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Allogeneic stem cell transplantation for patients with relapsed or refractory T-cell lymphoma: efficacy of lymphoma-directed conditioning against advanced disease

Subjects

Abstract

Salvage chemotherapy induces disease remissions in patients with relapsed or refractory (r/r) T-cell lymphomas, but fails to provide lasting tumor control. We analyzed the outcome after peripheral blood stem and bone marrow transplantation (PBSCT, n = 80; BMT, n = 4) from matched related (MRD, n = 22) or matched and unmatched unrelated donors (MUD and MMD, n = 53 and n = 9, respectively) following conditioning with fludarabine, busulfan, and cyclophosphamide (FBC) for 84 consecutive patients with r/r T-cell malignancies. At start of conditioning LDH was elevated in 50% of cases, and residual tumor (PD, SD, PR) was detectable in 84% of patients. In total, 38% (95% CI 33–44) of the patients were alive and disease-free after a median observation time of 14.5 (range 1.8 to 114) months. Univariate and multivariate analyses identified low ECOG status, as well as occurrence of acute GvHD as favorable factors for outcome. Lymphoma-directed conditioning with fludarabin, busulfan and cyclophosphamid (FBC-12), and allogeneic stem cell transplantation resulted in long-term survival for a proportion of patients with r/r peripheral T-cell lymphoma, including those with PR and SD only after salvage therapy.

Introduction

Polychemotherapy with CHOP is the preferred regimen for patients with peripheral T-cell lymphoma (PTCL), yet provides long-term remission for only one third of all patients [1, 2]. Dose escalation and autologous SCT are pursued to increase disease control in primary therapy [3,4,5,6], but for patients with progressive or relapsed disease chemotherapy approaches do not procure long-term disease control. Allogeneic bone marrow or stem cell transplantation had been offered to patients with relapsed/refractory T-cell lymphomas [7, 8], but it has not gained broad attention due to the rarity of the disease as well as the treatment related mortality associated with myeloablative protocols. Improved supportive measures and the introduction of reduced-intensity conditioning (RIC) protocols prompted the re-evaluation [9,10,11,12,13]. Patients with rapidly progressive disease, however, are underrepresented in the published transplant series so far and outcomes after RIC seem far from satisfactory. In an effort to meet also the need of patients with poorly responsive disease we set off to treat aggressive lymphoma patients with a specifically designed salvage and transplantation protocol, integrating a conditioning regimen of strong cytostatic intensity, FBC12, and transplantation early after salvage treatment [14,15,16]. Encouraged by significant efficacy of this approach against aggressive B-cell lymphoma, here we report our experience in 84 patients with relapsed or refractory T-cell lymphoma.

Patients and methods

This study included data from all consecutive patients who received an allogeneic stem cell transplantation from August 2003 through April 2013 for relapsed or refractory T-cell lymphoma of all aggressive histological subtypes at four DSHNHL centers. Institutional review board approvals for the retrospective analyses were obtained in accordance with the principles of the Declaration of Helsinki. Eighty-four patients received the lymphoma-directed myeloablative conditioning regimen FBC-12, which contains intravenous fludarabine 25 mg/m2 per day from day –8 to day –4 before transplantation; busulfan orally 4 mg/kg per day or intravenously 3.2 mg/kg per day from day –6 to day –4; and intravenous cyclophosphamide 60 mg/kg per day on day –3 and day –2. Prophylaxis against graft-versus-host disease started on day –1 and consisted of tacrolimus (8–12 μg/L) and mycophenolate mofetil (1 g twice a day until day 28). Additional antithymocyte globulin was applied in 32 of 84 patients for unrelated or mismatched transplants, i.e., either 10 mg/kg ATG-Fresenius S (Fresenius Biotech, Grafelfing, Germany) or 2.0 mg/kg Thymoglobuline (Genzyme Europe, Naarden, Netherlands) from day –3 to day -1. Recipients and related or unrelated donors were typed at HLA-loci A, B, C, DR, and DQ, and a match of at least 7/8 loci at HLA A, B, DR, and DQ was considered eligible for transplantation. Fifteen patients of this cohort participated in the DSHNHL R3 trial, where patients had been randomized to receive rituximab post transplantation in an attempt to prevent graft-versus-host disease [16]. Medical histories and presentations, biologic characteristics, histologic subtypes, disease status before allogeneic stem cell transplantation, and outcome parameters were reported by local investigators from the four participating centers. Acute and chronic GvHD were evaluated and scored according to international standards [17]. For outcome analysis, cases of acute GvHD were categorized into groups of overall grades 0 and I–IV, and cases of cGvHD into absent, mild, moderate and severe, respectively [18]. Response and outcome parameters were applied according to international criteria.

