Reinduction therapy with everolimus in combination with dexamethasone, high‐dose cytarabin and cisplatinum in patients with relapsed or refractory classical Hodgkin lymphoma: an experimental phase I/II multicentre trial of the German Hodgkin Study Group (GHSG HD‐R3i)

Abstract

Summary Reinduction chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second‐line standard of care for transplant‐eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high‐dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant‐eligible patients aged 18–60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase‐I‐part) was administered on day 0–13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end‐point of computed tomography (CT)‐based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT‐based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end‐point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.

Peroxisome proliferator-activated receptorα/γ agonist pioglitazone for rescuing relapsed or refractory neoplasias by unlocking phenotypic plasticity

“…Tissue editing approaches, and therapies including maximum tolerable doses to induce maximized apoptosis induction, seem to be mutually exclusive, as exemplified from the literature for mTOR inhibitors in r/rHL, interferon-α in RCCC or epigenetic modifiers ( 21 , 22 , 30 , 37 , 118 , 153 , 167 – 169 ).…”

“…In contrast to mLCH, only the addition of everolimus to the mLCH schedule induced cCR in r/r HL ( 22 , 23 , 151 , 152 ). Importantly, mTOR inhibition has been reported to be inefficacious in addition to pulsed chemotherapy ( Table 2 ) ( 22 , 151 , 153 ). Editing non-oncogene addiction for successful clinical access of mTOR inhibition might also enhance immunosurveillance in r/r HL ( 154 ).…”

Addressing Genetic Tumor Heterogeneity, Post-Therapy Metastatic Spread, Cancer Repopulation, and Development of Acquired Tumor Cell Resistance

“…The addition of everolimus to pulsed standard chemotherapy in r/r HL failed to show any beneficial clinical effect [ 142 ]. Therefore, the clinical data reveal that tissue editing effects in r/rHL are associated with an edited non-oncogene addiction to mTOR [ 142 ] ( Figure 1 ).…”

Advances in the treatment of Hodgkin's lymphoma (Review)

“…Another phase I/II multicenter trial conducted by the German Hodgkin Study Group evaluated the effect of adding everolimus to the standard DHAP towards improving the CR rate of reinduction chemotherapy. Although the addition of everolimus to DHAP was feasible, the efficacy of the combinatorial therapy failed to achieve an improvement (83).…”