Allogeneic Stem Cell Transplantation Compared with Chemotherapy ...

Allogeneic Stem Cell Transplantation Compared with Chemotherapy for Poor-Risk Hodgkin Lymphoma Luca Castagna,1 Barbara Sarina,1 Elisabetta Todisco,1 Massimo Magagnoli,1 Monica Balzarotti,1 Stefania Bramanti,1 Rita Mazza,1 Antonella Anastasia,1 Andrea Bacigalupo,2 Franco Aversa,3 Davide Soligo,4 Laura Giordano,5 Armando Santoro1 The aim of this study was to assess the role of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with poor-risk Hodgkin’s disease (HD) compared to chemotherapy. A donor was identified in 26 patients (14 HLA identical siblings and 10 alternative donors), and 24 received a transplant (Allo group). Twenty patients without a donor received different chemotherapy regimens and radiotherapy (CHEMO group). After a median follow-up of 28 months (range: 1-110), the 2-year overall survival (OS) was 71% in the ALLO group compared to 50% in the CHEMO group (P 5 .031). In the Allo group, the 2-year progression-free survival (PFS) was 47%. The 1-year nonrelapse mortality (NRM) in the ALLO group was 8% versus 0% in the CHEMO group. This study, suggests that allogeneic transplantation may prolong the survival in patients with a poor-risk HD. Biol Blood Marrow Transplant 15: 432-438 (2009) Ó 2009 American Society for Blood and Marrow Transplantation

KEY WORDS: Hodgkin lymphoma, High-dose chemotherapy, Salvage chemotherapy, Allogeneic transplantation

INTRODUCTION High-dose chemotherapy (HDC) with peripheral blood stem cell transplantation (PBSC-T) is the standard therapy for patients with resistant/relapsed Hodgkin lymphoma (HL) [1,2]. However, the 3- to 5-year progression-free survival (PFS) ranges from 30% to 60%, and the overall survival (OS) from 40% to 50% [2,3]. The prognosis of patients not cured by HDC is very poor, with median survival of \1 year [4,5,6]. The optimal management of this group of patients remains uncertain, ranging from involved field radiotherapy in localized disease to single agents

From the 1Hematology Oncology Department, Istituto Clinico Humanitas, Rozzano, Milano, Italy; 2Hematology Division 2, Ospedale San Martino, Genoa, Italy; 3HSCT Unit, Hematology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; 4Hematology Oncology Department, Bone Marrow Unit, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; and 5Statistic Unit, Istituto Clinico Humanitas, Rozzano, Milano Italy. Financial disclosure: See Acknowledgments on page 437. Correspondence and reprint requests to: Luca Castagna, M.D., Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano (Milano), Italy (e-mail: [email protected]). Received September 4, 2008; accepted December 22, 2008 Ó2009 American Society for Blood and Marrow Transplantation 1083-8791/09/154-0001$36.00/0 doi:10.1016/j.bbmt.2008.12.506

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used sequentially or multidrug chemotherapy and even a second high-dose procedure, supported by autologous or allogeneic hematopoietic cells [7-9]. Agents such as vinblastine, gemcitabine, and vinorelbine, are active in relapsed or refractory HL, but these therapies are unlikely to be curative [10-12]. Second HDC with autologous support is rarely considered in these patients, and should be reserved to patients with remission; better results are obtained when the remission lasts longer than 12 months after the HDC [13]. Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) seems to offer longterm survival to approximately 15% of patients, but it is associated with a high treatment-related mortality (TRM) rate ranging from 30% to 65% [14,15]. Allogeneic stem cell transplantation with a reduced-intensity conditioning regimen (ALLO-RIC) is less toxic than conventional allogeneic transplantation, and is considered the most challenging approach in this patient subset. The European Blood and Marrow Transplant (EBMT) group retrospectively reported on 52 poorprognosis HL patients showing a 2-year OS and PFS of 56% and 42%, respectively, and an acceptably low nonrelapse mortality (NMR) [16]. Other papers reported on the feasibility of allogeneic SCT with RIC [17,18]. However, in each of these studies only patients receiving the transplantation were analyzed, and information on the general population of relapsed or progressed HL patients was lacking.