Overall survival (OS) was defined as the time from stem cell infusion to death from any cause, and progression-free survival (PFS) as the time from stem cell infusion to relapse, disease progression, or death from any cause. Mortality post transplantation was classified in non-overlapping categories as associated with relapse or non-relapse. The probabilities for OS and PFS were calculated according to the Kaplan–Meier methods, with comparisons according to the variables indicated. Variables represented in several categories were tested by log-rank test. The variables assessed for prognostic significance were histopathologic subtype, gender, age < > median of 50 years, the IPI score before transplantation, elevated LDH (yes vs. no), ECOG status (0,1 vs. > 1), number of EN-manifestation ( 0,1 vs. > 1), the number of therapy lines before allogeneic SCT ( ≤ 2 treatment lines, > 2 treatment lines), disease status at transplantation (PD versus CR, PR, SD), source of stem cells (bone marrow versus peripheral blood, donor type (MRD vs. MUD, MMD), acute GvHD (grades 0 to 1–4), chronic GVHD, interval from diagnosis and allogeneic SCT ( < 12 months vs. > 12 months), autologous SCT before allogeneic SCT (yes vs. no). Variables with p-values below 0.05 by univariate testing were included in the multivariate analysis. Assumptions for proportional hazards were calculated for all factors. The indicated statistical tests were performed using STATISTICA version 10 for Windows and IBM SPSS Statistic 21 (www.statsoft.de/pro_version.html; www-01.ibm.com/software/analytics/spss/).

Results

Patient characteristics

Eighty-four consecutive patients with all histological T-cell lymphoma subtypes eligible for allogeneic transplantation were included. PTCL NOS, AITL, and ALCL (ALK negative: 4, ALK positive: 1, ALK status not known: 10) accounted for the major histological groups (Table 1). Patients with NK/T-cell lymphoma nasal type, T-lymphoblastic lymphoma und T-prolymphocytic leukemia were listed as distinct groups, whereas the group “other” comprised four patients with panniculitis-like T-cell lymphoma (PLTCL), one patient with dendritic progenitor cell leukemia, two patients with systemic T-cell lymphoma secondary to cutaneous T-cell lymphoma. All adult age groups were represented with a predominance of male patients in all subgroups (Table 1). Twenty-two patients experienced progressive disease (PD) and 62 patients had responded with disease stabilization (SD) or remission (CR, PR) to the last salvage treatment at start of conditioning. Half of all patients presented with elevated LDH values, and a median IPI of 2 (Table 1). All patients had experienced relapse or primary progression of the T-cell lymphoma, and 19 patients had received prior autologous stem cell transplantation within a median of three prior chemotherapy regimens (range 1–7, Table 1). High-dose chemotherapy and autologous stem cell transplantation had been applied previously as part of salvage treatment in 9 cases, and in 10 cases as consolidation treatment, which was not considered standard at that time. For patients with ALCL, Brentuximab Vedotin was not yet available at the time period under observation.

Table 1 Patients characteristic according to histological type

Following the recommendation of the German High Grade Lymphoma Study Group (DSHNHL), the combination of FBC12 had been given as conditioning treatment to all patients. Stem cell grafts had not been manipulated, and had been obtained from sibling and unrelated donors in 22 and 62 cases, respectively. GvHD prophylaxis consisted of tacrolimus/mycophenolat mofetil through day 28, with additional antithymocyte globulin (ATG) in 32 patients (Table 1).

