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Ferrata Storti Foundation
Haematologica 2021 Volume 106(7):1794-1804
Dose intensity for conditioning in allogeneic hematopoietic cell transplantation: can we recommend “when and for whom” in 2021?
Nico Gagelmann and Nicolaus Kröger
Department of Stem Cell Transplantation, University Medical Center Hamburg- Eppendorf, Hamburg, Germany
ABSTRACT
Allogeneic hematopoietic stem-cell transplantation is a potentially curative therapy for various hematologic diseases. An essential component of this procedure is the pre-transplant conditioning regimen, which should facilitate engraftment and reduce or eliminate tumor cells. The recognition of the substantial association of a graft-ver- sus-tumor effect and the high toxicity of the commonly used condition- ing regimen led to the introduction of more differentiated intensity strategies, with the aim of making hematopoietic stem-cell transplanta- tion less toxic and safer, and thus more applicable to broader populations such as older or unfit patients. In general, prospective and retrospective studies suggest a correlation between increasing intensity and non- relapse mortality and an inverse correlation with relapse incidence. In this review, we will summarize traditional and updated definitions for conditioning intensity strategies and the landscape of comparative prospective and retrospective studies, which may help to find the bal- ance between the risk of non-relapse mortality and relapse. We will try to underscore the caveats regarding these definitions and analyses, by missing complex differences between intensity and toxicity as well as the broad influences of other factors in the transplantation procedure. We will summarize evidence regarding several confounders which may influence decisions when selecting the intensity of the conditioning reg- imen for any given patient, according to the individual risk of relapse and non-relapse mortality.
Categorized traditional and updated definitions
Although full consensus has not been reached within the hematopoietic stem- cell transplantation (HSCT) community,1 conditioning regimens have usually been classified as high-dose (MAC), reduced-intensity (RIC), and non-myeloablative (NMA).2 Based on these criteria,3 myeloablative, or “high-dose” regimens, consist- ing of alkylating agents with or without total body irradiation (TBI), are expected to ablate marrow hematopoiesis, not allowing autologous hematologic recovery. In contrast, NMA regimens, although causing minimal cytopenia, do not require stem cell support.4 Regimens that do not fit the definition of MAC or NMA are classified as RIC regimens: they result in potentially prolonged cytopenia, and they require hematopoietic stem cell support. What differentiates RIC regimens from myeloablative regimens is that the dose of alkylating agents or TBI is gener- ally reduced by ≥30%. Notably, “intensity” was defined here on the basis of grade of reversible and irreversible myelotoxicity rather than of non-hematologic toxic- ity. Despite this imprecise definition of intensity and toxicity and the lack of their universality (agreement for these criteria was found in <75%), this classification has served as a clinical tool and enabled some, although still limited, comparability with registries such as that of the European Society for Blood and Marrow Transplantation (EBMT).5–7
It is important to recognize, however, that regimens classified as MAC or RIC can vary substantially, regarding intensity and toxicity, which is also reflected by so-called “sequential” strategies;8,9 and the rigidity of this scheme further impeded
Correspondence:
NICOLAUS KRÖGER
nkroeger@uke.uni-hamburg.de
Received: December 1, 2020. Accepted: February 2, 2021. Pre-published: March 18, 2021.
https://doi.org/10.3324/haematol.2020.268839
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