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Management of Relapses After Hematopoietic Cell Transplantation in T-Cell Non-Hodgkin Lymphomas

Seminars in Hematology, 1, 51, pages 73 - 86

T-cell non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies that represent 10%–15% of all NHLs. The prognosis of relapsed T-cell NHL is poor, especially for those relapsing after an autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT). Disease relapse post auto-HCT is best managed on a clinical trial. In the absence of an investigational protocol, the choice of salvage therapies should take into account patient performance status, eligibility for an allo-HCT, and surface CD30 expression. CD30-directed therapies or aggressive salvage regimens can be used as a bridge to allo-HCT in medically fit patients. In the elderly or more infirm patients, single-agent therapies could be offered, aiming at palliation. Similarly, relapse after an allo-HCT is not uncommon and is a real challenge. Reduction in ongoing immune suppression or donor lymphocyte infusion are often considered in this setting to augment graft-versus-lymphoma (GVL) effects and can occasionally provide durable disease control. Clinical trials designed to investigate novel therapeutic agents with immunomodulatory properties to augment GVL effects (eg, histone deacetylase [HDAC] inhibitors, proteasome inhibitor, lenalidomide) or targeted therapies (eg, aurora A kinase inhibitors, anaplastic lymphoma kinase [ALK] inhibitors) are sorely needed to improve the dismal outcomes of T-cell NHL relapsing after an allo-HCT.

T-cell non-Hodgkin lymphomas (NHLs) represent approximately 10%–15% of all NHLs in the Western countries. 1 The most common histological types include nodal peripheral T-cell lymphoma (PTCL), systemic anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma.1 and 2 The disease course in T-cell lymphomas is characterized by frequent relapses, and eventual development of refractory disease. 3 The prognosis of relapsed T-cell NHL is poor. In a recent study, the median overall survival (OS) and progression-free survival (PFS) of relapsed T-cell NHL were 5.5 and 3.1 months, respectively, and were only marginally better in patients who received chemotherapy at relapse (6.5 and 3.7 months, respectively). 4 Owing to the dismal outcomes of relapsed T-cell NHL when managed with conventional chemotherapy alone, several investigators have evaluated the role of autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT) as part of the initial therapy or at the time of progression (reviewed elsewhere in the current issue of Seminars in Hematology). Unfortunately, disease relapse following HCT remains problematic, with no prospective data available to guide therapy for post-transplant relapses. Reviewed here are management options for T-cell lymphomas relapsing after either an auto- or allo-HCT. For the purposes of this review, the available therapeutic agents are arbitrarily divided into options following relapse from either an auto-HCT or an allo-HCT. While such an assignment is partly based on available data, potential biological rationale, or (at times) authors’ opinions, it is important to emphasize that the agents discussed in the post allo-HCT relapse setting could be (and often are) used in the post auto-HCT setting and vice versa. Due to the relative paucity of data regarding HCT in cutaneous T-cell lymphomas (CTCLs), readers are referred to focused reviews on novel therapeutic agents for relapsed CTCL in the current issue of Seminars.

Patients at high-risk of relapse after HCT

Defining factors predicting a higher relapse risk is critical for improving HCT outcomes of T-cell NHL. Reliable identification of such “at risk” patients can potentially lead to development of personalized post-transplant maintenance and/or consolidation strategies or more vigilant surveillance in order to identify relapses early, where immune modulation or targeted therapies might have a better probability of providing disease control. Several large retrospective studies and smaller phase II trials have reported outcomes of auto- or allo-HCT for relapsed/refractory T-cell NHL. The heterogeneity of these reports in terms of the broad spectrum of histologies included and transplant procedures employed, makes reliable identification of factors associated with risk of relapse difficult. Nevertheless, it appears that the risk of disease relapse post HCT thematically follows the familiar trend for most malignancies where the patient’s performance status, depth of disease response, and tumor chemosensitivity plays a key role ( Table 1 ). Patients with a poor performance status,5, 6, 7, 8, and 9 high International Prognostic Index,10, 11, 12, 13, and 14 and those not in complete remission (CR)6, 11, and 15 or ones with refractory disease6, 15, and 16 appear to have a higher risk of relapse. The presence of acute or chronic graft-versus-host disease (GVHD) has also been shown to be associated with a lower probability of relapse following allo-HCT.5 and 7

Table 1 Factors Predicting a Higher Risk of Relapse Following Hematopoietic Cell Transplantation

