Treatment of relapsed/refractory systemic anaplastic large cell lymphoma (sALCL)

INTRODUCTION — Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive T cell non-Hodgkin lymphoma. There are two categories of sALCL:

●Anaplastic lymphoma kinase (ALK)-positive sALCL

●ALK-negative sALCL

While approximately two-thirds of patients with ALK-positive sALCL survive for five years, only one-half of patients with ALK-negative sALCL are alive. Some patients relapse after achieving a complete response, while others have an inadequate response or progress while receiving initial therapy (refractory disease). Prognosis and management of relapsed/refractory (r/r) ALK-positive sALCL and r/r ALK-negative sALCL differ significantly. Development of brentuximab vedotin, which targets CD30, and agents that can target ALK have led to changes in management of r/r sALCL. All patients should be encouraged to enroll in a clinical trial, where available.

This topic discusses management of r/r sALCL.

Evaluation and diagnosis of sALCL and initial treatment are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)" and "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)

PRETREATMENT EVALUATION

Clinical and laboratory

●Clinical – Evaluate constitutional symptoms (fever, sweats, weight loss) and size of liver and spleen.

●Laboratory

•Hematology – Complete blood count with differential.

•Chemistries – Basic metabolic panel; liver function tests, including lactate dehydrogenase; and renal function tests, including uric acid.

•Infectious – Hepatitis B and human immunodeficiency virus (HIV) testing.

●Clinical testing

•Bone marrow examination – Unilateral bone marrow aspiration and biopsy.

•Imaging – Positron emission tomography (PET)/computed tomography (CT) is performed prior to treatment. Contrast-enhanced CT of the chest, abdomen, and pelvis is helpful for staging and initial measurement of disease.

•Eyes – Patients with anaplastic lymphoma kinase (ALK)-positive disease who may receive an ALK inhibitor should have a baseline ophthalmology exam prior to treatment. (See 'ALK-positive sALCL' below.)

Pathology — Determination of subtype (ie, ALK-positive versus ALK negative) is based on immunohistochemistry, as described separately. (See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)", section on 'Pathology'.)

Repeat biopsy should be considered for persistent or new PET-positive lesions prior to treatment for r/r sALCL.

Medical fitness — We assess comorbid conditions (eg, heart, lung, kidney, liver disease) that might affect treatment, including eligibility for hematopoietic cell transplantation (HCT). Performance status should be assessed (table 1).

Transplant eligibility — Many institutions limit autologous HCT to patients ≤70 years and allogeneic HCT to patients ≤70 years without major medical comorbidities, but practices vary. Eligibility criteria for autologous HCT and allogeneic HCT are discussed separately. (See "Determining eligibility for autologous hematopoietic cell transplantation" and "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Note that eligibility criteria for transplantation may be relaxed, especially for patients with second or later relapse of sALCL, as discussed below. (See 'Transplantation' below.)

OVERVIEW

●Definitions

•Relapsed sALCL – Relapse refers to recurrence of sALCL after achieving a complete response (CR). The interval from completion of therapy to recurrence (ie, the duration of CR) has prognostic impact and affects management.

•Refractory sALCL – Failure to achieve a CR with initial induction therapy is called primary refractory disease or primary induction failure.

Patients with refractory sALCL generally have less favorable outcomes than patients with relapsed disease. For patients with relapsed peripheral T cell lymphoma (PTCL), shorter intervals (eg, <6 months) between initial therapy and relapse are associated with inferior outcomes. Among 420 evaluable patients in the COMPLETE registry, patients with relapsed and refractory PTCL had 12 month and 29 month median overall survival, respectively [1].

●Goals – The goals of management are influenced by prior therapy, age, fitness, and patient preference.

Hematopoietic cell transplantation (HCT) is the only proven method for long-term disease control and cure of relapsed/refractory (r/r) sALCL, but it is associated with substantial short- and long-term toxicity and transplant-related mortality in some patients. HCT is generally limited to patients ≤65 or ≤70 years without major medical comorbidities, as discussed above. (See 'Transplant eligibility' above.)

Treatment of r/r sALCL is guided by whether the patient intends to proceed to HCT:

•Younger, fit patients – For younger (ie, ≤70 years) without major comorbidities, we treat with the goal of long-term disease control/cure.

•Older or less-fit – For older or less-fit patients, the aim of treatment is to relieve symptoms and prolong survival.

●Phases of treatment

•Salvage therapy – Salvage therapy refers to initial treatment of r/r disease that seeks to achieve disease control. Selection of a salvage regimen is influenced by prior treatments and/or the duration of the initial CR. (See 'Salvage therapy' below.)

