Safety and efficacy of propylene glycol-free melphalan as conditioning in patients with AL amyloidosis undergoing stem cell transplantation
Abstract
High-dose melphalan is the standard conditioning regimen for patients with AL amyloidosis receiving autologous stem cell transplantation. Conventional formulations require propylene glycol (PG) as a co-solvent and melphalan has limited solubility and chemical stability after reconstitution, with potential risks for propylene glycol-related complications. Captisol-stabilized propylene glycol-free (PG-free) melphalan has been developed with improved solubility and chemical stability. We compared a cohort of patients with AL amyloidosis receiving PG melphalan (n = 96) to those receiving PG- free melphalan (n = 48) as conditioning for autologous stem cell transplantation. Median time to neutrophil and platelet engraftment was the same; 14 days PG melphalan vs 14 days PG-free melphalan, p = 0.73 and 16 days PG melphalan vs 16 days PG-free melphalan, p = 0.52, respectively. Hospitalization rate was similar in both cohorts, 68% PG melphalan vs 58% PG-free melphalan, p = 0.27. All-cause mortality at 100 days was not statistically significant, 3% PG melphalan vs 2% PG-free melphalan, p > 0.99. Overall response rate (ORR) and rates of complete response (CR) were similar (ORR 93% PG melphalan vs 94% PG-free melphalan, p > 0.99 and CR 39% PG melphalan vs 32% PG-free melphalan, p = 0.46). PG-free melphalan showed a comparable safety and efficacy profile to PG melphalan in patients with AL amyloidosis receiving stem cell transplantation.
Introduction
Autologous stem cell transplantation (ASCT) has been utilized as a treatment modality for AL amyloidosis for over two decades. The treatment regimen was adapted from its success in multiple myeloma. The conditioning regimen of choice based on clinical trials has been high-dose melphalan 200 mg/m2 [1, 2]. Melphalan is a cell-cycle nonspecific alkylating agent with anti-tumor activity in a variety of malignancies, with bone marrow suppression and mucositis being the primary dose-limiting toxicities [3]. Conventional melphalan formulations (e.g., Alkeran; GlaxoSmithKline, Research Triangle Park, NC, USA) have marginal solubi- lity, limited chemical stability after reconstitution (necessi- tating completed administration within 1 h of reconstitution), and require the use of propylene glycol as a co-solvent [4]. Intravenous administration of drugs con- taining propylene glycol has been associated with potential adverse effects including metabolic abnormalities, arrhyth- mia and clinical deterioration [5]. In an attempt to avoid potential toxicities of propylene glycol, a captisol-stabilized propylene glycol-free melphalan formulation (Evomela™; Spectrum Pharmaceuticals, Inc., Irvine, CA, USA) has been developed, with an early study in myeloma patients show- ing comparable safety and efficacy [4]. Data on its use in AL amyloidosis are limited with one small series published to date showing similar outcomes to propylene glycol-based melphalan formulations [6]. Herein we report on the safety and efficacy of propylene glycol-free melphalan used as conditioning in a large cohort of patients with AL amyloi- dosis receiving ASCT.
Results
Baseline characteristics for patients receiving PG melphalan and PG-free melphalan are summarized in Table 1. Both groups were well matched for age, organ involvement, baseline laboratory data, and Mayo stage. Data on stem cell transplant variables are summarized for both groups in Table 2. The majority of patients were transplanted within 12 months of diagnosis in both cohorts (86% PG melphalan vs 83% PG-free melphalan, p = 0.47). Conditioning was with full intensity melphalan 200 mg/m2 in 74% of patients receiving PG melphalan and 79% of patients receiving PG- free melphalan, p = 0.54. Median time to neutrophil and platelet engraftment was the same for both cohorts; 14 days PG melphalan vs 14 days PG-free melphalan, p = 0.73 and PG propylene glycol, IQR interquartile range, BMPCs bone marrow plasma cells, ALP alkaline phosphatase, dFLC difference between involved and uninvolved light chains 16 days PG melphalan vs 16 days PG-free melphalan, p = 0.52, respectively.
Safety
The rates of fever ≥38°C (within 30 days of transplant) were similar in both cohorts, 64% PG melphalan vs 69% PG-free melphalan, p = 0.62. Confirmed bacteremia on blood cul- ture was identified in 20% of patients receiving PG mel- phalan and 19% of patients receiving PG-free melphalan, p > 0.99. The effect on renal function post transplant from the two formulations was similar (median % rise in creati- nine 8.3% for PG melphalan (range -30 to 190%) vs 7.7% for PG-free melphalan (range -36 to 188%), p = 0.84).
