Interferon-α: A Potentially Effective Treatment for Minimal Residual Disease in Acute Leukemia/Myelodysplastic Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation

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Interferon-

a

: A Potentially Effective Treatment for Minimal

Residual Disease in Acute Leukemia/Myelodysplastic

Syndrome after Allogeneic Hematopoietic Stem

Cell Transplantation

Xiao-Dong Mo

1

, Xiao-Hui Zhang

1

, Lan-Ping Xu

1

, Yu Wang

1

, Chen-Hua Yan

1

, Huan Chen

1

,

Yu-Hong Chen

1

, Wei Han

1

, Feng-Rong Wang

1

, Jing-Zhi Wang

1

, Kai-Yan Liu

1

,

Xiao-Jun Huang

1

,

2

,

3

,

*

1Peking University People’s Hospital & Peking University Institute of Hematology, Beijing, China 2Peking-Tsinghua Center for Life Sciences, Beijing, China

3Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China

Article history: Received 8 March 2015 Accepted 15 June 2015

Key Words:

Donor lymphocyte infusion Hematopoietic stem cell transplantation IFN-a

Minimal residual disease Preemptive

a b s t r a c t

In this prospective clinical study, the safety and efficacy of preemptive interferon-

a

(IFN-

a

) treatment were investigated and compared with preemptive donor lymphocyte infusion (DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). Patients undergoing allogeneic HSCT were eligible if they had acute leukemia or myelodysplastic syndrome and were MRD-positive after HSCT. Patients who were able to receive DLI were assigned to a preemptive DLI group (n¼ 45); patients who could not or did not agree to receive DLI after HSCT received preemptive IFN-

a

. A total of 22 patients received preemptive IFN-

a

; the median treatment duration was 35 days (range, 4 to 180 days). Seven patients relapsed, and 1 patient died from severe pneumonia. The 1-year cumulative incidence of chronic graft-versus-host disease (cGVHD) after intervention was 90.9% for the IFN-

a

group and 62.9% for the DLI group (P< .001). MRD status after preemptive intervention was comparable in the 2 groups, and the 1-year cumulative incidence of relapse after intervention was 27.3% for the IFN-

a

group and 35.6% for the DLI group (P¼ .514). The 1-year cumulative incidence of nonrelapse mortality after intervention was 4.5% for the IFN-

a

group and 4.4% for the DLI group (P¼ .985). The 1-year probability of disease-free survival after intervention was 68.2% for the IFN-

a

group and 60.0% for the DLI group (P¼ .517). In multivariate analysis, early-onset MRD, persistent MRD after intervention, and absence of cGVHD after intervention were significantly asso-ciated with poorer clinical outcomes. Thus, preemptive IFN-

a

may be a potential alternative for MRD-positive patients who cannot receive preemptive DLI after HSCT.

Ó 2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION

Allogeneic

hematopoietic

stem

cell

transplantation

(HSCT) is one of the most effective treatments for

hemato-logic malignancies. Although HSCT has advanced signi

fi-cantly, post-transplantation relapse remains a major cause of

transplant failure, and further therapeutic options are

limited

[1]

. Prophylactic donor lymphocyte infusion (DLI) is

one of the most effective methods for relapse prophylaxis in

patients with advanced-stage acute leukemia receiving

allogeneic HSCT

[2-5]

. In addition, because impending

relapse can be indicated by minimal residual disease (MRD)

after HSCT, preemptive intervention with DLI based on MRD

status may be a more reasonable option for relapse

pro-phylaxis after HSCT. Previous studies observed that clinical

outcomes of MRD-positive patients receiving preemptive DLI

were comparable to those of MRD-negative patients, and

signi

ficantly better than those of MRD-positive patients who

received no interventions

[6,7]

.

Some patients cannot receive DLI because of provider

refusal, however, and some patients themselves refuse DLI

after HSCT. For these patients, further study into reasonable

alternative preemptive interventions is needed. Interferon-

a

Financial disclosure: See Acknowledgments on page 1946.

* Correspondence and reprint requests: Xiao-Jun Huang, MD, Peking University People’s Hospital & Peking University Institute of Hematology, No. 11 Xizhimen South St, Xicheng District, Beijing 100044, China.

E-mail address:huangxiaojun@bjmu.edu.cn(X.-J. Huang).

http://dx.doi.org/10.1016/j.bbmt.2015.06.014

1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.

Biology of Blood and

Marrow Transplantation

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(IFN-

a

) exerts a relatively strong immunomodulatory effect

and can kill acute myelogenous leukemia (AML) cells by

regulating T cell and natural killer cell functions

[8,9]

. It is

possible that IFN-

a

can induce a graft-versus-leukemia (GVL)

effect and clear tumor cells in patients after HSCT. This

GVL-promoting activity was

first observed during treatment of

patients with relapsed chronic myelogenous leukemia

[10,11]

. Singhal et al.

[12]

also reported a patient with

relapsed AML who developed limited chronic

graft-versus-host disease (cGVHD) at 4 months after IFN-

a

therapy. At

the same time, the number of bone marrow (BM) blasts

decreased from 16% to 1% to 6%. Gesundheit et al.

[13]

reported a patient with AML who experienced

post-transplantation relapse who received 2 doses of IFN-

a

at 18

days after DLI. GVHD was induced immediately, and the

patient remained in complete remission (CR) for 2 years after

the IFN-

a

treatment. In addition, several studies have

sug-gested that immunotherapy preferably should be started in

patients with leukemia with a relatively low tumor burden

[9]

, and our pilot study also observed that IFN-

a

could help

clear MRD after HSCT

[14]

. Thus, IFN-

a

may be a potentially

alternative treatment for MRD-positive patients after

allo-geneic HSCT.