Biol Blood Marrow Transplant 15:432-438, 2009

In this study, we evaluated all patients relapsing/ progressing after HDC in our institute for which a systematic search for an allogeneic donor was started at that time, and we compared them with those patients who did not undergo transplantation. PATIENTS AND METHODS Between January 1999 and May 2006, 49 consecutive patients with poor-prognosis HL were analyzed. Three patients considered too ill to receive any kind of treatment were excluded and 46 were reviewed for this analysis. Inclusion criteria were as follows: 1. patients refractory to second-line salvage IGEV regimen [19]. For this cohort of patients, an autoallo sequence was planned. 2. patients relapsing or progressing after HDC with autologous stem cell support program. According to the policy at our institute during different periods, patients received a single HDC procedure or tandem HDC [20]. For all these patients, the first step was to find an HLA-identical family donor. In the absence of an HLA-identical sibling, the second step was to search for a match unrelated donor (MUD). If MUD was not found either, the third step was to search for a nonidentical family donor. Some of these patients have been previously described [21]. Conditioning regimens and graft-versus-host disease (GVHD) prophylaxis were heterogeneous. Briefly, HLA-identical transplants were conditioned with 2 combinations of fludarabine and cyclophosphamide (Flu/Cy): a 5-day scheme (Flu/Cy-1, Flu 25 mg/m2/ day 5 days and Cy 60 mg/kg/day 2 days) and a 3day scheme (Flu/Cy-2, Flu 30 mg/m2/day 3 days and Cy 300 mg/m2/day 3 days) when the patient had received an HDC course \2 months previously. In the cohort of patients included in the auto-allo sequence, the ‘‘auto phase’’ consisted of melphalan 200 mg/m2 followed by autologous stem cell support, and the ‘‘allo phase’’ consisted of the Flu/Cy-2 conditioning regimen. GVHD prophylaxis consisted of cyclosporine (CsA 3 mg/kg/day), starting from day 21 associated or not with micromethotrexate (uMTX10 mg/m2 on day 11 and 8 mg/m2 on days 13, 16, 111). MUD transplants were conditioned with melphalan (Mel) 30 mg/m2 on day –8, campath-1H 20 mg/ day 4 days (from day 28 to day 25), Flu 30 mg/ m2/day 3 days (from day 24 to day 22) and totalbody irradiation (TBI) 200 cGy single dose on day 21. GVHD prophylaxis consisted of CsA 3 mg/kg/ day plus mycophenolate mofetil (MMF 30 mg/kg/day). Haploidentical transplants (3-loci mismatched donor) were conditioned with: thiotepa 10 mg/kg (day –8), Flu 40 mg/m2/days 4 days (from day –7 to –4), and ATG Fresenius 5 mg/kg/day (from –7 to –3)

