Anaplastic large cell lymphoma (ALCL) is one of the most common peripheral T-cell lymphomas, and the incidence is higher in blacks than non-Hispanic whites. ALK-positive and ALK-negative ALCL are distinct subtypes that have different characteristics and clinical outcomes. Breast implant–associated ALCL is a rare lymphoma that has a good survival outcome, and a recent study showed that total capsulectomy is essential for treatment. Brentuximab vedotin (BV) is a standard treatment for relapsed/refractory ALCL. The response rate is high at 80–90%; however, once the disease progresses in patients on BV, survival outcome is very poor, with a median overall survival of less than two months.
Key points
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Anaplastic large cell lymphoma (ALCL) is the second most common peripheral T-cell lymphoma, and the incidence is higher in blacks than non-Hispanic whites.
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ALK (anaplastic lymphoma kinase)-positive and ALK-negative ALCL are distinct subtypes that have different characteristics and clinical outcomes; ALK-positive ALCL is more common in younger patients and has a better overall survival.
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Breast implant–associated ALCL is a rare lymphoma that has very good survival outcome, and recent study indicates that total capsulectomy is essential for treatment of this disease.
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Brentuximab vedotin (BV) is a standard therapy for relapsed or refractory ALCL.
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Overall response rate is about 80% to 90%; however, once a patient’s disease progresses on BV, survival outcome is very poor with median overall survival of less than 2 months.
Introduction
Anaplastic large cell lymphoma (ALCL) is a distinct subtype of peripheral T-cell lymphoma (PTCL). ALCL accounts for 3% to 5% of all non-Hodgkin lymphoma and 10% to 20% of childhood lymphomas and consists of about 10% to 15% of PTCLs. The age-adjusted incidence in the United States. for ALCL is 0.2 to 0.25 per 100,000 person-years. Recently, a large study using population-based registry data suggested racial differences in the incidence of ALCL. Asian/Pacific Islanders have significantly lower incidence compared with non-Hispanic whites (incidence rate ratio: 0.59, 95% confidence interval [CI]: 0.49–0.70), while blacks have significantly higher incidence of ALCL compared with non-Hispanic whites (incidence rate ratio: 1.17, 95% CI: 1.03–1.32). In the most recent World Health Organization classification, 3 types of noncutaneous ALCL are recognized. One type associated with translocations involving the ALK gene leading to ALK overexpression (ALK + ALCL) is well established. The other category is morphologically and phenotypically similar to ALK + ALCL but lacks ALK abnormalities of overexpression, and ALK-negative ALCL (ALK − ALCL), which was previously considered a provisional category, is now defined as definite entity based on gene expression profile (GEP) studies that showed that ALK − ALCL has similar features to that of ALK + ALCL and is distinct from other CD30-positive PTCLs. Breast implant–associated ALCL (BIA-ALCL) was first described in 1997 and is now recognized as a distinct new entity, which usually is associated with excellent outcomes. Finally, primary cutaneous ALCL is a distinct subtype with a typically more indolent course and should be distinguished from systemic ALCL.
Introduction
Anaplastic large cell lymphoma (ALCL) is a distinct subtype of peripheral T-cell lymphoma (PTCL). ALCL accounts for 3% to 5% of all non-Hodgkin lymphoma and 10% to 20% of childhood lymphomas and consists of about 10% to 15% of PTCLs. The age-adjusted incidence in the United States. for ALCL is 0.2 to 0.25 per 100,000 person-years. Recently, a large study using population-based registry data suggested racial differences in the incidence of ALCL. Asian/Pacific Islanders have significantly lower incidence compared with non-Hispanic whites (incidence rate ratio: 0.59, 95% confidence interval [CI]: 0.49–0.70), while blacks have significantly higher incidence of ALCL compared with non-Hispanic whites (incidence rate ratio: 1.17, 95% CI: 1.03–1.32). In the most recent World Health Organization classification, 3 types of noncutaneous ALCL are recognized. One type associated with translocations involving the ALK gene leading to ALK overexpression (ALK + ALCL) is well established. The other category is morphologically and phenotypically similar to ALK + ALCL but lacks ALK abnormalities of overexpression, and ALK-negative ALCL (ALK − ALCL), which was previously considered a provisional category, is now defined as definite entity based on gene expression profile (GEP) studies that showed that ALK − ALCL has similar features to that of ALK + ALCL and is distinct from other CD30-positive PTCLs. Breast implant–associated ALCL (BIA-ALCL) was first described in 1997 and is now recognized as a distinct new entity, which usually is associated with excellent outcomes. Finally, primary cutaneous ALCL is a distinct subtype with a typically more indolent course and should be distinguished from systemic ALCL.