In this prospective study, the safety and ef

ficacy of

pre-emptive IFN-

a

were investigated and compared with those of

preemptive DLI in patients who were MRD-positive after

undergoing allogeneic HSCT.

PATIENTS AND METHODS Patients

A total of 465 consecutive patients with acute leukemia infirst or second CR [without t(9;22) mutation] or myelodysplastic syndrome-refractory anemia with excess blasts underwent non-T cell-depleted allogeneic HSCT at the Peking University Institute of Hematology (PUIH) between May 1, 2012, and January 1, 2014. A total of 365 subjects were MRD-negative at all time points tested after HSCT. One hundred subjects were MRD-positive; those who were able to receive DLI were assigned to a preemptive DLI group, and those who could not receive DLI or who refused DLI after HSCT were assigned to the IFN-agroup. Patients who received DLI after IFN-a treatment (n ¼ 3) or received IFN-atreatment after DLI (n¼ 4) were excluded from the analysis. A total of 67 patients were enrolled, including 22 in the preemptive IFN-agroup and 45 in the preemptive DLI group (Figure 1

andTable 1). Twenty-six patients were MRD-positive but did not receive any preemptive intervention because of active GVHD (n¼ 13) or active infection (n¼ 12), and 1 patient received only tapered immunosuppressive therapy.

Thefinal follow-up visits for endpoint analysis were conducted in January 2015. To further compare the clinical outcomes between MRD-positive pa-tients with and without preemptive intervention, a historical cohort (including MRD-positive patients without intervention) that had been re-ported by Zhao et al.[15]was enrolled as well (n¼ 14). Informed consent was obtained from all patients, and the study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Peking University People’s Hospital.

Transplantation Regimens

Preconditioning consisted of cytarabine (Ara-C), busulfan (4 mg$kg1$day1administered orally on days8 to 6 before January 2008 or 3.2 mg$kg1$day1administered i.v. on days8 to 6 after January 2008), cyclophosphamide (1.8 g$m2$day1on days5 to 4), and simustine (250 mg$m2on day3). Ara-C was administered at 4 g$m2

$day1on days10 to9 in the HLA-haploidentical related donor (haplo-RD) group and 2 g$m2$day1on day9 in the HLA-identical sibling donor (ISD) group; rabbit antithymocyte globulin (2.5 mg/kg on days5 to 2; Thymoglobulin, Sanofi, Gentilly, France) was administered in the haplo-RD group[16,17]. Granulocyte colony-stimulating factor (G-CSF)-mobilized, fresh, and unmanipulated BM and peripheral blood harvests were infused into recipients on the day of collection. In addition, patients received cyclosporine A (CSA), mycophenolate mofetil, and short-term methotrexate (MTX) as graft-versus-host disease (GVHD) prophylaxis[18]. Comorbidities in HSCT recipients were assessed based on the hematopoietic cell transplantation-specific comorbidity index (HCT-CI)[19]. Donor selection, HLA typing, and stem cell harvesting have been described in detail previously[20].

MRD Monitoring and Definition

Patients were monitored for MRD post-transplantation according to leukemia-associated aberrant immune phenotypes (LAIPs) and genes. LAIPs were detected by 4-colorflow cytometry (FCM) (FACSCalibur; BD Bio-sciences, San Jose, CA). FCM positivity was defined as >0.01% of cells with an LAIP in post-transplantation BM samples[21]. Expressions of leukemia-associated genes, including Wilms’ tumor gene 1 (WT1) and RUNX1/ RUNX1T1, were evaluated by TaqMan-based reverse-transcription poly-merase chain reaction (RT-PCR) of diagnostic specimens. PCR-positivity was defined as an RUNX1/RUNX1T1 transcript level >0.10% or a WT1 transcript level>0.60%[15].

Routine MRD monitoring was performed at 1, 2, 3, 4.5, 6, 9, and 12 months post-transplantation and at 6-month intervals thereafter. The tests were repeated 2 weeks after positive FCM or PCR results were detected. MRD-positive status was defined as FCM positivity in 2 consecutive BM samples within a 2-week interval, PCR positivity in 2 consecutive BM samples within a 2-week interval, or both FCM and PCR positivity in a single BM sample[22]. MRD status was also monitored at 1, 2, 3, 4.5, 6, 9, and 12 months postintervention and at 6-month intervals thereafter.

Preemptive Intervention after Detection of MRD

Post-transplantation immunosuppression was immediately tapered and discontinued in subjects who were MRD-positive at 100 days after

Figure 1. Diagram of preemptive intervention strategy based on MRD status. The patient who underwent only tapering immunosuppressive therapy (IST) was included in the MRD-positive without intervention group.

