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Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation
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Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation Upendra Mahat MD , Seth J. Rotz MD , Rabi Hanna MD PII: DOI: Reference:
S1083-8791(19)30838-9 https://doi.org/10.1016/j.bbmt.2019.12.003 YBBMT 55812
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
17 September 2019 3 December 2019
Please cite this article as: Upendra Mahat MD , Seth J. Rotz MD , Rabi Hanna MD , Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation, Biology of Blood and Marrow Transplantation (2019), doi: https://doi.org/10.1016/j.bbmt.2019.12.003
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy
Highlights: Prolonged thrombocytopenia after HSCT is a strong risk factor for transplant related mortality and morbidity. No common consensus exists for the uniform classification and management of prolonged thrombocytopenia after HSCT. Available literature inconsistently describes
post
HSCT
thrombocytopenia
as
either
Prolonged
Isolated
Thrombocytopenia (PIT) or Secondary Failure of Platelet Recovery (SFPR). Thrombopoietin Receptor Agonists (Eltrombopag and romiplostim) are being increasingly used in patients with prolonged post HSCT thrombocytopenia. Our extensive literature review suggests that patients with prolonged post HSCT thrombocytopenia may respond to both eltrombopag (Overall Response Rate 70%) and romiplostim (Overall Response Rate 82%) with no evidence of serious adverse effects. However, the overall strength of evidence is weak in view of the retrospective nature of the studies, lack of control groups, heterogeneity of data and the potential publication bias.
1
Title: Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. Upendra Mahat MD, Seth J Rotz MD, Rabi Hanna MD. Department of Pediatric Hematology Oncology and BMT Cleveland Clinic Children’s, Cleveland, Ohio.
Corresponding Author: Upendra Mahat MD Department of Pediatric Hematology Oncology and BMT 9500 Euclid Avenue, R-3 Cleveland Ohio 44195 Email: [email protected]
Key words: Thrombopoietin receptor agonists, Eltrombopag, Romiplostim, Prolonged Isolated Thrombocytopenia, Secondary Failure of Platelet Recovery.
2
Abbreviations: HSCT
Hematopoietic Stem Cell Transplant
PIT
Prolonged Isolated Thrombocytopenia
SFPR
Secondary Failure of Platelet Recovery
TPO-R
Thrombopoietin receptor
TPO-RA
Thrombopoietin receptor agonist
Abstract word count: 285 unstructured. Manuscript word count: 3079 Number of tables: 3 Number of figures: 2 Short
running
title:
Thrombopoietin
receptor
thrombocytopenia.
3
agonists
in
prolonged
post-HSCT
Abstract: Prolonged thrombocytopenia after HSCT is a strong risk factor for transplant related mortality and morbidity, and no standard treatment guideline exists. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, increases the platelet production, and are being increasingly used in various conditions with thrombocytopenia. In this review, we present an overview of these TPO-RAs and review their efficacy and safety in prolonged post HSCT thrombocytopenia. Through a systematic literature search, we identified 25 reports describing their use for this indication. Thirteen reports (8 case series and 5 case reports) described the use of eltrombopag in 78 patients with Prolonged Isolated Thrombocytopenia (PIT) and 43 patients with Secondary Failure of Platelet Recovery (SFPR). A consistent and durable response with the rise in platelet counts above 50 x 10 9/L for 7 consecutive days without platelet transfusion was seen in 85 out of 121 patients (Overall Response Rate, ORR 70%). Amongst the responders, 56 were patients with PIT (ORR for PIT of 72%) versus 29 patients with SFPR (ORR for SFPR of 67%). No serious grade 3 or 4 adverse effects were reported. Similarly, 12 reports (6 case series and 6 case reports) described the use of romiplostim in prolonged post HSCT thrombocytopenia (17 patients with PIT and 32 patients with SFPR). Response with the increment of platelet count was described in 40 out of 49 patients (ORR 82%). Amongst the responders, 10 patients had PIT (ORR for PIT of 59%) versus 30 patients had SFPR (ORR for SFPR of 94%). TPO-RAs have an overall favorable response rate for both PIT and SFPR with a reasonable safety profile. However, given the lack of control groups, study heterogeneity, and the potential publication bias, the results should be interpreted with caution.