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and PAM 140 mg/m2 (day –3) [22]. For these patients, GVHD prophylaxis consisted of ex vivo T cell depletion (CD34-positive selection with the Miltenyi system). Donors were mobilized with subcutaneous lenogastrim 10 to 16 mg/kg/day divided every 12 hours from day –4 to leukapheresis. The peripheral stem cells were harvested using a Cobe Spectra (Denver, CO) 3000 device on day 0. The target stem cell dose was fixed at least to 2 106/kg of recipient, for HLA-identical sibling and unrelated donors. The Seattle score [23] were used to evaluate acute GVHD (aGVHD): patients with Glucksberg grade II–IV were treated with methylprednisolone 2 mg// kg/day. The response was evaluated after 5 days and, in the case of a complete remission, the steroid dose was tapered by 0.3 mg/kg per week. Chronic GVHD (cGVHD) was classified as extensive or localized according to the revised Seattle classification [24]. Patients with extensive cGVHD received the Seattle alternate scheme [25] or CsA 12 mg/kg orally daily and MMF 30 mg/kg orally in 3 divided daily doses. Patients with localized, but symptomatic cGVHD were also treated with systemic therapy. Patients with no donor were managed with radiotherapy and/or conventional chemotherapy according to their previous treatment and disease extent. The response was evaluated using the International Working Group criteria [26]. Complete remission (CR) was defined as a total disappearance of previous sites of disease for at least 4 weeks; partial remission (PR) as a reduction of at least 50% in the product of major diameter, without the appearance of new lesions for at least 4 weeks; stable disease (SD) as no change in the lesions, and progressive disease (PD) as an increase of at least 25% of previous lesions. Patients with CR and PR before allogeneic transplantation were considered to have chemosensitive disease, whereas patients with SD or PD were considered to have chemoresistant disease. Statistical Analysis OS was defined as the time from date of failure of first HDC to death from any cause or to date of last follow-up. Survival curves were generated using the Kaplan-Meier method, and differences between groups in the univariate analysis were assessed using the log-rank test. For the ALLO group, PFS was calculated from the date of failure of first HDC to progression or death for HL, or to last visit date in the case of no events. A value of P \ .05 was considered to be the limit of statistical significance. RESULTS Patient characteristics at the time of inclusion are shown in Table 1, with no statistical difference

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Table 1. Patient Characteristics at Inclusion

No. of patients Sex Male Female Median age (range) Previous radiotherapy Yes No Previous HDC Single course Double HDC Stage at inclusion I-II III-IV Bulky disease Yes No B-symptoms Yes No Disease status before Allo* CR PR PD SD Donor type HLA-identical sibling HLA-mismatched sibling Haploidentical relative MUD Median follow-up (range)

ALLO Group N (%)

CHEMO Group N (%)

26

20

13 (50) 13 (50) 20 (18-44)

15 (75) 5 (25) 29 (19-43)

17 (65) 9 (35)

12 (60) 8 (40)

15 (58) 11 (42)

14 (70) 6 (30)

8 (31) 18 (69)

6 (30) 14 (70)

2 (8) 24 (92)

4 (20) 16 (80)

2 (8) 24 (92)

2 (10) 18 (90)

5 (21) 7 (29) 5 (21) 7 (29) 14 (54) 2 (8) 4 (15) 6 (23) 30 months (5-110)

23 months (1-87)

MUD indicates matched unrelated donor; CR, complete remission; PR, partial remission; allo, allogeneic transplantation; PD, progressive disease; SD, stable disease; HDC, high-dose chemotherapy. *Two patients with donor did not receive allogeneic transplantation.

between the 2 groups. The allocation to different treatments, based on donor availability, is illustrated in Figure 1. Twenty-six of 46 patients (56%) had a donor. Of these patients, 31% (8 of 26) were included in an ‘‘auto-allo’’ program, and 69% (18 of 26) relapsed or progressed after HDC. In 20 patients (44%) it was not possible to find a donor, and they received several chemotherapy regimens and/or radiotherapy. For patients treated after HDC, the median time to treatment failure (TTF) after HDC was 5 months (range: 1-30). Twenty-four patients out of 26 (92%) with a donor received allogeneic transplantation. All patients received debulking treatment before allogeneic transplantation. Two patients with a donor did not receive allogeneic transplantation because of disease refractory to several chemotherapies and poor performance status. Eight patients (30%) were treated within an auto-allo program; 3 patients (12%) with progressive disease after a first HDC course received a second noncrossreactive HDC; 13 patients (58%) received different salvage chemotherapies. Disease status at the time of allogeneic transplantation (n 5 24) was as follows: 29% (n 5 7) were in PR, 21% (n 5 5) in