First Author (year) No. of Patients (histology) Transplant Type Conditioning Regimen Risk Factors Predicting Relapse Risk
Rodríguez (2007) 10 123 (T-cell NHL) Autologous-HCT BEAM, BEAC or CY/TBI High IPI and β2-microglobulin associated with greater risk of progression
Mercadal (2008) 13 45 (T-cell NHL) Autologous-HCT BEAM or BEAC High IPI score associated with inferior outcomes
Reimer (2009) 11 83 (T-cell NHL) Autologous-HCT CY/TBI Patients not in complete remission and those with high PIT score had inferior outcomes
Yang (2009) 12 64 (T-cell NHL) Autologous-HCT - High IPI, PIT score, and LDH associated with greater risk of progression
Nademanee (2011) 14 67 (T-cell NHL) Autologous-HCT TBI-based or BEAM High PIT score associated with higher risk of relapse
d'Amore (2012) 9 160 (T-cell NHL) Autologous-HCT BEAM or BEAC Advanced age, bone marrow involvement, poor performance status and non-ALCL histology associated with greater risk of progression
Le Gouille (2008) 6 77 (all subtypes) Allogeneic-HCT RIC = 20 Refractory disease associated with higher risk of relapse
      MA = 57  
Kyriakou (2009) 5 45 (AITL) Allogeneic-HCT RIC = 25 Chronic GVHD associated with reduced risk of relapse
      MA = 20  
Dodero (2012) 16 52 (PTCL) Allogeneic-HCT RIC = 52 Refractory disease and >2 lines of prior therapy associated with higher risk of relapse
Kanakry (2013) 7 44 (T-cell NHL) Allogeneic-HCT RIC = 24 Acute and chronic GVHD associated with reduced risk of relapse
      MA = 20  

Abbreviations: ALCL, anaplastic large T-cell lymphoma; ATLL, adult T-cell leukemia/lymphoma; AITL, angioimmunoblastic T-cell lymphoma; BEAC, carmustine, etoposide, cytarabine, cyclophosphamide; BEAM, carmustine, etoposide, cytarabine, melphalan; CY/TBI, cyclophosphamide/total body irradiation; HCT , hematopoietic cell transplantation; IPI, International Prognostic Index; MA, myeloablative conditioning; PIT, Prognostic Index for PTCL; PTCL, peripheral T-cell lymphoma; RIC, reduced-intensity conditioning.

Manangement of Relapse After Autologous Transplantation

Treatment of relapsed T-cell NHL after an auto-HCT poses a real therapeutic challenge. In this setting, salvage chemotherapy or immunotherapy, is often offered as a bridging strategy to an allo-HCT. Unfortunately, only a minority of these patients are eligible for an allograft due to various reasons including the presence of resistant disease, unavailability of a suitable donor, and suboptimal performance status or organ impairment, among others. In this section we discuss therapies with potential to bridge patients to an allo-HCT or providing disease control in a noncurative setting. It is important to emphasize that randomized data in this setting are lacking and evidence is mainly based on uncontrolled single-arm studies or small case series. The role of a second auto-HCT is unknown in T-cell lymphoma and not recommended outside the setting of a clinical trial.

Targeted Therapies

Brentuximab Vedotin

Brentuximab vedotin (Adcetris, Seattle Genetics, Bothell, WA) is a CD30 antibody conjugated to a potent antimicrotubule agent, monomethylauristatin E. In the United States, it is approved for the treatment of Hodgkin lymphoma after failing an auto-HCT and for relapsed/refractory ALCL. 17 In a recent phase II study of patients (n = 58) with relapsed or refractory ALCL (anaplastic lymphoma kinase [ALK] negative = 72%), brentuximab showed an impressive overall response rate (ORR) of 86% (57% CR) 18 ( Table 2 ). Brentuximab was administered at a dose of 1.8 mg/kg intravenously every 3 weeks for up to 16 doses. The study included 15 (26%) patients who received a prior auto-HCT. However, the authors did not describe outcomes pertinent to this specific subgroup. The median duration of response was 13.2 months for six subjects who received a subsequent allo-HCT. These findings, and reports by others19 and 20 support the use of brentuximab in patients with ALCL (and potentially other CD30+ T-cell lymphomas) who are being considered for an allo-HCT after a failed autograft.