Hospitalization
Stem cell transplantation at our center is routinely per- formed as an outpatient, with patients being hospitalized ferent for the two groups, 3% (n = 3) PG melphalan vs 2% (n = 1) PG-free melphalan, p > 0.99. The three patients in the PG melphalan cohort died from line- related sepsis, interstitial pneumonia, and sudden death thought to be most likely from pulmonary embolism, respectively. The patient in the PG-free melphalan cohort that died within 100 days was admitted with a syncopal episode and associated femoral fracture, with subsequent development of aspiration pneumonia and multi-organ failure.
Hematologic response
Hematologic response is summarized in Fig. 1. The rates of overall response rate (ORR) and rates of complete response (CR) were similar in both groups (ORR 93% PG melphalan vs 94% PG-free melphalan, p > 0.99 and CR 39% PG melphalan vs 32% PG-free melphalan, p = 0.46).
Discussion
Despite the introduction of novel agents as therapeutic options in AL amyloidosis, ASCT remains a highly effec- tive therapy with significant improvement in safety over recent years as reflected in our early mortality rate of 2.4% [7]. Our study shows that PG-free melphalan has a similar safety and efficacy profile to PG melphalan when used as conditioning for ASCT in patients with AL amyloidosis. Two important points need to be considered with respect to use of PG-free melphalan as conditioning for ASCT. Firstly, patients with AL amyloidosis have an increased risk of post-transplant complications compared to patients with multiple myeloma, often owing to significant cardiac and renal organ involvement. PG-free melphalan has been shown to be bioequivalent to PG melphalan with a similar safety profile [9]. In addition, the potential risks associated with propylene glycol administration are obviated with the use of PG-free melphalan, a factor that may be relevant to this group of patients at high risk of transplant-related complications. However, it should be noted that the quan- tities of propylene glycol administered with traditional melphalan dosing for ASCT in AL amyloidosis are far lower than those administered in the reported cases of propylene glycol toxicity [5]. Secondly PG-free melphalan has been shown to be more soluble and stable when com- pared to PG melphalan [10, 11]. PG melphalan is recom- mended to be administered within 60 min of reconstitution and precipitates if refrigerated. Longer stability of the reconstituted formulation beyond 60 min has been reported [12]. Reconstituted PG-free melphalan is stable at room temperature for 1 h and may be refrigerated at 5 °C for up to 24 h without precipitation. If the reconstituted PG-free melphalan is mixed with 0.9% sodium chloride for intra- venous injection then the admixture solution is stable for an additional 4 h at room temperature. Thus choice of mel- phalan solution may have significant logistical implications for institutions with regards to chemotherapy preparation and delivery, particularly if the chemotherapy pharmacy is any distance from the transplant unit. Precipitate formation will require the reconstituted drug to be discarded with a waste monetized in thousands of dollars.
The rate of hospitalization in the two cohorts was similar. Importantly the primary cause for hospitalization did not appear to be affected by melphalan formulation. Patients with AL amyloidosis frequently encounter complications with volume and electrolyte balance. The rates of cardiac arrhythmia and volume overload were not significantly different in our study between PG-free melphalan and PG melphalan. We note that a number of patients were listed as being hospitalized for “other” indications. These patients were admitted to hospital for various reasons, often a
combination of physician preference, general decline, and/ or lack of care giver and were difficult to categorize in terms of medical indication for admission.
Our study is limited by the inherent biases of a retro- spective review. However both cohorts of patients were well matched for baseline characteristics and the numbers of patients receiving pre transplantation chemotherapy as well as the time interval between diagnosis and transplant were similar in both groups. Cause for hospitalization was identified retrospectively upon chart review and designated by the reviewer according to information available in the chart. Approximately 20% of patients had a hospitalization cause listed as “other” and these patients either did not have a clear inciting event for or unclear documentation regarding cause for hospitalization. This may have impacted our analysis regarding post transplant complications in the two groups.
Despite these limitations our study describes the largest cohort of patients in the published literature with AL amyloidosis treated with PG-free melphalan as conditioning for ASCT, and confirms its comparable safety and efficacy to PG melphalan. In addition the PG-free melphalan for- mulation may have practical benefits and be more con- venient to use in the hospital setting. Prospective studies are required to confirm our findings.
Compliance with ethical standards
Conflict of interest MAG received consultancy from Millenium and honoraria from Celgene, Millenium, Onyx, Novartis, SmithKline, Prothena, Ionis, and Amgen. SKK received consultancy from Celgene,Millennium, Onyx, Janssen, and BMS and research funding from Celgene, Millennium, Novartis, Onyx AbbVie, Janssen, and BMS. MQL received research funding from Celgene. DD received research funding from Karyopharm Therapeutics, and Millenium Pharmaceu- ticals. PK received research funding from Takeda, Celgene, and Amgen. AD received research funding from Celgene, Millennium, Pfizer, and Janssen and travel grant from Pfizer. The remaining authors declare that they have no conflict of interest.
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