4
Introduction: Hematopoietic Stem Cell Transplantation (HSCT) is a potentially curative therapy for many malignant and non-malignant conditions. With the improved cellular technologies, increasing use of reduced intensity conditioning and alternative graft sources, and the improved preventive/supportive care, the number, indications and the scope of HSCT is continuously evolving.1 Prolonged thrombocytopenia after HSCT is a strong risk factor for transplant related mortality (TRM).2-5 Platelet count below 100x109/L on day 100 post HSCT has been previously described by multiple reports as a harbinger of increased TRM and decreased overall survival.2,3,5,6 Decreased survival of the post HSCT patients with prolonged thrombocytopenia is often related to the increased incidence of treatment failure, secondary to severe acute and chronic graft versus host disease (GVHD), more often than due to the relapse of underlying disease.3 Aside from the disease recurrence, the etiology behind post HSCT thrombocytopenia is multifactorial, and includes either impaired production (due to poor graft function, infections or drug adverse effects), increased destruction (due to immune mediated processes) or combination of both.7,8 Despite being a common entity with the incidence of over 20% after allogenic HSCT4,9, no common consensus exists for the uniform classification or management of prolonged post HSCT thrombocytopenia. The treatment often consists of platelet transfusion and various other agents used primarily in the treatment of immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) bind to thrombopoietin receptor (TPO-R) and stimulate downstream signaling pathways, leading to the increased platelet production. Eltrombopag and romiplostim are two TPO-RAs, which are being increasingly used in the prolonged and/or refractory thrombocytopenia after HSCT. Here, we present an overview of the
5
biology of thrombopoiesis and the TPO-RAs, and then a detailed report of the use of these agents in the treatment of prolonged thrombocytopenia after HSCT.
Biology of Thrombopoiesis: Thrombopoietin as a unique hematopoietic growth factor: Shortly following the identification of v-mpl oncogene from murine myeloproliferative leukemia in 1990, the human homolog, C-MPL gene was successfully cloned from both murine as well as the human sources.10,11 Located on chromosome 1p34.2, C-MPL encodes a protein, CD110, which is a 635-amino acid transmembrane protein, with two extracellular cytokine receptor domains and two intracellular cytokine receptor box motifs. It is constitutively expressed on the hematopoietic progenitor cells, megakaryocytes, and platelets.12 The ligand for C-MPL was subsequently cloned by multiple groups in 1994.13-17 C-MPL ligand, which is encoded by a gene on chromosome 3q27.1, regulates the megakaryocyte proliferation and differentiation both in vivo as well as in vitro.18 With the improved understanding of the biology of thrombopoiesis, the C-MPL ligand has gotten its new and perhaps more appropriate name, the Thrombopoietin (TPO), and the C-MPL receptor, the Thrombopoietin receptor (CD110 or TPOR). Thrombopoietin, a 332 amino acid glycoprotein, is a humoral growth factor produced by liver, kidney, bone marrow stroma and several other tissues.19 Its amino‐ terminal 154 residue receptor binding domain shows homology to erythropoietin20, whereas the carboxyl‐ terminal domain bears no resemblance to any known cytokines, and is important for its structural integrity. Upon binding to its receptor, TPO stimulates cytoplasmic kinases to mediate activation of different signaling pathways, leading to the differentiation and maturation of committed hematopoietic stem cells to megakaryocyte and eventually platelets.21 In contrast to the 6
regulation of other hematopoietic growth factors, the regulation of TPO production is rather unclear and incompletely understood. In general, serum TPO level fluctuates inversely in response to the low blood platelet and marrow megakaryocyte counts.22 TPO production has been thought to be constitutive, and platelets bearing TPO receptors are thought to absorb the hormone and destroy it.23,24 This simple model explains the high endogenous TPO levels in bone marrow failure states such as aplastic anemia, congenital amegakaryocytic thrombocytopenia and post myeloablative chemotherapy, done as the conditioning regimen before HSCT.25-31 However, the normal to low level of TPO found in most patients with ITP is not explained by this hypothesis.28,30,32 Alternative hypothesis is that TPO is regulated by the level of marrow megakaryocyte number and size. In patients with ITP, megakaryocyte numbers are increased and hence the increased absorption of endogenous TPO leads to the decreased TPO levels.33,34 Still, the TPO level seen in many other clinical conditions are less well understood. For instance, the patients with reactive thrombocytosis as well as the thrombocytosis secondary to clonal myeloproliferative disorders (specifically essential thrombocythemia and polycythemia vera) shows higher than expected levels of TPO.35 Over last two decades, our understanding of the site TPO production has gained new and interesting insights. Although the liver is one of the sites of TPO production, patients with various liver diseases have elevated TPO level.36-38 Further investigations in these patients with liver disease have demonstrated the cytokine induced increased TPO production by bone marrow stromal cells 39 as well as by the hepatocytes.40 These variations in TPO regulation seen in various thrombocytopenic states have attributed to the heterogeneity in the treatment pattern seen across these conditions. Targeting Thrombopoietin receptor:
7
With the changing concept of ITP pathophysiology being multi-compartment immunological dysregulation involving both the bone marrow as well as the peripheral circulation and splenic extravascular space41, the ITP treatment paradigm has shifted towards the development of novel therapeutic agents which target TPO-R. These modalities are especially critical in patients, refractory to the conventional therapies. The first attempt to target TPO-R came with the development and extensive study of two such recombinant forms of TPO-RAs, recombinant human TPO (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). These agonists showed excellent initial response. However, many patients were later found to develop paradoxical persistent thrombocytopenia, associated with the production of antibodies cross reactive to endogenous TPO.42-44 Further efforts led to the development of new generations of TPO-RAs which targeted and stimulated these receptors without the production of cross-reactive antibodies. Two such agents, romiplostim and eltrombopag, are currently approved by the United States Food and Drug Administration (US FDA) for the treatment of chronic refractory ITP in adults and children older than 1 year of age. Eltrombopag is also approved for the upfront treatment of severe aplastic anemia along with the standard immunosuppressive therapy (IST).45 Additionally, two newer orally bioavailable small molecules with reportedly better safety profiles (avatrombopag and lusutrombopag) are currently approved in the United States for the use in adult thrombocytopenic patients with liver disease undergoing invasive procedures.46 Furthermore, FDA has recently expanded the approval for avatrombopag for the use in adults with chronic ITP refractory to previous treatment. Although these agents are currently being investigated in other thrombocytopenic states, their use in post HSCT thrombocytopenia has not been described.