The disease subtype (ie, anaplastic lymphoma kinase [ALK]-positive versus ALK-negative) does not influence the choice of salvage therapy for patients with a first relapse or primary refractory disease. However, disease subtype is a consideration for subsequent management and for treatment of second or later relapse.

•Restaging – Positron emission tomography (PET) is performed after three treatment cycles or three months of salvage therapy (PET3) and again after completing induction therapy. (See 'Salvage response and duration' below.)

•Duration of salvage therapy – Guided by eligibility for HCT (see 'Duration of salvage therapy' below):

-Transplant-eligible – (See 'Fit, younger patients' below.)

-Not suitable for transplant – (See 'Older or less-fit patients' below.)

●Monitoring – Monitoring for disease relapse and treatment-related effects is described below. (See 'Monitoring' below.)

SALVAGE THERAPY — Selection of salvage therapy is stratified as follows:

●Relapsed sALCL – Was the interval from initial treatment to relapse <6 months versus ≥6 months?

●Refractory sALCL – Did induction therapy include brentuximab vedotin (BV; anti-CD30 immunoconjugate)?

Later relapse or refractory disease without prior BV — For patients with first relapse ≥6 months from initial treatment and for patients with refractory disease that did not include BV in the induction regimen, we suggest salvage therapy using single-agent BV, rather than combination chemotherapy or other single agents (algorithm 1). BV is associated with the most favorable balance of disease response and toxicity, and it can be administered in the outpatient setting.

●Administration – BV 1.8 mg/m² is given intravenously (IV) every three weeks.

●Toxicity – Cytopenias account for most grade ≥3 adverse effects (AEs) associated with BV. Peripheral neuropathy is mostly mild, but for patients who experience peripheral neuropathy with prolonged BV treatment, dose reduction and/or increasing the interval between treatments can mitigate toxicity.

●Response-guided therapy – We assess the initial response to therapy by performing repeating positron emission tomography (PET) after three treatment cycles or three months of salvage therapy (PET3). (See 'PET3 assessment' below.)

●Duration of therapy – The duration of BV treatment is guided by the goals of therapy and whether the patient will proceed to consolidation with hematopoietic cell transplantation (HCT), as discussed below. (See 'Salvage response and duration' below.)

●Outcomes – BV is well-tolerated and effective in this setting.

•BV versus other salvage therapy – BV was associated with better outcomes than either combination chemotherapy or other single agents among 57 patients with BV-naïve r/r peripheral T cell lymphoma (PTCL) in the COMPLETE registry; the study included 7 patients with anaplastic lymphoma kinase (ALK)-negative and 3 with ALK-positive sALCL [2]. BV was associated with 45-month median overall survival (OS), 12-month median progression-free survival (PFS), and 58 percent rate of complete response (CR). Compared with 26 patients who received combination chemotherapy, the 31 patients treated with a single agent (including 12 patients receiving BV, 7 with romidepsin, and 5 with pralatrexate) had superior median OS (39 versus 17 months), improved median PFS (11 versus 7 months), and more CRs (41 versus 19 percent). Outcomes were not reported for the subset of patients with r/r sALCL. Combination chemotherapy was associated with a trend toward more grade ≥3 AEs.

•BV – Outcomes with BV monotherapy include the following:

-A multicenter study reported outcomes with BV monotherapy in 58 BV-naïve patients with r/r sALCL [3]. Treatment of 42 patients with ALK-negative sALCL was associated with 61 percent five-year OS, 39 percent five-year PFS, and 88 percent overall response rate (ORR; including 52 percent CR), while treatment of 16 patients with ALK-positive sALCL was associated with 56 percent five-year OS, 37 percent five-year PFS, and 81 percent ORR (including 69 percent CR). Median time to first response was 6 weeks, and median time to CR was 12 weeks; median duration of response (DOR) following CR was 13 months and did not differ between disease subtypes. However, with >5 years of follow up, only 14 percent of patients sustained a CR without transplantation or other new treatments [4]. The most common grade ≥3 AEs were neutropenia (21 percent) and thrombocytopenia (10 percent); 14 percent had grade 3 peripheral sensory neuropathy, with no grade 4 neuropathy [3].

-Another study reported that BV monotherapy in 56 patients with BV-naïve r/r sALCL was associated with 73 percent ORR, including 46 percent CR; for patients who achieved CR, median DOR was 28 months [5]. For patients with progressive disease during BV treatment, median OS was three months and two-year OS was 27 percent.

-A study of 40 patients treated with BV for r/r sALCL reported 63 percent ORR (including 45 percent CR) and 54 percent two-year disease-free survival [6]. Best response was observed after median of four cycles of BV. Treatment was well-tolerated, and no deaths were linked to drug toxicity.

Early relapse or BV-refractory disease — For patients with early relapse (initial CR ≤6 months) or sALCL refractory to BV-based induction therapy, the choice of salvage therapy is based on disease subtype (algorithm 1).

