Treatment of relapsed or refractory peripheral T cell lymphoma

INTRODUCTION — The peripheral T cell lymphomas (PTCL) are a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all non-Hodgkin lymphomas (NHLs) in adults. Among these, in decreasing frequency of occurrence, are:

●Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS)

●Anaplastic large cell lymphoma, primary systemic type (ALCL)

●Angioimmunoblastic T cell lymphoma (AITL)

●Extranodal NK/T cell lymphoma, nasal type

●Adult T cell leukemia-lymphoma

●Enteropathy associated T cell lymphoma

●Hepatosplenic T cell lymphoma

●Mycosis fungoides/Sézary syndrome

●Subcutaneous panniculitis-like T cell lymphoma

Treatment of relapsed or refractory PTCL will be reviewed here.

The clinical presentation, pathologic features, diagnosis, and prognosis of PTCLs and initial treatment of PTCL are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified" and "Initial treatment of peripheral T cell lymphoma".)

The following subtypes are discussed separately:

●Anaplastic large cell lymphoma (see "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)")

●Extranodal NK/T cell lymphoma, nasal type (see "Treatment of extranodal NK/T cell lymphoma, nasal type")

●Adult T cell leukemia-lymphoma (see "Treatment and prognosis of adult T cell leukemia-lymphoma")

●Enteropathy associated T cell lymphoma (see "Initial treatment of peripheral T cell lymphoma", section on 'Outcomes by PTCL subtype')

●Mycosis fungoides/Sézary syndrome (see "Treatment of advanced stage (IIB to IV) mycosis fungoides" and "Treatment of early stage (IA to IIA) mycosis fungoides")

EVALUATION OF SUSPECTED RESISTANCE OR RELAPSE — After initial therapy, patients are followed at routine intervals to monitor for treatment-related complications and progression. At these visits, patients are evaluated with a history, physical examination, blood work, and imaging studies. (See "Initial treatment of peripheral T cell lymphoma", section on 'Monitoring'.)

Progressive disease (PD) can present with systemic B symptoms (ie, fever, night sweats, weight loss), cytopenias, development of an extranodal mass, or as symptomatic or asymptomatic enlargement of the lymph nodes, liver, or spleen. By definition, PD reflects the appearance of any new lesion, an increase in previously identified lesion(s), or new/recurrent involvement of the bone marrow (table 1).

When relapse is suspected, we suggest a biopsy of the involved lymph node or mass to confirm relapse (eg, to exclude an inflammatory process) and evaluate for a potential change in histology (eg, development of a B cell lymphoma). Once relapse is confirmed, the patient should undergo a staging evaluation with a physical examination, and imaging studies (table 2). Bone marrow biopsy is not required unless otherwise clinically indicated (eg, unexplained cytopenias). (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

Refractory (resistant) disease is defined as those patients who fail to respond to initial treatment with at least a partial response (ie, at least 50 percent decrease in lesion size with no new lesions).

TREATMENT OF RELAPSED/REFRACTORY DISEASE

Overview — Most patients undergoing treatment for PTCL will either not achieve remission or will relapse. A meta-analysis reported 37 percent five-year overall survival (OS) among patients with PTCL treated with standard anthracycline-based chemotherapy [1]. There is a paucity of data regarding outcomes for patients treated for relapsed or refractory disease but, based on retrospective analyses and small prospective trials, long-term survival in the absence of hematopoietic cell transplantation (HCT) is generally poor [2-5]. As an example, a population-based study reported median OS and progression-free survival (PFS) of six and three months, respectively, among 153 adults with relapsed/refractory PTCL who did not undergo HCT [2].

Given that the optimal therapy for relapsed/refractory PTCL remains to be defined, we advocate participation in a clinical trial whenever possible. In the absence of an available clinical trial, we stratify patients by intent to proceed to HCT. For patients who are potential candidates for HCT, we favor salvage combination chemotherapy with the goal of achieving a response as a bridge to transplant. For patients who are not HCT candidates, we favor sequential single agents or newer agents.

As an important exception, we use brentuximab rather than traditional chemotherapy for patients with relapsed or refractory anaplastic large cell lymphoma (ALCL), even if the intent is to proceed to HCT. Palliation of symptoms is a reasonable goal for patients who fail to respond to second-line chemotherapy regimens or who relapse after transplant.