8
The binding of TPO-RA causes the conformational change in TPO-R, and the activation of various downstream signaling pathways including JAK2/STAT5, PI3K/AKT and ERK, ultimately leading to increased platelet production.47,48 Romiplostim is a peptibody, which binds to the extracellular domain, which is also the binding site for endogenous TPO. It is administered as subcutaneous injection. On the other hand, eltrombopag is an orally-active nonpeptide small molecule that binds to the transmembrane domain (TMD) of the TPO-R, which mechanistically makes it an attractive drug in conditions with elevated endogenous TPO level, such as severe aplastic anemia and various other bone morrow failure syndromes. Additionally, the eltrombopag appears to exert more stimulatory effects at the earlier stages of megakaryopoiesis whereas the romiplostim mostly stimulates mature megakaryocytic precursors.49 Although our experience with these two agents for last 10 years has shown safe and promising results, some theoretical concerns for serious long-term risks, particularly bone marrow fibrosis, thromboembolism and clonal evolution exist. Based on the current evidence, it does not seem that TPO-RA induce substantial fibrosis, and even those patients who develop increased reticulin and collagen will regress during or after the discontinuation of TPO-RA treatment.50,51 Similarly, the available evidence has not shown definitive correlation between the use of these agents and the risk of clonal evolution and malignancy.45,52 In spite of the evidence of increased risk of thrombosis in some patients treated with TPO-RAs, most available data on the risk of thrombosis are based on the retrospective and registry studies.46 Furthermore, specific adverse effects such as cataract and transaminitis are seen more frequently with eltrombopag, whereas the development of neutralizing antibodies and the injection site pain are seen with romiplostim.46
9
Prolonged
thrombocytopenia
after
Hematopoietic
Stem
Cell
Transplantation:
Thrombocytopenia is a common complication after HSCT, which often has multifactorial etiologies including poor graft function, GVHD, drugs, infections, and microangiopathy. The prolonged thrombocytopenia after HSCT, which is an independent adverse prognostic factor for transplant related mortality and overall survival, has not been systematically investigated.2,4,53 Apropos, no definitive guideline exists for the classification and management of patients with prolonged post HSCT thrombocytopenia. The existing literature categorizes these patients into the following two types according to the timelines of their presentation (as graphically depicted in Figure 1)
1. Prolonged Isolated Thrombocytopenia (PIT): is often defined as the platelet (PLT) count <20 x 109/L or platelet transfusion dependence for more than 60 days (although some reports describe >90 days) after HSCT, despite the engraftment of all other peripheral blood cell lines. PIT can be attributed to either a) delayed platelet engraftment (often defined as persistent severe thrombocytopenia with platelet count <20 x 109/L beyond 35 days after HSCT 54, b) primary graft failure (failure to achieve initial engraftment by day 28 after HSCT 55
or c) poor graft function (usually defined as persistent thrombocytopenia (platelet count
≤20 x 109/L) with neutropenia (ANC ≤0.5 x 109/L) and/or hemoglobin <7 g/dL for at least 3 consecutive days by 28 days after HSCT with transfusion dependence associated with hypoplastic-aplastic BM and complete donor chimerism without the concurrent GVHD or disease relapse.56 2. Secondary Failure of Platelet Recovery (SFPR): is the thrombocytopenia which subsequently develops after the initial platelet engraftment and is not due to graft rejection or
10