Table 2 Targeted Therapies in Relapsed/Refractory T-Cell NHL After Autologous Transplantation

First Author Targeted Therapy Antibody Dose/Schedule N1 N2 Histology Response Survival (median)
Pro 18 Brentuximab Vedotin 1.8 mg/kg every 3 wk (up to 16 doses) 58 15 ALCL ORR = 86% * PFS = 13.3 mo
            CR = 57% * OS = not reached
            DoR = 12.6 mo *  
Gibb 19 Brentuximab Vedotin 1.8 mg/kg capped at 100 kg every 3 wk 24 8 HL = 18 ORR = 88% PFS = 5.1 mo *
          ALCL = 5 CR = 25%  
          CD30+ T-cell NHL = 1    
Dang 21 Denileukin diftitox 18 µg/kg/d ×5 d every 3 wk 27 1 T-cell NHL ORR = 48 * PFS = 6 mo
            CR = 22% *  
Enblad 22 Alemtuzumab 30 mg, 3 times/wk x 12 wk 14 - T-cell NHL ORR = 36% Median duration of response was 6 mo
            CR = 21%  
Weidman 24 Alemtuzumab + FCD 10 mg on day 1, and 30 mg on d 2–3 of each cycle 11 0 T-cell NHL ORR = 55% PFS = 2.5 mo
              OS = 6.1 mo
Kim 23 Alemtuzumab + DHAP 70 mg or 40 mg/cycle divided over 3 d 24 0 T-cell NHL ORR = 50% OS = 6 mo
            CR = 21%  
Ishida 27 KW-0761 1.0 mg/kg/wk x 8 wk 28 - ATLL ORR = 50% * PFS = 5.2 mo
            CR = 31% * OS 13.7 = mo

lowast All treated subjects.

Responses for previously autografted patients only.

Abbreviations: N1, Total number of patients; N2, number of patients who had a prior autologous transplant; ORR, overall response rate; CR, complete remission; DoR, median duration of objective response; PFS, progression–free survival; OS, overall survival; HL, Hodgkin lymphoma; ATLL, adult T-cell leukemia/lymphoma; ALCL, anaplastic large cell lymphoma; T-cell NHL, T-cell non-Hodgkin lymphoma; AILT, angioimmunoblastic T-cell lymphoma; DHAP, dexamethasone, cytarabine, cisplatin; FCD, fludarabine, cyclophosphamide, doxorubicin (Campath-FCD).

Denileukin Diftitox

Denileukin diftitox (Ontak, Eisai, Ridgefield Park, NJ) is a CD25-directed cytotoxin indicated for treatment of persistent or recurrent CD25+ CTCL. It represents a genetically engineered recombinant DNA fusion protein that combines the enzymatically active A and B fragments of diphtheria toxin with the sequence of interleukin-2. Dang et al reported results of a multicenter phase II study in 27 subjects with relapsed/refractory T cell NHL, who had previously received more than two lines of therapies, showing an ORR of 48%. 21 Unfortunately, only one patient in this study had received a prior auto-HCT, limiting our ability to determine the efficacy of this agent in this particular setting ( Table 2 ). Serious side effects have been described with denileukin diftitox, including fatal infusion reactions, capillary leak syndrome, and loss of visual acuity and color vision among others. The role of denileukin diftitox as a bridge to allo-HCT for CD25-expressing T-cell NHL relapsing after an autograft warrants investigation.

Alemtuzumab

Alemtuzumab (Campath, Genzyme, Cambridge, NJ) is an anti-CD52 monoclonal antibody approved for the treatment of relapsed chronic lymphocytic leukemia (CLL). In a pilot study of 14 patients with relapsed T-cell NHL, alemtuzumab showed single-agent activity with an ORR of 36% 22 ( Table 2 ). Major adverse events included opportunistic infections, viral reactivations, and hematologic toxicity. In the relapsed/refractory setting, alemtuzumab has also been combined with multi-agent chemotherapy regimens in a handful of small prospective studies ( Table 2 ). The ORRs are generally modest (~30%–50%) and the remissions do not appear to be durable.23 and 24 Given that only 30%–40% of PTCLs express CD52,25 and 26 it is not known if restricting alemtuzumab to CD52+ T-cell lymphomas would provide more durable remissions. The ongoing randomized ACT-1 trial ( www.clinicaltrials.gov ; NCT00646854) is comparing chemotherapy alone with alemtuzumab plus chemotherapy in patients with PTCL. Given the frequency of infectious complication and modest efficacy data, alemtuzumab should be not be used outside of a clinical trial in T-cell lymphomas.