Chemotherapy — There is no standard therapy for patients with relapsed and refractory PTCL. As such, patients should be strongly encouraged to participate in a clinical trial. At present, no single chemotherapy regimen is clearly superior to others. Outside the context of a clinical trial, the selection of treatment should be based upon the goal of care, expected toxicities, patient comorbidities, and convenience.

For most patients with relapsed or refractory PTCL who are candidates for HCT, we treat with a traditional salvage combination chemotherapy regimen rather than a newer agent, because of higher response rates and the possibility of long-term survival following HCT in those who achieve a complete response (CR). However, we often treat with histone deacetylase inhibitors or other newer agents in the setting of primary refractory disease, early relapse (eg, within six months of initial therapy), subsequent relapses, or patients receiving treatment with non-curative intent. Patients with relapsed or refractory ALCL are treated with newer agents even if the intent is to proceed to transplant.

The largest case series investigating traditional chemotherapy regimens included 153 patients with relapsed or refractory PTCL, not otherwise specified (PTCL, NOS; 52 percent), angioimmunoblastic T cell lymphoma (AITL; 25 percent), and ALCL, primary systemic type (ALCL; 23 percent) treated at the British Columbia Cancer Agency from 1976 to 2010 [2]. Patients who underwent HCT were excluded. Management at first relapse consisted of combination or single agent chemotherapy (58 percent), supportive care alone (20 percent), irradiation (9 percent), corticosteroids (8 percent), and no treatment (4 percent). Median OS was 3.7 months for the group as a whole and 6.5 months for those who received chemotherapy. Rates of second PFS and OS at three years were 16 and 7 percent, respectively. Among the 78 patients treated after 2001, the median second PFS and OS after relapse were 4.6 and 6.7 months, respectively, and did not differ from the group as a whole. This experience confirms the poor prognosis of patients with relapsed or refractory PTCL. Since relapse is common and remissions are short, patients without significant comorbidities who have an available donor should proceed with HCT as soon as possible after attaining a response.

Traditional regimens — Patients who are transplant candidates may respond to traditional regimens used for aggressive lymphoma such as:

●ICE (ifosfamide, carboplatin, etoposide) [6]

●DHAP (dexamethasone, high dose cytarabine, and cisplatin) [7]

●ESHAP (etoposide, methyl-prednisolone, cytarabine, and cisplatin) [8]

●Single agent gemcitabine [9]

●GDP (gemcitabine, cisplatin, and dexamethasone) [10]

●Gemcitabine and oxaliplatin [11]

The Canadian Cancer Trials Group LY.12 trial randomly assigned 59 patients with relapsed or refractory PTCL to salvage chemotherapy with DHAP or GDP [12]. There was no difference in overall response after two cycles of DHAP versus GDP (36 versus 33 percent, respectively). For the group as a whole, one-year event-free survival (EFS) and OS were 16 and 28 percent, respectively. For those patients with PTCL who later underwent autologous HCT, two-year EFS and OS were 21 and 42 percent, respectively.

Other published experience is limited to case reports of patients with PTCL and phase II trials in which patients with PTCL comprised only a minority of those with various aggressive non-Hodgkin lymphomas. With these regimens, overall response rates for patients with PTCL are approximately 40 to 50 percent. Trials of various salvage regimens in aggressive lymphoma are discussed in more detail separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Selection of salvage chemotherapy'.)

Newer agents

Selection of agent — As described above, we suggest the administration of a traditional cytotoxic combination chemotherapy regimen for most patients with relapsed or refractory PTCL, particularly if they are candidates for either allogeneic or autologous HCT. Other, newer agents are typically reserved for subsequent relapses or patients receiving treatment with non-curative intent. As an important exception, patients with relapsed or refractory ALCL are treated with newer agents even if the intent is to proceed to transplant.

Our choice among the newer agents is generally guided by the specific subtype of PTCL and the toxicity profiles of the agents.

●For patients with relapsed or refractory angioimmunoblastic T cell lymphoma (AITL), we suggest use of belinostat rather than pralatrexate or brentuximab. (See 'Belinostat' below.)

●In all other settings, the choice between these agents should be based upon the patient's ability to tolerate anticipated toxicities. As an example, pralatrexate may be preferred in patients with a history of cardiac arrhythmia (particularly ventricular arrhythmia). Belinostat was studied in a proportion of patients with baseline thrombocytopenia and would be a reasonable first treatment option in this patient population. Belinostat appears to be more active than pralatrexate in angioimmunoblastic T cell lymphoma. A notable drawback of belinostat is the frequency of administration, which may be difficult for patients with transportation or mobility issues.