ALK-positive sALCL — For ALK-positive early relapse (ie, CR ≤6 months) or ALK-positive disease that was refractory to BV, we suggest crizotinib rather than combination chemotherapy or other single agents (algorithm 1), based on greater efficacy and acceptable toxicity.

●Administration – Crizotinib is taken 280 mg/m² twice daily by mouth.

The dose of crizotinib should be adjusted for patients with moderate or severe hepatic impairment or severe renal impairment. Baseline ophthalmology exam and routine ocular monitoring should be performed. Periodic liver function tests should be performed, as fatal hepatotoxicity has occurred. Strong CYP3A inhibitors, inducers, and substrates should be avoided.

We assess the interval response with PET after three treatment cycles or three months of salvage therapy (PET3). (See 'Salvage response and duration' below.)

The US Food and Drug Administration (FDA) has approved crizotinib for treatment of r/r ALK-positive sALCL in children ≥1 year and young adults [7]. The FDA label includes warnings about fatal hepatotoxicity, interstitial lung disease, QT interval prolongation, bradycardia, severe visual loss, gastrointestinal toxicity, and may cause embryo-fetal toxicity.

Toxicity – The most common grade ≥3 AEs in patients with r/r sALCL are neutropenia, thrombocytopenia, diarrhea, and muscle pain. Crizotinib has also been associated with hepatotoxicity, interstitial lung disease/pneumonitis, QT interval prolongation, bradycardia, severe visual loss, and fetal toxicity.

The patient should be promptly reevaluated by an ophthalmologist for any change in vision during or after treatment.

●Duration of therapy – For patients who continue to tolerate crizotinib and respond to therapy, treatment can be continued indefinitely. Importantly, disease may progress rapidly after interruption or discontinuation of crizotinib [8].

Long-term disease control with crizotinib is not well defined. Some fit, younger patients with a CR to crizotinib may favor proceeding to transplantation HCT rather than ongoing crizotinib therapy, as discussed below. (See 'ALK-positive' below.)

●Outcomes – Crizotinib is effective for ALK-positive sALCL, especially in children and young adults [9,10]. Outcomes for patients >21 years are less well defined.

Treatment using crizotinib in 26 patients (1 to ≤21 years) with r/r sALCL and ≥1 prior systemic treatment was associated with 88 percent ORR (including 81 percent CR) [7]. For the 23 responding patients, 39 percent maintained a response for ≥6 months and 22 percent for ≥12 months. The most common grade ≥3 AE was diarrhea (12 percent), but grade ≥3 laboratory abnormalities included neutropenia (77 percent), lymphopenia (38 percent), and thrombocytopenia (19 percent).

Crizotinib in 11 heavily-pretreated patients (ages 19 to 55 years) was associated with 73 percent two-year OS, 64 percent two-year PFS, and 82 percent ORR; clinical benefit occurred as early as 12 days after initiating therapy [11].

ALK mutations that reduce sensitivity to crizotinib have been reported [11,12].

ALK-negative sALCL — For patients with ALK-negative early relapse (ie, CR <6 months) or ALK-negative BV-refractory disease, we suggest single-agent belinostat, romidepsin, or pralatrexate (algorithm 1), rather than combination chemotherapy, based on better outcomes and a trend toward less toxicity.

Belinostat and romidepsin (histone deacetylase inhibitors) and pralatrexate (dihydrofolate reductase inhibitor) have similar efficacy and toxicity profiles. The preferred treatment may be influenced by the schedule for administration.

We assess the interval response by repeating PET after three treatment cycles or three months of salvage therapy (PET3). (See 'Salvage response and duration' below.)

Some experts favor combination chemotherapy for younger, fit patients in this setting. (See 'Second or later relapse' below.)

●Administration – Response rates and toxicity are similar, and no randomized trials have directly compared these agents or tested single agents versus combination chemotherapy for r/r sALCL.

•Belinostat – 1000 mg/m² IV over 30 minutes once daily on days 1 to 5 of a 21-day cycle. Absolute neutrophil count should be ≥1 x 10⁹/L and the platelet count ≥50 x 10⁹/L prior to the start of each cycle. Dose modifications for cytopenias or other AEs are described in the package label [13].

•Romidepsin – 14 mg/m² IV over a four-hour period on days 1, 8, and 15 of a 28-day cycle. Treatment is associated with cytopenias and QT prolongation.

•Pralatrexate – 30 mg/m² by IV push over three to five minutes, once weekly for six weeks in seven-week cycles. Patients receiving pralatrexate should be supplemented with vitamin B12 1 mg intramuscularly every 8 to 10 weeks and folic acid 1 to 1.25 mg orally daily.