KW-0761

CC chemokine receptor 4 (CCR4) is expressed by tumor cells in adult T-cell leukemia/lymphoma (ATLL) and has emerged as a potential target for therapy. KW-0761 (mogamulizumab) is a new humanized anti-CCR4 monoclonal antibody with a defucosylated Fc region that enhances antibody-dependent cellular cytotoxicity. Ishida et al 27 recently reported a multicenter phase II study in 28 ATLL patients, who had failed at least one previous chemotherapy regimen. ORR was 50%, including eight CRs ( Table 2 ). This targeted therapy warrants further investigation in ATLL and other T-cell lymphomas.

Conventional Single-Agent Chemotherapy

Gemcitabine

Single-agent gemcitabine (Gemzar, Eli Lilly, Indianapolis, IN) is active in relapsed T-cell lymphomas. 28 In a single-institution phase II study, 39 patients with relapsed/refractory PTCL (n = 20) or CTCL (n = 19) received gemcitabine 1,200 mg/m2 on days 1, 8, and 15 of a 28-day cycle. 28 ORR in PTCL patients was 55% (30% CR). Five of six PTCL cases remained in continuous CR at a median of 34 months (range, 5–60), suggesting that sustainable responses are possible. Single-agent gemcitabine is an attractive therapy option for T-cell NHL patients who are unfit for allo-HCT (especially those lacking surface CD30 expression). Gemcitabine-based combinations are also feasible as discussed below.

Pralatrexate

Pralatrexate (Folotyn, Allos Therapeutics, Westminster, UK) is a folate analog metabolic inhibitor currently approved for the treatment of relapsed or refractory PTCL. The landmark PROPEL study evaluated the efficacy of pralatrexate (30 mg/m2/wk for 6 weeks followed by 1 week of rest) in 111 relapsed/refractory PTCL patients, with a median age of 58 years. 29 Vitamin B12 1,000 µg intramuscularly every 8–10 weeks and folic acid 1–1.25 mg/d were required to be administered alongside pralatrexate. Treatment was continued until evidence of disease progression, development of unacceptable toxicity, or physician discretion. Eighteen (16%) patients had received a prior auto-HCT, and six (33%) demonstrated an objective response to pralatrexate. 29 The median duration of response was 10.1 months in all responders. Severe mucositis was common (any grade = 71%, grade III–IV = 22%). Pralatrexate demonstrates efficacy in relapsed/refractory T-cell NHL, but the durability of responses in previously autografted subjects is not known. Nonetheless, it represents a reasonable option for T-cell NHL relapsing after an auto-HCT. In the elderly or infirm patients, a lower-dose pralatrexate regimen (15 mg/m2, 3 weeks on/1 week off) is active (ORR = 45%) and better tolerated. 30

Pixantrone

A novel aza-anthracenedione, pixantrone dimaleate has demonstrated improved efficacy (CR 20% v 5.7%; P = .021) in patients with relapsed/refractory aggressive NHLs when compared with other chemotherapeutic agents in a recently published phase III trial. 31 Unfortunately, only six (PTCL = 3, ALCL = 3) (8.6%) of 70 patients with T-cell lymphomas received pixantrone dimaleate, limiting our ability to determine the efficacy of this agent in this particular setting.

Combination Chemotherapy Regimens

Combination chemotherapy regimens are best reserved for medically fit, younger patients requiring effective cytoreduction before a potential allo-HCT.

Gemcitabine-Based Combinations

Gemcitabine has shown activity in combination with other antineoplastic agents. Arkenau et al reported a regimen combining gemcitabine (1,000 mg/m2 on days 1, 8, and 15), cisplatin (100 mg/m2 on day 15), and methylprednisolone (1000 mg/d for 5 days) in 16 patients with T-cell lymphomas. ORR was 69% (19% CR). 32 The median time to disease progression was 123 (range, 0–288) days and OS was 68.2%. The main grade 3/4 toxicities were hematologic (leucopenia = 62%). 32 The combination of gemcitabine (1,000 mg/m2 on day 1), oxaliplatin (100 mg/m2 on day 1), and dexamethasone (20 mg/d for 4 days) is also active in previously treated T-cell lymphomas (ORR = 38%, CR = 8%). 33 Gemcitabine-based chemotherapy regimens represent a reasonable option to cytoreduce patients before a planned allo-HCT. Prior reports of serious pulmonary toxicity with gemcitabine and CD30 antibody (SGN30) combination 34 will likely preclude prospective investigation of gemcitabine and brentuximab–containing regimens.

