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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for a range of hematologic malignancies; however, graft-versus-host disease (GvHD) remains a significant and important complication associated with high mortality and reduced quality of life.1
The most widely used regimen for GvHD prophylaxis after myeloablative transplant consists of cyclosporin A (CsA) and methotrexate, with European guidelines recommending the addition of antithymocyte globulin. Standard prophylaxis after non-myeloablative transplant differs, consisting of CsA in combination with mycophenolate mofetil. More recently, posttransplant cyclophosphamide (PTCy) alone or combined with CsA has shown promising GvHD prophylactic potential.1
The HOVON-96 trial (NL2128) investigated prophylactic treatment with PTCy in combination with a short course of CsA (PTCy/CsA), compared with conventional immunosuppression with CsA and mycophenolic acid (CsA/MPA) after non-myeloablative allo-HSCT. The results, which have recently been published by Broers et al.1 in Blood Advances, are summarized below.
Figure 1. Dosing regimen for PTCy/CsA and CsA/MPA*
CsA, cyclosporine A; IV, intravenously; MPA, mycophenolic acid; PO, orally; PTCy, posttransplant cyclophosphamide.
*Data from Broers, et al.1
†CsA stopped without tapering at Day 70 in patients with GvHD.
‡CsA started between 3 and 5 days prior to transplant.
§CsA tapering started at Day 120 for patients without GvHD and from Day 180 for patients with GvHD.
There were no significant differences in baseline characteristics between the cohorts, as shown in Table 1. Overall, there were more males than females, and most patients had acute myeloid leukemia or non-Hodgkin lymphoma.
Table 1. Baseline patient characteristics*
Characteristic, % (unless otherwise stated) |
CsA/MPA |
PTCy/CsA |
---|---|---|
Median age (range), years |
58 (26–70) |
57 (20–70) |
Sex, male/female |
63/37 |
67/33 |
Diagnosis |
|
|
AML |
27 |
30 |
ALL |
13 |
10 |
MDS |
15 |
8 |
CML |
2 |
5 |
CLL |
4 |
6 |
NHL |
19 |
21 |
HL |
4 |
3 |
MPD |
2 |
3 |
MM |
4 |
7 |
Other |
10 |
6 |
Donor type |
|
|
MRD |
33 |
30 |
MUD |
67 |
70 |
Female donor/male recipient pairs |
19 |
17 |
CMV status |
|
|
Recipient positive, donor positive |
31 |
39 |
Recipient negative, donor negative |
40 |
34 |
Recipient positive, donor negative |
15 |
18 |
Recipient negative, donor positive |
13 |
8 |
Conditioning regimen |
|
|
Myeloablative |
4 |
— |
Reduced intensity |
2 |
1 |
Non-myeloablative |
94 |
99 |
Source of stem cells |
|
|
Bone marrow |
— |
4 |
Peripheral blood |
100 |
96 |
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia, CML, chronic myeloid leukemia; CMV, cytomegalovirus; CsA/MPA, cyclosporine A and mycophenolic acid; MDS, myelodysplastic syndrome; MM, multiple myeloma; MPD, myeloproliferative disease; MRD, matched related donor; MUD, matched unrelated donor; PTCy/CsA posttransplant cyclophosphamide and cyclosporine A. |
Of 160 patients that were initially randomized, 151 underwent allo-HSCT. The median follow-up of transplanted patients was 54.3 months and 56.4 months in the CsA/MPA arm and PTCy/CsA arm, respectively.
There was no significant difference seen in PG180, the primary endpoint of the study (Table 2). Patients in the CsA/MPA arm had significantly reduced GRFS (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.34–0.74; p<0.001). Improvement of GRFS following PTCy/CsA was irrespective of donor type.
