Initial treatment of systemic anaplastic large cell lymphoma (sALCL)

INTRODUCTION — 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. Anaplastic large cell lymphoma (ALCL) is a CD30-postive PTCL that is one of the more common types of PTCL, accounting for approximately 2 percent of NHL in adults but 15 percent of NHL in children.

Four distinct forms of ALCL are recognized, based on clinical and molecular features:

●Anaplastic lymphoma kinase (ALK)-positive sALCL

●ALK-negative sALCL

●Breast implant-associated ALCL (BIA-ALCL)

●Primary cutaneous ALCL (PC-ALCL)

ALK-positive sALCL and ALK-negative sALCL have different demographics and prognosis. ALK-positive sALCL is associated with translocations involving the ALK gene (on chromosome 2), mainly affects children and young adults, has a male predominance, and is associated with more favorable outcomes than ALK-negative sALCL. ALK-negative sALCL is associated with various molecular abnormalities. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Prognosis'.)

Management of sALCL is discussed in this topic.

Classification of T cell NHLs and diagnosis of sALCL, BIA-ALCL, and PC-ALCL are presented separately.

●(See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)

●(See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

●(See "Primary cutaneous anaplastic large cell lymphoma".)

●(See "Breast implant-associated anaplastic large cell lymphoma".)

PRETREATMENT EVALUATION — The pretreatment evaluation should establish the subtype of anaplastic large cell lymphoma (ALCL), disease stage, and suitability of the patient for intensive treatments, including hematopoietic cell transplantation (HCT).

Clinical and laboratory evaluation — Clinical evaluation, laboratory testing, imaging, and other studies establish the disease stage (table 1) and identify medical conditions that may affect treatment choices:

●History and physical examination – History evaluates constitutional symptoms ("B" symptoms; ie, unexplained fevers, sweats, weight loss), and physical examination should include node-bearing areas and the size of liver and spleen.

●Laboratory – Testing includes:

•Hematology – Complete blood count with differential count

•Serum chemistries – Basic metabolic panel; liver function tests, including lactate dehydrogenase (LDH); and renal function tests, including uric acid

•Infectious – Hepatitis B and human immunodeficiency virus (HIV) testing (see "Hepatitis B virus reactivation associated with immunosuppressive therapy")

●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.

Note that with response-guided therapy, PET is again performed after three cycles of chemotherapy (PET3) and following completion of induction therapy (end-of-induction PET). (See 'Interim restaging' below.)

●Heart – Electrocardiogram (ECG) and either echocardiogram or radionuclide ventriculogram (RVG; multigated acquisition [MUGA] scan) to assess left ventricular ejection fraction.

●Fertility – People of childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Pathology — A biopsy specimen is required to confirm the diagnosis of sALCL and to determine the subtype.

●Specimen – An excisional or incisional biopsy specimen is preferred, but core needle biopsies may be acceptable in some circumstances. A fine needle aspirate is not adequate for initial diagnosis and classification. The biopsy specimen should be reviewed by a hematopathologist with expertise in peripheral T cell lymphomas (PTCL).

●Diagnosis – The specimen should undergo immunohistochemistry (IHC) and/or flow cytometry to confirm its T cell origin. Membrane-associated CD30 is detected by IHC in all cases of ALCL. Molecular studies can analyze T cell receptor (TCR) or other genes for clonality.

Other diagnostic features of sALCL are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Pathologic features'.)

●sALCL subtypes – Anaplastic lymphoma kinase (ALK)-positive sALCL and ALK-negative sALCL differ regarding demographics, prognosis, and certain aspects of treatment. They are considered distinct subtypes of ALCL, according to both the International Consensus Classification [1] and the World Health Organization Classification 5^th edition [2].

Pathologic distinction among sALCL subtypes is typically determined by IHC, which has largely supplanted molecular testing for ALK gene rearrangement or expression. ALK expression is absent from all normal postnatal human tissue, except for rare cells in the brain [3].

●Cytogenetic/molecular studies – Both ALK-positive sALCL and ALK-negative sALCL include distinct subtypes that can be identified by cytogenetic and/or molecular studies, but defining these finer subtype distinctions is not currently required for clinical care.