Belinostat and pralatrexate received accelerated approval for r/r PTCL by the FDA. Accelerated approval of romidepsin for r/r PTCL was withdrawn by the FDA following publication of results from a phase 3 LYSA trial, which reported that romidepsin plus CHOP was not superior to CHOP alone in first-line therapy of PTCL (including sALCL) [14].

●Toxicity – The most common grade ≥3 AEs are cytopenias.

●Duration of therapy – The duration of treatment is guided by the goals of therapy, as described below. (See 'Duration of salvage therapy' below.)

●Outcomes – Among 57 BV-naïve patients with r/r sALCL in the COMPLETE registry, single agents were associated with better outcomes than combination chemotherapy [2]. Single-agent therapy included 12 patients treated with BV, 7 with romidepsin, and 5 with pralatrexate, while combination chemotherapy included gemcitabine- (10 patients), ifosfamide- (7 patients), or platinum- (4 patients) based regimens. Compared with combination chemotherapy, treatment with a non-BV single agent was associated with better median PFS (10 months versus 7 months) but similar median OS (19 versus 17 months) and CR rates (29 versus 19 percent). Compared with single agents, there was a trend toward more grade ≥3 AEs with combination chemotherapy.

Each agent is associated with similar outcomes and AEs, including potential embryo-fetal harm.

•Belinostat – Treatment of 120 evaluable patients with r/r PTCL (all had ≥1 prior systemic therapy) in the BELIEF study reported 8-month median OS, 2-month median PFS, 14-month median DOR, and 26 percent ORR (11 percent) [15]. Grade ≥3 AEs included anemia (11 percent), thrombocytopenia (7 percent), dyspnea (6 percent), and neutropenia (6 percent).

•Romidepsin – Treatment of 21 patients with r/r ALK-negative sALCL was associated with 24 percent ORR, including 19 percent CR [16,17]. Median PFS was longer for patients with CR ≥12 months, compared with either CR <12 months or partial response (PR; 29, 13, and 7 months, respectively). Median OS was not reached for patients who achieved CR and was 18 months for those who achieved PR. Most common grade ≥3 AEs were thrombocytopenia (24 percent), neutropenia (20 percent), and infections (19 percent).

•Pralatrexate – In the phase 2 PROPEL study (which included 17 patients with r/r sALCL among 109 patients with heavily pretreated r/r PTCL), median OS was 15 months, median PFS was 4 months, median DOR was 10 months, and ORR was 29 percent (including 11 percent CR) [18]. Grade ≥3 AEs included thrombocytopenia (32 percent), neutropenia (22 percent), anemia (18 percent), and mucositis (22 percent).

SALVAGE RESPONSE AND DURATION

PET3 assessment — Positron emission tomography (PET) is performed after three treatment cycles or three months of salvage therapy (PET3) to assess the initial response to salvage therapy. Further management is guided by the PET3 response:

●Complete response (CR) or partial response (PR) – Continue current salvage therapy. The duration of salvage therapy is guided by age and medical fitness, as described below. (See 'Duration of salvage therapy' below.)

●Stable or progressive disease – For patients with a response that is less than PR, choose an alternate salvage regimen. (See 'Second or later relapse' below.)

Duration of salvage therapy — The duration of salvage therapy is guided by the goals of therapy and transplant eligibility.

Older or less-fit patients — For patients who are not eligible for hematopoietic cell transplantation (HCT) because of age (ie, ≥65 or ≥70 years) or limited medical fitness, we suggest continuing salvage therapy for as long as there is no evidence of disease progression and treatment is tolerated.

The duration of therapy may vary with the agent:

●Brentuximab vedotin – We treat for at least one year, if possible. For some patients, this may require a dose reduction or adjustment of the treatment schedule.

After one year, the interval between treatments can be increased to every four or every six weeks or the patient can be observed.

●Single agents – For belinostat, romidepsin, or pralatrexate, we treat for at least two cycles beyond best response. We then offer the patient the option of continuing therapy or reducing the frequency of treatment (eg, every two weeks for romidepsin).

●Anaplastic lymphoma kinase (ALK) inhibitors – We continue ALK inhibitors indefinitely, as patients relapse quickly when they are stopped.

Monitoring for relapse or disease progression is discussed below. (See 'Monitoring' below.)

If clinical evaluation or PET indicates disease progression, we offer an alternative salvage regimen or palliate symptoms with best supportive care. (See 'Second or later relapse' below.)

Fit, younger patients — For fit, younger patients with CR or PR on PET3, further management includes completion of salvage therapy followed by a decision about whether to pursue HCT.

●CR – For patients with CR on PET3, treat for three cycles (or three months) beyond CR, then proceed to post-salvage management, as described below. (See 'Fit, younger patients with CR' below.)