The studies that support the use of these agents in PTCL are described in the following sections.

Pralatrexate — Pralatrexate (an antifolate compound) achieves responses in patients with relapsed/refractory PTCL and is generally well tolerated. Pralatrexate is approved for use in relapsed or refractory PTCL by the US Food and Drug Administration (FDA) [13].

Examples of studies in relapsed/refractory PTCL include:

●A phase I trial of pralatrexate in 20 patients with relapsed or refractory lymphoma included four patients with T cell lymphoma, all of whom attained a CR [14]. An expansion phase I/II trial of pralatrexate in 20 additional patients with PTCL reported 10 responses, 9 of which were complete. The drug demonstrated activity across histologies. The primary toxicities were mucositis and thrombocytopenia, although these were abrogated by the introduction of folic acid and vitamin B12 supplementation [15].

●An international, open label phase II registration trial (the PROPEL trial) evaluated the use of pralatrexate in 115 heavily pretreated patients with PTCL [16]. Patients received pralatrexate 30 mg/m² weekly for six of every seven weeks along with folic acid 1 mg by mouth daily and vitamin B12 injections monthly. Patients were heavily pretreated with a median of three prior therapies (range 1 to 12) and 16 percent of patients had failed a prior autologous HCT. Approximately 60 percent of patients were refractory after their most recent therapy and approximately 25 percent had never responded to any chemotherapy. The following outcomes were reported:

•The overall response rate (ORR) was 29 percent with 18 percent partial responses (PR) and 11 percent CR or CR, unconfirmed. Twenty-one patients (19 percent) had stable disease.

•The most common severe (grade 3/4) toxicities were thrombocytopenia (33 percent) and mucosal inflammation (22 percent).

•Responses were generally rapid with 63 percent of patients responding after one cycle. The median time on therapy for all responders was 186 days and the median duration of response was 10 months. The median OS and PFS times were 14.5 and 3.5 months, respectively.

•Responses were observed across all histologic subtypes, although patients with AITL were less likely to respond than patients with other common PTCL subtypes. Interestingly, the likelihood of response did not seem to correlate with the number of prior therapies.

Belinostat — Belinostat is a histone deacetylase inhibitor that has demonstrated responses in relapsed or refractory PTCL in a phase II trial. It has not been directly compared with other treatments in a randomized fashion. Belinostat was granted accelerated approval by the US FDA for the treatment of patients with PTCL who have received at least one prior therapy. This approval was based on tumor response rates and duration of response. An improvement in survival or disease-related symptoms has not been established.

A phase II trial (BELIEF trial) of belinostat (1000 mg/m² days 1 to 5 of a 21-day cycle) in 120 evaluable patients with PTCL reported overall and CR rates of 26 and 11 percent, respectively, with a median time to response of 5.6 weeks (range 4 to 50 weeks) [17]. The median duration of response was 14 months (>29 months among those achieving CR). The most frequent treatment-emergent adverse events included nausea (42 percent), fatigue (37 percent), and pyrexia (35 percent). There was one treatment-related death due to hepatic failure. There have been concerns regarding the potential for HDAC inhibitors to prolong the QT interval and result in cardiac arrhythmias, though no formal precautions are required in the product label.

The approved dose and schedule of belinostat is 1000 mg/m² administered over 30 minutes by intravenous infusion once daily on days 1 through 5 of a 21-day cycle [18]. Cycles can be repeated until disease progression or unacceptable toxicity. Patients must be monitored for hematologic and hepatic toxicity with complete blood counts weekly and liver function tests before the start of each cycle. Treatment discontinuation or interruption with or without dose reductions may be needed. Patients with advanced stage disease and/or high tumor burden may develop tumor lysis syndrome on this agent.

Brentuximab — Brentuximab vedotin (commonly referred to as brentuximab) is an antibody drug conjugate with a CD30-directed antibody linked to the antitubulin agent monomethyl auristatin E (MMAE) [19]. Brentuximab is approved by the US Food and Drug Administration (FDA) for the treatment of patients with systemic ALCL after failure of at least one prior multi-agent chemotherapy regimen [20]. (See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)

Brentuximab has also demonstrated activity in other histologic subtypes of CD30-positive PTCL but is not approved by regulatory agencies for this indication. In a single arm, phase II, multicenter trial, 35 patients with relapsed/refractory CD30-positive PTCL received single agent brentuximab (1.8 mg/kg every three weeks until disease progression or unacceptable toxicity) [21]. The overall response rate was 41 percent (24 percent complete). Among the 13 patients with angioimmunoblastic T cell lymphoma, five attained a CR and two had a PR, with a median PFS of 6.7 months. Among the 21 patients with PTCL, NOS, three attained a CR and four had a PR, with a median PFS of 1.6 months. Upon central review, the degree of response did not appear to correlate with CD30 expression, suggesting that very low levels of CD30 expression may be sufficient for drug activity. An ongoing randomized trial is evaluating the substitution of brentuximab for vincristine in CHOP chemotherapy for patients with previously untreated CD30-positive mature T cell lymphomas (NCT01777152).  

