Allogeneic haematopoietic stem-cell transplantation with ... - Nature

Bone Marrow Transplantation (2011) 46, 870–875 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11

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ORIGINAL ARTICLE

Allogeneic haematopoietic stem-cell transplantation with reduced intensity conditioning for advanced stage Hodgkin’s lymphoma in Sweden: high incidence of post transplant lymphoproliferative disorder J-E Johansson1, M Remberger2, VLj Lazarevic3, H Hallboö¨k4, A Wahlin5, E Kimby6, G Juliusson3, H Omar6 and H Ha¨gglund6 1

Department of Hematology and Coagulation, Sahlgrenska University Hospital, Go¨teborg, Sweden; 2Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden; 3Department of Hematology, Ska˚ne University Hospital, Lund University, Lund, Sweden; 4Department of Hematology, Uppsala University Hospital, Uppsala, Sweden; 5Department of Hematology, Cancer Centre, University Hospital, Umea˚, Sweden and 6Hematology Center, Karolinska University Hospital Huddinge, Stockholm, Sweden

Allogeneic transplantation after reduced intensity conditioning (allo-RIC) is a treatment option for patients with Hodgkin’s lymphoma (HL) relapsing after autologous transplantation. In all, 23 adult patients with HL underwent allo-RIC in Sweden between 2000 and 2007. The median number of previous treatment lines was five and 20 patients (87%) were previously autografted. TRM at 100 days and at 1 year was 13 and 22% respectively. Acute GVHD grades II–IV developed in 7 out of 23 patients (30%) and chronic GVHD in 10 out of 20 patients at risk (50%). The OS and EFS at three years was 59 and 27%, respectively. Four patients (17%) developed post transplant lymphoproliferative disease (PTLD) after a median time of 55 days (range 38–95); two of these patients later died. The study confirmed that allo-RIC is feasible, but associated with a substantial relapse rate: only 20% of the patients were still alive 7 years after the transplant. A finding of high incidence of PTLD needs to be confirmed in a larger trial that includes patients with non-HL and CLL. Bone Marrow Transplantation (2011) 46, 870–875; doi:10.1038/bmt.2010.238; published online 18 October 2010 Keywords: allogeneic; transplantation; Hodgkin’s lymphoma; post transplant lymphoproliferative disorder; reduced intensity conditioning

Introduction Although two randomised studies have demonstrated that high-dose therapy with autologous stem cell rescue—

Correspondence: Dr J-E Johansson, Department of Hematology and Coagulation, Sahlgrenska University Hospital, S-413 45 Go¨teborg, Sweden. E-mail: [email protected] Received 14 June 2010; revised and accepted 23 August 2010; published online 18 October 2010

compared with conventional dose salvage chemotherapy— can successfully treat patients with chemosensitive relapsed Hodgkin’s lymphoma (HL),1,2 no prospective, randomised studies have examined how to manage patients with relapse or progression after autologous transplant. Several retrospective reports have evaluated allogeneic transplantation after full intensity conditioning3–6 and several more recent studies have evaluated allogeneic transplantation after reduced intensity conditioning (allo-RIC).7–15 In these trials, the selected patients were in an advanced disease stage and heavily pre-treated and both TRM and the relapse rates were high. The present trial, the first national compilation study, summarises experiences of allogeneic transplantation after reduced intensity conditioning in adult HL patients in Sweden.

Patients and methods The patients and their donors were identified using the Swedish transplant centres’ UPN-lists. Data were collected locally at each participating centre from patient files, local registries and the European Group for Blood and Marrow Transplantation (EBMT) database for all adult patients (X18 years) who had been treated with allogeneic transplantation after reduced intensity conditioning due to HL. In total, 23 patients from five centres were transplanted between January 2000 and December 2007. Data were available for all 23 transplanted patients. One patient was reported in a previously published EBMT study,16 but data on the remaining 22 patients had not been used in earlier studies. The study protocol was approved by the Regional Ethical Review Board in Goteborg and patients gave informed consent before transplant. The median number of treatment lines before the allogeneic transplant was five (range 2–8), and 20 patients (87%) had previously undergone an autologous transplant. The median time from diagnosis to the allograft was 53 months (range 17–162 months). Three patients (13%) were chemorefractory at the time of the allograft. The donors