●PR – Treat for three additional cycles (or three additional months) of salvage therapy, then repeat PET (PET6).

•Limited PR – If PET6 demonstrates a limited PR (eg, single site of persistent disease), we offer radiation therapy (RT) prior to managing as a CR. For patients who plan to pursue HCT, RT can also be deferred until after transplantation.

•Lesser response – If PET6 demonstrates a PR that is not amenable to RT and for patients with stable or progressive disease on PET6, treat with an alternative salvage regimen. (See 'Second or later relapse' below.)

FIT, YOUNGER PATIENTS WITH CR — There is no consensus for management of transplant-eligible patients with a complete response (CR) after salvage therapy r/r sALCL. Management is stratified according to disease subtype.

ALK-positive — For patients with anaplastic lymphoma kinase (ALK)-positive r/r sALCL, management is stratified according to whether they underwent autologous hematopoietic cell transplantation (HCT) prior to the relapse (eg, as consolidation therapy following first CR [CR1]).

The role of HCT as consolidation therapy in CR1 is described separately. (See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)", section on 'Postinduction management'.)

No prior transplant — For patients with r/r ALK-positive sALCL who were not previously transplanted, we suggest autologous HCT rather than observation or allogeneic HCT, based on better long-term survival with autologous HCT than observation, and less toxicity than allogeneic HCT.

Compared with observation alone, transplantation is associated with increased toxicity but improved long-term survival. It is difficult to draw conclusions about the role of transplantation in this setting because most studies included heterogeneous patient populations (eg, various categories of r/r peripheral T cell lymphoma [PTCL]) or included transplantation for patients with sALCL in CR1. No randomized trials have directly compared transplantation versus observation for patients with r/r sALCL.

Relevant studies include:

●Observation – Only a small minority of patients experiences a sustained CR with observation alone after salvage therapy.

•Among 38 patients who achieved a CR with brentuximab vedotin for r/r sALCL (one-quarter with ALK-positive disease), only 14 percent experienced sustained disease-free survival without transplantation or other new treatments [4].

•Among 153 patients with r/r PTCL who were not eligible for HCT (which included 11 patients with ALK-positive sALCL and 27 with ALK-negative sALCL), median overall survival (OS) was 5.5 months [19].

●Transplantation – HCT is associated with long-term disease control in up to one-half of patients, but it entails additional toxicity and potential transplant-related mortality (TRM). Autologous transplantation has a more favorable toxicity profile than allogeneic HCT, but it is uncertain if the outcomes differ, because most studies included heterogeneous patient populations (eg, both ALK-positive sALCL and ALK-negative sALCL, along with other categories of PTCL).

•Autologous versus allogeneic HCT – Outcomes with autologous HCT versus allogeneic HCT for patients with r/r sALCL are not well defined; most relevant studies included a broader array of r/r PTCL.

-The United States CIBMTR registry analyzed 241 patients ≤60 years with PTCL (112 with sALCL, ALK status not reported) who underwent either autologous or allogeneic HCT; 68 patients were transplanted for primary refractory disease, 115 for relapse, and 58 were in CR1 [20]. Among patients with r/r PTCL, compared with allogeneic HCT, those who underwent autologous HCT had higher three-year OS (62 versus 33 percent) and lower TRM (5 versus 32 percent), with no difference in progression-free survival (PFS) or relapse/progression. Allogeneic HCT using myeloablative conditioning (MAC) was associated with inferior three-year OS (31 percent), compared with non-MAC allogeneic HCT (50 percent) or autologous HCT (53 percent). Among 39 patients with r/r sALCL who underwent autologous HCT, three-year OS and PFS were 65 and 50 percent, respectively; outcomes with allogeneic HCT in patients with r/r sALCL were not reported.

-A retrospective single-institution study reported that autologous HCT was associated with better survival than allogeneic HCT (50 versus 36 percent four-year OS, respectively) for 76 patients with r/r PTCL, which included 14 patients with r/r sALCL who underwent autologous HCT and 4 with r/r sALCL who had allogeneic HCT [21]. However, among patients with chemosensitive r/r PTCL, there was no difference in OS or PFS between autologous and allogeneic HCT.

•Outcomes with autologous HCT – These studies included patients transplanted in CR1 and/or various categories of PTCL.

-The GEL-TAMO registry described outcomes of 115 patients with PTCL who underwent autologous HCT, including 78 patients with r/r disease and 37 in CR1 [22]. Among 28 patients transplanted in second CR (ie, after a relapse), five-year OS was 50 percent. The number of patients with r/r sALCL was not presented, but only 8 of 115 patients had sALCL (ALK status not reported). There was no difference in OS or disease-free survival between patients with r/r sALCL compared with other categories of r/r PTCL.

