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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The immunostimulant plerixafor (MozobilTM, Figure 9.10) is a small-molecule chemokine receptor antagonist that mobilizes the movement of hematopoietic stem cells into peripheral blood for collection and subsequent autologous transplantation back into patients for the treatment of lymphoma or multiple myeloma. It is usually given under specialist supervision following four days’ treatment with a Granulocyte-Colony Stimulating Factor (G-CSF). The agent was developed by AnorMED, which was subsequently acquired by Genzyme in 2006. Plerixafor has orphan drug status in the US and EU, where it was approved for hematopoietic stem cell mobilization in 2008 and 2009, respectively. Structure of plerixafor (MozobilTM).
Collection of stem cells in (autologous) donors by apheresis
Published in Cut Adeya Adella, Stem Cell Oncology, 2018
As discussed, in the bone cavity, HPCs are bound to stromal cells and various extracellular proteins. Administration of G-CSF leads to the release of a variety of serine proteases from granulocytes. This takes days. These proteases disrupt the binding between stromal cells and stem cells and with it the release of the HPCs in the peripheral circulation. Unfortunately, G-CSF mobilization has a 5-30% failure rate among healthy donors and patients. Risk factors for a sub-optimal HPC mobilization are ages above 60 years, disease status, duration of the previous chemo- and radiotherapy. Mobilization in patients is preferably achieved with chemotherapy followed with G-CSF (“chemo mobilization”). Usually, a higher number of stem cells are available in the peripheral blood stream for harvesting than after G-CSF only. Since some years, plerixafor became available for autologous HPC mobilization. Plerixafor leads direct antibody mediated interference with the CXCR4 receptor binding leading to peak levels of CD34-positive cells in the peripheral circulation 6-9 hours after administration. Plerixafor is used in combination with G-CSF when G-CSF mobilization shows to be insufficient.
Dealing with Dropouts
Published in Ying Yuan, Hoang Q. Nguyen, Peter F. Thall, Bayesian Designs for Phase I–II Clinical Trials, 2017
Ying Yuan, Hoang Q. Nguyen, Peter F. Thall
An illustrative example is a phase I–II trial to find the optimal dose of plerixafor as salvage therapy for refractory or resistant AML, where Toxicity may occur at any time during the first 30 days from the start of treatment, while Efficacy is evaluated up to 90 days. Five plerixafor dose levels were investigated, 0.1, 0.3, 0.5, 0.7, 0.9 mg/kg, combined with a fixed dose of 10 mcg/kg G-CSF. Efficacy was defined as morphologic CR, or morphologic CR with incomplete blood count recovery (CRi). CR was defined as <5% blasts in bone marrow aspirate, with marrow spicules and > 200 nucleated cells, no blasts with Auer rods, no persistent extramedullary disease, absolute neutrophil account > 1,000/mm3, and platelet count > 100,000/mm3. CRi was defined as CR with the exception of neutropenia < 1,000/mm3 or thrombocytopenia <100,000/mm3. Toxicity was defined as grade 4 or higher adverse events attributable to either leukostasis or tumor lysis, grade 3 toxicities attributable to leukostasis or tumor lysis that did not improve with standard supportive care measures (e.g., intravenous fluids, supplemental oxygen, leukapheresis) within 24 hours to achieve ≤ grade 2, or persistent grade 3 or higher neutropenia. The goal was to find a dose with highest Efficacy subject to the constraint . Because the follow-up period for assessing YE was long, it was anticipated that a substantial number of patients might drop out before YE could be scored.