relapse. SFPR is defined as the decline of platelet counts below 20 x 109/L for 7 consecutive days or requiring transfusion support after achieving sustained platelet counts ≥50 x 109/L without transfusions for 7 consecutive days after HSCT.9 It is estimated to occur in as much as 20-40% of patients undergoing allogeneic HSCT.57,58 Although the exact etiology and mechanism of SFPR is not clearly understood, multiple factors have been reported to increase the risk of developing SFPR such as unrelated donor, grade II-IV GVHD, GVHD prophylaxis (especially combination of methotrexate with cyclosporine and prednisone compared to cyclosporine and prednisone alone59), renal or liver dysfunction, conditioning regimen with a combination of busulfan, cyclophosphamide and total-body irradiation, stem cell dose, infections (especially CMV, EBV and other opportunistic viral and bacterial infections), T-cell depletion and the use of ganciclovir or valganciclovir. 57,58,60
Use of thrombopoietin receptor agonists in post HSCT thrombocytopenia: We conducted a detailed systematic search of the databases PubMed, Embase, Ovid Medline, Cochrane and google scholar with the key search words “Prolonged Isolated Thrombocytopenia”, “delayed platelet recovery”, “Secondary Failure of Platelet Recovery”, “post HSCT thrombocytopenia”, “thrombopoietin receptor agonists”, “eltrombopag” and “romiplostim” with the aim of identifying all reports describing the characteristics and the outcomes of patients with post HSCT thrombocytopenia who were treated with TPO-RAs, eltrombopag or romiplostim. We also selected additional relevant articles listed in the references of the identified articles. Evidence available only as abstract form was excluded. Individual reports were reviewed in entirety to extract the data on the study characteristics and the outcomes. The schematic summary of the result of literature search is presented in Figure 2.
11
1. Eltrombopag use in prolonged post HSCT thrombocytopenia: We identified 13 reports (8 case series and 5 case reports), as detailed in Table 1, describing the use of eltrombopag for prolonged thrombocytopenia after HSCT.31,56,61-71 These reports included a total of 121 patients of varying age, with the median age of 48 years (Range: 10-70 years). Patients underwent
HSCT for wide range of conditions, which included 75
patients with leukemia, 14 patients with lymphoma, 27 patients with bone marrow failure, 4 patients with multiple myeloma, and 1 patient with Gaucher syndrome. One hundred and eleven out of 121 patients underwent allogenic transplants from various donor sources (54 haplo, 22 matched unrelated donor, 10 matched related donor, 25 unspecified source), whereas 10 patients underwent autologous transplantation. Seventy-eight patients developed PIT either due to primary graft failure or poor graft function. Forty-three patients initially engrafted, and subsequently developed thrombocytopenia due to SFPR. Eltrombopag was initiated at a median of 171.5 days after HSCT. Wide variability existed in the dosages (range 12.5 mg daily to 150 mg daily). Most of the studies reported initiating treatment within the lower dose range, and escalating the dose based on the response to treatment. Patients were treated for variable duration ranging from 2 weeks to 1 year depending on the severity of thrombocytopenia and the response to treatment. Most of the studies included small number of patients treated at a single center; and did not include the control group for comparison. Although there was no consistent measure of response to therapy across the studies, most of the studies measured response as either time to platelet transfusion independence or time to platelet count consistently above 50 x 10 9/L for 7 consecutive days without the need for platelet transfusion. Consistent and durable response with the rise of platelet count was seen in 85 out of 121 patients (Overall Response Rate ORR of
12
70%). Amongst the responders, stable platelet count with transfusion independence was reported following the discontinuation of eltrombopag after different time periods. However, few reports described a small number of patients, who had subsequent decline in the platelet count after the discontinuation of eltrombopag. These patients were mostly treated by switching to romiplostim.66,67 Re-introduction of eltrombopag to successfully maintain platelet count was described in one patient.63 In the intragroup comparison amongst the responders, 56 were patients with PIT (ORR for PIT of 72%) versus 29 patients with SFPR (ORR for SFPR of 67%). None of the reports described any serious grade 3 or 4 adverse effects.
