The Mexican Way: a feasible approach to avoid DMSO toxicity

We read with great interest the paper of López-Otero et al.,1 in which they describe a feasible approach of using high-dose chemotherapy and autologous transplantation in patients with multiple myeloma without cryopreservation of the PBSCs. In their study, they used a G-CSF-based steady-state mobilization strategy immediately followed by a single dose of high-dose melphalan (200 mg/m2, day −1) and transplantation of the fridge-stored (+4 °C) autologous, unmanipulated PBSCs on day 0. Using this regimen they observed response and survival rates comparable to those achieved by a classical transplantation strategy using cryopreserved autografts, which has also been previously demonstrated by Carey et al. and several other groups.2, 3 The major aim of this study, as already demonstrated in their previous studies, was reduction of costs by sparing the stem cell cryopreservation procedure. Thereby, their method was affordable and permitted access to high-dose therapy for individuals living in countries with limited access to medical high-tech facilities, such as Mexico.4, 5, 6 A major prerequisite of this approach is, as shown in vitro as well as in clinical studies, that PBSCs can be stored for 48 h up to 9 days without cryopreservation and still provide haematological reconstitution after myeloablative therapy. Nevertheless, the limited stem cell storage period permits only tight high-dose schedules. Therefore, given its short elimination half-life of 17–75 min and its proven therapeutic efficacy in plasma cell diseases such as amyloidosis and multiple myeloma, high-dose melphalan is an ideal agent for this approach.2, 6, 7 Besides the economical considerations mentioned above, there might be, at least for some patients, another potential clinical benefit of this approach—sparing DMSO toxicity. Using PBSCs, which have not been cryopreserved but have been stored in a refrigerator until transplantation, avoids the usage of the cryoprotectant DMSO. During transfusion of autologous PBSCs, DMSO can cause several toxic side effects, attributable to DMSO itself, DMSO-induced histamine release and cell lysis products from leukocytes within the graft. Mild adverse effects including transient nausea, vomiting, abdominal cramps, hypotension, bradycardia or headache are common, while serious side effects involving the cardiovascular and respiratory systems, such as hypertension, tachycardia, arrhythmias, respiratory arrest, diffuse alveolar haemorrhage and neurological complications are less frequent. However, the risk for such potentially life-threatening complications is increased in patients with risk factors such as, for example, primary AL-amyloidosis.8, 9 Considering this risk constellation, we treated five male patients (median age: 63 years, range: 55–68 years) with a combined mobilization and autologous transplant regimen comparable to that of López-Otero et al. facilitating high-dose chemotherapy in patients who were at high risk for DMSO-related complications. Three of these patients suffered from primary AL-amyloidosis and one patient from a light-chain deposition disease, involving the kidneys (n=4), heart (n=2), peripheral nerve system (n=2) and liver (n=1); while the fifth patient with a multiple myeloma type IgG kappa stage IIIA had experienced several grand mal seizures, probably as a consequence of the induction therapy with idarubicin and dexamethasone. In addition, he used a cardiac pacemaker because of symptomatic bradycardia probably related to cardiac amyloidosis. Detailed patients’ characteristics are given in Table 1. For steady-state mobilization, all patients received non-pegylated G-CSF (median 10 μg/kg body weight (BW)/day s.c., range: 6.2–12.8 μg/kg BW/day for 5 days). Apheresis was performed on days −3 and −2 with the aim of harvesting at least 2.0 × 106 CD34+ cells/kg BW. As the number of CD34+ cells measured in the peripheral blood of one patient on day −4 was <10/μL, the CXCR4 antagonist plerixafor (240 μg/kg BW) was given in addition on days −4 and −3 facilitating successful stem cell apheresis. High-dose melphalan was administered on day −1, while a lower dose range of 100–140 mg/m2 was chosen taking into account patients’ age, comorbidities and organ involvement. Refrigerator-stored PBSC were reinfused on day 0 with a minimal interval of at least 24 h between melphalan administration and transplantation. All patients received antimicrobial as well as antiviral prophylaxis as described previously and were treated on an inpatient basis.7 Using this mobilization strategy, a sufficient number of autologous PBSCs (median 5.87 × 106 CD34+ cells/kg BW, range 2.21–6.32) were harvested within one apheresis session on day −3, while in two patients an additional back-up transplant was harvested on day −2. As determined on the day of harvest, the median number of transplanted CD34+ cells was 5.87 × 106/kg BW for each recipient (range 2.21–6.32). Viability of the CD34+ cells during the time of storage was not serially measured in this group of five patients. However, using exactly the same storage conditions as described here, we have previously tested the viability of G-CSF-mobilized CD34+ cells from healthy donors over a storage period of up to 72 h, by propidium iodide staining. We found the viability of the CD34+ cells to be 98% after 72 h, which is in line with data previously published by Ruiz-Argüelles et al.6 All patients engrafted and the median time to achieve 0.5 × 109 granulocytes was 11 days (range: 9–16), while the median time to recover 20 × 109 plts without transfusion was also 11 days (range: 9–15). In general, this combined regimen for PBSC mobilization and subsequent high-dose chemotherapy was well tolerated. Only the patient with previous epileptic seizures suffered a further seizure during the apheresis session, most likely as a consequence of an electrolyte imbalance. Mucositis (WHO grade I–III) occurred in four of five patients due to high-dose melphalan, and hyperuricaemia occurred in one patient requiring rasburicase treatment. Despite the high rate of pre-existing renal insufficiency, there was a reversible increase of renal parameters not requiring hemodialysis in just one patient. No additional serious adverse events related to the mobilization, apheresis procedure or transplantation regimen were observed in this group of patients. There were no deaths within the first 100 days after auto-PBSCT. Following high-dose chemotherapy and auto-PBSCT, two patients achieved CR, two patients PR and one patient stabilization of the underlying disease in accordance with the international consensus guidelines. With a median follow-up of 549 days (range 136–1509 days), four patients are still alive. One patient died on day 260 from sepsis due to dialysis-catheter-associated peritonitis. As demonstrated in one of our patients, the availability of new mobilizing agents such as the CXCR 4 antagonist plerixafor can further help to make this tight treatment schedule practicable in patients with an insufficient response to G-CSF. The times to neutrophil as well as platelet recovery observed in our group were markedly shorter than in the group described by López-Otero et al.,1 as the melphalan dose in our group was only 100–140 mg/m2 compared with 200 mg/m2 and we administered a single dose of 6 μg pegylated filgrastim or a daily dose of 5 μg/kg BW non-pegylated G-CSF from day +1 until the WBC count had reached >1000/μL. The role of high-dose chemotherapy and autologous PBSCT in AL-amyloidosis is still unclear to date, but it remains a valuable treatment option for some patients.10 As this is a retrospective analysis and the number of patients is small, we cannot draw any definitive conclusions with regard to the outcome of this approach. However, as the primary aim of our regimen was to avoid excess toxicity in this high-risk group, we conclude that using the Mexican way of autografting provides a feasible and well-tolerated treatment option for patients with AL-amyloidosis or other risk factors for DMSO-related toxicity with the use of cryopreserved transplants. The authors declare no conflict of interest.