CR, 21% (n 5 5) had PD, and 29% (n 5 7) had SD. Overall, 79% of patients with active disease were transplanted. Twenty patients with no donor available were treated with several regimens (Table 2). Two patients (10%) received a second noncrossreactive HDC, 25% (n 5 5) received 1 line of chemotherapy, 60% (n 5 12) received .2 lines, and 1 patient received involved field radiotherapy. After these therapies, 25% (n 5 5) were in CR and 75% (n 5 15) progressed. Survival After a median follow-up of 28 months (range: 1110), the median OS for all patients was 27 months (Figure 2). In the intention-to-treat analysis, the median OS was 31 months for the ALLO group, and this did not reach statistical significance compared to patients not receiving allogeneic stem cell transplantation, where OS reached 22 months (P 5 .056). The 2year OS was 65% and 50%, in the ALLO group and CHEMO group, respectively. When the OS was calculated including patients receiving ALLO (n 5 44), there was a statistically significant difference (31 months versus 22 months, P 5.031, HR in ALLO group versus CHEMO group 5 0.45 (confidence interval [CI] 95%: 0.21; 0.95) (Figure 3). The 2-year OS was 71% and 50%, respectively. No difference was found on analyzing the OS in the ALLO group between patients with chemosensitive and those with chemoresistant disease (P 5 .610) or according to the duration of response after the HDC (.12 months versus \12 months (P 5 .174). For the ALLO group, the median PFS was 14 months, the 2-year PFS was 41% (Figure 4). Survival was analyzed separately for patients included in the ‘‘auto-allo’’ program, because in this cohort, allogeneic transplantation was applied early based on no response to second-line chemotherapy. The 2-year OS and PFS were 75% and 50%, respectively, and thus not significantly different from the whole cohort. All but 1 patient who relapsed after allogeneic transplantation (n 5 12) were retreated. The only patient not treated was considered too ill. Five patients received donor lymphocyte infusions (DLIs); the median number was 2 reinfusions (range: 1-8) and the median CD31 cell dose was 108/kg (range: 107-108/kg). All but 1 patient progressed, and 1 obtained a PR. After DLIs, 2 patients developed extensive cGVHD. Multiagent regimens were administered to 6 patients and radiotherapy to 9 patients. Overall, 31% (4 of 13) were alive, but only 1 without disease. The median OS for these patients was 15 months. At last follow-up, 12 patients (50%) who received allogeneic stem cell transplantation were alive: 9 (37%) without and 3 with disease (Table 3). On the



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Patients n=46

Donor identified n=26

Donor not found n=20

Not done for poor PS n=2

Mismatched sibling n=14 Mismatched related n=2

Haploidentical n=4

MUD n=4

Figure 1. Allocation to different treatments based on donor availability.

other hand, 4 patients (20%) in the CHEMO group were alive without disease. HL was the only cause of death in the CHEMO group. ALLO Toxicity The median number of CD341 cells infused was 6.6 106/kg (range: 2.1-16). All patients engrafted and the median time to reach an absolute neutrophil count (ANC) .0.5 109/dL and 1.0 was 12 days (range: 0-42) and 14 days (range: 0-56), respectively. The median time to platelet recovery .20 109/dL and 50 109/dL was 1 day (range: 0-33) and 11 days (range: 0-42), respectively. All evaluable patients (22 of 24) showed full donor chimerism between 100 and 120 days after transplantation. Nine patients developed pneumonia, 6 of them \100 days after transplantation. The pneumonia was associated with a viral infection (cytomegalovirus [CMV] and HHV-6 plus adenovirus) in 2 patients and Pneumocystis jirovecii in 1 patient. Others infective complications were: sepsis (3), clostridium infection (1), dermatomeric herpes zoster (1), urinary tract infection with stenotrophomonas (1). CMV infection was detected in 3 patients and 1 patient developed Epstein-Barr virus (EBV)-related lymphoproliferative lung disease. aGVHD occurred in 36% of evaluable patients (8 of 22). In all but 1 patient, aGVHD was grade I-II, and 6 of them were treated with steroids. Two patients Table 2. Status at Last Follow-up