•ALK-positive sALCL subtypes – Chromosome banding and/or fluorescence in situ hybridization can be used to identify the translocation partner of ALK, but identifying the rearrangement partner is not required if ALK staining is positive by IHC.

The most common ALK rearrangement partner is NPM1 (in association with t[2;5] translocation), but variant translocations involving chromosomes 1, 2, 3, 17, 19, 22, or X may be seen [3].

•ALK-negative sALCL subtypes – Two molecular subtypes of ALK-negative sALCL can be distinguished based on gene rearrangements and/or expression, but these distinctions are not currently used to stratify treatment.

ALK-negative sALCL subtypes are identified by rearrangements of DUSP22 versus TP63 [4,5]. TP63 rearrangement (<10 percent of cases) is generally associated with a worse prognosis than DUSP22 rearrangement (approximately 30 percent of cases) [4,5].

Medical fitness/transplant eligibility — Medical fitness influences management choices.

We assess comorbid conditions (eg, heart, lung, kidney, liver disease) that might affect treatment, including eligibility for autologous HCT. Many institutions limit autologous HCT to patients ≤65 to 70 years without major medical comorbidities, but practices vary. Eligibility criteria for autologous HCT are discussed separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

Performance status should be assessed (table 2A-B).

Prognosis — Prognostic scoring models can estimate outcomes of patients with sALCL and influence treatment choices.

●Prognostic scores – The International Prognosis Index (IPI) (table 3) [6] or the Prognostic Index for PTCL (PIT) [7] can be used to estimate prognosis in patients with PTCL. The IPI was originally developed for aggressive B cell lymphomas [6], but it is widely used for T cell lymphomas. PIT was specifically developed for patients with PTCL [7]. The IPI and PIT models and the association of outcomes with prognostic scores are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified", section on 'Prognosis'.)

Both the IPI and PIT scoring systems effectively define risk categories for patients with sALCL [7-9].

●Subtypes/pathologic features – ALK-positive sALCL is associated with a more favorable prognosis than ALK-negative sALCL.

The International PTCL Project reported 70 percent five-year overall survival (OS) and 60 percent five-year failure-free survival (FFS) for patients with ALK-positive sALCL; the corresponding rates were 49 and 36 percent, respectively, for ALK-negative sALCL [10]. In a series of German trials that used anthracycline-based chemotherapy, patients with ALK-positive sALCL had 90 percent three-year OS, compared with 62 percent three-year OS for those with ALK-negative disease [11]. Other studies have also reported superior outcomes for patients with ALK-positive sALCL [8,12-18].

OVERVIEW — For most patients with sALCL, management involves:

●Induction therapy – Initial treatment of sALCL is based on combination chemotherapy that includes brentuximab vedotin (BV; CD30-directed immunoconjugate). (See 'Induction therapy' below.)

●Response-guided induction therapy – We use response-guided therapy (algorithm 1) because it enables early recognition of an inadequate response to treatment and allows prompt implementation of care for primary refractory disease.

With response-guided therapy, positron emission tomography (PET) is repeated after three cycles of induction chemotherapy (PET3) and is again repeated at the end of induction therapy. (See 'Interim restaging' below.)

●Postinduction management – Postinduction management is informed by disease stage at presentation and disease subtype. (See 'Postinduction management' below.)

●Monitoring – Patients are followed for relapse or treatment-related complications. (See 'Monitoring' below.)

Management differs for children, frail individuals, and patients with breast implant-associated ALCL (BIA-ALCL) or primary cutaneous ALCL (PC-ALCL). (See 'Special populations' below.)

INDUCTION THERAPY — Disease subtype (ie, anaplastic lymphoma kinase [ALK]-negative sALCL versus ALK-positive sALCL) does not affect the choice of induction therapy for sALCL.

BV+CHP — For patients with sALCL, we recommend BV+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone) induction therapy, rather than CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), based on superior outcomes in a randomized trial [19].

●Administration – BV+CHP resembles the CHOP regimen (table 4), but it includes brentuximab vedotin (BV) 1.8 mg/kg intravenously on day 1 of each cycle, rather than vincristine. The dose of BV should be adjusted for mild hepatic impairment [20].