-Among 51 patients with chemosensitive r/r sALCL who underwent autologous HCT, the European Group for Blood and Marrow Transplantation (EBMT) Registry reported three-year rates of OS, PFS, relapse, and nonrelapse mortality (NRM), which were 73, 64, 34, and 2 percent, respectively [23].

-A retrospective review of 24 patients with r/r PTCL (4 with ALK-negative sALCL) who underwent autologous HCT after responding to second-line therapy reported 33 percent five-year OS and 24 percent five-year PFS [24].

-A retrospective series of 28 patients transplanted for relapsed PTCL reported 69 percent three-year OS [25]. Among patients with sALCL, three-year OS was 86 percent overall and was higher for those with ALK-positive sALCL versus ALK-negative sALCL (100 versus 0 percent).

Prior transplantation — For patients who relapsed with ALK-positive sALCL after undergoing autologous HCT in CR1, we suggest observation rather than allogeneic HCT. This approach avoids the substantial toxicity of allogeneic HCT and recognizes that in the event of a subsequent relapse, the patient can receive second-line salvage therapy with an ALK inhibitor, along with consideration of subsequent allogeneic HCT.

Monitoring for relapse is discussed below. (See 'Monitoring' below.)

Treatment with an ALK inhibitor as second-line salvage therapy for patients who relapse during observation is discussed below. (See 'ALK-positive' below.)

ALK-negative — For patients with r/r ALK-negative sALCL, we consider autologous HCT, allogeneic HCT, and observation acceptable options.

The choice of approach should be individualized according to age, fitness, availability of a suitable graft, and patient preference. We generally favor allogeneic HCT in this setting because we consider that the balance of improved survival and increased toxicity with allogeneic HCT outweighs the adverse prognosis in patients with r/r ALK-negative sALCL. No prospective trials have directly compared allogeneic HCT versus observation for patients with r/r sALCL.

Few studies of allogeneic HCT for r/r sALCL are available and most included heterogeneous populations of patients (ie, various types of PTCL).

●The EBMT registry reported that allogeneic HCT was associated with 74 percent three-year OS, 65 percent three-year PFS, 40 percent relapse rate, and 7 percent NRM among 44 patients with r/r sALCL [26].

●In a study of allogeneic HCT in 77 patients with PTCL, five-year OS was 55 percent for the 26 patients with sALCL [27]. For the entire population of transplanted patients, five-year TRM was 33 percent, and only 5 of 59 patients with CR or PR after transplantation later relapsed.

●A prospective trial of 17 patients with r/r PTCL who underwent reduced-intensity allogeneic HCT from a sibling or matched unrelated donor reported five-year OS and PFS rates of 54 and 49 percent, respectively [28].

Studies that compared allogeneic and autologous HCT are discussed above. (See 'No prior transplant' above.)

Other reports of allogeneic HCT for PTCL are discussed separately [21,29-31]. (See "Treatment of relapsed or refractory peripheral T cell lymphoma", section on 'Allogeneic HCT'.)

MONITORING — Patients are evaluated periodically for relapse and to monitor for complications of treatment.

The frequency and nature of follow-up visits depend on the comfort of both the patient and clinician. We generally schedule patient visits every three to six months during the first two years, every six months in years 3 to 5, and then annually or as clinically indicated.

Monitoring includes:

●Clinical – History and physical examination, complete blood count, chemistries, and lactate dehydrogenase.

●Imaging – We generally perform computed tomography every six months for the first two years, then annually for years three to five, or as clinically indicated. Some experts favor positron emission tomography surveillance.

SECOND OR LATER RELAPSE — Second-line salvage therapy is used for patients who were refractory to prior salvage therapy or who relapsed after a complete response (CR) with previous salvage therapy.

Hematopoietic cell transplantation (HCT) is the only approach proven to offer long-term disease control in the setting of a second or later relapse. Selection of salvage therapy for second or later relapse is discussed below. (See 'Second-line salvage therapy' below.)

The duration of therapy is guided by whether the patient will pursue HCT:

●Not transplant-eligible – For patients who decline or are not eligible for HCT, we continue salvage therapy for as long as it is tolerated, and disease does not progress. Sequential treatment with alternative salvage regimens can be considered for patients who have disease progression or are not able to tolerate salvage therapy.

●Transplant-eligible – Because of the dire prognosis without transplantation, we generally relax age and fitness requirements and allow transplantation for patients who achieve either a CR or partial response (PR) to salvage therapy.

Transplantation for the second or later relapse is addressed below. (See 'Transplantation' below.)

Second-line salvage therapy — The choice of second-line salvage therapy is guided by prior treatments, disease subtype, medical fitness, and patient preference. Patients with second or later relapse are less likely respond robustly to salvage therapy, and the prognosis declines with successive relapses.

