Biomodulatory Treatment Regimen, MEPED, Rescues Relapsed and Refractory Classic Hodgkin’s Disease

Abstract

Introduction: Current combined intensive chemotherapy and radiation regimens yield excellent survival rates in advanced classic Hodgkin’s lymphoma (cHL). However, acute toxicity in elderly, comorbid patients can be challenging and long-term survival in refractory patients remains poor.Patients and Methods: We report on six patients with r/r HL, three patients with long-term follow-up, three newly treated, after biomodulatory therapy. All patients received MEPED (treosulfan 250 mg p.o. daily, everolimus 15 mg p.o. daily to achieve serum trough levels of 15 ng/ml, pioglitazone 45 mg p.o. daily, etoricoxib 60 mg p.o. daily and dexamethasone 0.5 mg p.o. daily). Patients had either received every at that time approved systemic treatment or were ineligible for standard treatment, including immune checkpoint inhibition (ICPi) due to prior demyelinating autoimmune polyneuropathy, myasthenia gravis and previous allogeneic hematopoietic-stem-cell transplant (alloHSCT). Medication was administered continuously from day 1. One patient with relapse after alloHSCT received trofosfamide 50 mg daily instead of treosulfan to avoid risk of increased myelotoxicity. The patients were treated in individual healing attempts outside a clinical trial after institutional review board approval. 18F-fluoro-2-deoxy-d-glucose positron emission tomography combined with computed tomography scan (FDG-PET/CT) was performed to monitor treatment and follow-up.Results: In the three newly treated patients, CT scans showed partial remissions after 2–5 months on MEPED treatment. Two patients had achieved PET Deauville score 2 and 3, while the third remained positive at Deauville score 5. One patient achieving PR became eligible for alloHSCT, while the other two patients continued treatment with MEPED. All patients eventually achieved continuous complete remission (cCR), one after consecutive alloHSCT, one after discontinuing MEPED consolidation for >1 year and one on on-going MEPED consolidation, respectively. Only one patient experienced Grade 3 toxicity (bacterial pneumonia) requiring temporary discontinuation of MEPED for 10 days. All three previously published patients received allo HSCT for consolidation and have achieved cCR.Conclusions: MEPED is well tolerated with low toxicity and highly efficacious in relapsed/refractory cHL, including severely comorbid patients. Due to its immunomodulatory components, MEPED might also have a synergistic potential when combined with ICPi but requires further evaluation within a clinical trial.

Apoptosis as Driver of Therapy-Induced Cancer Repopulation and Acquired Cell-Resistance (CRAC): A Simple In Vitro Model of Phoenix Rising in Prostate Cancer

“…Recently, anakoinosis was proposed as a successful way of modulating cancer tissue homeostasis by re-establishing a new equilibrium via "tissue editing" [50]. Pro-anakoinotic drugs act as tissue master modulators, thereby preventing tissue defenses, providing a concerted regulative activity profile of a treatment schedule's single components, and may facilitate long-term tumor control or even continuous complete remission [51][52][53][54]. Importantly, this approach showed that classic pro-apoptotic drugs are un-necessary to induce long-term tumor control or continuous complete remission [55]: anakoinosis would thus bypass the intrinsic limitation of the current pro-apoptotic therapies by aiming at bio-modulation instead of cytotoxicity, possibly avoiding CRAC as suggested by in silico modeling [56].…”

Drug Repurposing by Tumor Tissue Editing

“…The two-step identification of drugs for repurposing encompasses the selection of appropriate combinations of approved drugs with pro-anakoinotic activity profiles for establishing novel functional status for therapeutically 'editing' tumor tissues by induction of differentiation, transdifferentiation, or establishing immunosurveillance and tumor cell death etc. (5,11,(19)(20)(21)(22)(23). The second step is to select approved targeted therapies for enhancing the biomodulatory effects or for establishing prerequisites for the induction of continuous complete remission (4,6,10,24,25).…”

“…Clinically, tumor tissue editing can adequately design tumor tissues, a prerequisite for efficacious use of mTOR inhibitors in refractory metastatic uveal melanoma or refractory Hodgkin's disease with metronomic low-dose chemotherapy and a PPARa/g agonist (21,23). In uveal melanoma long-term disease stabilization with significant improvement of ECOG status was achieved, in refractory Hodgkin's disease even induction of complete remission, moreover continuous complete remission after discontinuation of the metronomic schedule (26).…”

Editorial: Anakoinosis for promoting tumor tissue editing: Novel therapeutic opportunities for establishing clinically relevant tumor control by targeting tumor plasticity

“…Klicken oder tippen Sie hier, um Text einzugeben. But, tumor plasticity also opens a therapeutic window by tumor tissue editing, the possibility to induce completely novel tumor phenotypes by introducing therapeutically relevant editing techniques that redirect hallmarks of cancer into biologic hallmarks attenuating tumor growth or even facilitate tumor cell death as prerequisite for continuous complete remission (cCR), also in relapsed or refractory neoplasias ( 10 , 11 ). Aims of tumor tissue editing strategies may be differentiation induction in hematologic neoplasia or solid tumors, reconstitution of immunosurveillance, control of tumor-associated inflammation, inhibition of M-CRAC etc.…”