Table 2. Primary and secondary study endpoints after allo-HSCT*
Variable |
CsA/MPA |
PTCy/CsA |
p value |
---|---|---|---|
PG180, % |
29 |
38 |
0.26 |
Acute GvHD, % |
65 |
65 |
1.00 |
Grade I |
10 |
31 |
|
Grade II |
40 |
27 |
|
Grade III |
12 |
5 |
|
Grade IV |
4 |
1 |
|
Chronic GvHD, % |
69 |
49 |
0.025 |
Limited |
17 |
25 |
|
Extensive |
52 |
24 |
|
NRM (at 3 years PT), % (SE) |
14 (5) |
10 (3) |
0.51 |
Relapse at 3 years PT, % (SE) |
24 (6) |
32 (5) |
0.27 |
Survival outcome estimates, % (95% CI) |
|
|
|
3-year PFS |
63 (48–74) |
59 (48–68) |
0.57 |
3-year OS |
71 (56–81) |
65 (54–73) |
0.48 |
1-year GRFS† |
21 (11–33) |
45 (35–55) |
<0.001 |
allo-HSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; CMV, cytomegalovirus; CsA/MPA, cyclosporine A and mycophenolic acid; GvHD, graft-versus-host disease; GRFS, graft-versus-host disease-free, relapse-free survival; NRM, non-relapse mortality; OS, overall survival; PFS, progression-free survival; PG180, non-severe GvHD within 180 days posttransplant; PT, posttransplant; PTCy/CsA posttransplant cyclophosphamide and cyclosporine A; SE, standard error. |
The cumulative incidences of aGvHD and cGvHD are shown in Table 3. Multivariate analysis revealed immunosuppression with PTCy/CsA versus CsA/MPA was associated with a reduction in aGvHD Grade II-IV (HR, 0.48; 95% CI, 0.29–0.82; p = 0.007), as well as a reduction in extensive cGvHD (HR, 0.36; 95% CI, 0.21–0.64; p<0.001).
Table 3. Cumulative incidence of acute and chronic GvHD*
Cumulative incidence, % (SE) |
CsA/MPA |
PTCy/CsA |
p value |
---|---|---|---|
Acute GvHD Grade II–V |
48 (7) |
30 (5) |
0.007 |
Acute GvHD Grade III–IV |
12 (4) |
6 (2) |
0.14 |
Chronic GvHD (2 years PT) |
65 (7) |
43 (5) |
|
Extensive |
48 (7) |
16 (4) |
<0.001 |
CsA/MPA, cyclosporine A and mycophenolic acid; GvHD, graft-versus-host disease; PT, posttransplant; PTCy/CsA posttransplant cyclophosphamide and cyclosporine A. |
Adverse events are summarized in Table 4. A higher incidence of infection, mainly due to increased incidence of febrile neutropenia, was seen in the PTCy/CsA arm.
Table 4. Adverse events*
Grade III–V adverse events† <6 months posttransplant, % |
CsA/MPA |
PTCy/CsA (n = 99) |
p value |
---|---|---|---|
All events |
42 |
61 |
0.039 |
Infections |
21 |
41 |
0.019 |
Febrile neutropenia |
15 |
25 |
0.22 |
Invasive pulmonary aspergillosis |
4 |
4 |
1.00 |
Other pulmonary infections |
— |
3 |
0.55 |
CMV disease |
— |
1 |
1.00 |
Graft failure |
2 |
1 |
1.00 |
Cardiac |
4 |
3 |
1.00 |
CMV, cytomegalovirus; CsA/MPA, cyclosporine A and mycophenolic acid; GvHD, graft-versus-host disease; PTCy/CsA posttransplant cyclophosphamide and cyclosporine A. |
When compared to standard immunosuppression, PTCy/CsA prophylaxis resulted in significantly improved GRFS, and significantly lower incidence of aGvHD (Grade II–IV) and extensive cGvHD, without significantly impacting cumulative relapse rates. Both arms had an acceptable toxicity profile. Severe cGvHD and its ongoing treatment is associated with diminished quality of life, and improved prevention has been shown to increase quality of life scores. Therefore, Broers and colleagues suggest that PTCy prophylaxis may result in an increased quality of life; however, future studies of PTCy should consider patient-reported outcome measures of quality of life to confirm this.
The authors note some potential limitations of their study. The study initially set out to compare standard duration of immunosuppression versus time-restricted immunosuppression; the addition of the PTCy arm occurred later and therefore the primary endpoint should have been adapted to reflect this change. Also, different conditioning regimens were used between the two groups; in the CsA/MPA arm, conditioning was at the discretion of the treating physician, and more intensified conditioning was used in the PTCy/CsA arm. It is presumed that the higher incidence of febrile neutropenia seen in the PTCy/CsA arm is because of this intensified conditioning regimen, although further study of posttransplant infection would be prudent. Additionally, the incidence of cGvHD was reported according to the Seattle classification because at the time of initiation of the study, the National Institutes of Health (NIH) classification was published but was not yet standard in the European transplantation programs. Furthermore, patients received non-myeloablative conditioning regimens; therefore, findings should be considered with caution in allo-HSCT using reduced-intensity or myeloablative conditioning regimens and further study is warranted.
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