumulative incidence curves show outcomes for 33 patients with Hodgkin lymphoma who underwent nonmyeloablative allogeneic transplantation with TLI-ATG conditioning after failure of autologous transplantation. (A) OS. (B) PFS. (C) Nonrelapse mortality. (D) Acute GVHD grade 2-4. (E) Acute GVHD grade 3-4. (F) Chronic GVHD.

Figure 2.

Outcomes stratified by disease status before transplantation. Kaplan-Meier estimates of OS (A) and PFS (B) are shown stratified by disease status before allogeneic transplantation. Fourteen patients had a CR at the time of allogeneic transplantation and 19 patients had a PR, SD, or PD.

Figure 2.

Outcomes stratified by disease status before transplantation. Kaplan-Meier estimates of OS (A) and PFS (B) are shown stratified by disease status before allogeneic transplantation. Fourteen patients had a CR at the time of allogeneic transplantation and 19 patients had a PR, SD, or PD.

In summary, our data suggest that nonmyeloablative allogeneic HCT using TLI-ATG conditioning is an effective treatment strategy for HL after failure of autologous HCT, with excellent long-term OS exceeding 70% and a very low risk of NRM and GVHD. The low risk of NRM and GVHD was observed even among patients with a partially HLA-mismatched unrelated donor, which is consistent with our prior experience using TLI-ATG conditioning.9  Although it is certainly reasonable to first consider BV and the immune checkpoint inhibitors for HL patients who relapse after autologous HCT, our data lend strong support that appropriate patients should continue to be referred for transplant consultation because they may be effectively salvaged and achieve durable remissions with nonmyeloablative allogeneic HCT. It remains unclear whether the pretransplant use of immune checkpoint inhibitors may increase the risk for GVHD. Further studies are needed to determine whether a washout period should be implemented before proceeding with allogeneic HCT.10 

Authorship

Contribution: M.A.S. wrote the paper; R.H.A., R.T.H., R.L., and L.S.M. revised the paper; and R.T.H. provided data on radiotherapy.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Michael A. Spinner, Division of Oncology, Department of Medicine, Stanford University, 875 Blake Wilbur Dr, Stanford, CA 94305; e-mail: mspinner@stanford.edu.

References

References
1.
Peggs
KS
.
Should all patients with Hodgkin lymphoma who relapse after autologous SCT be considered for allogeneic SCT?
Blood Adv
.
2018
;
2
(
7
):
817
-
820
.
2.
Moskowitz
CH
.
Should all patients with HL who relapse after ASCT be considered for allogeneic SCT? A consult, yes; a transplant, not necessarily
.
Blood Adv
.
2018
;
2
(
7
):
821
-
824
.
3.
Chen
R
,
Gopal
AK
,
Smith
SE
, et al
.
Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma
.
Blood
.
2016
;
128
(
12
):
1562
-
1566
.
4.
Moskowitz
CH
,
Nademanee
A
,
Masszi
T
, et al
;
AETHERA Study Group
.
Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial
.
Lancet
.
2015
;
385
(
9980
):
1853
-
1862
.
5.
Connors
JM
,
Jurczak
W
,
Straus
DJ
, et al
;
ECHELON-1 Study Group
.
Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma
.
N Engl J Med
.
2018
;
378
(
4
):
331
-
344
.
6.
Younes
A
,
Santoro
A
,
Shipp
M
, et al
.
Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial
.
Lancet Oncol
.
2016
;
17
(
9
):
1283
-
1294
.
7.
Chen
R
,
Zinzani
PL
,
Fanale
MA
, et al
;
KEYNOTE-087
.
Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma
.
J Clin Oncol
.
2017
;
35
(
19
):
2125
-
2132
.
8.
Armand
P
,
Engert
A
,
Younes
A
, et al
.
Nivolumab for relapsed/refractory classic hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial
.
J Clin Oncol
.
2018
;
36
(
14
):
1428
-
1439
.
9.
Spinner
MA
,
Fernández-Viña
M
,
Creary
LE
, et al
.
HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity
.
Blood Adv
.
2017
;
1
(
17
):
1347
-
1357
.
10.
Merryman
RW
,
Kim
HT
,
Zinzani
PL
, et al
.
Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma
.
Blood
.
2017
;
129
(
10
):
1380
-
1388
.