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Table 1

Patient Characteristics

Characteristic DLI Group (n¼ 45) IFN-aGroup (n¼ 22) P Value Age at HSCT, yr, median (range) 24 (2-58) 28 (5-51) .873 Time from HSCT to MRDþ, d, median (range) 166 (55-497) 172 (90-576) .759 Time from HSCT to intervention, d, median (range) 194 (79-520) 182 (90-582) .378

Late-onset MRD, n (%) 36 (80.0) 17 (77.3) 1.000

Diagnosis, n (%) .716

AML 25 (55.6) 11 (50.0)

Acute lymphoblastic leukemia 15 (33.3) 7 (31.8) Myelodysplastic syndrome 5 (11.1) 4 (18.2)

Disease risk at diagnosis, n (%) .485

Low risk 8 (17.8) 5 (22.7) Intermediate risk 30 (66.7) 16 (72.7) High risk 7 (15.5) 1 (4.6) Sex, n (%) .092 Male 23 (51.1) 16 (72.7) Female 22 (48.9) 6 (27.3)

Disease status at transplantation, n (%) d

CR1 35 (77.8) 18 (81.8)

CR2 5 (11.1) 0 (0.0)

RAEB1 2 (4.4) 3 (13.6)

RAEB2 3 (6.7) 1 (4.6)

Donor-recipient sex match, n (%) .557

Male-male 15 (33.3) 9 (40.9) Male-female 16 (35.6) 6 (27.3) Female-male 8 (17.8) 6 (27.3) Female-female 6 (13.3) 1 (4.5) Donor-recipient relationship, n (%) 1.000 Father-child 15 (33.3) 8 (36.4) Mother-child 4 (8.9) 2 (9.1) Sibling-sibling 23 (51.1) 11 (50.0) Child-parent 3 (6.7) 1 (4.5) Donor type .667

HLA-identical sibling donor 14 (31.1) 8 (36.4) HLA-haploidentical related donor 31 (68.9) 14 (63.6)

HLA-A, -B, or -DR mismatches, n (%) .279 0 14 (31.1) 8 (36.4) 1 1 (2.3) 3 (13.6) 2 6 (13.3) 2 (9.1) 3 24 (53.3) 9 (40.9) ABO match, n (%) .866 Matched 25 (55.6) 12 (54.5) Major mismatched 7 (15.6) 2 (9.1) Minor mismatched 10 (22.2) 6 (27.3) Major-minor mismatched 3 (6.6) 2 (9.1) HCT-CI before HSCT, n (%) .236 0 35 (77.8) 20 (91.0) 1-2 9 (20.0) 1 (4.5) 3 1 (2.2) 1 (4.5)

MRD before preemptive intervention, n (%)* .278

Leukemia-associated genes positive 22 (48.9) 16 (72.7)

WT1 positive 18 (40.0) 13 (59.1)

RUNX1/RUNX1T1 positive 4 (8.9) 3 (13.6)

FCM positive 3 (6.7) 2 (9.1)

Leukemia-associated genes and FCM positive 20 (44.4) 4 (18.2) WT1 positive and FCM positive 17 (37.8) 3 (13.6) RUNX1/RUNX1T1 positive and FCM positive 3 (6.6) 1 (4.6) GVHD prophylaxis, n (%)

CSA 43 (95.6) d

MTX 2 (4.4)

Receipt of second DLI for MRDþ at 1 month, n (%) 4 (8.9) d

Acute GVHD after preemptive intervention, n (%) 1.000

None 39 (86.7) 19 (86.4)

Grade I 0 (0.0) 1 (4.5)

Grade II-IV 6 (13.3) 2 (9.1)

Chronic GVHD after preemptive intervention, n (%) .029

None 18 (40.0) 2 (9.1) Mild to moderate 10 (22.2) 9 (40.9) Severe 17 (37.8) 11 (50.0) Relapse, n (%) 18 (40.0) 7 (31.8) .516 NRM, n (%) 2 (4.4) 1 (4.5) 1.000 DFS, n (%) 25 (55.6) 14 (63.6) .529 GRFS, n (%) 5 (11.1) 1 (4.5) .655

Duration of follow-up, d, median (range) 528 (178-1410) 567 (248-1180) .292 RAEB indicates refractory anemia with excess blasts.

Statistical significance was set at P < .05.

*MRD-positive status was defined as FCM positivity in 2 consecutive BM samples within a 2-week interval, PCR positivity in 2 consecutive BM samples within a 2-week interval, or both FCM and PCR positivity in a single BM sample.

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transplantation. Immunosuppression was immediately discontinued in subjects who were MRD-positive at>100 days after transplantation. Preemptive IFN-a

Recombinant human IFN-a-2b injections (Anferon; Tianjin Hualida Biotechnology, Tianjin, China) were administered s.c. at a dosage of 3 million units 2e3 times per week, for a maximum of 6 months. Patients with active acute GVHD (aGVHD), active cGVHD, active infections, severe myelosup-pression (white blood cell count <1.0  109cells/L, absolute neutrophil

count [ANC]<0.5  109

cells/L, hemoglobin count<65 g/L, or platelet count <25  109

cells/L), organ failure, or relapse were excluded from IFN-a treatment. Patients with increasing MRD after preemptive IFN-atreatment were eligible for DLI. Only patients with grade II-IV aGVHD or moderate to severe cGVHD received immunosuppressive therapy after IFN-atreatment. Preemptive DLI

Patients with active aGVHD, active cGVHD, active infection, or organ failure were excluded from DLI treatment. The protocol for DLI has been described detail by Yan et al.[7]. G-CSFemobilized peripheral blood stem cells were administered instead of the more common unstimulated donor blood lymphocytes. The median doses of mononuclear cells, CD3þcells, CD4þlymphocytes, CD8þlymphocytes, and CD34þcells were 1.0 (range, 0.9 to 1.5) 108/kg, 3.4 (range, 1.8 to 7.4) 107/kg, 1.9 (range, 1.1 to 4.4) 107/

kg, 1.2 (range, 0.5 to 2.8) 107

/kg, and 0.3 (range, 0.1 to 1.2) 106

/kg, respectively. These median cell doses for infusion were comparable in the haplo-RD and ISD groups (Supplementary Table 1).

