Jason Gotlib, MD, MS
Dr. Gotlib indicated no
relevant conflicts of interest.
Kantarjian H, Fenaux P, Sekeres MA, et al. Safety
and efficacy of romiplostim in patients with lower-risk myelodysplastic
syndrome and thrombocytopenia. J Clin Oncol. 2010;28:437-44.
field of supportive care for myelodysplastic syndromes (MDS), an anthropomorphic
view would leave platelets feeling neglected. Erythropoiesis-stimulating agents
and granulocyte colony-stimulating factors were already available for clinical
use before the discovery of thrombopoietin and its receptor c-MPL in the mid
1990s. Development of first-generation thrombopoietins (e.g., recombinant human
megakaryocyte growth and development factor, rHuMGDF) ultimately faltered
because of the occasional appearance of neutralizing antibodies to endogenous
thrombopoietin and thrombocytopenia in trials of healthy volunteers undergoing
platelet donation. Other agents, such as interleukin-11, demonstrated modest
benefit in MDS but never gained traction. Non-immunogenic
thrombopoiesis-stimulating agents have now emerged, including the TPO nonpeptide
mimetic eltrombopag, TPO antibody mimetics, and the peptibody romiplostim.
Romiplostim and eltrombopag have demonstrated efficacy in short- and/or
long-term studies of immune thrombocytopenic purpura1 and are now FDA-approved
for this condition.
Because of the presence of
TPO receptors on early hematopoietic progenitors, and pre-clinical data
demonstrating that TPO can stimulate myeloid blasts,2 trepidation has
surrounded the use of TPO receptor agonists in MDS. The initial foray of
romiplostim in thrombocytopenic MDS patients is now reported by Kantarjian and
colleagues. The study was conducted in subjects with lowerrisk disease having
platelet counts <30,000/mm3, and treatments were done in dose cohorts of
300, 700, 1,000, and 1,500 mcg subcutaneously weekly. Increases in the median
platelet count at the respective doses were to 60, 73, 38, and 58 x 103/mm3 at
week 4. According to International Working Group (IWG), 2000 criteria, 45
percent of patients had complete or major platelet responses during the
treatment phase, with a higher proportion of responses in patients with a
platelet count >20,000/mm3 versus <20,000/mm3 (57 percent vs. 25 percent,
respectively). There was no difference in platelet response rates among the
dose cohorts. In the extension phase of 41 patients, 46 percent of patients experienced
durable platelet responses and the median duration of treatment was 37 weeks.
Bleeding events and platelet transfusions were less common among patients who
achieved a durable platelet response compared to those who did not (4.3 vs.
39.3 per 100 patient-weeks). Regarding clinically relevant safety issues, four
patients experienced transient increases in marrow blast counts, and two
progressed to acute myeloid leukemia; these results were felt to be within the expected
frequency of this MDS population. Of the 24 patients for whom pre- and
post-treatment marrow reticulin studies were available, the reticulin grade was
increased in seven, unchanged in 10, and decreased in seven. Neutralizing
antibodies to either romiplostim or endogenous TPO were not identified, and no
drug-attributable deaths occurred.
appears to be a feasible option for low/intermediate-1-risk MDS patients,
several points merit consideration. Although 700 mcg weekly was selected for future
studies, there was no dose-response relationship; therefore, evaluation of
clinical efficacy at lower dose ranges is justified. In addition, as this trial
was not designed to elucidate romiplostim’s impact on the rate of AML transformation,
a randomized, placebo-controlled study with longer followup is needed. Because
of the very low frequency of severe thrombocytopenia in de novo,
untreated low/intermediate-1-risk patients,4 this study group may have limited
applicability to the general MDS population. The greatest need for
platelet-stimulating agents will be in patients with clinically significant
bleeding and/or those requiring chronic platelet transfusions — features of
higher-risk patients. Trials assessing romiplostin and similar agents in
combination with lenalidomide and hypomethylating drugs are currently underway.
Reducing therapy-related thrombocytopenia may allow preservation of dose
intensity and frequency with the potential for optimizing the frequency and
quality of remissions.
- Bussel JB, Kuter DJ,
Pullarkat V, et al. Safety
and efficacy of long-term treatment with romiplostim in thrombocytopenic
patients with chronic ITP. Blood. 2009;113:2161-71.
- Bussel JB, Provan D,
Shamsi T, et al. Effect
of eltrombopag on platelet counts and bleeding during treatment of chronic
idiopathic thrombocytopenic purpura: a randomised, double-blind,
placebo-controlled trial. Lancet. 2009;373:641-8.
- Corazza F, Hermans C,
D’Hondt S, et al. Circulating
thrombopoietin as an in vivo growth factor for blast cells in acute myeloid
leukemia. Blood. 2006;107:2525-30.
- Kao JM, McMillan A,
Greenberg PL. International
MDS risk analysis workshop (IMRAW)/IPSS reanalyzed: impact of cytopenias on
clinical outcomes in myelodysplastic syndromes. Am J Hematol.
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