No. of Patients Status Alive Dead HL TRM Unknown Disease status ED NED

ALLO Group N (%)

CHEMO Group N (%)

24

20

12 (50) 12 (50) 10 (42) 2 (8) 0 (0)

4 (20) 16 (80) 15 (94) 0 (0) 1 (6)

3 (12) 9 (38)

0 (0) 4 (20)

HL indicates Hodgkin’s lymphoma; TRM, treatment-related mortality; ED, evidence disease; NED, non evidence disease.

developed grade IV aGVHD after DLI was performed for immunologic reconstitution and progressive disease. GVHD was fatal in 1 patient. Twenty-one patients were evaluable for cGVHD, and 48% (10 of 21) of them developed this complication; it was limited in 3 and extensive in 7. The nonrelapse-related mortality (NRM) was 4% at 100 days and 8% at 1 year. The causes of death were pneumonia and post-DLI aGVHD.

DISCUSSION HL progression following HDC and autologous PBSC-T is not uncommon, and the prognosis of patients is poor. In these patients, there is no defined strategy, and often in the past, the general approach consisted only in palliative care, with a reported survival of around 10 months [9,27]. Only a few data are Table 3. Conventional Therapies in Patienst without Donor Pts

Chemotherapies

ZM BC PB ZP SP GT MP BF BL ZC AP LD CS LE LC AR SS PG SP SG

RT, Chlorambucil, VBM, VNR + GEM RT, Vinblastine ESHAP DHAP, Chlorambucil Chlorambucil, ChlVPP, DHAP ChlVPP ChlVPP ChlVPP, GEM DHAP, ChlVPP, VBM MOPP, VNR, IGEV, Chlorambucil DHAP CAELYX, GEM, Vinblastine RT HDC, GEM ChlVPP ChlVPP, CTX+VP16, GEM IGEV, DHAP DHAP, ABVD, ChlVPP GEMCITABINE + VNR, Rituximab ESHAP, HDC

ChlVPP indicates Chlorambucil, Vinblastine, Procarbazine Prednisone; VBM, Vinblastine, Bleomicina, Methotrexate; DHAP, cisplatin, cytosine arabinoside, dexamethasone; IGEV, ifosfamide, gemcitabine, vinorelbine, prednisolone; VNR, vinorelbine; GEM, gemcitabine; HDC, high-dose chemotherapy; ESHAP, Etoposide, cytosine arabinoside, cisplatin, prednisone; MOPP, mechloretamine, vincristine, procarbazine, prednisone; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; pts, patients.

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Figure 2. OS for all patients (n 5 46).

Figure 4. PFS for patients receiving Allo (n 5 24).

available on second-line HDC with autologous PBSC and no firm conclusions are possible [13,28]. Myeloablative allogeneic transplantation in HL has historically been restricted by the high NRM, even if a graft-versus-HL reaction has been suggested [14,15]. Because of this, myeloablative allogeneic transplantation did not show any survival advantage over other therapies for these patients. Recently, the EBMT group reported that allogeneic transplantation with RIC is significantly less toxic than myeloablative transplantation (1-year NRM 23% versus 46%), with better OS (28% versus 22%). However, the relapse rate, particularly after TBI-based RIC, was higher in the RIC group [29]. More recently, the use of RIC before allogeneic stem cell transplantation to reduce the NRM and allow detection of a graft-versus-lymphoma effect has received renewed interest in this setting [17,30-32]. In