Patients also received antileukemic chemotherapy at 48 to 72 hours before DLI. Chemotherapy regimens included HAA (harringtonine 2 mg$m2$day1for 5 days, aclacinomycin 10 mg$m2$day1for 5 days, and Ara-C 100 mg$m2$day1for 5 days), AA (aclacinomycin 10 mg$m2$day1 for 5 days and Ara-C 100 mg$m2$day1for 5 days), or HA (harringtonine 2 mg$m2$day1for 5 days and Ara-C 100 mg$m2$day1for 5 days) in pa-tients with AML or myelodysplastic syndrome,; and MTX (1.0 g$m2$day1 for 1 day) or CODP (cyclophosphamide 800 mg$m2$day1for 2 days, vincristine 1 mg$m2$day1for 1 day, daunorubicin 40 mg$m2$day1for 3 days, and prednisone 60 mg$day1 for 7 days) in patients with acute lymphoblastic leukemia.

In patients who were MRD-positive at 1 month after DLI, salvage DLI with previous chemotherapy was administered at 3 or 6 months after the first DLI for those without or with GVHD, respectively. The cell doses for infusion in the subsequent DLI were comparable to those administered in thefirst DLI (data not shown). Patients received immunosuppressive drugs, such as CSA or MTX, to prevent GVHD after DLI. Patients receiving DLI from an ISD received GVHD prophylaxis for 4 to 6 weeks, and those receiving DLI from a haplo-RD received GVHD prophylaxis for 6 to 8 weeks at the discretion of the attending physician (and usually depending on the pa-tient’s GVHD status after DLI). The starting dosage of CSA was 2.5 mg$kg1$day1, which was adjusted to maintain a plasma concentration 150-250 ng/mL. MTX was administered at 10 mg i.v. on days 1, 4, 8, and weekly thereafter for 2 to 6 weeks.

Treatment of GVHD after preemptive intervention

When GVHD (grade II-IV aGVHD or moderate to severe cGVHD) occurred after IFN-aor after DLI when immunosuppressive agents had already been discontinued, CSA was administered as soon as possible and then adjusted to maintain a blood concentration>150 ng/mL. If GVHD was not controlled by CSA, then primary therapy, including methylprednisolone (MP) and MTX, was administered alone or in combination. MP was administered i.v. at a dose of 1 to 2 mg$kg1$d1for at least 3 days; MTX was administered at a dose of 5 or 10 mg on days 1, 4, and 8 and weekly thereafter. If there was no response or an inadequate response to primary therapy, then second-line therapy, such as an CD25 monoclonal anti-body (Basiliximab; Novartis, Basel, Switzerland), was administered at a dose of 20 mg on days 1, 3, and 8 and weekly thereafter, until the patient exhibited complete response or treatment failure[23,24].

Definitions and Assessments

The disease risk of diagnosis was reported according to the criteria of Armand et al.[25](Supplementary Table 2). Adverse events after preemp-tive intervention were scored using the National Cancer Institute’s Common Toxicity Criteria version 4.0, and GVHD was excluded as an adverse event. GVHD occurring after preemptive intervention was diagnosed according to accepted international criteria[26,27]. Clinical manifestations, and not the time to symptomatic onset after intervention, determine whether the clinical syndrome of GVHD is considered acute or chronic[27]. Relapse was defined as morphological evidence of disease in samples from the periph-eral blood, BM, or extramedullary sites or by the recurrence and sustained presence of pretransplantation chromosomal abnormalities. Patients who exhibited MRD were not classified as having relapsed. Nonrelapse mortality

(NRM) was defined as death after HSCT without disease progression or relapse. Disease-free survival (DFS) was defined as the survival period with continuous CR. GVHD-free/relapse-free survival (GRFS) events were defined as grade III-IV aGVHD, cGVHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause after preemptive intervention[28]. Performance status after preemptive intervention was evaluated according to the Karnofsky score, which was recorded at the last follow-up. Early-onset MRD (EMRD) was defined as MRD positivity at 100 days after HSCT, and late-onset MRD (LMRD) was defined as MRD positivity at>100 days after HSCT.

Statistical Analysis

Data were censored at the time of relapse, nonrelapse mortality (NRM), or last available follow-up. Continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared using the chi-squared and Fisher exact tests. Clinical outcomes were compared be-tween the DLI and IFN-agroup, and also among MRD-positive patients with preemptive intervention, MRD-positive patients without preemptive interventions in the present cohort (n¼ 26), and MRD-positive patients without intervention in the historical cohort (n¼ 14). The Kaplan-Meier method was used to estimate the probabilities of DFS and GRFS. For DFS, relapse or death (ie, treatment failure as defined by DFS) was considered an event, and data on patients who were alive and in continuous CR were censored at the last follow-up. For GRFS, GVHD (grade III-IV aGVHD or cGVHD requiring systemic immunosuppressive treatment), relapse, or death (ie, treatment failure as defined by GRFS) was considered an event, and data on patients who were alive without GVHD and in continuous CR were censored at the last follow-up. Cumulative incidences were estimated for NRM and relapse to accommodate for competing risks. Relapse was the competing event for NRM and vice versa[29].

A landmark analysis was performed to assess the effects of preemptive IFN-aand DLI on each outcome. The post-transplantation day of interven-tion was defined as the landmark day. Relapse was calculated from the landmark day to relapse. NRM was calculated from the landmark day to date of death after HSCT without disease progression or relapse. DFS was calculated from the landmark day to relapse, death from any cause, or date of last contact. GRFS was calculated from the landmark day to date of the first event.