We administer BV+CHP using response-guided therapy, in which positron emission tomography (PET) is performed after three initial treatment cycles (PET3) (algorithm 1). Subsequent management varies according to the disease stage at presentation:

•Advanced stage – For patients with advanced-stage sALCL who achieve a complete response (CR) or partial response (PR) on PET3, we administer three additional cycles (six total cycles) of BV+CHP. (See 'PET3' below.)

•Limited stage – Management of limited-stage sALCL is discussed below. (See 'Limited stage' below.)

BV is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) when used in BV+CHP for front-line treatment of sALCL. Prescribing information for BV carries a warning about the rare occurrence of progressive multifocal leukoencephalopathy. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

●ECHELON-2 trial – Patients with sALCL who were randomly assigned to BV+CHP achieved superior outcomes compared with CHOP in the ECHELON-2 trial [19]. The trial included 316 patients with sALCL (98 with ALK-positive disease and 218 with ALK-negative disease) among the 452 enrolled patients with CD30-positive peripheral T cell lymphomas (PTCL). Compared with CHOP, patients with sALCL who were treated with BV+CHP had superior five-year progression-free survival (PFS; 61 versus 48 percent; hazard ratio [HR] 0.55 [95% CI 0.39-0.79]) and a trend toward better five-year overall survival (OS; 76 versus 69 percent; HR 0.66 [95% CI 0.43-1.01]) [21]. Treatment-related adverse events (AEs) were similar in both trial arms, but there was more grade ≥3 diarrhea (6 versus 1 percent) with BV+CHP; other grade ≥3 AEs with BV+CHP included neutropenia (35 percent), nausea (2 percent), and peripheral sensory neuropathy (4 percent; which later resolved or improved in two-thirds of affected patients) [19,21]. AEs leading to death occurred in 3 and 4 percent of patients treated with BV+CHP and CHOP, respectively.

Although patients with favorable prognosis ALK-positive sALCL (ie, International Prognosis Index [IPI] score ≤2 or Prognostic Index for PTCL [PIT] score 0 to 1) were excluded from enrollment in ECHELON-2 because of their favorable prognosis, we treat such patients with BV+CHP because of its favorable efficacy and toxicity [19].

The FDA and the EMA have approved BV for treatment of adults with sALCL.

When BV is not available — In settings where brentuximab vedotin (BV) is not available, we stratify treatment according to age and medical fitness.

●Younger, fit patients – When BV is not available, we generally treat medically fit, younger (eg, ≤60 or ≤65 years) patients using CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) rather than CHOP, based on better outcomes in retrospective studies that included sALCL among various categories of PTCL.

The choice of treatment should be individualized, but CHOEP was associated with better outcomes than CHOP in younger, fit patients with PTCL in most studies; much of the survival benefit with CHOEP in these studies was associated with ALK-positive sALCL.

•CHOEP administration – In CHOEP, intravenous etoposide 100 mg/m² on days 1 through 3 of each 21-day cycle is added to the CHOP regimen (table 4). An alternate version of CHOEP administers intravenous etoposide 100 mg/m² on day 1 of CHOP, followed by oral etoposide 200 mg/m² on days 2 and 3 of each 21-day cycle.

We assess response to CHOEP after three treatment cycles (PET3) and add three further cycles (six cycles total) for patients with CR or PR on PET3, as described below. (See 'Interim restaging' below.)

•Outcomes – Studies that compared outcomes with CHOEP versus CHOP in PTCL include:

-Dutch tumor registry – Survival was better with CHOEP than CHOP for patients <65 years with ALK-positive sALCL, but this benefit was not seen in patients with ALK-negative sALCL or other types of PTCL [22]. For ALK-positive sALCL, CHOEP was associated with superior five-year OS (90 versus 61 percent), and when adjusted for age and IPI risk score, the HR for mortality using CHOP was 6.33 (95% CI 1.65-24.30). For patients with ALK-negative anaplastic large cell lymphoma (ALCL) and other types of PTCL, CHOEP was associated with similar survival but a trend toward superior CR rates (60 versus 49 percent).

-Swedish Lymphoma Registry – For patients ≥18 years with ALK-positive sALCL, CHOEP was associated with superior OS (HR 0.55 [95% CI 0.32-0.93]) and a trend toward better PFS (HR 0.66 [95% CI 0.41-1.07]), but no such survival benefit was seen for patients with ALK-negative sALCL [23].

