How is primary systemic anaplastic large cell lymphoma (ALCL) treated?

Updated: May 08, 2020
  • Author: Delong Liu, MD, PhD; Chief Editor: Emmanuel C Besa, MD  more...
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Doxorubicin-based combination chemotherapy stands out as a reference regimen from the trials of peripheral T-cell lymphomas. The CHOP regimen is the most common therapy for systemic ALCL.

However, the German high-grade Non-Hodgkin’s lymphoma study group (DSH-NHL) analyzed data from 289 patients with T-cell lymphomas who either received CHOP or CHOP with etoposide in various phase II and III trials of DSH-NHL. In their analysis, 78 patients had anaplastic lymphoma kinase (ALK)–positive ALCL and 113 had ALK-negative ALCL. Statistically significant improvement in event-free survival (EFS) from 57% to 91% at 3-year was noticed in patients with ALK-positive ALCL who were young (< 60 y) and had normal lactate dehydrogenase (LDH) levels at the time of diagnosis with the addition of etoposide in combination with standard CHOP. Overall survival was not different. [50]

Therefore, the addition of etoposide to the standard CHOP regimen is an important consideration for young patient with ALK-positive ALCL.

More intensive chemotherapy such as hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) did not improve outcome in these patients and was more toxic. [51]

Patients with ALK-positive ALCL have better outcomes than those with ALK-negative ALCL. In the analysis from the DSH-NHL group, 3-year event-free survival and overall survival rates were 76% and 89.8% for ALK-positive ALCL versus 46% and 62% for ALK-negative ALCL, respectively. [50]

The role of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDC/HSCT) in first remission in patients with systemic ALCL is controversial. No randomized controlled trials have compared this strategy with incorporation of the ALK-status. Because ALK-positive patients have a better prognosis, HDC/HSCT is generally reserved for salvage and investigational therapy for upfront disease. In contrast, ALK-negative ALCL is treated like aggressive T-cell lymphomas. A phase 2 trial evaluated an upfront strategy with HSCT in peripheral T-cell lymphoma patients and included 31 patients with ALK-negative ALCL (ALK-positive patients were excluded). Patients with ALK-negative ALCL performed the best, with 5-year overall survival and progression-free survival rates of 70% and 61%, respectively. [52]

Radiation therapy to bulky sites of disease may be necessary after completion of chemotherapy.

In relapse/refractory settings, HDC/HSCT is an important strategy in both ALK-positive and ALK-negative patients. Allogeneic transplantation has also been tried in chemoresistant patients in small series. [53, 54]

Brentuximab vedotin is a CD30-specific antibody-drug conjugate composed of a chimeric monoclonal antibody linked by a dipeptide linker to a cytotoxic antitubulin agent, monomethyl auristatin E (MMAE). It was evaluated in a multicenter phase 2 trial as a single agent in 58 patients with relapse/refractory systemic ALCL in whom 1 or more prior multidrug chemotherapy regimens had failed. The objective response rate (primary endpoint) was 86%, with complete and partial remission rates of 57% and 29%, respectively. ALK-positive patients had complete remission rate of 69%, while 52% of patients with ALK-negative ALCL achieved complete remission. The median progression-free survival following brentuximab vedotin was significantly longer compared with the most recent previous therapy (14.3 mo vs 5.9 mo). [55, 56]

Brentuximab vedotin is approved by the US Food and Drug Administration for relapsed/refractory systemic ALCL. In 2018, the FDA approved brentuximab vedotin for treatment of adult patients with previously untreated systemic ALCL or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP). Approval as frontline therapy was based on the ECHELON-2 phase 3 clinical trial (n = 452), in which brentuximab plus CHP was superior to CHOP with respect to progression free survival (P = 0.011) and overall survival (P = 0.024). [57]

ALK-positive systemic ALCL is also an attractive target for the small molecule ALK-inhibitor, crizotinib. It was approved for locally advanced or metastatic nonsmall cell lung cancer with ALK gene rearrangement in August 2011. A few cases of relapsed ALK-positive systemic ALCL treated with crizotinib have been reported in the literature. Significant clinical benefit was observed in these reports. [58, 59] Currently a phase 1/2 trial to evaluate crizotinib is under way for relapsed/refractory ALK-positive systemic ALCL.

Proteosome inhibitors and lenalidomide have also shown activity in small case series of relapsed refractory T-cell lymphomas, which included few cases of systemic ALCL. [60, 61]

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