Allogeneic transplantation for Hodgkin’s lymphoma J-E Johansson et al

871

were HLA-identical related in three cases (13%), HLA-A, -B and –DR identical unrelated in 14 cases (61%) and mismatched unrelated in six cases (26%). Patient characteristics are described in Table 1. Table 1

Patient characteristics of the 23 patients included

Characteristic

Measurement

Age (Years) Men Women

36 (19–49) 13 (57) 10 (43)

Donor Matched related Matched unrelated Mismatched unrelated

3 (13) 14 (61) 6 (26)

CMV serology (recipient/donor) / /+ +/ +/+

5 5 8 5

(22) (22) (35) (22)

EBV serology (recipient/donor) +/+ /+ +/ unknown/+ +/unknown unknown/unknown

12 2 1 4 3 1

(52) (9) (4) (17) (13) (4)

Female donor—male recipient Time from diagnosis to allograft (months) No. of previous treatment lines Previously autografted Time from autograft to allograft (months)

4 53 5 20 22

(17) (17–162) (2–8) (87) (9–63)

Histological subtype Nodular sclerosis Lymphocyte rich

22 (96) 1 (4)

Status at allo transplantation CR or CRu PR Refractory

2 (9) 18 (78) 3 (13)

Conditioning Flu/Mel Flu/Bu Flu/Cy/TBI Flu/Cy

14 4 3 2

Antilymphocyte antibodies used Yes No

20 (87) 3 (13)

(61) (17) (13) (9)

Stem cell source BM PBSC

6 (26) 17 (74)

CD34 dose ( 106/kg)

5.4 (2.1–12.4)

GVHD prophylaxis CyA/Mtx CyA

21 (91) 2 (9)

Abbreviations: Flu/Bu ¼ fludarabine 150 mg/m2, busulphan 8 mg/kg; Flu/Cy ¼ fludarabine 150 mg/m2, CY 60 mg/kg; Flu/Cy/TBI ¼ fludarabine 180 mg/m2, CY 60 mg/kg, TBI 3 Gy 2; Flu/Mel ¼ fludarabine 150 mg/m2, melphalan 140 mg/m2. Data are no. of individuals (%) or median (range). Percentage may exceed 100 owing to rounding.

Conditioning regimen The conditioning was considered reduced or non-myeloablative according to the consensus criteria proposed by the Regimen-Related Toxicity Working Committee of the Center for International Blood and Marrow Transplant Research, criteria that has been used in other studies.12,17,18 The conditioning regimens used are described in Table 1. GVHD prophylaxis In two cases, CYA alone was used and in the remaining 21 cases CYA together with a short course of MTX was used. Anti-thymocyte globuline was used for in vivo T-cell depletion before transplant if the donor was unrelated. Stem cell source In 17 cases (74%), PBSCs were used and in the remaining six cases (26%) BM was used. The median CD34 cell dose count was 5.4 106/kg (range 2.1–12.4). Statistics The analysis was performed in February 2010. The probabilities of overall survival and relapse-free survival were estimated using the method developed by Kaplan– Meier and compared with the log-rank test.19 The incidence of GVHD, TRM and relapse were estimated non-parametrically. Patients were censored at the time of death, relapse, or last follow-up. Relapse and non-relapse mortality are competing events. Their incidence rates were estimated using a non-parametric estimator of cumulative incidence curves.20 Predictive analyses for GVHD, TRM and relapse were based on the proportional hazard model for subdistribution of competing risk. Univariate and multivariate analyses were then performed using Gray’s test and the proportional sub-distribution hazard regression model developed by Fine and Gray.21 All tests were two-sided. The type I error rate was fixed at 0.05 for factors potentially associated with time-to-event outcomes. Analyses were performed using the cmprsk package (developed by Gray, June 2001), Splus 6.2 software (S-plus 6.2, Insightful, Seattle, WA, USA) and Statistica software (Statistica, StatSoft, Tulsa, OK, USA).