-German studies – For patients ≤60 years with ALK-positive sALCL, addition of etoposide to CHOP was associated with improved three-year event-free survival (EFS; 91.2 versus 57.1 percent), while there was a trend toward improved three-year EFS with CHOEP for other categories of PTCL, which included ALK-negative sALCL (60.7 versus 48.3 percent) [11].

-Korean studies – National registry data reported that for patients ≥20 years with PTCL, treatment with CHOEP was associated with inferior OS and increased transfusion requirements when compared with CHOP [24]. The study did not specifically report outcomes data for CHOEP versus CHOP in patients with sALCL.

Only limited data are available for treatment of sALCL with other regimens. As an example, dose-adjusted EPOCH (infusional etoposide, vincristine, doxorubicin, prednisone, cyclophosphamide) is associated with greater toxicity than CHOP with no evidence of better outcomes [25]. Additional details of these and other studies of treatments for PTCL are described separately. (See "Initial treatment of peripheral T cell lymphoma", section on 'Fit, younger patients'.)

●Older or less fit – For older or less-fit patients in settings where BV is not available, we generally treat with CHOP to avoid the increased toxicity of CHOEP.

•CHOP administration – The CHOP regimen (table 4) is administered every three weeks. We assess response by PET after three cycles of CHOP (PET3) and add three further cycles (six cycles total) after demonstration of a CR or PR on PET3, as described below. (See 'Interim restaging' below.)

The most common grade ≥3 AE is neutropenia (approximately 60 percent), while other AEs include mild to moderate alopecia, nausea, vomiting, and infusion-related reactions; treatment-related mortality with CHOP is approximately 1 percent.

•Outcomes – CHOP was associated with 69 percent five-year OS and 48 percent five-year PFS in the ECHELON-2 trial; two-thirds of the 452 enrolled patients had sALCL [19,21]. Grade ≥3 AEs occurred in two-thirds of patients treated with CHOP, including neutropenia in 34 percent, infections in 14 percent, anemia in 10 percent, and peripheral sensory neuropathy in 3 percent. AEs prompted treatment discontinuation in 7 percent and caused death in 4 percent. Additional details of the ECHELON-2 trial are presented above. (See 'BV+CHP' above.)

We do not support use of chemotherapy regimens other than CHOP and CHOEP when BV+CHP is not available. Other regimens that have been used for PTCL, such as dose-adjusted EPOCH, are more toxic, and there is no evidence of better outcomes with sALCL [25].

INTERIM RESTAGING — Positron emission tomography (PET) is repeated after the first three cycles of induction chemotherapy (PET3) and again after completing induction therapy (end-of-induction PET) (algorithm 1).

Response criteria — Response to treatment is judged using the five-point PET scale (Deauville score) (table 5), according to Lugano criteria [26]:

●Complete response (CR) – PET score 0 to 3 (with or without a residual mass) and no evidence of bone marrow involvement

●Partial response (PR) – PET score 4 or 5 with reduced uptake compared with baseline, no new progressive lesions, and bone marrow activity less than baseline

●Stable disease – PET score 4 or 5 (unchanged from baseline), no new lesions, and bone marrow activity unchanged from baseline

●Progressive disease – PET score 4 or 5 (increased compared with baseline), new sites of disease, and new or recurrent bone marrow activity

PET3 — Further management is guided by results of the first three cycles of induction chemotherapy (PET3) (algorithm 1):

●CR or PR – For patients with CR or PR on PET3, we suggest three additional cycles of induction chemotherapy (six cycles total) followed by end-of-induction PET. (See 'End-of-induction PET' below.)

●No response/progressive disease – For patients with no response (ie, stable disease) or progressive disease on PET3, we treat for refractory anaplastic large cell lymphoma (ALCL), as discussed separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

End-of-induction PET — Positron emission tomography (PET) is repeated within six to eight weeks after completing chemotherapy, and the response is judged as described above. (See 'Response criteria' above.)

Post-induction management is guided by the stage at presentation and the results of the end-of-induction PET:

●Advanced stage (See 'Advanced stage' below.)  