Other Combinations

The group in Princess Margaret Hospital recently reported a retrospective analysis of 40 patients, median age of 53 years, with relapsed/refractory PTCL. Most patients (>70%) were treated with DHAP (cisplatin, cytarabine, and dexamethasone) or ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) as salvage chemotherapy, 35 with an ORR of 62%. The proportion of patients who proceeded to receive an auto-HCT was 55%. This study demonstrates activity of DHAP or ESHAP in relapse/refractory PRCL; however, its specific efficacy in the setting of post auto-HCT relapse remains to be determined. Several other chemotherapy combination regimens have been evaluated in the treatment of relapsed/refractory T-cell lymphomas. Mikesch et al retrospective compared DexaBEAM (dexamethasone, carmustine, etoposide, cytarabine, and melphalan) and ICE (ifosfamide, carboplatin, and etoposide) in relapsed/refractory PTCL. 36 The investigators reported higher ORR (69% v 20%), CR (38% v 7%), and PFS (6.4 v 2 months, P = .01) with DexaBEAM. However, treatment associated toxicities were also seen more frequently with DexaBEAM. 36 Several limitations ought to be taken into account when interpreting these results, including the retrospective nature of the analysis and the small sample size.

T-cell NHL relapsing after an auto-HCT is best managed on prospective clinical trial designed to assess the activity of novel agents (or combinations) in this high-risk patient population. In the absence of an investigational protocol, the choice of salvage regimen should take into account patient performance status, donor availability, suitability for an allo-HCT, and surface CD30 expression. Brentuximab is an attractive (and perhaps preferred) option for CD30-expressing T-cell NHL, particularly for ALCL. Combination chemotherapy regimens are best reserved for medically fit patients, as a bridge to an allo-HCT, while for the elderly or infirm patients single-agent chemo- or immunotherapy with a palliative intent or supportive/end-of-life care options should be kept in mind.

Management of Relapse After Allogeneic Transplantation

Allo-HCT is a potentially curative modality for relapse/refractory T-cell NHL; however, approximately 25%–35% of allografted patients ultimately relapse.5, 16, and 37 Management of relapsed T-cell NHL after allo-HCT is challenging for several reasons: first, a large proportion of these patients have a performance status unsuitable for aggressive salvage therapies, second; ongoing myelosuppression, delayed immune reconstitution, GVHD, and compromised organ function often coexistent in this population, magnifying the adverse events of therapies tolerated in other settings, and third; these patients are frequently excluded from available clinical trials. No prospective studies are available to guide therapy in this setting. In the following sections we discuss risk factors associated with post allo-HCT relapse, available strategies to augment graft-versus-lymphoma (GVL) effects and review novel therapeutic agents that either have immunomodulatory properties (to support their application in post allo-HCT setting) or an adverse event profile feasible for a frail post allo-HCT patient.

Immunosuppression Withdrawal and Donor Lymphocyte Infusions

Augmentation of GVL effects, either by tapering immune suppression (IS) or by the administration of donor lymphocyte infusion (DLI),38 and 39 can provide durable disease control in a subset of patients relapsing after allo-HCT. In the absence of active and severe GVHD, reduction or withdrawal of immunosuppressive medications (if present), is generally considered a first step in managing post allo-HCT relapses in hematologic malignancies, and has anecdotally shown sustained remissions in a handful of T-cell NHL patients ( Table 3 ).8 and 40 For patients who are not on IS at the time of disease relapse, and in those where tapering IS does not induce a potent GVL effect, DLIs (if available) could be explored and have shown efficacy in small case series ( Table 3 ).5, 6, 8, 16, 37, and 41 Dodero et al 16 administered DLIs to 12 T-cell NHL patients relapsing after allo-HCT. Eight patients responded, including five CRs. Median survival of patients achieving a CR following DLI was 5 years, with no subsequent relapse reported. Itonaga et al 8 performed DLIs in nine ATLL patients. Four patients achieved a CR, but only two survived disease-free long-term. While DLI appears feasible in relapsed T-cell NHL, no randomized data are available to guide whether it is best administered alone, or following cytoreductive (schemo- or radio-) therapies. The optimal CD3+ cell dose, product type (cryopreserved cells v fresh cytokine-stimulated cells v fresh unstimulated cells), and interval between DLI infusions are not well defined. Limitations of DLI include development of GVHD and requirements for previously cryopreserved cells or donor availability to procure a fresh leukapheresis product. For obvious reasons, DLI is not an option for post cord blood transplant relapses.