Results Engraftment and GVHD All 23 patients were engrafted. The median time to reach an ANC of more than 0.5 109/L and to achieve a platelet count of more than 20 109/L was 17 and 16 days, respectively (Table 2). One patient’s platelet count was never below 20 109/L during the transplant course. Acute GVHD developed in 10 out of 23 patients (43%). Chronic GVHD (cGVHD) developed in 10 out of 20 patients at risk (50%). In all, 7 out of the 10 patients (70%) who developed cGVHD had no previous acute GVHD (de novo cGVHD). The extent of cGVHD was limited in two cases and extensive in eight cases. The 1-year and 3-year cumulative incidence of cGVHD was 45% (Figure 1). Transplant outcome is summarised in Table 2. Bone Marrow Transplantation


872 Transplantation outcomes (n ¼ 23)

1.0

Follow-up all patients (months) Follow-up of survivors (months)

25 (1–92) 46 (3–92)

Engraftment Neutrophils (days to 40.5 109/L) Platelets (days to 420 109/L)

17 (11–28) 16 (11–35)

Acute GVHD Grades 0–I Grades II–IV

16 (70) 7 (30)

Day of onset of acute GVHD Patients at risk of chronic GVHD

22 (16–59) 20

0.6 0.4 0.2 0.0 0

365

730

1095

Days after HSCT Figure 2 Transplant-related mortality.

Chronic GVHD None Limited Extensive

13 (65) 2 (10) 8 (40)

Day of onset of chronic GVHD De novo chronic GVHD

174 (100–362) 7 (70)

Patients at risk of CMV-infection/disease CMV-infection Day of onset of CMV-infection

18 9 (50) 32 (20–42)

CMV disease Day of onset of disease

2 (11) 39 (35–42)

PTLD Day of onset of PTLD

4 (17) 55 (38–95)

Non-relapse mortality (percent) 100 days 1 year 3 years

13 22 22

Causes of death GVHD Multi organ failure PTLD Relapse

2 1 2 8

(15) (8) (15) (62)

Abbreviation: PTLD ¼ post transplant lymphoproliferative disease. Data are no. of individuals (%) or median (range). Percentage may exceed 100 owing to rounding. De novo chronic GVHD: chronic GVHD without prior acute GVHD.

1.0 Chronic GVHD

100 days: 13% 1 year: 22%

0.8 TRM

Table 2

0.8 0.6 45% 0.4 0.2

Four patients (17%) developed post transplant lymphoproliferative disease (PTLD) after a median time of 55 days (range 38–95), two of these patients died. The patients who developed PTLD (one male and three females) were all transplanted from unrelated donors and had acute GVHD. Details of the patients are summarised in Table 3. In all, 9 out of 18 patients who were at risk (donor and/or recipient who were CMV-sero-positive) developed CMV infection after a median time of 32 days (range 20–42 days). Two of these patients developed non-fatal CMV disease.

Disease relapse and progression In all, 12 patients relapsed or progressed after a median time of 8.7 months (range 1–39 months) after transplant; four of these patients were still alive after a median followup time of 45 months (range 24–51 months). The cumulative incidence of relapse/progression was 57% at 3 years (Figure 3). Donor lymphocyte infusion (DLI) Nine patients were treated with DLI, two before clinical relapse and seven as a part of the salvage regimen. DLI only was given to four out of seven patients who relapsed. DLI combined with chemotherapy was given to the remaining three patients who relapsed. Four out of the seven patients (57%) who were given DLI as a part of the salvage regimen responded and were still alive after a median follow-up time from DLI of 19 months (range 2– 42). Five patients who relapsed were not treated with DLI mainly because of early and proliferative relapses or previous extensive cGVHD. None of these patients are alive. Details of the 12 patients who relapsed are summarised in Table 4.

0.0 0 Figure 1

365

730 1095 1460 Days after HSCT

1825

The cumulative incidence of cGVHD.