Potential prognostic factors for 1-year clinical outcomes after interven-tion were evaluated by multivariate analysis using Cox proporinterven-tional hazards regression with a backward-stepwise model selection approach. Factors included in the regression model for relapse, NRM, and DFS were sex, disease risk at diagnosis (high risk versus intermediate risk versus low risk), HLA disparity (ISD versus haplo-RD), type of preemptive treatment (IFN-aversus DLI), time from HSCT to MRD (EMRD versus LMRD), MRD status after pre-emptive intervention, and cGVHD after prepre-emptive intervention (negative versus mild-to-moderate versus severe cGVHD). All of the aforementioned factors except cGVHD were included in the regression model for GRFS.

Independent variables showing P> .10 were sequentially excluded from the model, and the level of significance was set at P < .05. All reported P values were based on 2-sided tests. Data analyses were conducted primarily with SPSS software (SPSS Inc., Chicago, IL), with the R version 2.6.1 (http:// www.r-project.org) used for competing risk analysis.

RESULTS

Clinical Outcomes of MRD-Positive Patients with and

without Preemptive Intervention

The 2-year cumulative incidences of relapse and DFS after

HSCT were 30.2% and 43.9% (P

¼ .480) and 64.2% and 53.8%

(P

¼ .620), respectively, in the preemptive IFN-

a

and DLI

groups. Both of these incidences were signi

ficantly better

than those of the MRD-positive patients without preemptive

interventions in the present cohort (n

¼ 26; 2-year relapse,

56.5%; 2-year DFS, 33.0%). The 2-year cumulative incidence

of NRM after HSCT was comparable in the MRD-positive

patients with and without preemptive interventions in the

present cohort (

Figure 2

A-C). Data for MRD-positive patients

receiving preemptive intervention in the present cohort and

MRD-positive patients without intervention in the historical

cohort (n

¼ 14) are compared in

Supplementary Figure 1A-C

.

Duration of Preemptive IFN-

a

The median duration of IFN-

a

therapy was 35 days (range,

4 to 180 days). One patient received IFN-

a

treatment for 6

(5)

months. Nineteen patients discontinued IFN-

a

treatment

because of grade III-IV aGVHD (n

¼ 1) or moderate to severe

cGVHD (n

¼ 18); in these patients, the median duration of

IFN-

a

therapy was 26 days (range, 4 to 106 days). Two

pa-tients discontinued IFN-

a

treatment at 19 days and 26 days

after intervention because of relapse.

Adverse Events of Preemptive Interventions

The adverse events associated with preemptive

inter-vention were summarized in

Supplementary Table 3

. In the

IFN-

a

group, 20 patients reported transient fever; however,

the maximum temperature did not exceed 39



C, and fever

resolved spontaneously in all cases. None of the patients

suffered severe hematology toxicity. In the DLI group, 36

patients experienced aplasia, with a median duration of 12

days (range, 6 to 29 days). Twenty-eight patients sustained

infection after DLI, 2 of whom with Escherichia coli septic

shock.

GVHD

Three patients developed aGVHD after preemptive IFN-

a

(1 each with grade I, II, and IV aGVHD). Six patients

devel-oped aGVHD after preemptive DLI (3 with grade II, 2 with

grade III, and 1 with grade IV) (

Table 1

). The median time

from intervention to occurrence of aGVHD was 13 days

(range, 2 to 17 days) in the IFN-

a

group and 44 days (range, 15

to 61 days) in the DLI group (P

¼ .048).

In the IFN-

a

group, 20 patients experienced cGVHD,

including 1 patient with mild cGVHD, 8 patients with

mod-erate cGVHD, and 11 patients with severe cGVHD (

Table 1

).

The rate of cGVHD was comparable between the haplo-RD

and ISD groups (85.7% versus 100%; P

¼ .515). In the DLI

group, 27 patients experienced cGVHD, including 2 with mild

cGVHD, 8 with moderate cGVHD, and 17 with severe cGVHD

(

Table 1

). The rate of cGVHD was higher in the haplo-RD

group compared with the ISD group (71.0% versus 35.7%;

P

¼.025). The median time from intervention to occurrence of

cGVHD was 36 days (range, 7 to 171 days) in the IFN-

a

group

and 72 days (range, 32 to 148 days) in the DLI group (P

¼.022).

Among the patients with cGVHD, 19 patients in the IFN-

a

group and 25 patients in the DLI group received systemic

immunosuppressive therapy. The 1-year cumulative

inci-dence of cGVHD after preemptive intervention was 90.9% in

the IFN-

a

group and 62.9% in the DLI group (P

< .001;

Figure 3

), and the 1-year cumulative incidence of mild to

moderate cGVHD and severe cGVHD was 40.9% versus 23.4%

(P

¼ 0.118) and 50.0% versus 39.5% (P ¼ 0.248) for patients

who received IFN-

a

versus DLI treatment, respectively.

MRD Status and Relapse after Intervention

The clinical outcomes were comparable among the

pa-tients in the 3 MRD status groups before the preemptive

interventions (

Supplementary Figure 2A and B

). Two

pa-tients relapsed within 1 month after receiving IFN-

a

. One

patient died from severe pneumonia within 1 month after

Figure 2. Clinical outcomes according to MRD status and preemptive interventions after HSCT. (A) Cumulative incidence of relapse at 2 years after HSCT: MRD-negative versus MRD-positive without intervention, P< .001; preemptive DLI versus MRD-positive without intervention, P ¼ .018; preemptive IFN-aversus MRD-positive without intervention, P¼ .027. (B) Cumulative incidence of NRM at 2 years after HSCT: MRD-negative versus MRD-positive without intervention, P ¼ .481; preemptive DLI versus MRD-positive without intervention, P¼ .069; preemptive IFN-aversus MRD-positive without intervention, P¼ .342. (C) Probability of DFS at 2 years after HSCT: MRD-negative versus MRD-positive without intervention, P< .001; preemptive DLI versus MRD-positive without intervention, P ¼ .004; preemptive IFN-aversus MRD-positive without intervention, P¼ .016. The red line represents the MRD-negative group (n ¼ 365); the blue line, the preemptive DLI group (n¼ 45); the gray line, the preemptive IFN-agroup (n¼ 22); the green line, the MRD-positive without intervention group (n ¼ 26). The patient who received only tapering IST was included in the MRD-positive without intervention group.