Table 3 Immune Suppression Withdrawal and Donor Lymphocyte Infusions for T-Cell Lymphomas Relapsing After Allogeneic Transplantation (studies with ≥2 patients)

First Author (year) Histology Total No. of Patients No. Intervened (IS withdrawal or DLI) Response to Intervention Duration of Response Comments
      Withdrawal of IS      
Hamadani (2008) 40 T-cell NHL 14 2 CR = 2
  • Retrospective
  • Authors stated prolonged response, but did not specify duration
Itonaga (2013) 8 ATLL 35 20 CR = 2 46+ mo
  • Retrospective
  • 8 developed GVHD
      DLI      
Corradini (2004) 41 T-cell NHL 17 3 CR = 1 17+ and 28+ mo
  • Retrospective
        PR = 1    
        NoR = 1    
Le Gouill (2008) 6 T-cell NHL 77 2 CR = 2 2+ yr
  • Retrospective
Kyriakou (2006) 5 AITL 45 2 CR = 2 14+ and 74+ mo
  • Retrospective
Dodero (2012) 16 T-cell NHL 52 12 CR = 5 All PR patients progressed
  • Retrospective
        PR = 3 All CR patients in remission at a median of 5 yr  
Itonaga (2013) 8 ATLL 35 9 CR = 4 2 alive in CR at 48+ and 69+ mo
  • Retrospective
  • 6 developed GVHD
  • 6 died due to progression
  • 1 died due to infections
        PR = 1    
        NoR = 3    

Abbreviations: ATLL, adult T-cell leukemia/lymphoma; AITL, angioimmunoblastic T-cell lymphoma; CR, complete remission; DLI, donor lymphocyte infusion; GVHD, graft-versus-host disease; IS, immune suppression; NHL, non-Hodgkin lymphoma; NoR, no response; PR, partial remission.

Recommendations

Acknowledging the lack of quality prospective data, withdrawal of post allo-HCT IS (if present) for relapsed T-cell NHL (in the absence of severe active GVHD) is a reasonable first step. In patients who are not on IS or where reducing IS is unsuccessful, consideration should be given to DLI. In patients with widespread, organ-threatening or bulky relapse, DLI is best administered after cytoreductive systemic therapies or involved-field radiation.

Aurora-A Kinase Inhibitor

Alisertib (MLN8237) is an oral investigational agent that inhibits Aurora A Ser/Thr kinase. It inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-lymphoma cell lines,42 and 43 supporting its role in PTCL. Preliminary results of a phase II clinical trial of alisertib in relapsed B- and T-cell NHL, showed encouraging signal of activity in PTCLs with 57% of patients responding ( Table 4 ). 44 Toxicities were mild and included leukopenia, fatigue, and diarrhea. Alisertib’s oral bioavailability, favorable toxicity profile, and efficacy make it an ideal investigational candidate for post allo-HCT maintenance or treatment of relapsed T-cell NHL. A phase III clinical trial comparing alisertib against investigator’s choice of chemotherapy is ongoing, but unfortunately excludes patients with a prior allo-HCT (NCT01482962).

Table 4 Agents With (potential) Activity in T-Cell NHL Relapsing After Allogeneic Transplant

First Author (year) Therapeutic Agent & Study Design Histology Total No. of Patients No. Post allo-HCT/allo-HCT Excluded? Response Rate Duration of Response
Friedberg (2011) 44 Alisertib T-cell NHL 8 0/Excluded ORR = 57% NR
  Phase II          
Damaj (2013) 55 Bendamustine T-cell NHL 60 NR/NoC ORR = 50% Median 3.5 mo
  Phase II       CR = 28%  
          PR = 22%  
Dueck (2010) 57 Lenalidomide T-cell NHL 24 3/Not excluded PR = 30% Median 96 d
  Phase II          
Uike (2012) 58 Lenalidomide T-cell NHL 13 NR/NoC PR = 31% Median 280 d
  Phase I          
Lee (2008) 69 Bortezomib + CHOP T-cell NHL 13 NR/NoC CR = 61.5% NR
  Phase I          
Evens (2011) 70 Bortezomib + gemcitabine T-cell NHL 16 NR/NoC ORR = 25% NR
  Phase I/II       CR = 19%  
Tan (2012) 49 Bortezomib + panobinostat T-cell NHL 11 NR/NoC ORR = 54.5% NR
  Phase II       CR = 18%  
Pohlman (2009) 50 Belinostat T-cell NHL 20 NR/NoC ORR = 25% Median 6 mo
  Phase II       CR = 10%  
          PR = 15%  
Piekarz (2011) 45 Romidepsin T-cell NHL 47 18 * /Not excluded ORR = 38% Median 8.9 mo
  Phase II       CR = 18%  
          PR = 20%  
Coiffier (2012) 48 Romidepsin T-cell NHL 130 0/Excluded ORR = 25% Median 17 mo
  Phase II       CR = 15%  

