Page 1081 - Hematology_ Basic Principles and Practice ( PDFDrive )

964 Part VII Hematologic Malignancies

retrospective studies have provided circumstantial evidence for delete- inflammatory state, and is an imperfect marker of total body iron
rious effects of iron overload. For instance, one study has shown a burden. For quantitative assessment of hepatic iron overload, T2*-
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higher rate of death from heart failure among MDS patients, and weighted magnetic resonance imaging of the liver has supplanted
another has shown increased rates of heart and liver failure among biopsy as the preferred method of validation. 440
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MDS patients with high lifetime numbers of transfusions, but
these observations again cannot prove causality.
There are two major formulations of chelating agent available in Other Therapies for Lower-Risk Disease
the United States, deferoxamine and deferasirox (a third agent,
deferiprone/L1, is available only for thalassemia patients via a The literature is replete with attempts to treat lower-risk MDS with
restricted distribution program). Deferoxamine is administered as a a variety of different drugs, especially so-called differentiating agents
continuous subcutaneous or IV infusion, a cumbersome mechanism such as retinoic acid or arsenic trioxide (ATO). With the exception
that has limited its applicability in widespread practice. Deferasirox, of lenalidomide for 5q− syndrome, most of these have been incon-
an oral formulation, is more convenient so is much more widely used, sistently effective at best.
but is quite costly.
Deferasirox is typically started at 20 mg/kg (14 mg/kg for the new
tablet form of deferasirox FDA approved in 2015) once daily and Lenalidomide
escalated to 30–40 mg/kg/day (28 mg/kg for the new tablet form of
deferasirox FDA approved in 2015), depending on iron kinetics and As described previously, lenalidomide is a derivative of thalidomide
patient tolerance. Although deferasirox has been shown to rapidly that is uniquely effective in reversing the severe anemia associated
mobilize stored iron and reduce labile plasma iron species, it is fre- with isolated del(5q). This was previously thought to be related to
quently discontinued either as a result of disease progression or caused poorly characterized immunomodulatory effects (as implied by
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by side effects, which include gastrointestinal distress, renal impair- “Imid,” the name given to the class of thalidomide derivatives).
ment, and rash. However, more recent work has shown that lenalidomide actually
To date, there have been no randomized controlled trials to exerts its effect in 5q− syndrome by mediating the binding of the E3
definitively evaluate the impact of iron chelation on outcomes in ubiquitin ligase cereblon to casein kinase 1α, thus triggering casein
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MDS. The largest prospective trial to date, a single-arm cohort study kinase’s proteasomal degradation. Casein kinase 1α is an essential
of 1744 patients treated with deferasirox, included a prespecified kinase whose gene, CSNK1A1, lies within the minimally deleted
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MDS subgroup of 341 patients. Over the study’s single year, median region on 5q. In normal cells, treatment with lenalidomide is
ferritin levels decreased significantly compared to baseline regardless insufficient to deplete casein kinase 1α to lethal levels, but the hap-
of whether patients were chelation naive or not, as did the median loinsufficiency of CSNK1A1 induced by loss of 5q renders 5q− cells
alanine aminotransferase, which was tracked as a marker of hepatic sensitive to the drug through a p53-dependent mechanism and allows
toxicity from iron overload. On the other hand, 48.7% of the MDS for repopulation of the marrow by wildtype hematopoietic progeni-
patients discontinued treatment because of side effects. Since there tors. This activity appears to be unique to lenalidomide and is not
was no control arm and the study period was short, no conclusions shared, for instance, by thalidomide. Unfortunately, the effect is not
could be drawn about the impact of chelation on more meaningful permanent and resistance eventually develops in most cases, often
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clinical outcomes. Other studies have shown improvements in through inactivating mutations in TP53. Hopefully, however, these
hematopoiesis in patients started on chelation therapy, 433,434 but these new insights will enable further studies of how these resistance
observations were not tied to longer-term outcomes either. mechanisms arise.
There are data from retrospective studies showing better out- Lenalidomide’s efficacy was first observed in MDS-001, a phase I
comes for patients who undergo iron chelation, but all of these study of 32 patients with symptomatic anemia who had not responded
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are subject to patient selection bias. In one, a Canadian study of to ESAs. Twenty of the 32 patients became independent of transfu-
178 patients, only 18 received chelation therapy, suggesting that sion for some period of time, including 10 of 12 patents with del(5q).
these patients were carefully selected and destined to have a better Of the responders, those with del(5q) had a significantly longer
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outcome anyway. In another, a French study of 97 patients in duration of response. This prompted further study of lenalidomide
whom 46% received chelation, the regimen and duration of chelation specifically in del(5q) patients in MDS-003, a phase II study in which
therapy varied considerably, and no baseline assessment of iron stores 76% of 148 enrolled patients had an improvement in anemia and
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was performed. A recent metaanalysis of iron chelation studies 67% achieved transfusion independence, with a median improve-
in MDS found that use of chelation therapy was associated with ment in hemoglobin near 5 mg/dL. A second phase II trial, MDS-
an increase in length of survival (overall 61.2 months longer for 002, showed that lenalidomide was also effective in a substantially
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patients receiving chelation), but since the analysis included only smaller subset of patients without del(5q), with an overall response
retrospective studies, it is very possible that these numbers are again rate of 43% and a transfusion independence rate of 26%. The factors
largely reflective of selection bias, with healthier or younger patients that determine lenalidomide responsiveness in non-del(5q) MDS
more likely to receive chelation therapy than those who were older or have not been determined.
sicker. The most conclusive evidence of lenalidomide’s efficacy in del(5q)
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Despite the limitations of the available data, there are several comes from the phase III MDS-004 trial, a randomized, double-
published consensus opinion guidelines regarding the use of chelation blinded study in which patients were randomized 1 : 1:1 to receive
therapy in MDS. 324,438 Although they differ with respect to their lenalidomide 10 mg/day on days 1–21 of a 28-day-cycle, lenalido-
specific recommendations, most operate on similar principles that the mide 5 mg/day on days 1–28, or placebo on days 1–28. Those
patients best suited to iron chelation therapy are either those with without an erythroid response at 16 weeks were unblinded and
lower-risk disease and significant anemia who presumably face a long became eligible for open-label treatment. At the conclusion of the
period of transfusion dependency, or those who could potentially be study, significantly more patients in both lenalidomide groups had
eligible for stem cell transplantation, since in the transplant setting achieved transfusion independence for at least 26 weeks than those
numerous studies have shown that a high ferritin is associated with in the placebo group (56% in the 10-mg group versus 43% in the
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inferior outcomes. A third category of patients comprises those 5-mg group versus 5.9% in the placebo group), with those in the
with suspected end-organ damage as a result of iron overload. 10-mg group having a longer median duration of response (82.9
Some of the guidelines recommend waiting to start chelation weeks) than those in the 5-mg group (41.3 weeks). Intriguingly,
therapy until the ferritin is greater than 1000 µg/L or the patient has treatment with lenalidomide also appeared to lower the risk of
had more than 20–30 lifetime transfusions, but they also note that transformation to AML; at a median follow up of around 3 years,
neither of these criteria is supported by high-level evidence. Serum 36.4% of patients who had received placebo only and 30.4% who
ferritin is problematic since it is subject to variability based on had started with placebo and crossed over to lenalidomide had