Figure 3. Cumulative incidence of cGVHD at 1 year after preemptive IFN-aand DLI treatments (P< .001). The red solid line represents the DLI group (n ¼ 45); the blue dashed line, the IFN-agroup (n¼ 22).

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receiving DLI, and 3 patients relapsed within 1 month after

receiving DLI. These 6 patients were excluded from our

analysis. A total of 61 patients (IFN-

a

, n

¼ 20; DLI, n ¼ 41)

were enrolled in the analyses of MRD status after preemptive

interventions and outcomes.

Eighteen patients (90.0%) turned MRD-negative after

receiving IFN-

a

, including 11 (55.0%) at 1 month, 3 (15.0%) at

2 months, 2 (10.0%) at 3 months, and 2 (10.0%) at

>3 months

after preemptive IFN-

a

. Ten patients discontinued IFN-

a

treatment before becoming MRD-negative because of active

GVHD; in these patients, the median time from IFN-

a

cessation to MRD-negative status was 23 days (range, 4 to 34

days). Eight patients continued IFN-

a

after turning

MRD-negative; in these patients,

the median

time from

MRD-negative status to IFN-

a

cessation was 117 days (range,

35 to 151 days). Twenty-nine patients (70.7%) turned

MRD-negative after DLI, including 16 (39.0%) at 1 month, 7

(17.1%) at 2 months, 3 (7.3%) at 3 months, and 3 (7.3%) at

>3

months after preemptive DLI.

Two patients (10%) did not turn MRD-negative after

IFN-

a

; 1 of these patients (5%) died from severe pneumonia

before becoming MRD-negative, and the other (5%)

continued IFN-

a

treatment but relapsed 2 months after the

intervention. Twelve patients (29.3%) did not achieve

MRD-negative status after DLI. Two of these patients

received salvage DLI treatment at 3 months after the

first

DLI, and the other patients did not receive additional DLI

treatments because of active GVHD. Ten patients (24.4%)

patients relapsed, including 3 (7.3%) who relapsed within 2

months after DLI, 5 (12.2%) who relapsed within 3 months

after DLI, and 2 (4.9%) who relapsed more than 3 months

after DLI.

Five patients who achieved MRD-negative status after

preemptive IFN-

a

turned MRD-positive again. One of these

patients received IFN-

a

again, and the other 4 patients did

not receive further intervention because of active GVHD. Two

patients (40%) turned MRD-negative again, and both

ach-ieved continued CR; 1 patient with persistent MRD relapsed.

Seven patients who achieved MRD-negative status after

preemptive DLI turned MRD-positive again. Two received a

second DLI treatment, 1 received chemotherapy, and 4

pa-tients did not receive any further intervention because of

active GVHD. Two (28.6%) turned MRD negative again and all

achieved continued CR, and 3 patients with persistent MRD

relapsed.

Seven patients relapsed after preemptive IFN-

a

, and 18

patients did so after preemptive DLI. The median time from

intervention to relapse was 136 days (range, 19 to 536 days)

in the former group and 90 days (range, 24 to 598 days) in

the latter group (P

¼ .423). The cumulative incidence of

relapse at 1 year after preemptive intervention was 27.3% in

the IFN-

a

group and 35.6% in the DLI group (P

¼ .514;

Figure 4

A). In multivariate analysis, persistent MRD after

intervention was signi

ficantly associated with increased risk

of relapse (

Table 2

).

NRM

One patient died from severe pneumonia at 131 days after

receiving IFN-

a

; 2 patients died from severe pneumonia and

GVHD at 20 days and 143 days, respectively, after receiving

DLI. The cumulative incidence of NRM at 1 year after

pre-emptive intervention was 4.5% in the IFN-

a

group and 4.4% in

the DLI group (P

¼ .985;

Figure 4

B). In multivariate analysis,

none of variables was signi

ficantly associated with increased

NRM, and IFN-

a

recipients did not show increased risk of

NRM compared with DLI recipients (hazard ratio, 0.99; 95%

CI, 0.09 to 10.94; P

¼ .995).

DFS, Performance Status after Intervention, and GRFS

The probabilities of DFS at 1 year after preemptive

inter-vention were 68.2% in the IFN-

a

group and 60.0% in the DLI

group (P

¼ .517;

Figure 5

A). In multivariate analysis,

persis-tent MRD and non-cGVHD after preemptive intervention

were signi

ficantly associated with poorer DFS.

The median Karnofsky score was 70 (range, 50 to 90) in the

IFN-

a

group and 70 (range, 20 to 90) in the DLI group (P

¼.100).

The median score was 80 (range, 20 to 90) in patients without

cGVHD and 75 (range, 60 to 90) in those with mild to moderate

cGVHD (P

¼ .283), both significantly higher than the median

score in patients with severe cGVHD (60; range, 40 to 80)

(non-cGVHD versus severe (non-cGVHD, P

< .001; mild to moderate

cGVHD versus severe cGVHD, P

¼.002). The probability of GRFS

at 1 year after preemptive intervention was 4.5% in the IFN-

a

group and 7.2% in the DLI group (P

¼.030;

Figure 5

B), and EMRD

was associated with poorer GRFS (

Table 2

).