lowast Number includes patients undergoing autologous transplantation.

Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete remission; NHL, non-Hodgkin lymphoma; NR, not reported; NoC, not clear from the publication; ORR, overall response rate; PR, partial remission.

Histone Deacetylase Inhibitors

Histone deacetylase (HDAC) inhibitors are epigenetic therapies that induce acetylation of histones and other proteins, 45 resulting in antitumor activity due to increased tumor-suppressor gene transcription, growth inhibition, cell cycle regulation, and apoptosis.46 and 47 Romidepsin (Istodax, Celgene, Summit, NJ), a potent, bicyclic class 1 selective HDAC inhibitor, is approved for relapsed CTCL and PTCL. In the two published phase II studies romidepsin therapy in relapsed/refractory T-cell NHL showed promising activity (response rates = 25%–38%), with median duration of response ranging from 9–17 months.45 and 48 Common toxicities were nausea, fatigue, and transient cytopenias. Romidepsin and other HDAC inhibitors with activity in T-cell NHL are summarized in Table 4 .45, 48, 49, and 50 In addition to their activity in T-cell NHL, HDAC inhibitors have also been shown to prevent acute GVHD disease by reducing proinflammatory cytokines, modulating antigen-presenting cell function, and increasing regulatory T cells.51, 52, and 53 These data suggest the feasibility of administering HDAC inhibitors post allo-HCT. Since romidepsin is approved for relapsed T-cell NHL, it represents a reasonable therapeutic option for such patients relapsing after an allograft.

Bendamustine

Bendamustine (Treanda; Teva, Frazer, PA) a bifunctional alkylating agent approved for patients with CLL and indolent B-cell NHL, 54 has only partial cross-resistance to other alkylating agents. In a recently published phase II clinical trial, single-agent bendamustine showed promising activity ( Table 4 ) in relapsed/refractory PTCLs, with an encouraging safety profile. 55 While efficacy data for T-cell NHL relapsing after allo-HCT are not available, bendamustine’s single-agent activity in PTCL and favorable toxicity profile makes it an attractive agent to investigate in often frail patients relapsing after an allo-HCT, potentially as a cytoreductive therapy before a planned DLI.

Lenalidomide

Lenalidomide (Revlimid; Celgene, Summit, NJ) is an immunomodulatory agent with several potential mechanisms of action, including direct cytotoxicity, enhanced natural killer/T-cell function, and alternation of microenvironment. 56 In addition to its known activity in multiple myeloma (MM) and myelodysplastic syndrome (MDS), limited data also suggest that lenalidomide is active in T-cell NHL ( Table 4 ).57 and 58 The overall response rates with lenalidomide in the two published studies were approximately 30%,57 and 58 with thrombocytopenia being the most frequently encountered adverse event. Investigation of lenalidomide as an immunomodulatory agent in T-cell NHL relapsing after allo-HCT is particularly attractive, since administration of lenalidomide to MM, or MDS patients after allo-HCT has been shown to augment graft-versus-malignancy effects, supported by induction of GVHD and concurrent disease responses in several patients.59, 60, and 61 However, owing to the risks of inducing severe GVHD, lenalidomide administration to T-cell NHL relapsing following an allo-HCT should be limited to well-designed prospective trials.

Crizotinib

Crizotinib (Xalkori; Pfizer, Mission, KS) an oral inhibitor of ALK, is active in ALK-expressing non-small cell lung cancers. 62 Approximately 50% of ALCL patients are ALK-positive, 63 and potentially represent an area where the role of targeted therapy with crizotinib warrants investigation. This agent has shown dramatic activity in three cases of relapsed ALK-positive ALCL, with two patients achieving durable remissions.64 and 65 Several ongoing early-phase clinical trials are investigating the role crizotinib in relapsed/refractory ALK-positive ALCL (NCT00939770, NCT01606878, NCT01524926), including two studies that are also enrolling ALCL relapsing after an allo-HCT (NCT01606878, NCT01524926).