2. Romiplostim use in prolonged post HSCT thrombocytopenia:
We identified 12 reports, as detailed in Table 2, describing the use of romiplostim in prolonged thrombocytopenia after HSCT.72-83 These reports included a total of 49 patients of varying age, with the median age of 48 years (range 3-68 years). Forty-eight patients underwent allogenic HSCT for wide range of conditions, which included 29 patients with leukemia, 6 patients with various types of lymphomas, 9 patients with bone marrow failure and 4 patients with other conditions (1 primary immunodeficiency, 1 X-linked adrenoleukodystrophy, 1 Xlinked chronic granulomatous disease and 1 neuroblastoma). The remaining one patient underwent consolidation with autologous HSCT for AML and HIV, due to the unavailability of matched donor. Graft sources in the allogenic HSCT were matched unrelated donor (MUD) in 27 patients, matched related donor (MSD) in 14 patients and haploidentical in 7 patients. Umbilical cord blood (UCB) was used as the graft source in 6 patients. A total of 17 patients developed PIT either due to primary graft failure or poor graft function, whereas 32 patients were diagnosed as SFPR. Romiplostim was initiated at the median of 85 days (range 27-365 days) after HSCT at a 13
minimum starting dose of 1 mcg/kg/dose subcutaneously. In majority of the studies, the dose was gradually escalated weekly to the maximum weekly dose of 10 mcg/kg/dose until the platelet response was achieved. Patients were treated for variable duration ranging from 2 weeks to 1 year depending on the severity of thrombocytopenia and the response to treatment. Most of the studies described response to treatment as the platelet count consistently above 50 x 10 9/L for 7 consecutive days without platelet transfusion. Forty out of 49 patients (ORR 82%) responded to romiplostim after a median of 31.5 days (14-126 days) of initiation of treatment. Amongst the responders, 10 patients had PIT (ORR for PIT of 59%) versus 30 patients had SFPR (ORR for SFPR of 94%). Most of the patients who responded to romiplostim were successfully titrated off the treatment at variable time period with the durable transfusion independence. One report described a patient who developed recurrent thrombocytopenia after the discontinuation of therapy.83 The patient was successfully treated with the re-initiation of romiplostim. None of the reports described any serious grade 3 or 4 adverse effects or any thromboembolic events or evidence of new bone marrow fibrosis. As with the eltrombopag studies, all these studies were retrospective, included small sample size and lacked the control group for the comparison of drug effect. Nonetheless, the response to romiplostim appeared robust with no indication of serious adverse effects.
Conclusion and future directions: The prolonged thrombocytopenia after HSCT is a common entity with a complex and often multifactorial etiology. It is considered a bad prognostic factor for transplant related morbidity and mortality. Aside from the platelet transfusion, no common consensus guidelines exist for the management of prolonged post HSCT thrombocytopenia. In view of their efficacy
14
and safety, TPO-RAs, eltrombopag and romiplostim, are being increasingly utilized as a new avenue of treatment in various thrombocytopenic conditions aside from ITP. Post HSCT thrombocytopenia is one of these attractive targets, which could potentially benefit from these agents. Existing reports, as described above, are retrospective case series and case reports, published from single center experience describing the small number of patients. Although the majority of these reports describe the measurable response to TPO-RAs treatment with the reduction in platelet transfusion requirement, the overall strength of their quality is weak. In view of their retrospective nature, small sample size, lack of controls and the non-randomized treatment pattern, these results should be critically analyzed before making a clinical treatment decision. In addition, the publication bias towards the successful treatment outcomes are likely to exist. Although the lack of matched control groups limits our ability to make a comparative analysis, the response to eltrombopag appeared similar in post HSCT thrombocytopenia due to PIT compared to SFPR, whereas the patients with SFPR had seemingly higher ORR to romiplostim than patients with PIT. These studies do not suggest any report of serious adverse effects, at least in short term. Currently there are multiple ongoing clinical trials evaluating the efficacy and safety of these agents for this indication (as listed in Table 3). Results from these trials should provide better insight in the treatment of these patients with prolonged post HSCT thrombocytopenia. Additionally, measuring the levels of endogenous TPO and the other cytokines in post HSCT thrombocytopenia (PIT and SFPR) merits further investigation, and perhaps will provide important insight on the future therapeutic development. Newer TPO-RAs (avatrombopag and lusutrombopag) appear safe and attractive agents, but needs further investigation for the use in prolonged post HSCT thrombocytopenia.
15
Conflict of interest: In this report, we discuss the use of medications which currently do not have US FDA approval for the discussed indication. We have no conflict of interest to disclose.
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20
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Buchbinder D, Hsieh L, Krance R, Nugent DJ. Successful treatment of post-transplant thrombocytopenia with romiplostim in a pediatric patient with X-linked chronic granulomatous disease. Pediatr Transplant. 2014;18(7):E252-254. Poon LM, Di Stasi A, Popat U, Champlin RE, Ciurea SO. Romiplostim for delayed platelet recovery and secondary thrombocytopenia following allogeneic stem cell transplantation. Am J Blood Res. 2013;3(3):260-264. DeRemer DL, Katsanevas K, Bradley A, Awan FT. Romiplostim resistance in secondary failure of platelet recovery. J Oncol Pharm Pract. 2013;19(4):369-372. Gangatharan SA, Cooney JP. Persistent thrombocytopenia post auto-SCT for AML treated with romiplostim in a patient with HIV. Bone Marrow Transplant. 2011;46(9):1280-1281. Beck JC, Burke MJ, Tolar J. Response of refractory immune thrombocytopenia after bone marrow transplantation to romiplostim. Pediatr Blood Cancer. 2010;54(3):490-491. Bollag RJ, Sterett M, Reding MT, Key NS, Cohn CS, Ustun C. Response of complex immune-mediated thrombocytopenia to romiplostim in the setting of allogeneic stem cell transplantation for chronic myelogenous leukemia. Eur J Haematol. 2012;89(4):361-364.