Figure 4. Cumulative incidence of relapse (A; P ¼ .514) and NRM (B; P ¼ .985) at 1 year after preemptive IFN-aand DLI treatments. The red solid line represents the DLI group (n¼ 45); the blue dashed line, the IFN-agroup (n¼ 22).

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DISCUSSION

Although preemptive DLI based on MRD status can

signi

ficantly improve the clinical outcomes of patients after

HSCT

[6,7]

, some patients cannot receive preemptive DLI

after HSCT because of either provider refusal or patient

refusal. In the present study, we observed a 1-year

cumula-tive incidence of relapse and DFS after intervention of 35.6%

and 60.0%, respectively, in patients receiving preemptive DLI.

Patients receiving preemptive IFN-

a

had similar clinical

outcomes as the DLI recipients, suggesting that IFN-

a

may be

a potential alternative for MRD-positive patients who refuse

or are unable to receive preemptive DLI.

Our previous study reported a relapse rate exceeding 70%

in patients who were MRD-positive after HSCT but not

receiving any interventions

[15]

; the 2-year relapse rate of

only 30.2% in the present study suggests that preemptive

IFN-

a

is effective for MRD-positive patients. IFN-

a

may exert

an immunomodulatory effect in HSCT recipients, which can

promote the GVL effect and further clear tumor cells

[8,9]

.

We also observed that even though IFN-

a

treatment was

discontinued in 10 of the IFN-

a

recipients because of active

GVHD, MRD remained signi

ficantly decreased and

MRD-negative status was achieved, indicating that IFN-

a

indeed

might promote the GVL effect and clear tumor cells. In

addition, because chemotherapy and immunosuppressive

Table 2

Multivariate Analysis of Prognostic Factors for 1-Year Clinical Outcomes in Patients after Preemptive Interventions Variable Relapse Treatment Failure as Defined

by DFS

Treatment Failure as Defined by GRFS

HR 95% CI P HR 95% CI P HR 95% CI P Sex

Male 1.00 .705 1.00 .316 1.00 .861

Female 1.22 0.43-3.48 1.65 0.62-4.42 1.05 0.60-1.85 Disease risk at diagnosis

Low risk 1.00 1.00 1.00 Intermediate risk 1.31 0.45-3.86 .622 2.27 0.79-6.58 .130 1.49 0.68-3.28 .321 High risk 0.77 0.14-4.24 .768 3.42 0.68-17.19 .136 0.79 0.26-2.46 .681 Donor type ISD 1.00 .600 1.00 .262 1.00 .569 Haplo-RD 0.76 0.27-2.14 0.59 0.24-1.48 1.20 0.64-2.23 Type of preemptive intervention

DLI 1.00 .518 1.00 .609 1.00 .093

IFN-a 0.64 0.16-2.52 1.32 0.45-3.84 1.66 0.92-3.01 MRD status postintervention

Persistent MRD after intervention 1.00 1.00 1.00

MRD-negative 1 mo after intervention 0.08 0.03-0.25 <.001 0.08 0.03-0.26 <.001 0.97 0.51-1.87 .937 MRD-negative beyond 1 mo after intervention 0.03 0.01-0.25 .001 0.07 0.02-0.32 .001 0.63 0.31-1.28 .197 Time from HSCT to MRD-positive status

EMRD 1.00 .171 1.00 .053 1.00 .041

LMRD 0.45 0.15-1.41 0.35 0.12-1.01 0.53 0.29-0.97

Chronic GVHD after intervention d

None 1.00 1.00

Mild to moderate 0.49 0.17-1.45 .199 0.25 0.07-0.87 .030 Severe 0.54 0.21-1.44 .219 0.56 0.22-1.39 .211 HR indicates hazard ratio.

Bold type indicates statistical significance (P < .05).

Figure 5. Probability of DFS (A; P ¼ .517) and GRFS (B; P ¼ .030) at 1 year after preemptive IFN-aand DLI treatments. The red solid line represents the DLI group (n¼ 45); the blue dashed line, the IFN-agroup (n¼ 22).

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agents may abrogate the effector cells of the GVL effects, in

the present study IFN-

a

was administered without

chemo-therapy and immunosuppressive agents to maximize the

GVL effect. On the other hand, in vivo and in vitro studies

have found that IFN-

a

can dramatically inhibit the

prolifer-ation of acute leukemia cells

[30-32]

. Thus, IFN-

a

may clear

MRD through different mechanisms. Similarly, Klingemann

et al.

[33]

reported that 9 of 14 high-risk patients with

re-fractory/relapsed hematologic malignances who received

preemptive IFN-

a

after HSCT achieved continued CR.

In the present study, we found a higher incidence of cGVHD

and shorter median time from intervention to occurrence of

cGVHD in the IFN-

a

group compared with the DLI group.

Several previous studies have observed that cGVHD is closely

related to the GVL effect

[34,35]

. It is possible that IFN-

a

may

rapidly induce the GVL effect and clear the MRD. We observed

that 55.0% of the IFN-

a

recipients and 39.0% of the DLI

re-cipients achieved MRD-negative status by 1 month after

intervention, a key factor in reducing relapse and improving

DFS in our multivariate analysis. This may partially account for

the fact that IFN-

a

recipients can achieve similar relapse and

DFS rates as DLI recipients. Some authors have reported that

cGVHD might have an adverse effect on NRM after

myeloa-blative conditioning HSCT

[36]

; however, Arai et al.

