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Treating classical Hodgkin lymphoma: Spotlight on targeted therapies
with Gilles Salles, Paul Bröckelmann, and Ann S. LaCasce
Saturday, November 2, 2024
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The standard approach to prevent graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) is the use of a combination therapy including calcineurin inhibitors (CNIs).1 However, CNIs need regular pharmacokinetic monitoring, may increase the risk of renal toxicity and thrombotic microangiopathy, and their prolonged use may predispose patients to infections and reduce graft-versus-tumor effects, ultimately precluding the effectiveness of post-HSCT therapies. Chronic GvHD (cGvHD) is common post HSCT, affecting 35–55% of transplantation survivors, with higher rates and severity in peripheral blood stem cell (PBSC) compared with bone marrow (BM) grafts. More recently, CNI-free approaches using donor T-cell depletion of PBSC grafts with an intensified myeloablative conditioning regimen or in vivo post-transplantation cyclophosphamide (PTCy) as a single agent have shown promising results for GvHD prophylaxis.1
Here, we summarize the key findings published by Luznik et al.1 in Journal of Clinical Oncology of a phase III trial (NCT02345850) comparing CD34+ selected PBSCs, PTCy after a BM graft, or tacrolimus (Tac) + methotrexate (MTX) after a BM graft in patients with acute myeloid leukemia or myelodysplastic syndromes with a human leukocyte antigen (HLA)-matched donor.
This was a three-arm, phase III, multicenter, open-labelled, randomized controlled study performed by the Blood and Marrow Transplant Clinical Trial Network (BMT-CTN). The study compared HSCT approaches among patients aged ≤65 years undergoing HLA-matched myeloablative HSCT for acute leukemia in complete remission, complete remission with incomplete hematologic recovery, or myelodysplastic syndromes with <5% blasts in the BM. Patients were enrolled from 26 centers across Germany and the USA. HLA-matched related or unrelated donors were defined as 8 out of 8 matches. Patients were randomly allocated to one of the three treatment arms (Figures 1 and 2).
Figure 1. Treatment allocation*
BM, bone marrow; Cy, cyclophosphamide; GCSF, granulocyte colony stimulating factor; HSCT, hematopoietic stem cell transplantation; IV, intravenous; MTX, methotrexate; PBSC, peripheral blood stell cell; Tac, tacrolimus.
*Data from Luznik et al.1
Figure 2. Consort diagram*
MTX, methotrexate; PTCy, post-transplantation cyclophosphamide; Tac, tacrolimus.
*Adapted from Luznik et al.1
†Excluding patients who withdrew from the study, died, or were lost to follow up.
The primary endpoint was a composite of moderate to severe cGvHD, disease relapse, and chronic relapse-free survival (CRFS). Secondary endpoints included overall survival (OS), acute GvHD (aGvHD), cGvHD, disease relapse, relapse-free survival, transplant-related mortality (TRM), immunosuppression-free survival, hematologic recovery, toxicities, infections, and health-related quality of life.
The primary analysis was performed using the intent-to-treat population, with estimates of CRFS described for each group along with pairwise comparisons.
A total of 346 patients were enrolled, of which 327 underwent transplantation. The median age was 51 years (range, 13−66 years) and the median time from diagnosis to HSCT was 5 months (range, 1.3−231 months). Treatment non-compliance rates were 14.4%, 8.2%, and 2.6% in the CD34+, PTCy, and Tac + MTX arms, respectively. Patient characteristics are shown in Table 1.
Table 1. Baseline characteristics*
Characteristics, % |
CD34+ selected graft |
PTCy |
Tac + MTX |
---|---|---|---|
Male |
54.4 |
62.3 |
54.2 |
Age group, years |
|
|
|
1−18 |
0.0 |
0.0 |
1.7 |
19−40 |
25.4 |
24.6 |
23.7 |
41−60 |
55.3 |
60.5 |
64.4 |
>60 |
19.3 |
14.9 |
10.2 |
Lansky or Karnofsky score |
|
|
|
70−80 |
44.7 |
36.8 |
48.3 |
90−100 |
55.3 |
63.2 |
51.7 |
Primary disease |
|
|
|
ALL |
26.3 |
23.7 |
19.5 |
AML |
55.3 |
64.9 |
63.6 |
MDS |
16.7 |
9.6 |
13.6 |
CMML |
0.9 |
0.9 |
0.8 |
Disease stage for AML and ALL |
|
|
|
First CR |
72.0 |
68.4 |
78.6 |
≥ Second CR |
17.3 |
20.8 |
16.3 |
CRi |
2.1 |
6.9 |
0.0 |
MDS status |
|
|
|
No prior treatment |
52.6 |
81.8 |
56.3 |
Hematologic improvement |
5.3 |
18.2 |
6.3 |
No response or SD |
42.1 |
0.0 |
25.0 |
Donor type |
|
|
|
Related |
37.7 |
37.7 |
38.1 |
Unrelated |
62.3 |
62.3 |
61.9 |
Post-transplant maintenance therapy |
12.3 |
11.4 |
5.1 |
Tyrosine kinase inhibitor |
50.0 |
46.2 |
66.7 |
FLT3 inhibitor |
50.0 |
53.8 |
33.3 |
DRI |
|
|
|
Low or moderate |
58.8 |
58.8 |
60.2 |
High |
31.6 |
34.2 |
33.9 |
HSCT comorbidity index |
|
|
|
0 |
36.5 |
37.6 |
38.6 |
1−2 |
35.6 |
39.4 |
43.0 |
≥3 |
27.9 |
22.9 |
18.4 |
Pre-transplant status |
|
|
|
Positive |
43.3 |
49.5 |
50.0 |
Negative |
56.7 |
50.5 |
50.0 |
Donor CMV status |
|
|
|
Positive |
29.8 |
49.5 |
37.7 |
Negative |
70.2 |
50.5 |
62.3 |
Stem cell source |
|
|
|
Peripheral blood |
94.2 |
10.1 |
10.5 |
BM |
5.8 |
89.9 |
89.5 |
Conditioning regimen |
|
|
|
TBI + Cy + thiotepa + rATG |
26.0 |
0.0 |
0.0 |
Bu + Mel +Flu + rATG |
65.4 |
0.0 |
0.0 |
Bu + Cy |
3.8 |
37.6 |
27.2 |
Bu + Flu |
2.9 |
35.8 |
52.6 |
Cy + TBI |
1.0 |
24.8 |
19.3 |
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; Bu, busulfan; CMML, chronic myelomonocytic leukemia; CMV, cytomegalovirus; Cy, cyclophosphamide; DRI, disease risk index; Flu, fludarabine; GvHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; Mel, melphalan; MTX, methotrexate; PTCy, post-transplantation cyclophosphamide; rATG, rabbit antithymocyte-globulin; SD, stable disease; Tac, tacrolimus; TBI, total body irradiation. |
CRFS was 50.6%, 48.1%, and 41.0% in the CD34+, PTCy, and Tac + MTX arms, respectively (Table 2).