Bortezomib

Bortezomib (Velcade; Millennium, Cambridge, MA), a dipeptide boronic acid that selectively and potently inhibits the proteasome 26S complex, is approved for MM and mantle cell lymphoma. 66 It induces apoptosis in T-lymphoma cell lines, 67 and downregulates positive regulatory domain I–mediated chemoresistance in human T-NHL cells. 68 Bortezomib in combination with other therapeutic agents has shown activity (response rates ranging from 25%–60%) in relapsed/refractory T-cell NHL ( Table 4 ).49, 69, and 70 However, no studies focusing on role of bortezomib in T-cell NHL relapsing after allo-HCT are available. Bortezomib’s activity in T-cell NHL, and its recently shown efficacy in preventing acute GVHD, 71 warrant evaluating the role of bortezomib maintenance or consolidation after allo-HCT in T-cell lymphomas.

Other Options for Post Allo-HCT Relapse

A myriad of other therapeutic agents are in clinical trials for patients with relapsed T-cell NHL, including monoclonal antibodies (eg, siplizumab [anti-CD2], zanolimumab [anti-CD4], LMB-2 [anti-CD25]),72, 73, and 74 anti-angiogenic agents, 75 protein kinase C inhibitors (eg, enzastaurin), 76 mammalian target of rapamycin (mTOR) inhibitors, and novel nucleoside analogues (eg, nelarabine, clofarabine), 77 to name a few. However, exclusion of post allo-HCT patients in most of these studies unfortunately continues to limit access of allografted patients to these novel agents.

Limited retrospective studies suggest feasibility of second allo-HCT in select patients with hematologic malignancies. 78 T-cell NHL patients with good performance status and organ function, as well as an excellent response to salvage therapies can occasionally be considered for a second allo-HCT (from the previously used, or a different donor). At the same time, in patients with poor performance status, compromised organ function, or heavily pretreated refractory disease, the option of palliative/end-of-life care without further chemotherapeutic interventions should always be kept in mind. 79

Conclusions

Figure 1 and Figure 2 describe suggested algorithms for T-cell NHL relapsing after an auto- or allo-HCT respectively. While the routine use of peripheral blood grafts, growth factor administration, improved human leukocyte antigen (HLA)-typing techniques, and modern supportive measures have undoubtedly improved the safety of transplantation, disease relapse post HCT in T-cell NHL remains a challenge. This is an exciting time for developmental therapeutics in T-cell NHL, with several agents showing promising activity.45, 47, and 77 Moving forward, efforts ought to be focused on evaluating novel consolidation or maintenance strategies post auto- or allo-HCT, especially in patients at higher risk of relapse. Trials evaluating the role of maintenance with immunomodulatory agents (eg, lenalidomide; NCT01035463) post auto-HCT are ongoing. In the post allo-HCT relapse setting strategies to activate donor T-cells by administrating an anti-CTLA4 antibody, ipilimumab (Yervoy; Bristol-Myers Squibb, New York, NY) are being investigated (NCT01822509). An ongoing Southwest Oncology Group study (S1106) is evaluating role of alisertib in relapsed T-cell NHL. Rationally designed clinical trials employing novel agents against unique targets in malignant T cells or tumor microenvironment (eg, mTOR/AKT/PI3K pathways, ALK protein, surface antigen, etc), will be the key for improving the dismal outcomes of T-cell NHL relapsing after HCT.

gr1

Figure 1 Practical approach towards a T-cell lymphoma patient relapsing after an autologous transplant (auto-HCT).

gr2

Figure 2 Practical approach towards a T-cell lymphoma patient relapsing after an allogeneic transplant (allo-HCT). DLI = donor lymphocyte infusion; GVHD = graft-versus-host disease.

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Footnotes

a Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI

b Division of Hematology-Oncology, American University of Beirut Medical Center, Beirut, Lebanon

c Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR

d Hematology and Stem Cell Transplantation Section, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN

e Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute and University of South Florida College of Medicine, Tampa, FL

lowast Address correspondence to Mehdi Hamadani, MD, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226

Conflicts of interest: none.