Transplant-related mortality and morbidity Five patients died of transplant-related causes. TRM at 100 days and at 3 years was 13 and 22%, respectively (Figure 2). Bone Marrow Transplantation

Survival Ten patients were still alive after a median follow-up time of 48 months (range 3–243 months). The cumulative proportions of patients surviving at 1, 3 and 5 years after transplant were 62, 54 and 41%, respectively. The 5-year progression-free survival was 22% (Figure 4). GVHD (acute or chronic), chemosensitive disease or any other factor did not significantly affect OS or PFS (data not shown).


873 Characteristics of the four patients who developed post transplant-lymphoproliferative disease

Table 3

Patient PAD Donor

ATG EBVserology patient

aGVHD cGVHD Onset PAD PTLD EBVPTLD serology donor

M/40

NS

Mismatched Yes URD

Negative Positive II

Nil

F/37

NS

Mismatched Yes URD

Positive

Positive I

NA

F/30

NS

Matched URD

Yes

Positive

Positive I

Nil

F/29

NS

Matched URD

Yes

Positive

Not tested

Ext

IV

d+95 Lymphocyte infiltration, EBER+, EBNA+ d+38 B cell lymphoma, EBER+, EBNA+, LMP1+ d+52 Polymorph PTLD, Lambda monoclonal B cell population, EBER+ d+57 EBV-PCR-positive on d +48, PAD not performed, FNA inconclusive

Local

Colon liver

Treatment

Outcome

Ganciclovir IVIG rituximab 1 Lung liver Rituximab 1 ganciclovir lymphnodes LymphRituximab 4 nodes EBV-CTL IVIG

Dead of PTLD d +101 Dead of PTLD d +51 Resolution of PTLD Alive in CR d +1466

Lung liver Rituximab 4 Resolution of PTLD Dead of spleen GVHD d +227 lymphnodes

Abbreviations: ATG ¼ Anti-thymocyte globuline; CTL ¼ cytotoxic T-lymphocytes; EBER ¼ Epstein-Barr encoded RNA (in situ hybridisation); EBNA ¼ Epstein-Barr nuclear Ag (immunohistochemistry); FNA ¼ fine needle aspiration; LMP ¼ EBV latent membrane protein 1 (immunohistochemistry); NS ¼ nodular sclerosis; PAD ¼ preliminary anatomic diagnosis; PTLD ¼ post transplant lymphoproliferative disease; URD ¼ unrelated donor.

1y 2y 3y

Relapse/progression

1.0 0.8

38% 53% 57% 63%

0.6 0.4 0.2 0.0 0

365

730 1095 Days after HSCT

1460

1825

Figure 3 The cumulative incidence of relapse/progression.

Discussion The present study is the first national comprehensive report summarising the results of allo-SCT for HL in Sweden. As in previously published reports, the patients in our cohort were in an advanced disease stage and heavily pre-treated before allotransplant—87% of the patients were previously autografted. The study confirmed that reduced intensity conditioning in this situation was associated with a substantial relapse rate: only 20% of the patients were still alive 7 years after the transplant. A previous study from the EBMT presented the results of allotransplantation in advanced HL patients who were transplanted between 1999 and 2001.16 In the present study, only one of the patients was transplanted during that period, so the two reports do not overlap. On the basis of the results from non-randomised trials, it may be concluded that allo-RIC in advanced HL is feasible and possibly superior to alternative salvage therapy in this subset of patients.14,22 However, the long-term results have been quite discouraging, mainly because of high relapse rates. In our study, 52% of the patients relapsed, a finding that agrees with earlier reports. Recent studies exploring

