Short Communication Received: January 7, 2015 Accepted after revision: February 18, 2015 Published online: April 15, 2015

Oncology DOI: 10.1159/000381101

Allogeneic Hematopoietic Stem Cell Transplantation in Mantle Cell Lymphoma: A Retrospective Analysis of 7 Patients Wolfgang Lamm a Philipp Wohlfarth b Marija Bojic b Christian Schörgenhofer b Peter Kalhs b Markus Raderer a Werner Rabitsch b   

 

 

 

 

Clinical Division of Oncology, and b Bone Marrow Transplant Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria  

 

Key Words Mantle cell lymphoma · Relapse · Allogeneic hematopoietic stem cell transplantation · Outcome

Abstract Mantle cell lymphoma (MCL) is a B cell non-Hodgkin’s lymphoma characterized by a poor prognosis. Many different therapeutic approaches including intensive chemotherapy as well as new targeted therapies are established. However, overall survival remains unsatisfying. As the sole curative option, allogeneic hematopoietic stem cell transplantation (HSCT) has been described, but only a limited number of patients qualify for this procedure. We have retrospectively analyzed 7 patients with stage IV MCL undergoing allogeneic HSCT at our institution. A myeloablative regimen was used in 1 patient, while the other 6 patients received reduced-intensity conditioning. Four patients had an HLAidentical sibling, and the remaining 3 patients had an HLAidentical unrelated donor. One patient developed acute graft-versus-host disease (skin, grade III; intestine, grade II). Two patients died from transplant-related causes, 3 patients died due to progressive disease and the remaining 2 patients are still in complete remission 147 and 8 months after transplantation. Allogeneic HSCT offers a therapeutic treat-

© 2015 S. Karger AG, Basel 0030–2414/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/ocl

ment option for selected patients in a relapsed/refractory setting. The incorporation of novel agents has improved the outcome of patients with MCL. Thus, the role and optimal time point of allogeneic HSCT should be reevaluated in randomized trials. © 2015 S. Karger AG, Basel

Introduction

Mantle cell lymphoma (MCL) is a subtype of B cell non-Hodgkin’s lymphoma (NHL), accounting for approximately 6% of all NHL. Most patients are presenting with stage IV disease at a median age of around 60 years at diagnosis [1]. Approximately 5% of the patients suffer from blastic variant MCL, which is more aggressive when compared to common type MCL [2]. The most common chromosomal translocation is the t(11;14)(q13;q32), resulting in an overexpression of cyclin D1 [3]. The MCL International Prognostic Index (MIPI) combines age, performance status, lactate dehydrogenase and leukocyte count and separates patients with MCL into three distinct risk groups (low, intermediate and high risk) in terms of overall survival (OS) with poor outcome for patients with high-risk disease [4]. Prof. Werner Rabitsch, Bone Marrow Transplant Unit Department of Medicine I, Medical University of Vienna Waehringer Guertel 18–20 AT–1090 Vienna (Austria) E-Mail werner.rabitsch @ meduniwien.ac.at

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a

 

 

IVB

Patients and Methods Patients In this study, we retrospectively analyzed 7 male patients with MCL who received allogeneic HSCT at the Medical University of Vienna between 1999 and 2014. The median age at the time of allogeneic transplantation was 59 years (range: 43–66). All patients had relapsed/refractory disease and were rated as stage IV. A detailed list of prior chemotherapies is outlined in table 1. Sites involved with MCL immediately before allogeneic HSCT were lymph nodes and bone marrow in all patients (100%). Mean bone marrow infiltration was 30% (range: 20–90) at the time of diagnosis. According to the MIPI prognostic index, 3 patients (43%) had low- and intermediate-risk disease, whereas 1 patient (14%) had high-risk disease. The most commonly used initial therapy consisted of CHOP (57%) followed by CEOP (cyclophosphamide, epirubicin, vincristine and prednisone; 29%) without R at that time. Five out of 7 patients (71%) had received prior autologous HSCT. The median number of therapies before allogeneic HSCT was 3 (range: 2–4). Three patients had a partial remission (PR), 3 patients had stable disease and 1 patient had a complete

