Fifty Years of Melphalan Use in Hematopoietic Stem Cell Transplantation

Bayraktar, Ulas D.; Bashir, Qaiser; Qazilbash, Muzaffar H.; Champlin, Richard E.; Ciurea, Stefan O.

doi:10.1016/j.bbmt.2012.08.011

Cited by 101 publications

(68 citation statements)

References 157 publications

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“…As mentioned in many current reviews, even in responding patients, high-dose melphalan provides an additional benefit to most patients and the most recent review even suggests targeting exposure is worthwhile. 2 …”

Section: Under-utilization Of Pk Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Not too little, not too much—just right! (Better ways to give high dose melphalan)

Shaw

Nath

Lazarus

2014

Bone Marrow Transplant

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Of the 13 286 autologous haematopoietic cell transplant procedures reported in the US in 2010-2012 for plasma cell disorders, 10 557 used single agent, high-dose melphalan. Despite 30 years of clinical and pharmacokinetic (PK) experience with high-dose melphalan, and its continuing central role as cytoreductive therapy for large numbers of patients with myeloma, the pharmacodynamics and pharmacogenomics of melphalan are still in their infancy. The addition of protectant agents such as amifostine and palifermin allows dose escalation to 280 mg/m 2 , but at these doses it is cardiac, rather than gut, toxicity that is doselimiting. Although combination with additional alkylating agents is feasible, the additional TRM may not be justified when so many post-consolidation therapies are available for myeloma patients. Current research should optimise the delivery of this single-agent chemotherapy. This includes the use of newer formulations and real-time PKs. These strategies may allow a safe and effective platform for adding synergistic novel therapies and provide a window of lymphodepletion for the addition of immunotherapies. To best assess the contribution that the dose of drug makes to clinically meaningful endpoints in haematopoietic cell transplantation (HCT), one would choose one drug, ideally used as monotherapy, for one disease and with one source of haematopoietic progenitor cells (HPC). Although this approach may appear quite restrictive, these criteria are fulfilled when high-dose melphalan is used in the context of autologous HCT for plasma cell myeloma. Indeed, melphalan, which has been in use for 60 years, has been used in this way for 30 years. One might think we would know all there is to know about the use of this agent for this indication. However, in fact, we know very little. Several years ago, we briefly reviewed this subject, but the focus was on the various settings in which high-dose melphalan and autologous HCT were used. 1 In this present review, we will not discuss the role of high-dose melphalan in HCT but would direct readers to an excellent recent review on this topic. 2 Instead, we will use that review as our starting point for what we know about the pharmacokinetics (PK) of melphalan for high-dose therapy, in particular for myeloma, and how we may move forward. EARLY WORKHigh-dose melphalan has been in use for decades. The relatively few and reversible non-hematologic toxic effects make it suitable for high-dose therapy, whereas its profound marrow toxicity makes it unsuitable for repeated low-dose exposures. Today, most patients are naïve to melphalan exposure as it is only infrequently used as initial cancer therapy. The toxicity profile means that infusion of HPC can rescue or protect against most of the toxicity of the drug-hence, melphalan is the ideal agent for high-dose therapy with rescue by autologous HCT.Amongst the variety of solid tumours for which subjects first underwent HCT using melphalan were paediatric patients with neuroblastoma; these early reports garnered the inte...

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Section: Under-utilization Of Pk Studiesmentioning

confidence: 99%

“…1 In this present review, we will not discuss the role of high-dose melphalan in HCT but would direct readers to an excellent recent review on this topic. 2 Instead, we will use that review as our starting point for what we know about the pharmacokinetics (PK) of melphalan for high-dose therapy, in particular for myeloma, and how we may move forward.…”

mentioning

confidence: 99%

Not too little, not too much—just right! (Better ways to give high dose melphalan)

Shaw

Nath

Lazarus

2014

Bone Marrow Transplant

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“…Melphalan is an alkylating agent with broad antitumor effects including for myeloid and lymphoid diseases [34]. A modified fludarabine-melphalan-based conditioning regimen has been used successfully for these patients, which was initially reported for patients treated with T-cell depletion [29].…”

Section: Ptcy For Gvhd Preventionmentioning

confidence: 99%

Haploidentical Donors: Can Faster Transplantation Be Life-Saving for Patients with Advanced Disease?

et al. 2016

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Haploidentical stem cell transplantation is a therapeutic option for patients without an HLA-matched donor. It is increasingly being used worldwide due to the application of posttransplantation cyclophosphamide and is associated with lower incidence of graft-versus-host disease and treatment-related mortality. Haploidentical donors are generally available for most patients and stem cells can be rapidly obtained. Delays in transplantation while waiting for unrelated donor cells can be potentially problematic for patients with advanced disease at risk for progression; thus, the use of haploidentical donors, especially in this setting, can be life-saving. Here we reviewed the literature on haploidentical stem cell transplantation performed with posttransplantation cyclophosphamide.

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“…1 As a consequence, the procedure is now considered as the standard of care for the treatment of patients with newly diagnosed multiple myeloma (MM) generally up to the age of 65-70 years without significant comorbidities. 2 However, for the vast majority of patients, cure remains elusive and the disease will eventually relapse. The use of ASCT at relapse (salvage ASCT) presents an appealing option because of the potential for long-term disease control although, until recently, only retrospective, registry-based or single-center analyses investigating the use of salvage ASCT in the relapse setting after a prior ASCT have been published.…”

mentioning

confidence: 99%

“…2 Given the established role of novel agents in myeloma, the incorporation of novel agents into conditioning therapies is an attractive strategy. Pre-clinical data have demonstrated synergy between melphalan and novel agents 9 and such combinations might therefore be expected to yield augmented post-ASCT response rates and durability.…”

mentioning

confidence: 99%

Re-invigorating rather than re-inventing the wheel: augmenting the impact of salvage autologous stem cell transplantation for multiple myeloma in the era of novel agents

Cook

2015

Bone Marrow Transplant

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-3369/15 www.nature.com/bmt patient stratification and the use of currently evolving technology to delineate key biomarkers of response prediction. This is an area that has yet to be defined in relation to salvage ASCT.Although salvage ASCT has been utilized in clinical practice for relapsed myeloma after a prior ASCT for many years, it is only in recent times that prospective studies have demonstrated the utility of this compared with a no-transplant strategy, as well as the evolution of investigational-conditioning regimens. The direction of travel is clearly to establish as good a durable response to the second ASCT as to the first ASCT, such that there can be an expected improvement in the overall survivorship. More studies are planned in this setting, which is to be welcomed. CONFLICT OF INTERESTGC has received honoraria, research funding and speakers bureau fees from Janssen, Celgene, Amgen and Takeda Millennium.G Cook

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Fifty Years of Melphalan Use in Hematopoietic Stem Cell Transplantation

Cited by 101 publications

References 157 publications

Not too little, not too much—just right! (Better ways to give high dose melphalan)

Not too little, not too much—just right! (Better ways to give high dose melphalan)

Haploidentical Donors: Can Faster Transplantation Be Life-Saving for Patients with Advanced Disease?

Re-invigorating rather than re-inventing the wheel: augmenting the impact of salvage autologous stem cell transplantation for multiple myeloma in the era of novel agents

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