Infusion reactions are uncommon, but anaphylaxis has been reported. Progressive multifocal leukoencephalopathy is a rare complication of brentuximab treatment and typically presents with subacute neurologic deficits, which may include altered mental status, visual symptoms, weakness, ataxia, and seizures [22]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Brentuximab' and "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Brentuximab'.)

Romidepsin — Romidepsin is an intravenously administrated histone deacetylase inhibitor that was granted accelerated approval by the US FDA in 2011 for treatment of relapsed or refractory PTCL, based on studies that reported responses in 25 to 38 percent of patients [23,24]. Approval was voluntarily withdrawn by the manufacturer in 2021.

Romidepsin has been associated with grade ≥3 granulocytopenia and lymphopenia and mild nausea, fatigue, electrolyte abnormalities, and electrocardiogram changes (eg, T-wave and ST-segment changes) of uncertain clinical significance, as described separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Romidepsin'.)

Transplantation

Autologous versus allogeneic HCT — Allogeneic hematopoietic cell transplantation (HCT) and autologous HCT administered after response to second-line chemotherapy offer a chance of long-term survival. Patients who achieve a CR before transplant have a higher chance of long-term survival. The efficacy varies with PTCL subtype. Decisions regarding transplant eligibility should be made on a case-by-case basis based on a risk-benefit assessment and the needs and wishes of the patient.

For medically fit patients, the choice between allogeneic HCT and autologous HCT depends upon whether the patient has already received an autologous HCT, the response to salvage chemotherapy, and the PTCL subtype:

●For patients who have not undergone a prior autologous HCT and who achieve a CR with salvage chemotherapy, we suggest autologous HCT rather than allogeneic HCT.

●For patients who have undergone a prior autologous HCT, have a PR with salvage therapy, or require several therapies at relapse to achieve a CR, we favor allogeneic HCT given the likely intrinsic chemoresistance of the disease in these instances. Reduced intensity allogeneic HCT may be considered for older patients who cannot tolerate myeloablative conditioning.

Allogeneic HCT — Allogeneic HCT has been studied in a selective group of patients with relapsed or refractory PTCL. Rates of OS at five years post-transplant are approximately 50 to 60 percent, with non-relapse mortality rates of 20 to 25 percent.

Small, uncontrolled prospective trials and retrospective analyses have investigated the use of allogeneic HCT in PTCL [25-30]:

●An uncontrolled prospective trial of 17 patients with relapsed (15 patients) or refractory PTCL who underwent salvage chemotherapy with cisplatin, cytarabine, and dexamethasone followed by a reduced intensity allogeneic HCT from a sibling (16 patients) or matched unrelated donor reported five-year PFS and OS rates were 49 and 54 percent, respectively [25]. At a median follow-up from enrollment of 28 months, 14 patients were still alive, two patients had died of progressive disease, and one had died with sepsis.

●An uncontrolled prospective trial investigated the use of a nonmyeloablative preparative regimen (2 Gy total body irradiation plus fludarabine) followed by allogeneic HCT in 17 patients with T cell or NK cell non-Hodgkin lymphoma that was relapsed/refractory (14 patients) or in first CR [28]. After a median follow-up of 3.3 years, estimated rates of OS and PFS at three years were 59 and 53 percent, respectively. Estimated rates of non-relapse mortality and relapse at three years were 19 and 26 percent, respectively.

●Analysis of the Center for International Blood and Marrow Transplantation Research (CIBMTR) database identified 112 patients with PTCL who had undergone allogeneic HCT in first CR (14 percent), second or greater CR (16 percent), primary induction failure (36 percent), chemotherapy sensitive relapse (17 percent), or other stage of disease [30]. The estimated rates of PFS and OS at one year were 42 and 55 percent, respectively. Corresponding rates at three years were 37 and 46 percent. Non-relapse mortality was 34 percent at three years. Survival was worse for patients not in CR at the time of HCT and for those who had received more than two lines of chemotherapy.