Outcome and pre-transplantation factors

Kaplan–Meier estimates for OS and disease-free survival were 38.2% (95% CI 33–44) and 37.2% (95% CI 32–43), respectively, at a median follow-up of 14.5 months (1.5–114 months). Noteworthy, no death from disease relapse occurred after month 11, compatible with cure from the disease (Fig. 1).

Fig. 1
figure1

Survival of patients with relapsed/refactory T-cell lymphomas following allogeneic stem cell transplantation. Kaplan–Meier estimates of overall survival (OS, bold line) and progression-free survival (PFS, dashed line) following allogeneic stem cell transplantation for all patients

Analyzing factors relevant for transplantation outcome, we found congruent results for OS and PFS. Histological subtype or gender, or patient age at transplantation did not separate subgroups of patients with different OS (Supplementary Fig. 1). Factors associated with disease activity significantly impacted on OS. Pre-transplantation IPI > 3 separated a subgroup of patients with very poor survival (Fig. 2 Chi2-test; p = 0.0285; Table 2 univariate log-rank test IPI 0, 1, 2 versus IPI 3,4 p = 0.01210). Elevated serum LDH and ECOG status, but not stage or extranodal disease ≥ 2, determined overall survival (Fig. 3a–d; Table 2). Similarly, particularly patients with progressive disease experienced a dismal outcome compared to patients with SD, PR, or CR response to salvage chemotherapy (Fig. 4, log-rank test; p = 0.0866). In addition, more than two lines of chemotherapy before transplantation, i.e., more than primary treatment and one salvage regimen, a time interval from diagnosis to transplantation < 1 year and the status of prior high-dose therapy with autologous transplantation had no impact (Table 2). In 71 patients, data on remission status at day 100 post transplantation were available, documenting CR, PR, SD, and PD in 45, 7, 2, and 17 patients, respectively. Compared with the remission status before transplant (Table 1), the increase in patients with CR and PR indicate a considerable short-term cytostatic effect of the FBC-12 regimen. Thus, those pre-transplant factors indicating disease activity, i.e., elevated LDH and clinical progression by imaging, indicators for resistance to cytostatic therapy and the ECOG status were relevant factors for survival after allogeneic stem cell transplantation of T-cell lymphoma.

Fig. 2
figure2

Overall survival stratified to International Prognostic Index. Kaplan–Meier estimates of overall survival (OS) in all patients with relapsed/refractory T-cell lymphomas stratified according to international prognostic index (IPI) before transplantation (log-rank test; p = 0.02852). No patient with IPI 5 received allogeneic stem cell transplantation

Table 2 Univariate and multivariate analysis of OS
Fig. 3
figure3

Overall survival stratified according to single IPI factors. Kaplan–Meier estimates of overall survival (OS) stratified according to (a) serum LDH (log-rank test p = 0.0188), (b) ECOG status 0/1 versus > 1 (log-rank test, p = 0.0160) before transplantation, (c) Ann–Arbor stage at transplantation (log-rank test, p = 0.498), and (d) extend of extranodal disease (log-rank test, p = 0.402). n.s. not significant

Fig. 4
figure4

Overall survival stratified according to disease status at transplantation. Kaplan–Meier estimates of overall survival (OS) with relapsed/refractory T-cell lymphomas stratified according to the response to last salvage therapy (log-rank test; p = 0.00866)

GvL, GvHD, and TRM

Patients had received peripheral blood stem cell (n = 80) and bone marrow grafts (n = 4) from related (n = 22; 26%), matched unrelated (n = 53; 63%), and mismatched unrelated (n = 9; 11%) donors, with ATG given to 7, 24, and 1 of the MRD, MUD and MMD transplant recipients, respectively. Donor type or the use of ATG did not separate patient subgroups with significantly different outcome (Fig. 5 a, b). Furthermore, we found a significant better OS for patients experiencing aGvHD, with an improvement for patients with overall aGvHD grades 1–4 (Fig. 5c; Table 2, univariate log-rank test aGvHD 0 versus aGvHD 1–4 p = 0.0035). For cGvHD, we found no survival differences for patients experiencing extensive cGvHD versus those with no or limited cGvHD (Fig. 5d, p = 0.7241).