all these studies, RIC was feasible in patients relapsing after HDC, with NRM ranging from 16% to 35% and a 2-to 3-year OS and PFS ranging from 32% to 64% and 11% to 55%, respectively. The largest study published from the EBMT data on 374 patients showed that the 2-year OS and PFS were 40% and 29%, respectively. However, the results reported in the literature are evaluated only for patients receiving allogeneic transplantation, whereas no data are available for patients relapsing after HDC not treated with allogeneic transplantation. Recently, in a case-controlled study of 38 patients receiving an alemtuzumab-based ALLORIC were compared with 34 historic patients who relapsed after HDC and were treated conventionally. The 5-year OS was statistically higher for ALLORIC patients than for the control group (48% versus 15%), and the 5-year PFS in the ALLO group was 42%. This study suggests that allogeneic transplantation should be strongly considered in poor-prognosis HL patients [33]. In the present study, we analyzed the data on 46 consecutive poor-risk HL patients followed in our institution and candidates for allogeneic transplantation. Inclusion criteria were failure of HDC and not CR after the first salvage chemotherapy. This second group of patients was considered to have a poor prognosis [34]. At time of inclusion, a search for an HLA-identical sibling was started for all patients, and if none was available, a donor search was launched in a matched unrelated registry. Finally, when an HLA identical donor was not found, the availability of a nonidentical family donor was explored. Consequently, we were able to compare 2 groups of patients on the basis of donor availability. After a median follow-up of 28 months, the OS was significantly better in the ALLO group of patients who received allogeneic transplantation

Figure 3. OS for patients receiving ALLO (dotted line) versus other treatments (solid line) (n 5 44).


(n 5 24) (71% versus 50%, P 5 .031). When the analysis of OS was calculated in an intention-to-treat analysis, the significativity was slightly lower. At last follow-up, more patients in the ALLO group were alive compared to conventionally treated patients (50% versus 20%). The 1-year NRM in the ALLO group was low at only 8%. These results are in line with those previously reported, and confirm that allogeneic transplantation can cure a proportion of patients failing HDC. However, they clearly confirm that to reserve this treatment to the late phase of the disease when HDC has failed could jeopardize its full therapeutic potential. One of the most important prognostic factors predictive of survival after ALLORIC is the disease status before transplantation [16,29,35]. In fact, the widespread use of [18-F]-fluorodeoxyglucose-positron emission tomography (FDGPET) allows this response to be defined more accurately, and, consequently, for patients with different prognosis to be distinguished [36,37]. In the present cohort, 8 patients were treated because they were not in complete remission after second-line chemotherapy, and the survival was not different compared to the whole population. However, more patients should be treated to allow definitive conclusions. Another point of discussion is how much the conditioning regimen should be reduced in patients with HL. In this study, conditioning regimens were quite heterogeneous, and no firm conclusions can be drawn. However, more ‘‘intensive’’ conditioning regimens (mainly Mel based) seemed to reduce the relapse rate compared to less intensive low-dose TBI-based RIC [29,38]. Furthermore, it has been suggested that when alemtuzumab was added to RIC, the 4-year OS and PFS were significantly better (62% versus 39% and 39% versus 25%, respectively) compared to antibody free RIC [35]. These results were associated with a lower NRM after alemtuzumab-based RIC (7% versus 29%, respectively) and with a more durable response after DLI. The results of this study should be interpreted with caution because of several limitations such as the small cohort of patients analyzed, the heterogeneity of the conditioning regimens and immunosuppressive schemes, the short follow-up, and the nonrandomized nature. On the other hand, all patients with inclusion criteria were ‘‘enrolled’’ in this study, thus providing a denominator. In conclusion, the majority of poor-prognosis HL patients treated with a ‘‘conventional’’ approach have a poor clinical course after failure of HDC. Allogeneic transplantation seems to prolong the survival of HL patients who have relapsed and are refractory after HDC. ALLO-RIC should probably be performed at an early phase of the disease, that is, in patients who are PET-positive after salvage chemotherapy, possibly preceded by a debulking phase with HDC.


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ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose.

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