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Use of propylene glycol-free melphalan conditioning in light-chain amyloidosis patients undergoing autologous hematopoietic cell transplantation is well tolerated and effective

To the Editor: Light-chain amyloidosis (AL) is a malignant plasma cell disorder, characterized by misfolded fibrillar protein deposition in vitals organs of the body, leading to organ failure and eventually death [1]. Treatment is directed at eradicating the underlying plasma cell clone using systemic chemotherapy [2]. Autologous hematopoietic cell transplantation (auto-HCT) has been a preferred approach in transplant-eligible patients to improve long-term outcomes [3]. High-dose melphalan conditioning is the standard of care for auto-HCT in patients with plasma cell disorders [4]. The lyophilized melphalan formulation has inadequate solubility and stability after reconstitution, and propylene glycol (PG), which is used as a co-solvent to improve solubility and chemical stability of lyophilized melphalan, is associated with cardiac, neurologic, metabolic, and renal toxicities [5, 6]. A novel PG-free melphalan preparation, Evomela® (PG-free melphalan), uses captisol as a solubilizing agent and thus may be less toxic than PG melphalan formulations. In a phase IIb study of multiple myeloma (MM) patients undergoing auto-HCT, PG-free melphalan showed an acceptable safety profile and comparable efficacy [7]. Consequently, PG-free melphalan was granted FDA approval for use as a conditioning regimen in patients undergoing auto-HCT. Since AL patients have increased peri-transplant complications, we sought to determine the safety and efficacy of PG-free melphalan conditioning in AL patients undergoing auto-HCT compared to PG melphalan.

We switched to PG-free melphalan for auto-HCT conditioning on 15 November 2016. Herein, we compare early post-transplant outcomes of AL patients in the year before and after the change. We retrospectively analyzed AL patients who underwent auto-HCT from 31 October 2015 to 31 October 2017 at our institution (N = 18), nine each in PG melphalan and PG-free melphalan group. AL staging was determined using the 2012 revised staging system [8]. Hematologic response was defined according to the 2012-updated AL response criteria [9]. Chart review was conducted to identify events in the first 100 days following auto-HCT, including arrhythmias, cardiac and/or renal failure, mucositis, engraftment syndrome, days in hospital, rehospitalization, and transfer to intensive care unit (ICU). We also reviewed charts for need of platelet and pack red blood cell (PRBC) transfusion post auto-HCT in PG melphalan and PG-free melphalan group. The threshold for PRBC transfusion was hemoglobin <7 g/dl and for platelet transfusion was <10,000/mm3 during this entire period. Incidence and severity of chemotherapy-induced mucositis was determined based on documentation of oral mucositis in the charts and use of opioid medications for oral, throat, or abdominal pain. We also took into account the use of intravenous dexamethasone, intubation to protect airway, and ICU transfer due to suspected oropharyngeal mucositis. Categorical variables between groups were compared using χ2 test. Continuous variables were compared by non-parametric t test using analysis of variance.

Baseline characteristics are summarized in Table 1 and the two groups were comparable. One patient in the PG melphalan arm received BEAM (carmustine, etoposide, cytarabine and melphalan) conditioning before auto-HCT due to concurrent diagnosis of Waldenstrom macroglobulinemia with IgM AL. The median time to neutrophil and platelet engrafment was similar in both groups as well as the incidence of post-transplant cardiac or renal failure. The median number of PRBC transfusion in PG melphalan were 1.5 (range, 0–8) compared to 0 (range, 0–2) in PG-free melphalan group, p = 0.03 (Fig. 1). The proportion of patients with mucositis in PG melphalan compared to PG-free melphalan group was 33% vs. 11% respectively, p = 0.57. Lastly, the median number of days in hospital post transplant was significantly longer in PG melphalan (23 days) compared to PG-free melphalan (17 days), p = 0.01. There was no difference in rehospitalization rate between the 2 groups (Table 1). Day 100 hematologic response rate was 100% in both groups. At a median follow-up of 8.4 (range 0.4–18.6) months from transplant, all patients are alive and in active follow-up.

Table 1 Baseline characteristics and outcome
Fig. 1
figure1

Bar chart showing number of transfusion relative to melphalan dose (mg/m2) and baseline hemoglobin (Hb g/dl) for PRBC (above) and platelet transfusion (below) in patients after PG Mel and PG-free Mel conditioning

This is the first profile report of PG-free melphalan conditioning in patients with AL undergoing auto-HCT and comparative analysis with PG melphalan. Our analysis suggests that PG-free melphalan was well tolerated, had similar safety profile and effective. Conventional PG melphalan at higher doses of 140–200 mg/m2 can cause significant toxicities in patients undergoing auto-HCT. The toxicities reported in the literature are time- and dose-dependent [5, 6]. Approximately 6 g of PG is used for every 50 mg of lyophilized melphalan, resulting in patient being exposed to up to 24 g of PG with high-dose melphalan conditioning at 200 mg/m2. PG-free melphalan demonstrated better safety profile and comparable efficacy in patients with MM and lymphoma requiring high-dose melphalan conditioning for auto-HCT [7, 10], thus providing a safer and equally efficacious alternative. Lesser number of post-transplant PRBC transfusion requirement was observed in PG-free melphalan group compared to PG melphalan group. Hypothetically, this may be due to lesser incidence of mucositis-associated gastrointestinal (GI) bleeding in the PG-free melphalan group although the small numbers in our series lead us to exhibit caution in over-interpreting the results. Although, the patients in PG Mel group had a longer post-transplant hospital stay compared to PG-free Mel group, but this should be interpreted carefully, as there is a heterogeneity between two groups in terms of baseline hemoglobin, AL organ involvement, variability in conditioning regimen, and dosage. Our findings suggest an at least equal, if not superior, safety profile of PG-free melphalan compared to PG melphalan.

Overall, no transplant-related mortality was observed in either the PG-free melphalan and PG melphalan groups. Likewise, the day 100 post-transplant response rate was 100% in both groups. Equivalent tolerability and responses observed in our cohort of AL patients receiving PG-free melphalan is parallel to the observation in the pivotal clinical trail of MM patients undergoing auto-HCT [7]. In that study, neutrophil and platelet engraftment was observed on 12 and 13 days post transplant, respectively. Grade III mucositis was observed in 10% of patients, while none of the patients had a grade IV event. The longer time for neutrophil engraftment in our cohort may have been due to the fact that granulocyte colony stimulating factor (G-CSF) was avoided post transplant in order to reduce the risk of cardiovascular side effects in AL amyloid patients.

In conclusion, while acknowledging the small sample size and retrospective nature of our analysis, we confirm the safety and efficacy of PG-free melphalan conditioning in AL patients undergoing auto-HCT. Further prospective study is needed to validate our findings.

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Acknowledgements

This publication is funded in part by the Research and Education Program Fund, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin and by KL2TR001438 from the Clinical and Translational Science Award program of the National Center for Advancing Translational Sciences (A.D.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Author contributions

T.B. and A.D. designed the research, analyzed the data, interpreted the results, and wrote the manuscript; P.H., S.C., B.D., W.R.D., T.S.F., M.H., M.P., W.S., N.N.S., and B.E.S. assisted in interpretation and manuscript preparation; all authors approved the final draft of the manuscript.

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Correspondence to Anita D’Souza.

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Badar, T., Hari, P., Chhabra, S. et al. Use of propylene glycol-free melphalan conditioning in light-chain amyloidosis patients undergoing autologous hematopoietic cell transplantation is well tolerated and effective. Bone Marrow Transplant 53, 1210–1213 (2018). https://doi.org/10.1038/s41409-018-0178-5

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