●Limited stage (See 'Limited stage' below.)

POSTINDUCTION MANAGEMENT — Postinduction management is guided by the disease stage at initial presentation and by the results from positron emission tomography (PET)/CT performed at the end of induction therapy.

Limited stage — For patients with limited-stage (stages I to II) sALCL, management is guided by results from the end-of-induction PET (algorithm 1). (See 'End-of-induction PET' above.)

Complete response (CR) — For patients with limited-stage sALCL who achieve a CR with end-of-induction PET, we suggest either observation or radiation therapy (RT), rather than hematopoietic cell transplantation (HCT). The choice of observation versus RT should be individualized and made with shared decision making. Adverse effects of transplantation outweigh its potential benefit in this favorable prognosis setting.

Some experts manage stage II sALCL as advanced disease. (See 'Advanced stage' below.)

Limited-stage sALCL is generally associated with good outcomes. In one study, five-year overall survival (OS) was 95 percent and five-year progression-free survival (PFS) was 77 percent for patients with stage I sALCL, while corresponding rates for patients with stage II sALCL were 75 and 52 percent, respectively [27].

No randomized trials have compared observation versus RT consolidation in this setting, and only limited retrospective data are available:

●RT was associated with a trend toward superior outcomes among 118 patients with stage I to II peripheral T cell lymphomas (PTCL) in data from the Swedish Lymphoma Registry; outcomes of patients with sALCL were not analyzed separately [23]. Compared with observation, there were trends toward improved five-year OS (73 versus 53 percent, respectively; hazard ratio [HR] 0.58 [95% CI 0.32-1.05]) and five-year PFS (60 versus 45 percent; HR 0.57 [95% CI 0.32-1.03]) for the 32 patients who received RT. However, when compensating for other risk factors, multivariate analysis reported that RT was not associated with improved outcomes.

●In a single-institution study of 39 patients with stage I to II PTCL (including 20 patients with sALCL), consolidative RT was not associated with differences in OS, PFS, or local control [28].

●Patients with limited-stage anaplastic lymphoma kinase (ALK)-positive sALCL and a favorable prognostic score (International Prognosis Index [IPI] ≤2 or Prognostic Index for PTCL [PIT] 0 to 1) had 90 percent three-year OS in a series of German trials [11]. Prognostic scores for sALCL are described above. (See 'Prognosis' above.)

Partial response (PR) — Further management is guided by the nature of the PR (algorithm 1):

●PR with limited residual disease – For PR with a single site of residual disease (ie, amenable to RT), we suggest RT followed by autologous HCT. (See 'Complete response (CR)' above.)

●PR with more extensive residual disease – For PR with more extensive disease (ie, not suitable for RT), we manage as described for advanced disease. (See 'Advanced stage' below.)

Stable disease or progressive disease — For patients with stable disease or progressive disease after induction therapy, we treat for refractory disease, as discussed separately. (See "Treatment of relapsed/refractory systemic anaplastic large cell lymphoma (sALCL)".)

Advanced stage — For patients with advanced-stage sALCL (stages III to IV), postinduction management is guided by the disease subtype (ie, anaplastic lymphoma kinase [ALK]-positive versus ALK-negative) and results of the end-of-induction PET (algorithm 2). Some experts manage stage II sALCL as advanced-stage disease.

ALK-negative sALCL — For patients with ALK-negative sALCL, we stratify management according to suitability for HCT.

Younger, fit patients — Management of transplant-eligible patients with advanced-stage, ALK-negative sALCL is guided by the end-of-induction PET response (algorithm 2):

●CR – For patients with CR after induction therapy for advanced-stage, ALK-negative sALCL, we suggest either observation or autologous HCT rather than allogeneic HCT. There is no conclusive evidence that autologous HCT is associated with superior survival compared with observation in this setting. The substantial toxicity associated with allogeneic HCT outweighs its potential benefits in this setting.

The choice of approach should be individualized using shared decision making that weighs the potential risks and benefits of autologous transplantation. Experts vary, but the decision may be influenced by prognostic score (table 3), institutional approach, and patient preference.

●PR – Management of patients with PR is guided by the nature of the residual disease:

•Limited residual bulk – For patients with limited residual disease, we suggest RT to convert the response to a CR, followed by autologous HCT. Some experts proceed directly to transplantation without administering RT.

