Early PET-driven treatment de-escalation can safely guide subsequent treatment in patients with advanced Hodgkin lymphoma

PET performed after 2 cycles of escalated BEACOPP (BEACOPPesc) can be safely used to guide subsequent treatment in patients with advanced Hodgkin lymphoma (HL). Results of the randomized phase III AHL 2011 study support the response adapted strategy delivering 4 cycles of ABVD for patients not responding to 2 cycles of BEACOPPesc without impairing the disease control.

ABVD is the most widely chemotherapy regimen used as standard treatment of advanced Hodgkin lymphoma. The BEACOPPesc regimen, which delivers more drugs at higher dose intensity, was shown to improve patients PFS but not OS when compared to ABVD, and is associated with a higher risk of hematological toxicity, secondary leukemia and infertility.

The rationale behind the Lymphoma Study Association AHL 2011 trial was that PET performed after 2 cycles of upfront BEACOPPesc (PET2) could identify early responding patients who might benefit from a strategy of dose intensity de-escalation, without impairing the disease control.

The AHL 2011 trial (NCT01358747) evaluated in 16-60 year old HL patients with stage III, IV or high risk IIB, a treatment strategy driven by PET after 2 BEACOPPesc cycles, delivering 4 cycles of ABVD for PET2 negative patients and 4 cycles of BEACOPPesc for PET2 positive patients. This PET driven strategy (experimental arm) was randomly compared to a standard treatment not adapted by PET delivering 6 cycles of BEACOPPesc (standard arm). The allocation of treatment in the experimental arm was based on the central review of PET2 interpreted according to Deauville criteria within 48 hours. PFS was the primary endpoint of the study with a hypothesis of non-inferiority of the PET driven arm compared to the standard arm. 

From May 2011 to May 2014, 823 patients were registered, including 413 and 410 patients in the standard and experimental arm, respectively. Patients characteristics were well balanced between both arms: median age was 30 y, 63% were male, 74% had nodular sclerosis HL, 11% stage IIB, 28% stage III, 60% stage IV, and 58% an IPS ≥3. PET2 positivity rate was similar in the standard (12%) and experimental arm (13%). Based on PET2 results, 346 (84%) patients received 4 cycles of ABVD and 51 (12%) 4 additional cycles of BEACOPPesc in the experimental arm.

The treatment toxicity was significantly higher in patients receiving 6 cycles of BEACOPPesc compared to those who received 2 cycles of BEACOPPesc + 4 cycles of ABVD, with more frequent grade ≥3 AE (anemia [69% versus 28%], leukopenia [92% versus 90%], thrombocytopenia (66% versus 40%), and sepsis (7% versus 4%). 192 serious adverse events (SAE) related to treatment occurred in 110 (27%) patients treated with 6 cycles of BEACOPPesc (leading to death in 6 cases), compared to 114 SAE (leading to death in 2 cases) in 71 (17%) patients treated with 2 x BEACOPPesc + 4 x ABVD (p<0.002). In these latter patients most of SAE (66%) occurred during the 2 first cycles of chemotherapy. Twenty-eight patients (6.8%) in the standard arm discontinued treatment due to toxicity, compared to 4 patients (1%) in the experimental arm (p<0.001).

With a median follow up of 50.4 months, the 4-year PFS was similar in the standard arm (87.4%) and the PET driven arm (87.1%; p=0.68). PET2 positivity was related to a significantly lower 4-year PFS compared to PET2 negative patients in the whole population (75.4% vs 92.5%; p<0.001). OS was similar in both arms.

PET performed after 2 cycles of BEACOPPesc can be safely used to guide subsequent treatment and supports the response-adapted strategy delivering 4 cycles of ABVD for patients with negative PET2 reducing the treatment-related immediate toxicity without impairing the disease control. PET positivity after 2 cycles of BEACOPPesc is related to a higher risk of disease progression, encouraging to develop new treatment options in patients with PET2 positive advanced stage HL.

Reference

Casasnovas O, Brice P, Bouabdallah R, et al. Final analysis of the AHL2011 randomized phase III LYSA study comparing an early PET driven treatment de-escalation to a not PET-monitored strategy in patients with advanced stages Hodgkin lymphoma. Presenterd during EHA 2018; Abstract S110.