Brentuximab vedotin (BV) may be considered if the most recent CR was ≥6 months. Efficacy of BV in this setting is uncertain, but in the ECHELON-2 trial, among 23 patients who relapsed after BV+CHP (cyclophosphamide, doxorubicin, prednisone) induction therapy (including 16 with sALCL), BV-based salvage (monotherapy in 21, BV-based combination therapy in 2) was associated with 65 percent overall response rate (ORR; including 40 percent CR), but the interval between initial CR with BV-CHP and relapse was not specified [32].

For others, second-line salvage therapy is informed by disease subtype.

ALK-positive — We favor treatment with an anaplastic lymphoma kinase (ALK) inhibitor in this setting, but single agents or combination chemotherapy are also acceptable, especially for patients who progressed on or did not tolerate two or more ALK inhibitors.

Treatment with single agents or combination chemotherapy is discussed below. (See 'ALK-negative' below.)

●No prior ALK inhibitor – We treat with crizotinib if the patient did not previously receive an ALK inhibitor. (See 'ALK-positive sALCL' above.)

●Prior crizotinib – For patients who progressed on crizotinib or had severe adverse effects (AEs), we generally treat with ceritinib, but other ALK inhibitors also show promising preliminary results. Some experts treat with an ALK inhibitor plus chemotherapy.

•Ceritinib – The usual dose of ceritinib (for adults with metastatic ALK-rearranged lung cancer) is 450 mg orally once daily with food. Concurrent treatment with strong CYP3A inhibitors, inducers, and substrates and CYP2C9 substrates should be avoided.

Ceritinib is more potent than crizotinib in vitro and has demonstrated responses in patients with ALK-rearranged lung cancer that progressed on crizotinib. The ASCEND-1 trial, which evaluated efficacy of ceritinib in patients with ALK-rearranged tumors, included three patients with ALK-positive sALCL; two of the three achieved a CR, while one had a PR with 95 percent reduction in tumor size [33]. All responses were ongoing at the time of the report, with the duration of response ranging from ≥20 to ≥26 months.

In addition to the AEs associated with crizotinib, ceritinib is also associated with pancreatitis.

Ceritinib is not approved by the US Food and Drug Administration (FDA) for treatment of r/r ALK-positive sALCL.

•Other ALK inhibitors – The FDA has approved three other ALK inhibitors (alectinib, brigatinib, lorlatinib) for treatment of ALK-mutated non-small cell lung cancer, but none has been approved for sALCL.

As an example, alectinib 300 mg twice daily in 10 patients with r/r sALCL was associated with a response in 8 of 10 patients (including 6 CRs), 70 percent one-year OS, and 58 percent one-year PFS [34]. Second-generation ALK inhibitors have shown activity on crizotinib-resistant (ALK-L1196M mutation) cell lines and xenografts [35,36].

•ALK inhibitor with chemotherapy – Crizotinib has also been combined with chemotherapy for multiply-relapsed sALCL, but it is uncertain if the combination is more effective and/or toxic than crizotinib alone.

Compared with 27 patients treated with chemotherapy, treatment of 16 patients with crizotinib plus the same chemotherapy was associated with superior two-year PFS (69 versus 45 percent; hazard ratio [HR] 0.42 [95% CI 0.17-0.99]), similar two-year OS (86 versus 79 percent), and similar ORR (81 versus 74 percent) [37].

ALK-negative — For patients with second or later relapse of ALK-negative sALCL, we treat with a single agent or chemotherapy.

●Single agents – Sequential treatment with different single agents can be useful in this setting. Single agents with activity for r/r sALCL include belinostat, romidepsin, and pralatrexate, as described above. (See 'ALK-negative sALCL' above.)

●Chemotherapy – Combination chemotherapy is an acceptable option for medically-fit patients. No treatment has proven superior in this setting, but regimens that have been used for treatment of r/r T cell lymphomas include:

•GDP – Gemcitabine, dexamethasone, cisplatin [38].

•DHAP – Dexamethasone, cytarabine, plus a platinum compound (ie, carboplatin, cisplatin, or oxaliplatin) [39-41].

•ESHAP – Etoposide, methylprednisolone, cytarabine, plus either cisplatin or oxaliplatin [42-44].

•GemOx – Gemcitabine, oxaliplatin [45].

•ICE – Ifosfamide, carboplatin, etoposide.

A randomized trial that compared DHAP to GDP in patients with r/r aggressive lymphomas included 23 patients with sALCL among 65 patients with peripheral T cell lymphoma (PTCL) [46]. With median follow up of 53 months, there was no difference in OS, PFS, transplantation rate, or ORR between trial arms according to intention-to-treat analysis. However, GDP was associated with better quality of life, and it was less toxic than DHAP (eg, fewer hospitalizations due to toxicity, less need for platelet transfusions). Patients with PTCL/sALCL were not analyzed separately.