•More extensive disease – For patients with more extensive residual disease, we generally treat as r/r PTCL. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

There is no conclusive evidence that autologous HCT is associated with superior survival compared with observation for patients with advanced-stage, ALK-negative sALCL. Most of the following studies included sALCL among other PTCL subtypes and yielded mixed results.

●Autologous HCT versus observation:

•Meta-analysis – A meta-analysis reported that, compared with observation, there was a trend toward superior survival with autologous HCT in first CR (CR1) for patients with sALCL or other PTCL [29]. Among four studies that compared autologous HCT in CR1 (128 patients) versus observation (468 patients), the HR for OS with transplantation was 0.81 (95% CI 0.31-2.13). The study did not analyze outcomes according to PTCL subtype (ie, sALCL versus other subtypes).

•Swedish Lymphoma Registry – Autologous HCT in CR1 was associated with superior OS (HR 0.58) and PFS (HR 0.56) compared with no-transplant in a retrospective study that included 115 patients with ALK-negative sALCL among 755 patients with PTCL [23].

•LYSA – A retrospective review by the Lymphoma Study Association (LYSA) of 269 patients ≤65 years with PTCL, which included 68 with ALK-negative sALCL, reported that survival was similar for 134 patients assigned to autologous HCT compared with 135 who were not assigned to transplantation [30]. OS and PFS did not differ according to ALK-negative sALCL versus other PTCL subtypes.

•COMPLETE – There was no significant difference between outcomes with autologous HCT in CR1 versus observation among 30 patients with ALK-negative sALCL in the multicenter Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) registry [31]. Among the entire cohort of 119 patients with PTCL (36 transplanted versus 83 not transplanted), transplantation was associated with improved OS and PFS, but this was primarily due to benefits in patients with non-sALCL types of PTCL. Among patients with ALK-negative sALCL, two-year PFS for the four transplanted patients was 100 percent, compared with 84 percent for the 26 patients who were not transplanted. Survival was better for patients with sALCL compared with patients with other PTCL subtypes.

•ECHELON-2 – This trial, which randomly assigned patients to BV+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone) versus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for induction therapy, included 113 patients with ALK-negative sALCL (among 177 patients) [32]. Clinicians were allowed to choose autologous HCT in CR1 versus observation for their patients; transplantation was used in 22 percent of patients who received BV+CHP and in 17 percent who received CHOP. PFS was superior for transplanted patients compared with no-transplant (HR 0.35 [95% CI 0.13-0.98]). Median PFS for patients with ALK-negative sALCL was not reached for either approach after four years of follow-up.

•Others – Other studies that included patients with sALCL also reported mixed results for autologous transplantation in CR1 versus observation [33-38].

In addition to the above studies of transplantation versus observation, autologous HCT was not associated with better outcomes than sequential consolidation chemotherapy in a series of randomized trials from Groupe d'Etude des Lymphomes de l'Adulte (GELA) [39-41].

●Autologous HCT versus allogeneic HCT – Autologous HCT was compared with allogeneic HCT in the following studies:

•LYSA-German Lymphoma Alliance – There was no difference in OS among 67 patients with PTCL who were randomly assigned to autologous HCT in CR1 versus allogeneic HCT in CR1, but the causes of death differed significantly; the trial was closed prematurely in the face of high rates of transplantation-related mortality (TRM) with allogeneic HCT [42]. Relapses were more frequent with autologous HCT (36 versus 0 percent), while 31 percent of patients who underwent allogeneic HCT died from TRM compared with no such deaths among 41 patients who underwent autologous HCT. Among 14 patients with ALK-negative sALCL, nine were assigned to autologous HCT and five to allogeneic HCT, but the data were not analyzed according to PTCL subtype.

•Italian study – There was no difference in survival among patients ≤60 years with PTCL (including 12 with ALK-negative ALCL) who underwent autologous HCT versus allogeneic HCT in CR1 [43]. Among 38 patients who had an adequate response to induction therapy, 23 underwent allogeneic HCT and 14 underwent autologous HCT (due to lack of a suitable graft donor). With median follow-up of 40 months, there was no difference in OS or PFS between transplant techniques, but the study was not designed or powered to evaluate differences among transplant types or disease subtypes.