●A single-center retrospective analysis included 52 patients with relapsed/refractory (42 patients) or newly diagnosed (10 patients) PTCL or advanced mycosis fungoides/Sézary syndrome who underwent myeloablative (60 percent) or reduced intensity allogeneic HCT and reported rates of PFS and OS at three years of 30 and 41 percent, respectively [31]. When compared with reduced intensity regimens, myeloablative regimens were associated with higher non-relapse mortality (36 versus 14 percent at three years) and lower relapse rates, resulting in similar survival. When compared with predominantly extranodal histologies (eg, NK/T cell lymphoma, cutaneous lymphomas), patients with a predominantly nodal histologies had superior PFS (45 versus 6 percent) and OS (52 versus 23 percent) at three years. At a median follow-up of 49 months, there appeared to be a plateau in the survival curves suggesting possible cure of a subset of patients.

●A retrospective study of 45 patients with relapsed/refractory (34 patients) or newly diagnosed (11 patients) angioimmunoblastic T cell lymphoma (AITL) treated with myeloablative (25 patients) or reduced intensity allogeneic HCT reported rates of five-year PFS and OS of 57 and 64 percent, respectively. Again, the non-relapse mortality rates were 29 and 24 percent for patients who received myeloablative or reduced intensity allogeneic HCT, respectively [27].

Together, these studies suggest that some patients with relapsed or refractory PTCL who undergo allogeneic HCT will achieve long-term disease control.

Autologous HCT — Autologous HCT is frequently incorporated into the initial treatment of patients with PTCL as consolidation therapy after initial combination chemotherapy. Autologous HCT appears to be less effective in the treatment of relapsed or refractory disease, except perhaps for patients with ALK-positive ALCL [32]. When compared with patients transplanted in first CR, OS and PFS rates are significantly lower when autologous HCT is performed on patients in subsequent CR, PR, or those with progressive disease.

The following are examples of the prospective and retrospective studies that have investigated autologous HCT for relapsed or refractory PTCL:

●A retrospective series of 28 patients transplanted for relapsed PTCL reported a three-year OS rate of 69 percent. A subset analysis of patients with ALCL found a three-year OS rate of 86 percent. ALK-positive patients had an EFS of 100 percent at three years compared to zero percent in ALK-negative cases [33].

●An analysis of the Center for International Blood and Marrow Transplantation Research (CIBMTR) database identified 115 patients with PTCL (including ALCL) undergoing autologous HCT in first CR (35 percent), second or greater CR (21 percent), primary induction failure (19 percent), chemotherapy sensitive relapse (15 percent), or other (11 percent) [30]. The estimated rates of PFS and OS at one year were 58 and 68 percent, respectively. Corresponding rates at three years were 47 and 59 percent. Non-relapse mortality at one and three years was 4 and 6 percent.

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

There is no standard therapy for patients with relapsed or refractory PTCL. As such, patients should be strongly encouraged to participate in a clinical trial. A decision to refer the patient for a clinical trial should be determined by the overall clinical situation and the enthusiasm of the patient for palliative measures. Ongoing trials are evaluating traditional chemotherapy agents in new combinations for the treatment of relapsed or refractory PTCL. The following sections describe some of the newer agents being studied in PTCL.

Bortezomib — Small prospective trials have evaluated the proteosome inhibitor bortezomib for the treatment of patients with PTCL. The primary toxicity of bortezomib in this setting appears to be similar to that seen in patients with multiple myeloma and mainly consists of neuropathy and thrombocytopenia. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)

●A phase II trial of bortezomib (1.3 mg/m² on days 1,4, 8, and 11 of a 21-day cycle) in 15 patients with relapsed/refractory PTCL (two patients) or cutaneous T cell lymphoma reported an overall response rate of 67 percent with two CRs and six PRs [34]. Of the two patients with PTCL, one attained a CR. The responses were durable, lasting on average 7 to 14 months.

●A phase I study evaluated the use of standard dose CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) plus bortezomib in 13 patients with advanced, aggressive T cell or NK/T cell lymphoma [35]. No dose-limiting toxicities were observed up to the maximal dose of bortezomib of 1.6 mg/m². The CR rate was 62 percent. No data were given for PFS or OS.

These data suggest that the combination of bortezomib and CHOP is feasible in PTCL although it is impossible to say at present whether it improves outcomes over CHOP alone.