Patient and disease characteristics
ALK-Positive Anaplastic Large Cell Lymphoma
Patients with ALK + ALCL are commonly young, with a median age in the 30s; this is also one of the most common lymphoma diagnoses in children. Patients with ALK + ALCL usually present with lymph node enlargement and have frequent extranodal involvement of skin, bone, soft tissue, lung, and liver. About 60% of cases present with advanced stage (stage III/IV) at presentation and often have B symptoms at diagnosis, particularly fever.
ALK + ALCL exhibits a wide histologic spectrum. Several morphologic patterns have been recognized: common type (60%), lymphohistiocytic (10%), small cell (5%–10%), Hodgkin-like (3%), and others as well as mixed or composite patterns (15%). The common type pattern is characterized by large lymphoma cells infiltrating sinuses and/or showing cohesive features ( Fig. 1 ). In all variants, the lymphoma cells have eccentric, horseshoe- or kidney-shaped nuclei, often with an eosinophilic region near the nucleus (so-called hallmark cells). The cytoplasm is abundant and usually basophilic.
ALK + ALCL is a lymphoma of T-/null-cell lineage that is characterized by strong and diffuse CD30 and ALK expression. Most of cases are CD2+, CD4+, CD43+, and CD3−, CD8−, and BCL2−. CD15 and PAX5 are negative (unlike classical Hodgkin lymphoma). Typical genetic abnormality in ALK + ALCL is t(2;5)(p23;q35), which leads to nucleophosmin (NPM1)-ALK fusion protein and is present in 80% of the cases. Different gene partners to ALK have been described, and the pattern of ALK expression by immunohistochemical staining, in part, can predict molecular abnormalities. ALK expression tends to be localized in both the cytoplasm and the nucleus in cases with NPM1-ALK fusion, whereas different partners with ALK show a cytoplasmic restricted or rarely a membranous pattern of expression.
ALK + ALCL is associated with generally good prognosis, with the best outcome among systemic PTCLs. Results from the International Peripheral T-Cell Lymphoma Study demonstrated a 5-year failure-free survival (FFS) and overall survival (OS) of 60% and 70%, respectively. However, at relapse, the FFS for further therapies after relapse is not significantly different from ALK − ALCL.
ALK-Negative Anaplastic Large Cell Lymphoma
Patients with ALK − ALCL are older, with a median age in the 50s. Similar to ALK + ALCL, patients present with advanced stage disease with lymph node enlargement, frequent extranodal involvement, and B symptoms. The morphologic spectrum of ALK − ALCL is similar to ALK + ALCL, except that the neoplastic cells may be more pleomorphic. The neoplastic cells have a T-/null-cell immunophenotype and strongly and uniformly express CD30, but are negative for ALK expression.
Studies have shown that ALK − ALCL is molecularly and genetically heterogeneous. Rearrangement of DUSP22, marked by t(6;7), was found in 30% of cases and is associated with excellent prognosis with 90% long-term survival, whereas TP63 rearrangement, marked by inv(3), was seen in 8% of cases and is associated with poor prognosis with only 17% long-term survival. ERBB4 and COL29A1 are expressed in 24% of ALK − ALCL, mutually exclusive with TP63 rearrangement, and are associated with Hodgkin-like morphology. However, several GEP studies have shown that ALK − ALCL has common signature with ALK + ALCL. Crescenzo and colleagues have shown kinase fusions and the presence of recurrent JAK1 and STAT3 somatic mutations that lead to constitutive activation of JAK/STAT3 pathway in ALK − ALCL. The JAK/STAT pathway is also a downstream signaling pathway of the ALK fusion proteins of ALK + ALCL. This study suggests the importance of the JAK/STAT3 pathway in the pathogenesis of ALCL and supports a rationale for the morphologic and phenotypic similarities between ALK + ALCL and ALK − ALCL.
The survival outcome of ALK − ALCL is worse than ALK + ALCL but better than PTCL-not other specified (PTCL-NOS). The International Peripheral T-Cell lymphoma Study has shown a 5-year FFS and OS of 49% and 36%, respectively. The Group d’Etude des Lymphomes de l’Adulte (GELA) reported that age (<40 or ≥40) and beta 2-microglobulin were key prognostic indicators for ALK − ALCL. The 8-year OS rates of patients in group 1 (age <40 years and beta 2-microglobulin <3 mg/L) and group 4 (age ≥40 years and beta 2-microglobulin ≥3 mg/L) were 84% and 22%, respectively.