Not transplant eligible — Patients with advanced-stage, ALK-negative sALCL who are not eligible for transplantation are observed for relapse, as described below. (See 'Monitoring' below.)

ALK-positive sALCL — For patients with CR after induction therapy for extensive-stage, ALK-positive sALCL, we suggest observation rather than transplantation, based on generally favorable outcomes with observation and limited experience with transplantation in this setting (algorithm 2).

Observation was associated with superior outcomes in patients with ALK-positive sALCL compared with patients with ALK-negative sALCL according to the Swedish Lymphoma Registry [23]. Compared with the outcomes of patients who were observed for ALK-negative sALCL together with patients with other types of PTCL who underwent autologous HCT in CR1, observation for patients with ALK-positive sALCL was associated with superior survival (HR 0.55 [95% CI 0.33-0.94]).

For older or less-fit patients with any stage of sALCL who have less than CR after induction therapy, we manage for r/r disease, as described separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

MONITORING — Patients are periodically evaluated 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 (LDH).

●Imaging – We generally perform CT no more than every six months for the first two years, then annually for years 3 to 5 or as clinically indicated. Positron emission tomography (PET) may be useful in certain circumstances (eg, monitoring bone disease), but it is associated with greater radiation exposure. Some experts favor PET surveillance.

Care should be taken to limit PET and/or CT, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)

Relapse can be suggested by changes on imaging studies, but it must be confirmed by biopsy. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

SPECIAL POPULATIONS — Management of children, frail adults, favorable prognosis sALCL, breast implant-associated anaplastic large cell lymphoma (BI-ALCL), and primary cutaneous (PC)-ALCL differs from the approach described above.

Frail patients — For patients who cannot tolerate anthracycline-based chemotherapy, we suggest single-agent brentuximab vedotin (BV) rather than other treatments. Palliative radiation therapy (RT) or best supportive care are also reasonable options. Treatment with single-agent BV is discussed separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

BV is not approved as a single agent for front-line treatment of sALCL by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

Pediatric sALCL — sALCL accounts for 15 percent of pediatric non-Hodgkin lymphoma (NHL) and 90 percent of cases are anaplastic lymphoma kinase (ALK) positive [44].

Most sALCL in children is ALK positive, and its treatment is associated with better outcomes compared with adults. We encourage participation in a clinical trial.

For children with sALCL, we suggest enrollment in a clinical trial; outside of a trial, we suggest treatment according to ALCL99 protocol.

ALCL99 (NCT00006455) is the current standard treatment for sALCL in children ≤21 years [45,46]. This multiagent regimen was associated with 93 percent two-year overall survival (OS) and 74 percent two-year event-free survival (EFS) in a phase 3 international study that enrolled 352 children [45,46]. The ALCL99 regimen is toxic and was associated with grade 4 neutropenia in 60 percent of patients, significant weight gain in 20 percent, and mucositis in 15 percent [47]. Some experts consider APO (doxorubicin, prednisone, and vincristine)-based treatment (eg, POG9315) acceptable, but it may have more long-term toxicity (eg, cardiac events) [48].

Prognosis of sALCL in children is considerably better than in adults, and multiagent chemotherapy has been associated with OS >90 percent; however, relapses occur and EFS was only 70 percent [45,46]. As with adults, OS is better for children with ALK-positive sALCL than with ALK-negative disease (eg, EFS 65 to 75 percent versus 15 to 46 percent, respectively) [49,50].

Relapse and long-term toxicity are significant challenges in children with ALCL, and there is interest in testing BV, vinblastine, and various ALK inhibitors (eg, crizotinib, ceritinib, alectinib) in the front-line setting.

BV+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone) is approved by the FDA only for the treatment of adults with sALCL. However, BV in combination with chemotherapy is approved for the treatment of patients aged ≥2 years with advanced-stage classic Hodgkin lymphoma.

Primary cutaneous ALCL — Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a rare and generally indolent disease that is confined to skin.

PC-ALCL is treated with surgical excision and/or RT. It is generally not necessary to treat with chemotherapy, except for relapse, as described separately. (See "Primary cutaneous anaplastic large cell lymphoma".)

