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

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.

To date, combination chemoimmunotherapies, such as cladribine and rituximab, have shown the best results in HCL-V. Future directions include targeted therapies such as moxetumomab pasudotox, ibrutinib, trametinib, and binimetinib and potentially anti-CD22 chimeric antigen receptor T cell therapy. The purpose of this review is to provide an outline of the diagnostic approach and an update on the therapeutic advancements in HCL-V.

In relapsed/refractory HCL, other drugs are needed: BRAF inhibitors: vemurafenib monotherapy with or without rituximab or dabrafenib in combination with trametinib, an MEK inhibitor (MEKi), as well as the anti-CD22 antibody drug conjugate moxetumomab pasudotox.There are arguments for the use of Bruton's tyrosine kinase inhibitors (BTKi). No mutations were identified in patients with progressive disease, suggesting that the mechanisms of resistance could be different between HCL and CLL. The BTKi that are not yet approved are challenged by the new other targeted treatments.

Most patients respond to purine nucleoside analogs (PNA) like cladribine or pentostatin...Chemo-immunotherapy using PNA and rituximab (R), BRAF, MEK, or Bruton Tyrosine Kinase (BTK) inhibitors may be used. Good results were recently published and achieved with moxetumomab pasudotox (Moxe), an anti-CD22 immunoconjugate. In this review, we will present an update on HCL and HCL-V, focusing on pathophysiology and recent therapeutic advances.

However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22 lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20.

Novel agents have good efficacy in HCL in patients with multiple relapses.

Purine analogs significantly improve survival in patients with HCL. However, patients often relapse, require multiple treatments, and may become refractory. The introduction of novel agents has expanded the spectrum of therapy possibilities in those patients. In the coming years, they will assist standard therapy for patients with HCL who may currently have suboptimal results.

In the event of a first relapse, the preferred option is treatment with immunochemotherapy i.e. a combination of cladribine plus rituximab. Subsequent relapses are treated with moxetumomab pasudotox or BRAF inhibitors which provide indisputable benefits if third-line treatment is required. We will discuss in patients with relapsed/refractory hairy cell leukemia the needs for personalized medicine and the advantages and disadvantages of each treatment modality. The good prognosis for LT requires treatments that are not immunosuppressive, non-myelotoxic, and do not increase the risk of secondary cancers.

The CD22 targeted immunotoxin Moxetumomab pasudotox (Moxe) was approved for the treatment of relapsed/refractory hairy cell leukemia...Resulting immunotoxins were purer and more potent. With some modifications, the method may be applicable for any chromatography-based purification processes and may be run entirely on column.

Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy.

This article covers some of the highlights from the last 6 decades that have led to our current understanding of this fascinating leukaemia - from elucidation of its B-cell origin to discovery of the almost universal occurrence of the BRAF V600E mutation; from the initial successes reported with splenectomy to the more recent development of targeted therapies such as Vemurafenib and Moxetumomab Pasudotox. It also pays tribute to some of the outstanding research in this field focusing particularly on the significant contributions made by the clinical and scientific community in the UK.

While the use of non-chemotherapy based approaches have been developed in recent years, including moxetumomab pseudotox, vemurafenib and ibrutinib, these are used post relapse and there is a need to identify which patients require additional monitoring and/or treatment prior to relapse of their disease. This is the first study to provide a high multiplex analysis of HCL BM microenvironment demonstrating significant immune dysregulation of the BM that does not recover with therapy and identify biomarkers of response to standard of care CDA. Prospective application of these biomarkers will allow early identification and increased monitoring/treatment in patients at increased relapse risk post CDA treatment.

Rituximab has limited single-agent activity, but frequent CR without MRD when combined with purine analog, albeit with chemotherapy toxicities. The anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox can achieve MRD-negative CR in multiply relapsed HCL without chemotherapy toxicities and was FDA approved in 2018 as Lumoxiti. Investigational oral non-chemotherapy options also include Vemurafenib or Dabrafenib/Trametinib targeting BRAF V600E ± MEK, and Ibrutinib targeting Bruton's tyrosine kinase.

Patients in first relapse are also offered this combination if they were initially treated with a single-agent PNA, or if the remission duration was ≥5 years after first-line cladribine plus rituximab. Patients who relapse within 5 years are offered therapy with a novel agent that may include the BRAF inhibitor vemurafenib, alone or in combination with rituximab, dabrafenib in combination with trametinib, the BTK inhibitor ibrutinib, or moxetumomab pasudotox.

Anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox (Moxe), CD20 Mabs rituximab and obinutuzumab, BRAF/MEK inhibitors vemurafenib and dabrafenib-trametinib, and Bruton's tyrosine kinase (BTK) inhibitor ibrutinib have been tested for HCL. High-risk disease including HCL variant and IGHV4-34+ unmutated HCL require further investigation. (197 words).

Eligible pts had received ≥ 2 prior systemic therapies, including ≥ 2 courses of a purine nucleoside analog (PNA) or 1 course of a PNA followed by ≥ 1 course of rituximab or a BRAF inhibitor. An EMA registration dossier has been submitted and validated for review in Dec. 2019.

Eligible pts had received ≥ 2 prior systemic therapies, including ≥ 2 courses of a purine nucleoside analog (PNA) or 1 course of a PNA followed by ≥ 1 course of rituximab or a BRAF inhibitor. An EMA registration dossier has been submitted and validated for review in Dec. 2019.

Eligible pts had received ≥ 2 prior systemic therapies, including ≥ 2 courses of a purine nucleoside analog (PNA) or 1 course of a PNA followed by ≥ 1 course of rituximab or a BRAF inhibitor. An EMA registration dossier has been submitted and validated for review in Dec. 2019.

Eligible pts had received ≥ 2 prior systemic therapies, including ≥ 2 courses of a purine nucleoside analog (PNA) or 1 course of a PNA followed by ≥ 1 course of rituximab or a BRAF inhibitor. An EMA registration dossier has been submitted and validated for review in Dec. 2019.

Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. A phase 3 trial met its endpoint of durable CR with acceptable toxicity, leading to FDA approval of Moxe for relapsed/refractory HCL, under the name Lumoxiti. Moxe combined with rituximab is currently being evaluated in relapsed/refractory HCL to improve the rate of MRD-free CR.

Moxetumomab Pasudotox (Lumoxiti) contains an anti-CD22 Fv and a 38 kDa portion of PE...LMB-100 is a de-immunized variant of the toxin with a humanized antibody that targets mesothelin and a PE toxin that was rationally designed for diminished reactivity with antibodies and B cell receptors...Here we review the immunogenicity of the original and de-immunized PE immunotoxins in mice and patients, the development of anti-drug antibodies (ADAs), their impact on drug availability and their effect on clinical efficacy. Efforts to mitigate the immunogenicity of immunotoxins and its impact on immunogenicity will be described including rational design to identify, remove, or suppress B cell or T cell epitopes, and combination of immunotoxins with immune modulating drugs.

Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 courses of a purine nucleoside analog (PNA) or 1 course of a PNA followed by ≥ 1 course of rituximab or a BRAF inhibitor...Moxetumomab pasudotox-tdfk treatment was associated with a manageable safety profile. Moxetumomab pasudotox-tdfk achieved a high rate of durable responses, demonstrating the ability to achieve MRD negativity in heavily pretreated patients with HCL.