Discussion
To our knowledge, this is the first case series to report on the
real-world use of TPO-RAs to treat thrombocytopenia in pediatric and AYA
patients with hematologic malignancies. Our study demonstrated that
treatment with TPO-RAs effectively increased platelet counts and reduced
transfusion requirements in 93% (14/15) of patients. Platelet counts
significantly increased within two weeks of initiating TPO-RA therapy,
with sustained responses and an associated significant reduction in
platelet transfusion requirements. These findings align with previous
studies in adult populations and other pediatric contexts focused
predominantly on their use in solid malignancies, suggesting that
TPO-RAs can be valuable in managing thrombocytopenia in pediatric and
AYA patients with hematologic
malignancies.5,6,9,10,25,26
Refractory thrombocytopenia was the most common reason for TPO-RA
administration. Nine patients (60%) had either an existing bleeding
complication or a comorbidity that placed them at high risk of severe
bleeding events and insufficient response to platelet transfusions. No
patients experienced adverse events related to TPO-RA therapy. Three
patients experienced self-resolving thrombocytosis without
thromboembolic events, a known but manageable risk associated with
TPO-RA use.
While more data are required to identify appropriate indications for
TPO-RA therapy, our data suggest that both romiplostim and eltrombopag
are safe across a range of doses, durations of therapy, diagnoses, and
stages of treatment. Three representative patient courses are detailed
in vignettes to highlight the broad range of potential contexts in which
TPO-RAs may be useful (Supplemental Data). Despite the broad potential
utility of TPO-RAs in managing thrombocytopenia, their use was limited
in this cohort due to the high cost of these agents. The cost of 125mcg
romiplostim is approximately $1390, and a two-week supply of 50 mg
eltrombopag is approximately $6500. As such, in our cohort, use of
TPO-RA therapy was limited to those patients with thrombocytopenia
refractory to platelet transfusions and/or those with comorbidities that
predisposed to high bleeding risk.
Notably, our study included a high proportion of patients (67%) with
multiple life-threatening comorbidities and patients with relapsed
disease, nearly half of whom had received prior HSCT. As such, more than
half of the patients died of complications unrelated to TPO-RA use. In
addition, about one third of patients in this cohort with high-risk
hematologic malignancies experienced relapse after initiation of TPO-RA
therapy.
Historically, concerns have been raised about the potential for TPO-RAs
to stimulate the proliferation c-MPL-expressing myeloid
blasts.27 Subsequent preclinical
studies28 and clinical
trials25,26,29 of TPO-RAs in the context of AML and
MDS have not supported these concerns. In our study, two of four
patients with myeloid malignancies relapsed after receiving TPO-RA
therapy: one patient with TCF3-ZN384-postive B/myeloid MPAL (patient 3)
and one with GATA2-driven MDS transformed to AML (patient 4). Patient 7
with t(8;21) AML had a transiently rising RUNX1-RUNX1T1 fusion
transcript by reverse transcription polymerase chain reaction but did
not experience overt hematologic relapse. Patient 14 with inv(16) AML
has been relapse-free for 48 months. While this study was neither
designed nor powered to assess a causal relationship between TPO-RA use
and leukemia relapse, the relapse rates both in the overall cohort and
specifically among patients with myeloid malignancies are concordant
with those reported in the literature for similar
populations30,31.
Although our cohort represents a highly pretreated group with multiple
comorbidities, including severe infections, bleeding complications, and
hyperinflammation, 14/15 (93%) of patients achieved a platelet count of
50 x 109/L or greater and had decreased platelet
transfusion requirements within 8 weeks (range 1-8 weeks, median 3
weeks). Seven patients became transfusion independent during this time.
We hypothesize that the magnitude of benefit may be even greater in
populations with fewer comorbidities and prior cancer-directed
therapies.
This study has several limitations that may restrict the external
generalizability of our findings, including the retrospective design,
single institution nature, and small sample size comprising a highly
heterogeneous population enriched for patients with poor clinical
outcomes. Further prospective studies with larger, more homogenous
cohorts are needed to confirm these findings and establish standardized
guidelines for the use of TPO-RAs in pediatric and AYA patients with
hematologic malignancies. Moreover, our study did not include a matched
control group of patients who did not receive TPO-RA therapy, raising
the possibility that some patients could have experienced spontaneous
platelet recovery. However, the close temporal association between
TPO-RA administration and the significant increase in platelet counts in
nearly all patients, most of whom had severe, transfusion-refractory
thrombocytopenia, make it likely that platelet recovery was attributable
to TPO-RA treatment. In addition, the rationale for selecting a specific
TPO-RA among the four available agents was not available from our chart
review. While we postulate that practical considerations, such as
patient preferences around route of administration, dosing frequency,
cost, and insurance coverage influenced the choice of therapy, we are
unable to draw conclusions about the comparative efficacy and safety of
these agents in this patient population. More detailed prospective data
collection, including clinician rationale for therapy selection, would
help to better understand these decision-making factors and optimize
treatment strategies.
Despite these limitations, our findings suggest that romiplostim and
eltrombopag are safe and effective agents that may be incorporated into
supportive care regimens to manage thrombocytopenia in pediatric and AYA
patients with hematologic malignancies and thrombocytopenia across a
broad range of clinical contexts. However, neither eltrombopag nor
romiplostim takes effect immediately, requiring a median of three weeks
to improve platelet counts; therefore, these agents should not be a
substitute for platelet transfusions during this period. Given the
dearth of data on TPO-RA use in pediatric and young adult patients with
hematologic malignancies, prospective clinical trials are warranted to
validate our findings and explore the long-term outcomes of TPO-RA
therapy. Additionally, future research should focus on identifying
patient-specific factors that predict response to TPO-RAs, optimizing
dosing strategies, and evaluating the cost-effectiveness of TPO-RA
therapy in this population.