Figure/Table legends: Figure 1: Graphic depiction of the post HSCT thrombocytopenia in relation to different post HSCT complications. PIT is defined as the platelet counts < 20 × 109/L or dependence on platelet transfusions >60 days after HSCT whereas SFPR refers to the decline in platelet count to < 20 × 109/L for 7 consecutive days, or a requirement for transfusion support after achieving a sustained platelet count ≥ 50 × 109/L without transfusions for 7 consecutive days post-HSCT (GVHD, Graft-versus-Host Disease, SOS, Sinusoidal Obstruction Syndrome, PIT, Prolonged Isolated Thrombocytopenia, SFPR, Secondary Failure of Platelet Recovery, HSC: Hematopoietic Stem Cells)
Figure 2: Graphic summary of the result of literature search of TPO-RAs use in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. 21
(PIT: Prolonged Isolated Thrombocytopenia, SFPR: Secondary Failure of Platelet Recovery, ORR overall response rate)
Table 1: Use of Eltrombopag in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. Table 2: Use of Romiplostim in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. Table 3: Currently active clinical trials using TPO-RAs (eltrombopag and romiplostim) in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation.
22
Stud De y sig n
N Age (yrs, median and range)
Dis ease
HSCT type
TCP type
Fu et Ca al. se 2019 ser ies
3 28 (128 54)
AM L14 AL L-
Haplo-38
PIT 23(DPE8, PoGF15), SFPR-15
Ti m e to E p a g fr o m H S C T (d a ys , m e di a n, ra n g e) 1 7 9 (7 423
Max daily dose, (mg, maximum, range)
D ur ati on of tre at m en t (m ed ia n, ra ng e)
Response to Epag
Time to PLT> 50 x109/ L (medi an, range)
Adve rse effec ts
100 (25100)
O ve ral l:
24 responders (63.2%) PLT transfusion independence rate 63.2%, >=50 x 10 9/L rate 52.3%
32 (7127) days
None
17 SA A-1 MD S-6
Rive ra et al. 2018
Ca se ser ies
1 56 (254 69)
AL L-2, AM L-4 MD S-2, MP N-2 SA A1, NH L-3
5 2 9)
Haplo-7 MRD-3 MUD-4
PIT-3, SFPR-11
N 150 (50R 150) (f ro m o ns et of T C P 2, 24
64 (1 419 5) da ys 77 (2 419 4) da ys in res po nd ers 91 (820 6 ) da ys in res po nd ers an
8 out of 14 patients (57%) showed PLT recovery ≥50 × 109/L.
No grad e 3/4 adve rse effec ts. 42% (6/14 ) grad e 1-2 AEs
11 5 5 d a ys )
Yuan Ca et al. se 2019 ser ies
Raut et al Ca 2014 se ser ies
1 56 (363 70)
1 29.5 2 (18-57)
AM L/M DS9, AL L-2, HD1, SA A-1 AM L-2 SA A-1 MM -3 Ly mph oma -6
AlloHSCT (graft source NR)
PIT-6 (PEF>+1 00 days) SFPR-7
8 1 (3 63 0 0)
Starting dose 25-50. Max dose not reported.
2 Allo (AML-1, SAA-1), 10- Auto SCT (MM-3, lymphoma6-, AML-1)
PIT
2 1 (1 76 0)
25-50
25
d 21 (993 ) in no nres po nd ers N R
29 (1 311 4) da ys
ORR 62% (8/13) No difference between pt with normal vs decreased BM megakaryocyte (67% vs 60%)
33 (1168) days
None
Gradual increase in PLT
NR
None
Tana ka et al 2016
Ca se ser ies
1 53(192 63)
Tang Ca et al se 2018 ser ies
1 34 (212 53)
Mar otta et al 2019
1 48.5 2 (26-67)
Ca se ser ies
7 AM L, MD S-2, TA LL/ Ly1, LL 1, FL 1 AL L-4, AM L-3, MP AL1, SA A3, MF1 AM L-5, MD S-2, MM -1, CM L-1,
MSD-3 URD-9
PIT-5 SFPR-7
1 6 8 (6 31 7 8 5)
12.5-50
11 6 da ys (4 927 3)
CI of PLT recovery (>50 x 10 9/L) 71% in SFPR and 60% in PIT
54 (14195) days
None
Allo HSCT
PIT (PoGF)
1 7 5 (6 51 1 8 0)
25-75
8 (223 ) we ek s
ORR 83.3%, Complete response (trilineage 66.7%)
29 (1049) days
None
Haplo-8, MUD-2, MRD-2
PIT (PoGF)
7 9 (4 23 6 7)
50-150
10 7 (2 815 5) da ys
Hematologic response in 7 pts with complete response in 6 pts.