[37]

re-ported signi

ficantly higher NRM in patients with severe

cGVHD compared with those with mild or moderate cGVHD.

In the present study, the incidence of severe cGVHD was

comparable in the IFN-

a

and DLI groups. In addition, several

previous studies found that even severe cGVHD was not

associated with an increased risk of NRM

[38,39]

. On the other

hand, PUIH is the largest HSCT center in China, performing

more than 1000 HSCTs to date. We have extensive experience

in treating cGVHD, particularly severe cGVHD, and have found

that many patients with cGVHD can avoid NRM. In our present

cohort, despite the high incidence of cGVHD, the presence of

cGVHD did not signi

ficantly increase the risk of NRM in the

IFN-

a

group compared with the DLI group; however, severe

cGVHD did not signi

ficantly improve DFS in our multivariate

analysis, and the performance status of these patients was

poor. Previous studies also have reported signi

ficantly

impaired quality of life in patients with severe cGVHD

[40,41]

.

Given the 50% incidence rate of severe cGVHD in the present

study, controlling cGVHD severity after IFN-

a

is important for

further improvement of this preemptive intervention.

In the present study, the 1-year NRM after intervention

was 4.5% in the IFN-

a

group, and most patients experienced

only transient fever during therapy. No severe myelotoxicity

was observed, and only 1 patient had a fatal infection. In the

study reported by Klingemann et al.

[33]

, it was necessary to

reduce the dose of IFN-

a

by 25% in only 1 patient because of

grade 2 nausea, vomiting, and anorexia. No life-threatening

complications were seen and all side effects were reversed,

usually within 1 week after discontinuation of IFN-

a

. These

observations suggest that IFN-

a

may be a safe preemptive

intervention for MRD-positive patients after HSCT. In

addi-tion, we found a comparable incidence of NRM in the IFN-

a

and DLI groups.

Along with the comparable incidence of severe cGVHD

after intervention described above, the similar incidences of

NRM also may be related to comparable rates of severe

aGVHD after intervention. Severe aGVHD is one of the most

signi

ficant causes of NRM after post-HSCT immunotherapy.

In the present study, the ratio of patients with grade II to IV

aGVHD was 9.1% in IFN-

a

group, comparable to the 13.3% in

the DLI group. Finally, pre-HSCT comorbidities strongly

predict NRM after HSCT

[19,42]

; however, the proportion of

patients with an HCT-CI score of

3 was comparable in the

IFN-

a

and DLI groups, suggesting comparable pre-HSCT

co-morbidity burden in the 2 groups.

GRFS, a composite endpoint, represents ideal recovery

from HSCT and a measure of cure without ongoing morbidity.

The probability of GRFS at 1 year after preemptive

inter-vention was only 4.5% in the IFN-

a

group and 7.2% in the DLI

group; however, inducing a GVL effect was one of the most

important objectives of preemptive immunotherapy in

pa-tients who were MRD-positive after HSCT, and GVHD may be

inevitable. Thus, the improved DFS after preemptive IFN-

a

or

DLI may come at the cost of impaired quality of life. New

preemptive interventions that can enhance the GVL effect

while decreasing the toxicity of GVHD may further improve

the GRFS.

This study has several limitations. First, the number of

patients receiving preemptive IFN-

a

was somewhat small,

which could have in

fluenced the accuracy of our findings.

Second, the relatively short observation period hindered the

evaluation of long-term relapse after IFN-

a

treatment. Third,

more than 75% of patients in our cohort had LMRD, and thus

the ef

ficacy of preemptive IFN-

a

in EMRD patients requires

further investigation. Fourth, one-half of our MRD-positive

patients could not receive preemptive intervention because

of active GVHD, and the GVL effect might clear the MRD;

thus, our data might not fully re

flect the clinical outcomes of

MRD-positive patients without intervention. This also may

account for the better clinical outcomes of our MRD-positive

patients without intervention compared with the historical

cohort. Finally, patients with acute leukemia in nonremission

before HSCT routinely received prophylactic DLI after HSCT,

and patients with a t(9;22) mutation routinely received

prophylactic or preemptive imatinib after HSCT; thus, these

patients were not enrolled in the preemptive DLI or IFN-

a

treatment in the present study. Because patients with

advanced-stage acute leukemia compose approximately 25%

of the patients with acute leukemia receiving HSCT at PUIH

[17]

, the number of patients with poor-risk cytogenetics was

relatively small in the present study. The ef

ficacy of

pre-emptive IFN-

a

treatment in patients with poor-risk

cytoge-netics merits further study.

In summary, preemptive IFN-

a

may be safe and effective

for MRD-positive patients and may provide a potential

alternative for patients unable to receive preemptive DLI

after HSCT. The ef

ficacy of IFN-

a

should be further con

firmed

in large-scale, prospective clinical studies.

ACKNOWLEDGMENTS

The authors thank Editage for their assistance with

edit-ing the manuscript.

Financial disclosure: This work was supported by the Key

Program of the National Natural Science Foundation of China

(Grant 81230013), the National High Technology Research

and Development Program of China (Program 863) (Grant

2013AA020401), the National Natural Science Foundation of

China (Grant 30971292), and the National Natural Science

Foundation of China (Grant 81400145).

Con

flict of interest statement: The authors have no conflicts

of interest to report.

SUPPLEMENTARY DATA

Supplementary data related to this article can be found at

http://dx.doi.org/10.1016/j.bbmt.2015.06.014

.

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Figure

Updating...

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