Responses to these regimens are similar to those of aggressive B cell lymphomas. Details of regimens and outcomes are presented separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Salvage regimens'.)

Bendamustine and lenalidomide have shown activity in sALCL [47,48], but neither is approved by the FDA for this indication.

Transplantation — A decision to pursue HCT for a patient with second or later relapse is made on a case-by-case basis after assessment of the balance of risks and benefits and the wishes of the patient. For second or later relapse of sALCL, we generally relax age and fitness criteria for transplantation because of the dire prognosis. Suitability for transplantation is discussed above. (See 'Medical fitness' above.)

For patients with a CR or PR to second-line salvage therapy, further management is guided by whether the patient previously underwent autologous HCT and/or allogeneic HCT.

●No prior HCT – Autologous or allogeneic HCT.

●Prior autologous HCT – Allogeneic HCT.

●Prior allogeneic HCT – Donor lymphocyte infusion (if available) or successive salvage regimens, radiation therapy, or palliative care to relieve symptoms and prolong survival.

SUMMARY AND RECOMMENDATIONS

●Description – There are two categories of systemic anaplastic large cell lymphoma (sALCL): Anaplastic lymphoma kinase (ALK)-positive and ALK-negative disease. Patients who relapse after achieving a complete response (CR) or with disease that was refractory to initial therapy have adverse prognoses and are encouraged to participate in a clinical trial.

●Overview – Treatment for relapsed/refractory (r/r) sALCL begins with salvage therapy and may be followed by consolidation with hematopoietic cell transplantation (HCT) in fit, younger patients. Long-term disease control/cure is the goal for patients who seek HCT, while symptom control and prolonged survival are the goals for others. (See 'Overview' above.)

Salvage therapy is stratified according to:

•Relapse – Duration of initial CR <6 versus ≥6 months.

•Refractory – Whether induction included brentuximab vedotin (BV).

●Late r/r disease with no prior BV – For first relapse ≥6 months from initial treatment or BV-naïve primary refractory disease, we suggest single-agent BV (algorithm 1), rather than combination chemotherapy or other single agents (Grade 2C). (See 'Later relapse or refractory disease without prior BV' above.)

●Early relapse/BV-refractory – For early relapse (<6 months) or BV-refractory disease, salvage therapy is stratified according to disease subtype (algorithm 1):

•ALK-positive – We suggest crizotinib, rather than combination chemotherapy or other single agents (Grade 2C). (See 'ALK-positive sALCL' above.)

•ALK-negative – We suggest single-agent belinostat, romidepsin, or pralatrexate, rather than combination chemotherapy (Grade 2C). (See 'ALK-negative sALCL' above.)

●Interim response assessment – Positron emission tomography (PET) is performed after three treatment cycles or three months of salvage therapy (PET3), with further treatment according to response. (See 'Salvage response and duration' above.)

•CR or partial response (PR) on PET3 – Continue salvage therapy for two or three additional cycles/months, then:

-Older or less-fit patients – Continue treatment until relapse or drug intolerance. (See 'Older or less-fit patients' above.)

-Fit, younger patients – Proceed to post-CR management according to disease subtype (below). (See 'Fit, younger patients' above.)

•Response less than PR – Change to second-line salvage therapy. (See 'Second-line salvage therapy' above.)

●Post-CR management in fit, younger patients:

•ALK-positive – (See 'ALK-positive' above.)

-No prior transplant – For patients with r/r ALK-positive sALCL who were not previously transplanted, we suggest autologous HCT rather than observation or allogeneic HCT (Grade 2C). (See 'No prior transplant' above.)

-Prior transplant – For patients who previously underwent autologous HCT, we suggest observation rather than allogeneic HCT (Grade 2C). (See 'Prior transplantation' above.)

•ALK-negative – For r/r ALK-negative sALCL, we consider autologous HCT, allogeneic HCT, and observation acceptable. (See 'ALK-negative' above.)

●Monitoring – Described above. (See 'Monitoring' above.)

●Second or later relapse – For patients who do not achieve CR or who experience another relapse, treatment follows:

•Salvage therapy – The preferred second salvage regimen varies with disease subtype:

-ALK-positive – We favor treatment with an ALK inhibitor. (See 'ALK-positive' above.)

-ALK-negative – Treat with an alternative single agent or combination chemotherapy. (See 'ALK-negative' above.)

•Transplantation – HCT is the only option for long-term disease control/cure. The choice of autologous versus allogeneic HCT varies with prior transplantation. (See 'Transplantation' above.)