NR
1 pt with iron overl oad devel oped skin
26
Li et Ca al. se 2019 ser ies
Reid Ca et al se 2012 rep ort
IMF -1, SA A1, AL L-1 3 12.4(11 SA .4-15.6) A-2 Gau cher dise ase1 2 42-63 AM L-2
Ca 1 55 Fuji se mi et rep al ort 2015 Dyb a et al 2016
Ca 1 56 se rep ort
Foll icul ar lym pho ma Acu te undi ffer
hype rpig ment ation .
MUD-2, Haplo-1
PIT-1 SFPR-2
MUD-1 Auto HSCT-1
PIT
Allo-HSCT
PIT
PB MUD Mismatched (6/8) x2
PIT (PoGF)
27
7 9 (5 01 5 6) 2 8 0 (1 4 04 2 0) 4 4 3
50
40 (2 269 ) da ys 6 we ek s
CR-2 NR-1
P1-7 P2-62 P3NR
None
Transfusion independent within 2 weeks. PLT remained at 20-40 x 109/L
Not reache d
None
NR
N R
PLT to normal
NR
NR
3 4 3
50
N R
Quick improvement in counts. Transfusion independent in several wks.
Severa None l weeks
50
Ali Ca 1 10 et al se 2017 rep ort
enti ated leuk emi a SA A
MSD
SFPR
3 0 9
25-75
10 .7 m on ths 1 ye ar
PLT to normal
26 weeks
None
Mast Ca 1 26 AM MSD PIT 7 50 Increase of trilineage 72 None er et se L (PoGF) 2 days al rep 2018 ort Note: N number of patients, pts patients, HSCT hematopoietic stem cell transplant, TCP thrombocytopenia, Epag eltrombopag, MUD matched unrelated donor, MRD Matched related donor, Allo allogenic, UCB umbilical cord blood, PIT Prolonged Isolated Thrombocytopenia, DPE delayed platelet engraftment, SFPR Secondary Failure of Platelet Recovery, PoGF poor graft function, PFE primary engraftment failure, NR not reported, PLT platelet, SAA severe aplastic anemia, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MDS myelodysplastic syndrome. MF myelofibrosis, MM multiple myeloma, CML chronic myeloid leukemia, MPN myeloproliferative neoplasm, HD Hodgkin disease, NHL Non Hodgkin lymphoma, FL Follicular lymphoma, IMF inherited marrow failure, MPAL mixed phenotype acute leukemia
28
Study, De N Age year of sig (yrs, public n median, ation range)
Hartra nft et al 2017
Ca se ser ies
13
48 (1768)
Diag H nosis SC T ty pe
AML -5, CML -2, CLL1ALL -1, NHL 1, MDS -1, NB-1, BL-1
M U D7 M R D6
TCP type
SFPR-9 PIT-4
Time from HSCT to RPM (days, median, range)
R P M do se, (m cg /k g, m ax im u m, ra ng e)
No. of RPM dosage s (media n, range)
Response
91 (21-208) for SFPR pts. NR for PIT pts.
10 (110 )
Respon ders 17 (3-60) Non respond ers 6 (112)
Response in 7 out of 13 patients (54%). Median survival in responder vs non responder: 753 days vs 266 days (p: 0.0375)
29
Time to PLT>50 x109/ L (median, range)
A d v er se ef fe ct s
35 (14-56) days in responders
N on e
Ca
8
53 (1667)
7
57(2 5-60)
Battip se aglia ser et al ies 2015
Ca
Calmet se tes et ser al ies 2011
Maxim ova et al 2014
Ca se ser ies
7
11 (813)
AML -5, MDS -1, NHL1, 1 TAL L/Ly
Ha plo -5 M R D1 M U D2 AML M -2, R NHL- D2, 2, ALL- M 1, U MDS D-1, 4 SAA- U 1 CB -1 ALL- M 3, U AML D-1 3 SAA- M 1 R PID-1 DFanco 3 ni-1 Ha plo -1
SFPR-5 PIT3(PEF/BK hemorrhagi c cystitis)
72.5 (42-381)
10 (110 )
10 (532)
PLT recovery with median of 2 dosages in SFPR. Median time to HC recovery on 3 pts was 44 days (9-106) after median of 4 injections.