Lamm/Wohlfarth/Bojic/Schörgenhofer/ Kalhs/Raderer/Rabitsch

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Oncology DOI: 10.1159/000381101

ASCT = Autologous SCT; SIB = sibling; Flud30 = fludarabine 30 mg/kg BW; Cyclo60 = cyclophosphamide 60 mg/kg BW; SD = stable disease; MMF = mycophenolate mofetil; MTX = methotrexate; CMV = cytomegalovirus; ICE = ifosfamide, carboplatin, etoposide; R-BENDA = rituximab, bendamustine; BORID = bortezomib, rituximab, dexamethasone; m = months; N.A. = not available.

8 alive yes (skin) CR donor no CSA/MMF Flud30/TBI2Gy RIC URD

CR

1 dead PD no N.A. no CSA/MMF FC SIB

intermediate 3 risk low risk 2 IVA

R-BENDA, yes R-CHOP R-CHOP, BORID, yes R-ICE R-CHOP/ yes R-DHAP, R-BAC 2 high risk IVB

male/ 66 male/ 66 male/ 47

IVA

RIC

FC SIB

SD

18 dead CR no donor no CSA/MMF

4 dead yes PD (intestine) donor CMV CSA/MTX Cyclo60/ TBI13.2Gy CEOP, ICE

no

URD

Myeloab- SD lative regimen RIC PR

38 dead PR no donor no CSA/MMF Flud30/TBI2Gy RIC

intermediate 2 risk intermediate 2 risk IVA

CHOP, ICE

low risk IVA

2

no

SIB

SD

147 alive CR no donor no CSA/MMF Flud30/TBI2Gy RIC yes

SIB

PR

2 dead PR no N.A. sepsis CSA/MMF PR Flud30/TBI2Gy RIC URD yes

CHOP, VACPE, FC Radiation, CHOP low risk IVA

male/ 47 male/ 59 male/ 62 male/ 43

3

Response Status PFS, m Infection Chimerism GvHD (site) CondiStatus Immunotioning prior to suppression intensity allogeneic SCT Auto Donor Conditioning ASCT allogeneic SCT Prior Kind of prior thera- therapy pies, n Stage MIPI Sex/ Age, years

Table 1. Patient characteristics

2

Conventional chemotherapy in combination with the CD20 antibody rituximab (R) has shown a clinical benefit but did not result in a clearly improved OS [5]. However, maintenance therapy with R has become standard in elderly patients due to the demonstration of a prolonged PFS in patients responding to R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy [6]. High-dose chemotherapy including Ara-C followed by autologous SCT in the frontline setting has improved the outcome for young patients with MCL in terms of survival when compared to conventional chemotherapy schedules [7, 8]. In patients in the relapsed setting, the prognosis remains poor. The incorporation of novel agents in the treatment of MCL, including the proteasome inhibitor bortezomib [9], immunomodulatory drugs, thalidomide and lenalidomide [10, 11] as well as bendamustine [12] and ibrutinib [13], have shown activity in MCL patients. Allogeneic hematopoietic stem cell transplantation (HSCT) in patients with MCL has been evaluated since the 1990s, but only in small series [14, 15]. As this procedure is highly dependent on age, disease status and comorbidities [16], only some retrospective data exist from patients with MCL, with 3 and 5 year OS rates between 37 and 66% [17–22]. In view of these limited data, we have performed a retrospective analysis on the efficacy and tolerance of allogeneic HSCT in pretreated patients with MCL who were treated at our department.

