Hematopoietic SCT with cryopreserved grafts: adverse reactions after transplantation and cryoprotectant removal before infusion

Abstract

Transplantation of hematopoietic stem cells (HSC) has been successfully developed as a part of treatment protocols for a large number of clinical indications, and cryopreservation of both autologous and allogeneic sources of HSC grafts is increasingly being employed to facilitate logistical challenges in coordinating the collection, processing, preparation, quality control testing and release of the final HSC product with delivery to the patient. Direct infusion of cryopreserved cell products into patients has been associated with the development of adverse reactions, ranging from relatively mild symptoms to much more serious, life-threatening complications, including allergic/gastrointestinal/cardiovascular/neurological complications, renal/hepatic dysfunctions, etc. In many cases the cryoprotective agent (CPA) used — which is typically dimethyl sulfoxide (DMSO), is believed to be the main causal agent of these adverse reactions and thus many studies recommend depletion of DMSO before cell infusion. In this paper, we will briefly review the history of HSC cryopreservation, the side effects reported after transplantation, along with advances in strategies for reducing the adverse reactions, including methods and devices for removal of DMSO. Strategies to minimize adverse effects include medication before and after transplantation, optimizing the infusion procedure, reducing the DMSO concentration or using alternative CPAs for cryopreservation, and removing DMSO prior to infusion. For DMSO removal, besides the traditional and widely applied method of centrifugation, new approaches have been explored in the last decade, such as filtration by spinning membrane, stepwise dilution-centrifugation using rotating syringe, diffusion-based DMSO extraction in microfluidic channels, dialysis and dilution-filtration through hollow-fiber dialyzers, and some instruments (CytoMate™, Sepax S-100, Cobe 2991, microfluidic channels, dilution-filtration system, etc.) as well. However, challenges still remain: development of the optimal (fast, safe, simple, automated, controllable, effective, and low-cost) methods and devices for CPA removal with minimum cell loss and damage remains an unfilled need.

Adverse reactions during stem cell infusion in children treated with autologous and allogeneic stem cell transplantation

“…25 Although many infusion-related ARs are attributable to DMSO, cellular therapy labs have established protocols to reduce this risk such as lowering the DMSO concentration to 5% in the final product, fractionated infusions and washing. 9 Many studies have shown a clear relationship between DMSO and incidence and/or severity of ARs. 2,3,22 Interestingly, in our pediatric population, we found no association with DMSO volume and ARs.…”

“…1,2 Rare but serious side effects of cryopreserved products include severe respiratory depression, 7 neurotoxicity resulting in amnesia, loss of consciousness or seizure 5,6 and fatal cardiac arrhythmia. 4 Efforts aimed at reducing the DMSO content of infused grafts either by washing or other means have resulted in a reduction of ARs among some studies, 8,9 but not others. 10 No relationship between DMSO and ARs in cord blood transplants has been observed.…”

A Young Patient with Refractory Multiple Myeloma and Dialysis-Dependent Renal Failure has been Cured by Non-Cryopreserved Autologous Stem Cell Transplantation Followed by Live-Related Kidney Transplantation

“…Dimethyl sulfoxide (DMSO) is widely used as a cryopresevant agent for various types of stem cells and other body tissues [21]. DMSO has the following adverse effects: skin irritation; garlic breath or body odor; abdominal pain, nausea, vomiting and diarrhea; bronchospasm, chest tightness and dyspnea; altered heart rate and blood pressure, arrhythmias, heart block and myocardial ischemia; various degrees of neurotoxicity, renal and hepatic dysfunction and death [20,21]. Also, it has in vitro toxicity in the form of induction of red blood cell hemolysis and reduction in platelet aggregation and activity [21].…”

“…For most types of transplants, cryopreservation of HSCs is necessary and is an essential component of the clinical protocol [20]. Dimethyl sulfoxide (DMSO) is widely used as a cryopresevant agent for various types of stem cells and other body tissues [21].…”

“…The diagnostic criteria of MM include: (1) clonal bone marrow (BM) plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma, and (2) at least one of the following: evidence of end-organ damage such as hypercalcemia, anemia, lytic bone lesions and renal insufficiency; clonal BM plasma cells ≥ 60%; involved: uninvolved serum free light chain ratio ≥ 100 and > one focal lesion on magnetic resonance imaging [2,3]. Highrisk features at the diagnosis of MM include: (1) cytogenetic abnormalities that include: 17 p deletion, t(14,16) and t(14, 20), (2) international scoring system stage II or III, (3) presence of comorbid medical conditions that limit therapy, and (4) renal failure, high serum lactic dehydrogenase and plasma cell leukemia [3,5]. In patients with MM having high-risk features, the incorporation of bortezomib into the multi-agent chemotherapeutic regimen VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide) has proven to be effective not only in induction therapy prior to hematopoietic stem cell transplantation (HSCT), but also in consolidation and maintenance therapy post-autologous HSCT (auto-HSCT) [6,7].…”