Lumoxiti (moxetumomab pasudotox)

Three ADCs: Mylotarg, Besponda and Lumoxiti have improved overall survival and event=free survival as well as reduced relapse in 3 types of Leukaemia: AML, ALL and HCL, respectively. Lessons from these three SOC successful ADCs should guide other new ADCs in addressing the ADC-related off target toxicity due to the cytotoxic payload that limits their therapeutic index by using the successful approach of administrating lower doses in a fractionated regimen over time in separate days of the cycle to reduce the severity and frequency of the ADC-related serious toxicities that include ocular damage, long-term peripheral neuropathy and hepatic toxicity etc.

P1, N=15, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Jun 2024 --> Jul 2023

Purine nucleoside analogs remain the cornerstone of treatment, and the addition of rituximab has deepened and prolonged responses in the upfront and relapsed setting...Future efforts will focus on identifying patients with high-risk disease who require intensified regimens. Multicenter collaborations are the key to improving overall survival and quality of life in this rare disease.

Complete remissions in hairy cell leukemia (HCL) with anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox (Moxe) are more durable if minimal residual disease (MRD) negative, but anti-drug antibodies (ADA) can limit the effectiveness of the consolidation cycles needed to eliminate MRD. To prevent ADA, Rituximab or Ruxience was added to Moxe (MoxeR) and 9 (64%) of 14 evaluable patients so far achieved MRD-free CR. ADA was less frequent than Moxe alone historically.

Brexucabtagene autoleucel (brexu-cel), or KTE-X19, is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the United States for adults with R/R mantle cell lymphoma (MCL) and R/R adult acute lymphoblastic leukemia, and in the European Union for adults with R/R MCL after ≥2 prior treatments including a Bruton tyrosine kinase inhibitor (BTKi)... The study will use a basket study design spanning 4 single-armed substudies with the following populations: i) R/R WM (n=60) after ≥2 prior lines of therapy that must have included a BTKi; ii) R/R RT DLBCL variant (n=60) after 1 line of therapy; iii) R/R BL (n=20) after 1 line of therapy; or iv) R/R HCL (n=20) after ≥2 lines of therapy including at least one purine nucleoside analog and moxetumomab pasudotox (if available)... ZUMA-25 is open and enrolling patients at clinical trial sites across North America and Europe (NCT05537766).

Vemurafenib and dabrafenib were assessed in clinical trials. The BRAF mutation is missing in SDRPL and SBLPN: mitogen-activated protein kinase 1 (MAP2K1) mutations were found in 40% of SBLPN and VH4-34+ HCL patients, making possible to use MEK inhibitors (MEKi) such as trametinib, cobimetinib or binimetinib in monotherapy or associated with BRAFi...In this article, we will discuss the main mutations identified in HCL and HCL-like disorders and the signaling pathways potentially involved in the pathogenesis of the different hairy cell disorders. We will discuss the results of the recent clinical trials, which will help us to propose an algorithm useful in clinical practice and we will highlight the different new drugs that may be used in the near future.

Study Design and The study will use a basket study design spanning 4 single-armed substudies: R/R WM (n=60) after ≥2 prior lines of therapy that must have included a BTKi; R/R RT DLBCL variant (n=60) after 1 line of therapy; R/R BL (n=20) after 1 line of therapy; or R/R HCL (n=20) after ≥2 lines of therapy including at least one purine nucleoside analog and moxetumomab pasudotox (if available). Pts will not be eligible if they had received prior CAR T-cell or CD19-targeted therapy or have central nervous system disease. With the aim to potentially provide a new treatment option for pts with rare hematological malignancies that are associated with poor prognosis, this study will be open and enrolling pts at sites in North America and Europe (NCT05537766).

Recently, the Hairy Cell Leukemia Consortium created a platform to work on a definition for MRD, and establish the optimal time point, tissue type and method for measuring MRD. This.

Single-agent rituximab can be a suitable treatment options in patients relapsing after repeated courses of purine analogs, if purine analogs are contraindicated (e.g. in case of poor bone marrow cellularity, high disease infiltration predicting long-lasting aplasia), especially if newer agents (such as moxetumomab or vemurafenib) are not easily available (as it happens in several countries). Rituximab is an effective salvage therapy in pretreated HCL patients after failure of purine analogs, as it permits an adequate disease control with considerably long TTNT periods. It may be repeated if no alternatives are available, although it seems to reduce its efficacy in the following courses.

2-deoxyglucose (2-DG), which competitively inhibits protein glycosylation in the endoplasmic reticulum (ER), induced UPR in B cell lymphoma cell lines. An additional block of protein synthesis by CD22-targeted immunotoxin Moxetumomab pasudotox (Moxe) prevented the upregulation of the protective binding immunoglobulin protein (BiP), although UPR signaling remained active...Furthermore, drug synergy was not only reversed by addition of mannose, which restores proper glycosylation, but was also mimicked by the two other UPR-inducers tunicamycin and bortezomib indicating UPR as cause of synergy... Blocking UPR counter-regulation by simultaneous inhibition of protein synthesis induces synergistic cell death in several malignancies. Synergy depends on IRE1α-mediated deregulation of BID which enhances MCL-1-mediated mitochondrial apoptosis. The broad applicability suggests a cancer cell-specific vulnerability which, together with a cell-targeted arrest of protein synthesis by immunotoxins, generates a unique therapeutic window supporting clinical evaluation.