Paroxysmal atrial fibrillation after high-dose melphalan in five patients autotransplanted with blood progenitor cells

Propylene Glycol-Free melphalan HCL for Injection (PGF-Mel) is a new formulation that incorporates Captisol, a specially modified cyclodextrin, to improve melphalan stability. In this phase IIa, open-label, randomized, cross-over design bioequivalence study, the pharmacokinetics of PGF-Mel were compared with the marketed formulation of melphalan, or Alkeran. Patients received half of the total dose of melphalan in the form of Alkeran and the other half in the form of PGF-Mel in an alternating manner. The pharmacokinetic measures were determined using WinNonlin 6.2 and bioequivalence was assessed using log-transformed systemic exposure parameters. Twenty-four patients, 11 females and 13 males, were enrolled between 4 February 2010 and 16 May 2011 at The University of Kansas Medical Center and The University of Kansas Cancer Center. The median age of enrolled subjects was 58 years (range: 48-65). All patients achieved myeloablation 3 days post autologous graft followed by successful neutrophil engraftment with a median of 11 days after transplant. Pharmacokinetic analysis showed that PGF-Mel was bioequivalent with Alkeran and also revealed that maximum plasma concentration (C max ) and area under the plasma concentration − time curve (AUC) were higher (~10%) after PGF-Mel administration. In conclusion, PGF-Mel is considered bioequivalent to Alkeran while also demonstrating a marginally higher systemic drug exposure.

Section: Discussionmentioning

confidence: 99%

Phase IIa cross-over study of propylene glycol-free melphalan (LGD-353) and alkeran in multiple myeloma autologous transplantation

Aljitawi

Ganguly

Abhyankar

et al. 2014

“…While there are reports of paroxysmal arrhythmia following melphalan administration, 12,13 prospective studies have not shown that melphalan significantly affects cardiac contractility. Although fludarabine has rarely been implicated, 8 other purine analogues have shown evidence of cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Acute left ventricular failure following melphalan and fludarabine conditioning

Ritchie

Seymour

Roberts

et al. 2001

Summary:Cardiotoxicity has rarely been reported as a complication of melphalan or fludarabine administration as single agents. Recently, melphalan and fludarabine have been used in combination as non-myeloablative conditioning chemotherapy prior to allogeneic stem cell transplantation. We have observed the development of severe left ventricular failure in three of 21 patients treated with this combination. Cardiotoxicity in this context has not previously been reported and has implications for the assessment, monitoring and treatment of patients undergoing pre-transplant conditioning with melphalan and fludarabine. Bone Marrow Transplantation (2001) 28, 101-103. Keywords: emlphalan; fludarabine; BMT; cardiotoxity The alkylating agent melphalan, either alone or in combination with other agents such as busulphan and total body irradiation, has been widely used in myeloablative conditioning regimens prior to stem cell transplantation for diseases such as multiple myeloma, 1 non-Hodgkin lymphoma 2 and Hodgkin's disease. 3 The clinical utility of melphalan has recently been extended by the development of nonmyeloablative transplant regimens intended to exploit the graft-versus-tumour effect of allogeneic T cell chimerism whilst reducing the toxicities associated with myeloablative conditioning. 4 Non-myeloablative regimens have seen melphalan used in novel combinations with agents such as the purine analogue, fludarabine. 5 The application of these novel regimens is particularly attractive in patients considered too old for standard allografts.It is conceivable that these regimens may lead to unexpected toxicities due to the cumulative or synergistic effects of the individual drugs, particularly in an older patient population. Although cardiac dysfunction is well described with other alkylating agents such as cyclophosphamide, 6 single-agent melphalan has not been shown to affect cardiac contractility in prospective studies. also only been rarely associated with cardiac dysfunction, with a single report of non-fatal congestive heart failure in two of 27 patients treated for chronic lymphocytic leukaemia. 8 Conditioning regimens combining fludarabine and melphalan have been associated with veno-occlusive disease and mucosal toxicity, but development of cardiotoxicity had not been specifically assessed in earlier reports. 5,9 Recently, in an updated series, reduced-intensity conditioning with melphalan and purine analogues was associated with the development of Bearman grade 3-4 cardiotoxicity in four of 86 patients. 10 The clinical features of cardiotoxicity in this setting have not, however, been documented. We describe the development of severe left ventricular failure (LVF) in three of 21 patients undergoing non-myeloablative stem cell transplantation (NMSCT) following conditioning with these agents. Case reportsTwenty-one patients have undergone NMSCT following conditioning with melphalan and fludarabine at our institution for multiple myeloma (11), chronic lymphocytic leukaemia (3), chronic myeloid leukaemia (2),...

“…59 HD melphalan has not been shown to be cardiotoxic, 7,9,25,50,[60][61][62][63][64] with the exception of atrial fibrillation. [65][66][67] Fludarabine has also been rarely associated with cardiac dysfunction. 68 Surprisingly, after an initial report 59 of about 2.5% incidence of grade IV/V cardiac toxicity with this combination, this unexpected side effect has been confirmed in three other reports, with incidence up to 14% and outcomes variable from complete reversibility with standard medical treatment 69 to toxic deaths.…”

Section: Other Chemotherapeutic Agentsmentioning

confidence: 99%

Cardiac toxicity of high-dose chemotherapy

Morandi

Ruffini

Benvenuto

et al. 2004

149

104

Summary:Cardiac toxicity is an uncommon but potentially serious complication of high-dose (HD) chemotherapy and little is known about incidence, severity and underlying mechanisms. We have systematically reviewed the literature of the last 30 years to summarize and appraise the published evidence on cardiac toxicity associated with HD chemotherapy. HD cyclophosphamide-containing regimens have been most commonly associated with cardiac toxicity, with a progressively decreasing incidence over time. Dosage, application regimens and coadministration of other chemotherapeutic agents emerged as risk factors. While cardiac toxicity has been rarely associated with other cytotoxic drugs, an unexpected incidence of severe cardiotoxicity resulted from reduced-intensity conditioning regimens containing melphalan and fludarabine. Predictive value of cardiologic examination of patients is limited, and patients with a slight depression of cardiac performance could tolerate HD chemotherapy. Clinical examination, resting electrocardiography and dosage adjustment in overweight patients remain the mainstay of prevention, with bidimensional echocardiography (2D echo) for patients with a history of anthracycline exposure. Strategies to decrease the long-term negative impact of anthracycline administration on cardiac performance are being investigated. New 2D echo-based techniques and circulating markers of cardiac function hold promise for allowing identification of patients at high risk for and early diagnosis of cardiac toxicity.