Bendamustine — An open-label, phase 2 trial evaluated the use of bendamustine in 60 patients with relapsed or refractory PTCL [36]. The overall response rate was 50 percent (28 percent complete). The median duration of response, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most common severe (grade 3/4) toxicities were neutropenia (30 percent), thrombocytopenia (24 percent), and infections (20 percent).

Lenalidomide — A phase 2 trial evaluated the use of lenalidomide (25 mg daily on days 1 to 21 of a 28-day cycle) in 31 patients with relapsed or refractory T cell lymphoma and 8 patients with previously untreated T cell lymphoma who were not candidates for combination chemotherapy [37]. Ten patients had responsive disease (three complete, seven partial), and three patients had stable disease for at least five cycles. The estimated median OS and PFS were 12 and 4 months, respectively. The median duration of response was 13 months, including five responses that lasted longer than one year. Toxicities were consistent with those seen in other trials of lenalidomide.

Alisertib — Alisertib is an oral inhibitor of aurora A kinase, which is essential for mitosis and expressed at high levels by PTCL [38-40]. In a multicenter trial, 271 patients with relapsed/refractory PTCL were randomly assigned to receive alisertib (50 mg twice daily days 1 to 7 in 21 days cycles) versus investigator-selected single agent (pralatrexate, gemcitabine) [41]. Overall response rate (ORR) to alisertib was 33 percent, which was not superior to the 45 percent ORR with the comparators; the study was terminated early due to the unlikelihood of the superior outcome with alisertib. Median PFS with alisertib was 115 days. Alisertib was generally well tolerated, with the most common adverse events being anemia and neutropenia.

SUMMARY AND RECOMMENDATIONS

●Peripheral T cell lymphomas (PTCL) are a heterogeneous group of generally aggressive neoplasms. While most are treated similarly, anaplastic large cell lymphoma requires specialized management, which is detailed separately. (See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)

●Initial treatment of PTCL generally consists of combination chemotherapy with or without consolidation by autologous hematopoietic cell transplantation (HCT) or radiation therapy, but most patients will relapse or develop refractory disease. Initial treatment of PTCL is discussed separately. (See "Initial treatment of peripheral T cell lymphoma".)

●When relapse is suspected, we suggest a biopsy of an involved lymph node or mass to confirm relapse and to evaluate a possible change in histology. Patients with relapsed PTCL should undergo staging with a physical examination, imaging studies, and a bone marrow biopsy, if warranted (eg, to evaluate unexplained cytopenias) (table 2). (See 'Evaluation of suspected resistance or relapse' above.)

●There is no general consensus regarding the optimal treatment regimen for relapsed/refractory PTCL, so patients should be encouraged to participate in clinical trials. (See 'Overview' above and 'Clinical trials' above.)

●In the absence of an available clinical trial, we stratify patients by the nature of the relapse and intent to proceed to transplant:

•For most patients who are eligible for HCT, we suggest salvage treatment with combination chemotherapy as a bridge to transplant rather than newer agents or sequential single chemotherapy agents (Grade 2C).

•For patients with primary refractory disease, early relapse (eg, <6 months), or multiple relapses, we suggest treatment with a newer agent rather than either sequential single agent chemotherapy or combination chemotherapy (Grade 2C). (See 'Newer agents' above.)

•For patients who are not transplant candidates, we suggest sequential single agent therapy (newer agents or chemotherapy) rather than salvage combination chemotherapy (Grade 2C). This preference places a high value on decreased toxicity in the absence of a known survival benefit. (See 'Chemotherapy' above.)

●Allogeneic HCT and autologous HCT administered after response to second-line chemotherapy offers a chance of long-term survival. The choice between autologous HCT versus allogeneic HCT depends upon whether the patient has already received an autologous HCT and the response to salvage chemotherapy, and the PTCL subtype (see 'Autologous versus allogeneic HCT' above):

•For most patients who have not previously undergone autologous HCT and who achieve a complete remission (CR) with salvage chemotherapy, we suggest autologous HCT rather than allogeneic HCT (Grade 2C). (See 'Autologous HCT' above.)

•For most patients who have undergone a prior autologous HCT, have a partial remission (PR) with salvage therapy, or require several therapies at relapse to achieve a CR, we suggest allogeneic HCT given the likely intrinsic chemoresistance of the disease (Grade 2C). Reduced intensity allogeneic HCT may be considered for older patients who cannot tolerate myeloablative conditioning. (See 'Allogeneic HCT' above.)