graft-vs-tumour effects have investigated allo-RIC in relapsed HL. These studies are looking at the disease response to DLI for residual masses, mixed chimerism, or documented disease progression post transplant. This antitumor effect appears to be related to (and at the cost of) cGVHD in most but not all cases.9 In our study, 7 out of 12 relapsed patients were treated with DLI. Three patients also had additional chemotherapy, making the true effect of this form of immunotherapy difficult to determine with confidence. The five patients who were not given DLI, progressed and died shortly after the relapse. The majority of these patients were considered to have a far too proliferative relapse and/or previously too much of cGVHD to be eligible for DLI. Thus, the effect of DLI seems to be modest in proliferative relapse, but DLI may have a role to play in patients with early, not very proliferative, relapse or as prophylaxis against manifest relapse in patients with mixed chimerism with previous, none, or mild GVHD. In the present trial, cGVHD did not have any influence on the relapse rate possibly owing to small numbers, as in larger studies a graft-vs-tumour effect has been demonstrated.16 A novel and surprising finding in the present trial was the high incidence of PTLD. Four patients (17%) developed PTLD, two of whom died. The incidence of PTLD after allogeneic transplantation has been shown to be between 0.2 and 8.1% depending on the number of risk factors.23,24 It is true that a substantial part of the patients in the present trial was burdened with one or two risk factors for PTLD, such as the use of T-cell antibodies (83% of patients) and the fact that 26% of the donors were mismatched; nevertheless, it is unlikely that these facts explain more than a doubling of the expected incidence of PTLD. In this context, it is important to note that in the reports identifying risk factors for developing PTLD after allogeneic transplantation, patients with a lymphoma diagnosis have been excluded owing to the difficulty of separating PTLD from relapse of lymphoma. Accordingly, the true incidence of PTLD after allogeneic transplantation Bone Marrow Transplantation


874 Characteristics of patients and treatment of patients who relapsed (n ¼ 12)

Table 4 Sex/ Age

Donor

DLI

DLI doses

Chemo

aGVHD/ cGVHD

DLI before/after cGVHD

Allo to relapse (months)

Relapse to DLI (months)

Status at follow-up (months after allo)

F/28 M/39 M/39 M/49 F/46 M/24 F/23 M/39 M/27 F/19 M/36 F/32

URD URD URD RD RD URD URD URD URD URD URD URD

No Yes Yes No No Yes No No Yes Yes Yes Yes

0 1 1 0 0 3 0 0 2 1 5 3

Yes Yes No Yes Yes No Yes Yes No No Yes Yes

0/Nil II/Ext 0/Ext II/Ext 0/Ext 0/Lim 0/Nil 0/Nil 0/Ext 0/Nil 0/Ext 0/Nil

— After Before — — Before — — After — After —

12 18 9 6 14 4 3 9 7 9 16 8

— 60 0 — — 0.5 — — 1 2 10 days 2

53/Dead 81/Dead 46/Dead 20/Dead 67/Dead 9/Dead 6/Dead 20/Dead 51/Alive 50/Alive 40/Alive 24/Alive

Abbreviations: DLI ¼ donor lymphocyte infusion; RD ¼ related donor; URD ¼ unrelated donor.

a

OS

Cumulative proportion surviving

1.0 1year 69% 3year 59% 5year 42%

0.8

0.6

0.4

0.2

Conflict of interest 0.0 0

365

730 1095 1460 1825 2190 2555 2920 3285 Days after HSCT

b

The authors declare no conflict of interest.

PFS 1.0

Progression-free survival

further controlled studies are warranted to identify the patients who would gain by a transplant and to determine when in the treatment course allo-RIC should be introduced. Thankfully, the subsets of patients with HL that may be considered for such treatment are small and therefore, it is necessary that large organisations accomplish these trials. The finding of the unexpected high incidence of PTLD might be a chance finding with small numbers and needs to be confirmed in a larger trial that also includes other lymphomas than HL.

References 1year 46% 3year 27% 5year 22%

0.8

0.6

0.4

0.2

0.0 0

365

730 1095 1460 1825 2190 2555 2920 3285 Days after HSCT

Figure 4

OS and PFS.

for lymphoma is unknown and therefore, it would be of interest to more closely investigate the development of PTLD in patients undergoing an allogeneic transplant for a lymphoma diagnosis. In summary, the present trial confirms that allo-RIC is a treatment option for patients with advanced HL, but Bone Marrow Transplantation

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