Conditioning Regimens and Graft-versus-Host Disease Prophylaxis Myeloablative conditioning performed in 1 patient consisted of intravenous (i.v.) cyclophosphamide (FC) at 60 mg/kg body weight (BW) for 2 days and fractionated total body irradiation [TBI; 13.2 Gy (gray) for URD]. Reduced-intensity conditioning (RIC) consisted of fludarabine with 2 Gy TBI (n = 4) and FC in 2 patients. Graft-versus-host disease (GvHD) was rated by a biopsy of the skin, gut and liver and clinically graded as 0 to IV for acute GvHD and as ‘non’, ‘limited’ or ‘extensive’ for chronic GvHD [23, 24]. For GvHD prophylaxis, the patients received cyclosporine A (CSA; target plasma level: 150–200 ng/ml) and methotrexate (15 mg/m2, day +1, 10 mg/m2, days +3, +6 and +11) according to the Seattle protocol [25] in case of myeloablative conditioning therapy and CSA and mycophenolate mofetil (15 mg/kg BW 3 times a day for patients with URD and 15 mg/kg BW 2 times a day in patients with a related donor) until complete donor cell chimerism was established [26] in case of RIC. Engraftment In all patients, peripheral blood and reticulocyte counts were determined on a daily basis, starting 7 days before SCT until hematopoietic engraftment. Absolute neutrophil counts were calculated from leucocyte and differential counts. Engraftment was defined as an absolute neutrophil count of at least 0.5 g/l for at least 3 days, platelet (PLT) counts of at least 20 g/l and independence from red blood cell transfusions. Chimerism analyses were performed serially on unseparated peripheral blood, CD3+ and CD33+ subsets on days 28, 56, 84 and 180 and then every 6 months in patients receiving RIC. Supportive Care All patients received red cell concentrations to maintain a hemoglobin level of >8.0 g/dl. PLT concentrates were administered to keep the PLT count >10 g/l. In case of severe infection or mucositis, cytomegalovirus-negative PLT concentrates were transfused to maintain PLT counts >20 g/l [27]. All blood products were irradiated with 30 Gy. Approved informed consent was obtained from all patients. All patients were hospitalized in isolation rooms with laminar air flow or reverse isolation and received Pneumocystis carinii prophylaxis with cotrimoxazole and acyclovir for cytomegalovirus prophylaxis according to established guidelines [28].

Results

Engraftment In all but 2 patients, successful engraftment was documented. The remaining 2 patients died due to TRM 1 month after allogeneic HSCT. The median time to neutrophil recovery for the other 5 patients was 10 days (range: 8–12), and the median time to PLT recovery was 10 days (range: 1–14). Outcome and Survival Following allogeneic HSCT, 2 patients achieved PR and 3 patients achieved CR, with an objective response rate (ORR) of 71%. Two out of these 3 patients who achieved CR are still alive after allogeneic HSCT and are in continuous CR 147 and 8 months after allogeneic HSCT. These 2 patients have a Karnofsky performance status of 100% and have no late toxicity due to allogeneic HSCT. The third patient died 9 months after allogeneic HSCT due to relapse and rapidly progressing MCL. One of the 2 patients who achieved a PR after allogeneic HSCT died due to TRM (sepsis: n = 1) within 1 month after allogeneic HSCT, and the other progressed 22 months after allogeneic HSCT and died due to progressive disease (PD). Two patients did not respond to allogeneic HSCT. One died due to TRM within 1 month of allogeneic HSCT (PD: n = 1), and the other died 4 months after allogeneic HSCT due to disease progression. The rate of TRM in our 7 patients was 29% (2/7). The remaining 2 patients had PD and received further chemotherapy with R and bortezomib. However, they died due to progressive MCL 22 and 4 months after allogeneic HSCT. Two out of the 7 patients (29%) developed acute GvHD (intestine: n = 1; skin: n = 1). Median PFS for all 7 patients was 9.2 months (95% CI: 0–20.9; fig. 1a), and median OS was 17.9 months (95% CI: 0–45.6; fig. 1b).

Discussion

Statistical Analysis OS was calculated from the day of allogeneic HSCT until death from any cause. Patients who were alive or lost to follow-up were censored. Disease-free survival was calculated from the day of allogeneic HSCT until relapse. The probabilities were estimated using the Kaplan Meier method. The software package SPSS 17.0 (SPSS Inc., 1999) was used for these statistical analyses. Transplant-related mortality (TRM) was defined as mortality after allogeneic HSCT not related to relapse. p values

Allogeneic Hematopoietic Stem Cell Transplantation in Mantle Cell Lymphoma: A Retrospective Analysis of 7 Patients.

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma characterized by a poor prognosis. Many different therapeutic approaches including inten...
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