Fig. 5
figure5

Overall survival stratified according to donor source, use of ATG and GvHD. a Stratification according to transplantation with grafts of matched related donors (MRD), and matched unrelated donors (MUD) or mismatched unrelated donors (mMUD) (log-rank test; p = 0.500). b Stratification according to grafts from MRD and MUD with use of ATG versus MUD without use of ATG and MMD with and without use of ATG (log-rank test; p = 0.076). c Stratification according to aGvHD, separated in no aGvHD versus aGvHD grade 1–4 (log-rank test, p = 0.0035). d Stratification according to cGvHD manifestations, separated in no/limited, versus extensive disease (n = 56, log-rank test; p = 0.724)

Non-relapse mortality occurred in 35 patients of this cohort, resulting in estimates for one, three and five years NRM of 13.1%, 32.3%, and 46%, respectively (Fig. 6). In 15 of these 35 cases, GvHD was present at the time of death. As a composite parameter for GvHD-/relapse-free survival (GRFS), the estimate for GRFS [19] at one year was 50.9% (CI 45.4%–56.4%).

Fig. 6
figure6

Cumulative incidence of non-relapse mortality. Estimates of cumulative incidence for non-relapse mortality after allogeneic stem cell transplantation for all patients amounting to 36.7% at 1 year, and 49.1% at 3 and at 5 years of observation

Sixteen patients experienced disease relapse after transplantation. In order to trigger graft versus lymphoma (GvL) activity, withdrawal of immunosuppression (WI) and donor lymphocyte infusions (DLI) were initiated in 10 and 6 cases, respectively. These procedures led to complete remission in three patients (one each PTCL secondary to CTCL, 1 PTCL NOS, 1 ALCL) and PR in one patient (PTCL NOS). In the remaining six patients, the responses to WI/DLI were PD (4 PTCL NOS, 1 ALCL, 1 DPCL). Of the patients with CR after WI/DLI, remissions were longlasting in two patients (1 PTCL NOS, 1 ALCL), while one patient died in CR by complications of GvHD. Thus, both acute and chronic GvL appeared to contribute to disease control, albeit with the risk for GvHD.

Multivariate analysis

By univariate analysis, the IPI (IPI 3 and 4 versus 0–2), elevated LDH, ECOG status (0,1 versus > 1) and the remission status (PD vs. CR, PR, SD) were associated with a significantly inferior outcome, while the occurrence of aGvHD was associated with an improved outcome (Table 2). Multivariate analysis, confirmed the low ECOG status as well as occurrence of aGvHD as independent favorable prognostic factors.

Discussion

In this retrospective analysis allogeneic stem cell transplantation provided disease remission for an estimate of 38% at 3 years for patients with relapsed or progressive T-cell malignancies, an otherwise dismal situation [20]. Death from disease recurrence occurred no later than 11 months after transplantation, and long-term survival was observed only in those patients who remained free of disease (Fig. 1). These observations differ from high-dose chemotherapy approaches followed by autologous stem cell support, where relapse would continuously occur over time and a plateau of progression-free survival is rarely observed [21,22,23,24]. Also in this series, PFS was associated with both acute GvHD (Table 2, Fig. 5C), and immunomodulatory manipulations induced remissions at relapse after allogeneic transplantation. Taken together, these observations demonstrate a significant contribution of graft versus lymphoma effect to the disease control of T-cell lymphoma. As such, these data are in line with previous retrospective and prospective data from other studies, which reported long-term disease control for T-cell lymphoma patients receiving allogeneic stem cell transplantation [10, 11, 25]. In these studies, the proportions of patients with active lymphoma disease at transplantation, quantified as patients in SD or PD, ranged between 25% and 40%. Different from these studies, however, half of the patients in our cohort featured attributes of advanced disease, such as elevated LDH levels in 50%, as well as stable disease and progressive disease in 16% and 26% of cases, respectively (Table 1). The combination of fludarabine, busulfan at 12 mg/kg body weight and 120 mg/kg cyclophosphamide (FBC12) has already shown significant efficacy in advanced aggressive lymphoma, both of B- and T-cell origin [15, 16]. Due to its robust cytostatic efficacy, this regimen induces a tumor mass reduction sufficient to open a time window, in which the immune response against the lymphoma cells arises. Thus survival was achieved also in patients with lymphomas progressive or only stable disease after last salvage treatment (Fig. 4). This finding supports the concept that rather than seeking an optimal response by pre-transplantation salvage regimens, fast planning of allogeneic transplantation and integrating a major cytostatic component into the conditioning protocol appear relevant for best lymphoma control.

