Standard Treatment Options for Anaplastic Large Cell Lymphoma

POG-8314/POG-8719/POG 9219: Three cycles of chemotherapy (no radiation or maintenance therapy) for stage I and stage II disease.[20]

GER-GPOH-NHL-BFM-90: Prephase plus three cycles of chemotherapy (only for completely resected disease).[15]

APO regimen: Doxorubicin, prednisone, and vincristine.[16] This regimen can be administered in the outpatient setting. The duration of therapy is 52 weeks, and the cumulative dose of doxorubicin is 300 mg/m2. No alkylator therapy is given.

FRE-IGR-ALCL99: Dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, intravenous (IV) methotrexate (3 g/m2 in one study arm), cytarabine, prednisolone, and vinblastine.[21] This regimen usually requires hospitalization for administration. The total duration of therapy is 5 months, and the cumulative dose of doxorubicin is 150 mg/m2.

The POG-9219 study for patients with low-stage lymphoma used three cycles of doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP).[20]

The POG-9219 study for patients with low-stage lymphoma used three cycles of doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP).[20]

The 5-year event-free survival (EFS) rate was 88% for patients with large cell lymphoma (anaplastic large cell lymphoma and diffuse large B-cell lymphoma).

The FRE-IGR-ALCL99 trial used three cycles of chemotherapy after cytoreductive prophase for patients with stage I, completely resected disease. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease.[22][Level of evidence B4]

The FRE-IGR-ALCL99 trial used three cycles of chemotherapy after cytoreductive prophase for patients with stage I, completely resected disease. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease.[22][Level of evidence B4]

Only 6 of 36 patients with stage I disease had complete resections. No treatment failures were reported for these 6 patients.

The FRE-IGR-ALCL99 trial used three cycles of chemotherapy after cytoreductive prophase for patients with stage I, completely resected disease. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease.[22][Level of evidence B4]

The 3-year EFS (77%) and overall survival (OS) (97%) rates for patients without complete resections were not statistically different from the outcomes for patients with higher-stage disease.

The German Berlin-Frankfurt-Münster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell NHL therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]).[15,23,24]; [21][Level of evidence A1] Building on these results, the European Intergroup for Childhood NHL group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen).

The German Berlin-Frankfurt-Münster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell NHL therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]).[15,23,24]; [21][Level of evidence A1] Building on these results, the European Intergroup for Childhood NHL group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen).

First, this randomized study demonstrated that methotrexate 1 g/m2 infused over 24 hours plus intrathecal methotrexate and methotrexate 3 g/m2 infused over 3 hours without intrathecal methotrexate yielded similar outcomes.[23][Level of evidence A3] However, methotrexate 3 g/m2 over 3 hours had less toxicity than methotrexate 1 g/m2 over 24 hours.[23]; [21][Level of evidence B1]

The German Berlin-Frankfurt-Münster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell NHL therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]).[15,23,24]; [21][Level of evidence A1] Building on these results, the European Intergroup for Childhood NHL group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen).

Second, patients in the FRE-IGR-ALCL99 trial were randomly assigned to receive either limited vinblastine or prolonged (1 year) vinblastine exposure. Patients who received the vinblastine-plus-chemotherapy regimen had a better EFS rate in the first year after therapy (91%) than did those who did not receive vinblastine (74%). However, after 2 years of follow-up, the EFS rate was 73% for both groups.[24][Level of evidence B1] This suggests that the longer therapy in the vinblastine group delayed, but did not prevent, relapse.