Table 2. Primary and secondary outcomes*
Outcomes, % (95% CI) |
CD34+ selected graft |
PTCy |
Tac + MTX |
p value† |
---|---|---|---|---|
CRFS at 2 years |
50.6 |
48.1 |
41.0 |
0.224 |
OS at 2 years |
60.1 |
76.2 |
76.1 |
0.006 |
Moderate to severe cGvHD at 2 years |
8.9 |
27 |
33.7 |
<0.001 |
TRM at 2 years |
21.5 |
15.7 |
7.9 |
0.020 |
Relapse at 2 years |
21.4 |
13.9 |
25.6 |
0.076 |
RFS at 2 years |
57.1 |
70.3 |
66.5 |
0.029 |
Grade II−IV aGvHD at 100 days |
16.3 |
37.6 |
29.8 |
0.026 |
Grade III−IV aGvHD at 100 days |
2.9 |
10.1 |
3.5 |
0.037 |
IFS at 1 year |
57.8 |
67.6 |
57.9 |
0.24 |
Delayed engraftment |
2.9 |
8.3 |
3.5 |
0.13 |
Secondary graft failure |
2.9 |
0 |
0.9 |
0.15 |
CMV reactivation by 180 days |
11.6 |
9.2 |
9.6 |
0.97 |
EBV reactivation by 180 days |
12.5 |
0.9 |
0.9 |
<0.001 |
aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; CI, confidence interval; CMV, cytomegalovirus; CRFS, chronic relapse-free survival; EBV, Epstein-Barr virus; HR, hazard ratio; IFS, immunosuppressive-free survival; MTX, methotrexate; OS, overall survival; PTCy, post-transplant cyclophosphamide; RFS, relapse-free survival; Tac, tacrolimus; TRM, transplant-related mortality. |
Table 3. Pairwise treatment comparison*
Outcomes |
CD34+ vs Tac + MTX |
PTCy vs Tac + MTX |
CD34+ vs PTCy |
|||
---|---|---|---|---|---|---|
HR (95% CI) |
p value |
HR (95% CI) |
p value |
HR (95% CI) |
p value |
|
CRFS at 2 years |
0.80 |
0.237 |
0.86 |
0.413 |
0.93 |
0.717 |
OS at 2 years |
1.74 |
0.020 |
1.02 |
0.953 |
1.77 |
0.019 |
Moderate to severe cGvHD at 2 years |
0.25 |
<0.001 |
0.79 |
0.342 |
0.32 |
0.002 |
TRM at 2 years |
2.86 |
0.008 |
1.88 |
0.127 |
1.53 |
0.188 |
Relapse at 2 years |
0.89 |
0.672 |
0.52 (0.28−0.96) |
0.037 |
1.76 |
0.091 |
RFS at 2 years |
1.35 |
0.172 |
0.84 |
0.463 |
1.64 |
0.034 |
Grade II−IV aGvHD at 100 days |
0.54 |
0.036 |
1.43 |
0.120 |
0.40 |
0.002 |
Grade III−IV aGvHD at 100 days |
0.82 |
0.798 |
2.95 |
0.064 |
0.28 |
0.050 |
aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; CI, confidence interval; CRFS, chronic relapse-free survival; HR, hazard ratio; MTX, methotrexate; OS, overall survival; PTCy, post-transplant cyclophosphamide; RFS, relapse-free survival; Tac, tacrolimus; TRM, transplant-related mortality. |
This phase III study demonstrated that CD34+ selection or PTCy were not superior to Tac + MTX with BM in patients with HLA-matched transplantation. CD34+ selection showed significant reduction in cGvHD, however had higher rates of TRM. Although TRM, cGvHD, CRFS, and OS were similar for PTCy and Tac + MTX, PTCy was associated with more aGvHD. However, PTCy showed a trend towards improved relapse rate and relapse-free survival in comparison to Tac + MTX and CD34+ selection, respectively. Therefore, PTCy may be a transplant option in patients contraindicated to CNI or who require a CNI-free approach. Interestingly, this study demonstrated better TRM and OS for Tac + MTX compared with the experimental arms, but it was associated with the highest rate of cGvHD. Tac + MTX or PTCy and a BM graft offer improved survival rates >75% and should be considered the new standard approach for patients with hematologic malignancies. Further studies are warranted that focus on improving cGvHD and disease relapse using Tac + MTX, as well as investigating the effectiveness of PTCy + Tac + mycophenolate mofetil and anti-thymocyte globulin + Tac + MTX.
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