Intensive conditioning yet came at the prize of considerable non-relapse cumulative mortality, with estimates of 36% (CI 25–46%) at 1 year and 49% (CI 35–60%) at 5 years after transplantation (Fig. 6). These figures correspond to the data of previous reports, which also reported TRM rates of 30–40% when applying intensive conditioning regimens [7, 8, 11]. Noteworthy, in a series of patients treated with reduced-intensity regimens, such as fludarabine, thiotepa (10 mg/kg bw), and cyclophosphamide (30 mg/kg bw), TRM was considerably lower at 12%, albeit with a high relapse mortality of 49% [9, 25]. Very similarly, Jacobsen et al. described an inverse association of conditioning intensity and relapse rate [13].

With the intention of exploiting a strong graft-versus-lymphoma effect by lean prophylactic immunosuppression, the use of ATG had been optional in our patient cohort. We found, that the use of ATG did not alter the overall incidence of aGvHD, which occurred in 26 of 52 patients without ATG and 16 of 32 patients with ATG. However, ATG reduced the occurrence of severe grade 3 and 4 aGvHD from 5 in 52 patients without ATG to 1 in 32 patients with ATG. At the same time the occurrence of aGvHD was associated with improved OS (Fig. 5c), suggesting that further modifications of GvHD prophylaxis e.g., dose modifications of ATG or novel agents, might offer the chance for further improvements of the FBC-12 regimen [16, 26].

We analyzed both patient characteristics and therapeutic parameters for their effects on treatment outcome. While histological subtype of T-NHL, age, gender, and extranodal manifestations > 2 had no impact, prior high-dose chemotherapy with autologous stem cell transplantation, increasing IPI, elevated LDH, ECOG above 1 and remission status before transplantation were each associated with lower OS by univariate analysis (Figs. 2, 3, Table 2). The role of salvage treatment in relapsed or refractory T-cell lymphoma before stem cell transplantation is poorly defined [27]. However, agents or combinations with higher efficacy should improve both the proportion of patients reaching transplantation, and the chances of successful remission consolidation by the transplantation.

In conclusion, allogeneic stem cell transplantation is a curative option for a significant proportion of patients with T-cell lymphoma. FBC12 serves as an efficient conditioning regimen even in advanced stages of disease. Further improvements may arise from more efficient salvage treatment prior to transplant, increased control of GvHD, and potentially allogeneic stem cell transplantation earlier in the course of the disease.

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Author contributions

Conception and design: GW, BG, NS, LT. Collection and assembly of data: GW, BG, GH, CW. Patient care: all coauthors. Data analysis and interpretation: GW, BG, NS, LT. Paper writing: GW, BG, NS, LT, MP. Final approval of paper: all coauthors.

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Correspondence to Gerald Wulf.

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Wulf, G., Hasenkamp, J., Jung, W. et al. Allogeneic stem cell transplantation for patients with relapsed or refractory T-cell lymphoma: efficacy of lymphoma-directed conditioning against advanced disease. Bone Marrow Transplant 54, 877–884 (2019). https://doi.org/10.1038/s41409-018-0360-9

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