Breast implant-associated ALCL — Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare form of peripheral T cell lymphoma (PTCL) that arises in the setting of textured-surface breast implants placed for reconstructive or cosmetic indications.

The malignant cells of BIA-ALCL are confined to the fluid within the capsule surrounding the implant. Patients with BIA-ALCL are managed with removal of the implant, resection of any disease mass with negative margins, and total capsulectomy. Other aspects of management are discussed separately. (See "Breast implant-associated anaplastic large cell lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Description – Anaplastic large cell lymphoma (ALCL) is a CD30-positive peripheral T cell lymphoma (PTCL) with four distinct subtypes:

•Anaplastic lymphoma kinase (ALK)-positive sALCL

•ALK-negative sALCL

•Primary cutaneous ALCL (PC-ALCL)

•Breast implant-associated ALCL (BIA-ALCL)

Management of PC-ALCL and BIA-ALCL is discussed separately. (See "Primary cutaneous anaplastic large cell lymphoma" and "Breast implant-associated anaplastic large cell lymphoma".)

●Pretreatment evaluation – Pretreatment evaluation must establish the subtype of sALCL, disease stage, and suitability for intensive treatments:

•Disease stage – Limited (stages I to II) versus advanced stage (stages III to IV) (table 1)

•ALK status – ALK-positive versus ALK-negative sALCL (see 'Pathology' above)

•Medical fitness – Suitability for transplantation is based on age and fitness (see 'Medical fitness/transplant eligibility' above)

•Prognostic score – International Prognosis Index (IPI) (table 3) or Prognostic Index for PTCL (PIT) (see 'Prognosis' above)

●Induction therapy – For patients with sALCL, we suggest BV+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone) induction therapy rather than CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (Grade 2B). (See 'BV+CHP' above.)

Management when brentuximab vedotin (BV) is not available is discussed above. (See 'When BV is not available' above.)

●Response-guided therapy – We perform positron emission tomography (PET) after three treatment cycles (PET3) and at end-of-induction (six cycles) (algorithm 1). Response is judged by the five-point PET scale (Deauville score) (table 5), according to Lugano criteria (table 6). (See 'Interim restaging' above.)

•Complete response (CR) or partial response (PR) – For CR or PR on PET3, we suggest completing six cycles of induction therapy (Grade 2C). (See 'PET3' above.)

•Stable or progressive disease – Treat for relapsed/refractory (r/r) sALCL. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

●Postinduction management (see 'Postinduction management' above):

•Limited stage – Based on end-of-induction PET (algorithm 1) (see 'Limited stage' above):

-CR – For patients with limited-stage disease who achieve CR, we suggest observation or consolidation with radiation therapy (RT) rather than hematopoietic cell transplantation (HCT) (Grade 2C).

-Limited PR – For patients with limited residual disease, we suggest RT to convert the response to CR, followed by HCT (Grade 2C). HCT followed by RT is a reasonable alternative.

•Advanced stage (algorithm 2)

-ALK negative – For transplant-eligible patients with CR, we suggest either observation or autologous HCT rather than allogeneic HCT (Grade 2C). (See 'ALK-negative sALCL' above.)

For limited PR, we suggest RT followed by autologous HCT (Grade 2C).

-ALK positive – For CR in patients with advanced-stage, ALK-positive sALCL, we suggest observation rather than transplantation (Grade 2C). (See 'ALK-positive sALCL' above.)

For limited PR in patients with advanced-stage, ALK-positive sALCL, we suggest RT (Grade 2C).

For more extensive PR in patients with either ALK-negative or ALK-positive, advanced-stage sALCL, we treat for r/r sALCL. (See "Treatment of relapsed/refractory systemic anaplastic large cell lymphoma (sALCL)".)

●Special populations

•Frail – For frail patients who are candidates for treatment, we suggest single-agent BV rather than other treatments (Grade 2C). (See 'Frail patients' above.)

•Children – We suggest enrollment in a clinical trial; outside of a trial, we suggest treatment according to ALCL99 protocol (Grade 2C). (See 'Pediatric sALCL' above.)

●Monitoring – Surveillance for relapse and treatment-related adverse effects is described above. (See 'Monitoring' above.)