The COG-ANHL0131 (NCT00059839) trial showed that the addition of vinblastine to the doxorubicin, prednisone, and vincristine (APO) regimen increased toxicity, but did not improve the survival of patients with anaplastic large cell lymphoma.[13]

The earlier Pediatric Oncology Group (POG) trial (POG-9317) demonstrated no benefit of adding methotrexate and high-dose cytarabine to 52 weeks of the APO regimen.[16]

The Italian Association of Pediatric Hematology/Oncology group used a leukemia-like regimen for 24 months in the LNH-92 trial. The results of this study were similar to those of studies that used other regimens, although the duration of first remission was prolonged by the longer therapy.[17]

The CCG-5941 study tested an approach similar to that used in the LNH-92 trial, with more intensive induction and consolidation with maintenance for a total duration of therapy of 1 year. Similar outcomes and similar significant increase in hematologic toxicity were observed.[18][Level of evidence B4]

One arm of the COG ANHL12P1 (NCT01979536) study added brentuximab vedotin to the ALCL99 trial chemotherapy backbone, and 68 patients were enrolled.[25]

One arm of the COG ANHL12P1 (NCT01979536) study added brentuximab vedotin to the ALCL99 trial chemotherapy backbone, and 68 patients were enrolled.[25]

Patients who received the brentuximab vedotin–containing regimen had a 2-year EFS rate of 79% (95% confidence interval [CI], 67%–87%) and an OS rate of 97% (95% CI, 88%–99%). Patients who received the ALCL99 trial therapy without brentuximab vedotin had an estimated 5-year progression-free survival (PFS) rate of approximately 70%.

One arm of the COG ANHL12P1 (NCT01979536) study added brentuximab vedotin to the ALCL99 trial chemotherapy backbone, and 68 patients were enrolled.[25]

All events occurred after completion of therapy, with median time from diagnosis to relapse of 7.5 months (range, 5.5–22.0 months).

One arm of the COG ANHL12P1 (NCT01979536) study added brentuximab vedotin to the ALCL99 trial chemotherapy backbone, and 68 patients were enrolled.[25]

The addition of brentuximab vedotin to ALCL99 trial chemotherapy produced toxicity similar to what was observed in the ALCL99 trial.

One arm of the COG ANHL12P1 (NCT01979536) study added brentuximab vedotin to the ALCL99 trial chemotherapy backbone, and 68 patients were enrolled.[25]

This study confirmed the poor prognosis associated with minimal disseminated disease (MDD) in the peripheral blood at diagnosis. Patients with MDD (n = 22; 37%) had a 5-year EFS rate of 57.8%, compared with patients without MDD (n = 37; 63%) who had a 5-year EFS rate of 84.9%.

The second arm of the COG ANHL12P1 study added crizotinib to the ALCL99 trial chemotherapy backbone, and 66 patients were enrolled.[26]

The second arm of the COG ANHL12P1 study added crizotinib to the ALCL99 trial chemotherapy backbone, and 66 patients were enrolled.[26]

Patients who received the crizotinib-containing regimen had a 2-year EFS rate of 76.8% (95% CI, 68.5%–88.1%) and a 2-year OS rate of 95.2% (95% CI, 85.7%–98.4%). Patients who received ALCL99 trial therapy without crizotinib had an estimated 5-year PFS rate of approximately 70%.

The second arm of the COG ANHL12P1 study added crizotinib to the ALCL99 trial chemotherapy backbone, and 66 patients were enrolled.[26]

All events occurred after completion of therapy, with median time from diagnosis to relapse of 7.4 months (range, 4.2–28.9 months).

The second arm of the COG ANHL12P1 study added crizotinib to the ALCL99 trial chemotherapy backbone, and 66 patients were enrolled.[26]

The addition of crizotinib produced an unexpectedly high rate of thromboembolic events. Eleven of the first 41 patients (26.8%; 95% CI, 14.2%–42.9%) experienced grade 2 or higher thromboembolic adverse events. Among 25 patients enrolled after instituting mandatory prophylactic anticoagulation, 2 patients (8%) experienced grade 2 or higher thromboembolic events. Given the high rate of thromboembolic events, the authors recommend not using crizotinib with ALCL99 trial chemotherapy.

The second arm of the COG ANHL12P1 study added crizotinib to the ALCL99 trial chemotherapy backbone, and 66 patients were enrolled.[26]

Patients with MDD in the peripheral blood at diagnosis (n = 20) had a 5-year EFS rate of 58.1%, while patients without MDD (n = 37) had a 5-year EFS rate of 85.6%.