Breast Implant–Associated Anaplastic Large Cell Lymphoma
BIA-ALCL usually presents as an accumulation of seroma fluid between the implant and the surrounding fibrous capsule. Greater than 90% of cases are limited stage (stage I/II) at the time of diagnosis. Both saline- and silicone-filled implants can be associated with BIA-ALCL, and the risk factors for developing this disease remain unclear. In a multicenter study of 60 patients, the median time from breast implant to ALCL was 9 years (range: 1–32 years). The median OS in all patients was 12 years, and patients who presented with a mass lesion instead of only effusion had a shorter progression-free survival (PFS), although the median OS was still 12 years. A recent study showed significantly better OS and event-free survival (EFS) in patients who received total capsulectomy compared with patients who received partial capsulectomy, systemic chemotherapy, or radiation therapy. Only 11.4% of patients who received total surgical excision without chemotherapy or radiation experienced events, whereas 54.5% of patients who received chemotherapy alone experienced events indicating the importance of surgical removal of breast implant in this disease. There are no data that suggest a survival benefit from removal of contralateral breast implant in nonbilateral limited stage BIA-ALCL; thus, the removal of contralateral breast implant remains controversial.
Treatment
Front-Line Treatment
There is no one standard treatment for both ALK + ALCL and ALK − ALCL due to a lack of randomized trials; however, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the most commonly used chemotherapy, although the benefit of anthracycline in the treatment of PTCLs has been questioned. The overall response rate (ORR) with CHOP is 70% to 80%, with complete response (CR) rates of around 50% in ALK − ALCL, and a higher response rate of around 90% in ALK + ALCL. The long-term PFS rate for ALK − ALCL after CHOP is only about 30%, whereas ALK + ALCL has a relatively favorable outcome with 5-year PFS exceeding 60%. Based on this survival outcome, ALK + ALCL is generally treated differently than other nodal PTCLs including ALK − ALCL.
Given the poor outcome with conventional chemotherapy, a more intensive approach has been investigated particularly in non-ALK + ALCL PTCLs. The MD Anderson Cancer Center (MDACC) conducted a phase II study of hyper-CVIDD/MA (cyclophosphamide, vincristine, pegylated liposomal doxorubicin, dexamethasone alternating with high-dose methotrexate and cytarabine) for the first-line therapy for non-ALK + ALCL PTCLs, to evaluate if intensive chemotherapy improves the outcome. Although hyper-CVIDD/MA showed a high CR rate of 83% in patients with ALK − ALCL, median PFS was only 7.5 months with a 3-year PFS of 43%, which is not significantly different from historical data for CHOP therapy. The GELA group performed a retrospective review of patients with ALCL treated in 3 prospective trials. Almost all patients received anthracycline-based combination chemotherapy. Intensive chemotherapy (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) was not associated with improved outcomes as compared with the CHOP regimen.
Other studies showed a potential benefit from adding etoposide to CHOP. The German High-Grade Non-Hodgkin Lymphoma Study Group evaluated the outcome of 320 patients with T-cell lymphoma enrolled in clinical trials. This study included 78 patients with ALK + ALCL and 113 patients with ALK − ALCL. The addition of etoposide to CHOP (CHOEP, etoposide 100 mg/m 2 intravenously on days 1–3 in addition to standard CHOP) improved response rates and was associated with longer EFS in younger patients (18–60 years) with normal lactate dehydrogenase (LDH). In young patients with ALK + ALCL and a normal LDH, the 3-year EFS with CHOEP and with CHOP was 91% and 57%, respectively. In patients with non-ALK + ALCL PTCLs including ALK − ALCL, the 3-year EFS with CHOEP and CHOP was 61% and 48%, respectively. Ellin and colleagues evaluated 755 patients with PTCLs (68 ALK + ALCL, 115 ALK − ALCL) in the Swedish Lymphoma Registry and confirmed that the addition of etoposide to CHOP was associated with superior PFS in patients age 60 or younger, even though no subtype-specific results were provided. Based on these studies, CHOEP is now increasingly used in the first-line treatment of ALCL.