Novel systemic treatment approaches for metastatic pancreatic cancer
Published in Expert Opinion on Investigational Drugs, 2022
Klara Dorman, Volker Heinemann, Sebastian Kobold, Michael von Bergwelt-Baildon, Stefan Boeck
Over the past years, the CXCL12/CXCR4/7 axis has gained attention as a mechanism of tumor cell survival, metastasis, and immune resistance [88]. CXCL12, a ligand for CXCR4 and CXCR7 could be detected abundantly in pancreatic and colorectal cancer tissue [89]. Plerixafor, a CXCR4 inhibitor usually known to mobilize stem cells, has also attracted interest as investigational drug in PDAC, after preclinical studies could show that inhibition of the CXCR4 pathway leads to increased chemotherapeutic efficacy [90]. After targeting the CXCL12/CXCR4 interaction by plerixafor in a phase I trial, an integrated immune response was detectable in metastatic sites [89]. Building on this, the phase IIa COMBAT study set out to investigate the combination of a CXCR4 antagonist, pembrolizumab, and chemotherapy, demonstrating increased CD8+ effector T cell tumor infiltration after CXCR4 inhibition and showing promising results regarding ORR, mOS and mPFS (NCT02826486) [91]. Multiple phase II trials targeting the CXCL12/CXCR4/7 axis are currently ongoing (NCT04177810, NCT02907099, NCT04543071, NCT03193190, NCT04901741, NCT03168139).
Feasibility of six cycles of lenalidomide-based triplet induction before stem cell collection for newly diagnosed transplant-eligible multiple myeloma
Published in Hematology, 2021
Satoshi Yoshihara, Kyoko Yoshihara, Yoshifumi Shimizu, Takehito Imado, Hiroyuki Takatsuka, Hiroyuki Kawamoto, Mahito Misawa, Hideki Ifuku, Yokiko Ohe, Masaya Okada, Yoshihiro Fujimori
In our study, 8 of 9 patients mobilized with CY + G-CSF achieved the minimally required number of CD34+ cells (2 × 106/kg). Nonetheless, the median number of CD34+ cells was relatively low, which might be associated with the prolonged lenalidomide exposure. Previous studies have shown that lenalidomide is not toxic to hematopoietic stem cells [15], but it induces the localization of CXCR4 to the cell surface and blockage of receptor internalization [16]. Increased binding of CXCR4 to the SDF-1α secreted by the bone marrow niche might subsequently block the mobilization of hematopoietic stem cells. Blocking the CXCR4 receptor by plerixafor disrupts this cycle and permits mobilization. Indeed, the use of plerixafor overcomes the negative effect of lenalidomide in stem cell mobilization [16–18]. In our study, 2 patients, including 1 patient who had poor mobilization with CY + G-CSF, achieved ≥ 4 × 106 CD34+ cells/kg with G-CSF + plerixafor. Taken together, mobilization after 6 cycles of lenalidomide-based treatment seems to be practicable, particularly when G-CSF + plerixafor is used in the mobilization protocol.
Mantle cell lymphoma: insights into therapeutic targets at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
C-X-C receptor type 4 (CXCR4) chemokine receptor for the stromal derived factor 1 (SDF-1) plays an important role in the migration of MCL cells toward lymph node and bone marrow microenvironments, as well as in prosurvival stromal-cell interactions and drug resistance [144]. It was reported that SOX11 directly transactivates CXCR4 gene thereby contributing to biological aggressiveness of the classical (nodal) MCL subtype (compare to SOX11-negative subtype) [144]. Transcriptional and protein upregulation of CXCR4 was observed in lymphoma cells after pharmacological inhibition of BCR and PI3K signaling. Adaptive upregulation of CXCR4 might via multiple mechanisms confered drug resistant phenotype of lymphoma cells in the bone marrow compartment [145,146]. Anti-CXCR4 blocking antibody plerixafor is currently used during hematopoietic stem and progenitor cell collection in patients, who do not adequately respond to granulocyte colony-stimulating factor. Various CXCR4 antagonists including plerixafor might potentially by used as sensitizers for BTK and PI3K inhibitors [147]. CXCR4 targeted drug delivery might be an alternative strategy to effectively eliminate CXCR4high lymphoma cells [148].