About 30% to 40% of patients with ALK + ALCL and ALK − ALCL are diagnosed with early (stage I/II) stage disease. Currently, there are very limited data available to guide the management of these patients, and most patients are commonly treated similarly to those who have aggressive B-cell lymphoma minus the CD20-directed therapy rituximab. MDACC conducted a retrospective analysis of patients with early stage PTCLs and showed relatively favorable outcomes with 5-year PFS and OS of 74% and 79%, respectively. The role of radiation therapy and the optimal number of chemotherapy cycles remain controversial and still need to be addressed.
Consolidative Stem Cell Transplant in First Remission
Given the favorable outcomes with chemotherapy, stem cell transplant as part of first-line treatment is not often considered in patients with ALK + ALCL. In fact, most clinical trials of stem cell transplant in first remission have excluded ALK + ALCL. For other non-ALK + ALCL PTCLs, several studies have evaluated the role of autologous stem cell transplant (auto-SCT) in first-line treatment either in single arm nonrandomized studies or in randomized studies including a minority of patients with PTCL. A German study evaluated CHOP followed by auto-SCT in patients with newly diagnosed PTCLs (excluding ALK + ALCL). Among 83 patients treated, the ORR after high-dose chemotherapy was 66% with a CR rate of 56%. The 3-year OS and PFS were 48% and 36%, respectively. For patients who actually underwent transplant (66% of patients), the 3-year OS was 71%. By comparison, the Nordic group evaluated 6 cycles of CHOEP (etoposide was omitted for patients >60 years) followed by auto-SCT in patients with PTCLs (excluding ALK + ALCL). Among 160 patients treated, the ORR after CHOEP was 82% with CR rate of 51%. By the subtype stratified analysis, 5-year OS of ALK − ALCL was 70%. These outcomes also seem better than historical patients treated by conventional chemotherapy like CHOP. Based on these studies, auto-SCT in first remission in non-ALK + ALCL PTCLs is considered a reasonable option in clinical practice. There are also data suggesting the potential benefit of allogeneic stem cell transplant (allo-SCT) in first remission for patients with PTCLs. Among 29 patients (4 ALK − ALCLs) who were able to undergo upfront allo-SCT, the 2-year OS was 72.5%, 1-year nonrelapse mortality (NRM) was 8.2%, and there seems to be a plateau in OS after 2 years although with short follow-up. However, allo-SCT is associated with significant toxicities, and this approach is still considered highly investigational and thus should only be performed on well-designed clinical trials (See Tejaswini M. Dhawale and Andrei R. Shustov’s article, “ Autologous and Allogeneic Hematopoietic Cell Transplantation in Peripheral T/NK-cell Lymphomas: A Histology-Specific Review ,” in this issue).
Treatment for Relapsed/Refractory Disease
Generally, the survival outcome of patients with PTCLs who experienced relapse or progression following first-line treatment is very poor. The British Columbia Cancer Agency analyzed 153 patients with relapsed/refractory PTCLs (11 ALK + ALCL, 27 ALK − ALCL) and showed that the median PFS and OS after the first recurrence or disease progression were only 3.1 and 5.5 months, respectively, without stem cell transplant. Of note, patients who received chemotherapy after progression of relapse did not have significantly improved survival with a median OS and PFS of only 6.5 and 3.7 months, respectively. However, the study included patients who were diagnosed between 1976 and 2010, and none of the new agents described in later discussion were used during that time period. Notably, there was no difference in PFS and OS after first recurrence or disease progression by PTCL subtypes.
MDACC has assessed the survival outcome of patients with ALCL diagnosed between 1999 and 2014 who experienced disease progression or relapse after first-line and subsequent therapy. A total of 176 patients (74 ALK + ALCL, 102 ALK − ALCL) diagnosed between 1999 and 2014 were retrospectively analyzed. The median age of the patients was 50 (range: 18–89). With a median follow-up of 64 months, 111 patients (38 ALK + ALCL, 73 ALK − ALCL) experienced progression/relapse after first-line therapy. The median PFS following second-line therapy in patients with ALK + ALCL and ALK − ALCL was 5.2 and 3.0 months, respectively ( Fig. 2 ).
Related posts:
Peripheral T-Cell Lymphoma: The Beginning of the End of the Beginning
Peripheral T-Cell Lymphoma, Not Otherwise Specified
Uncommon Variants of T-Cell Lymphomas
Mycosis Fungoides and Sezary Syndrome
Autologous and Allogeneic Hematopoietic Cell Transplantation in Peripheral T/NK-cell Lymphomas
Angioimmunoblastic T-Cell Lymphoma
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