SFPR
7-61 (27)
10 (110 )
NR
TCP corrected in all patients
7
4
SFPR (4 viral infection, 2 immune, 1 both)
85 (62-104)
30
6 of 7 achieved PLT transfusion independence in second week of treatment
SFPR-2 wks HC pts-44 days to HC recovery
54(24-84) days
4 weeks
N on e
N on e
N on e
Ca
5
39 (3541)
ALL3, AML -1 SAA1
3
57(3 6-62)
HL, Ha AML, plo MF -1 M U D2
Lancm se an et ser al ies 2018
Ca
Poon se et al ser 2013 ies
dU SFPR-2 CB PFE-3 -4 M SD -1
SFPR-1, PIT-2
59 (38-396)
8 (18)
10 (617)
Yes-4 No-1 (response is PLT >50 x109/ L for 7 days)
34.5 (1458) amongst responders
361(166-480)
10 (110 )
NR
All 3 responded
126(72127)
31
4no ne 1fo ca l 01 + fi br os is on B M B x N on e; B M bx af te r R x di d no
Ca
1
3
XL CGD
1 year
5 (15)
NR (6 months total treatme nt)
Sustained increase in PLT
3 weeks
Ca 1 se rep ort
5
Fanco U SFPR ni CB anemi a
117
10
4 (d+117149)
By D+130, PLT >25 x109/L
? by Day +149 (32 days)
N on e
Ca 1 se rep ort
59
CLL
M U D
SFPR
202
10
11
No
No response
N on e
Ca 1 se rep ort
58
AML (HIV +)
Au to
PGF
80
Yes
31 days N (>20x109/L) on e
4
X linke d
M U D
SFPR
~83
37 21 5 mc g we ekl y 3 4
Yes
~ 4 weeks
Buchbi se nder et rep al ort 2007 Buchbi nder et al 2015 DeRe mer et al 2013 Ganga tharan et al 2011
Beck Ca et al se rep
1
M U D
SFPR
t sh o w fi br os is N R
32
N on e
2010 ort
Bollag Ca 1 et al se 2012 rep
48
adren oleuk odyst rophy CML
M SFPR SD -1
NR
6
NR
PLT increased.
~3 weeks
ort
Note: N=number of patients, HSCT hematopoietic stem cell transplant, MUD unrelated donor, MRD Matched related donor, Allo: allogenic, Auto: autologous, UCB umbilical cord blood, PIT prolonged isolated thrombocytopenia, SFPR secondary failure of platelet recovery, PoGF poor graft function, NR: not reported, PLT: platelet, SAA: severe aplastic anemia, HC: Hemorrhagic cystitis.
33
N on e
ClinicalTrials.g ov identifier
Phase
Status
Title
NCT01791101
2
Recru iting
Eltrombopag in Patients with Delayed Post Transplant Thrombocytopenia
NCT01000051
2 (single group randomized)
Comp leted
Eltrombopag for Post-HSCT Thrombocytopenia
1/2
Comp leted
Using ROMIPLOSTINE for Persistent Thrombocytopenia with Transfusion-dependent Patients Who Received Allogeneic Hematopoietic Stem Cell.
2
Activ e, not recrui ting
Eltrombopag Olamine 34 in Increasing Platelet Counts in Patients Undergoing Transplant
NCT01980030
NCT01927731
Sponsors Gruppo Italiano Malattie EMatolo giche dell'Adul to, Italy M.D. Anderso n Cancer Center Novartis Pharmac euticals (collabor ator) Assistan ce Publique Hôpitaux de Paris M.D. Anderso n Cancer Center NCI (collabor ator)
Condition
Age inclusion
Thromboc ytopenia
18 years and older.
Thromboc ytopenia
18 years and older.
Thromboc ytopenia
18 years and older.
Thromboc ytopenia
18 Years and older
NCT02046291
1
Activ e, not recrui ting
NCT03515096
3
Recru iting
Safety of Romiplostim (Nplate®) Following UCBT
Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
35
Masonic Cancer Center, Universit y of Minnesot a Shenzhe n Second People's Hospital, China
Thromboc ytopenia
18 Years and older
Thromboc ytopenia
18 Years and older
36
37
Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation Upendra Mahat MD , Seth J. Rotz MD , Rabi Hanna MD PII: DOI: Reference:
S1083-8791(19)30838-9 https://doi.org/10.1016/j.bbmt.2019.12.003 YBBMT 55812
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
17 September 2019 3 December 2019
Please cite this article as: Upendra Mahat MD , Seth J. Rotz MD , Rabi Hanna MD , Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation, Biology of Blood and Marrow Transplantation (2019), doi: https://doi.org/10.1016/j.bbmt.2019.12.003
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy
Highlights: Prolonged thrombocytopenia after HSCT is a strong risk factor for transplant related mortality and morbidity. No common consensus exists for the uniform classification and management of prolonged thrombocytopenia after HSCT. Available literature inconsistently describes
post
HSCT
thrombocytopenia
as
either
Prolonged
Isolated
Thrombocytopenia (PIT) or Secondary Failure of Platelet Recovery (SFPR). Thrombopoietin Receptor Agonists (Eltrombopag and romiplostim) are being increasingly used in patients with prolonged post HSCT thrombocytopenia. Our extensive literature review suggests that patients with prolonged post HSCT thrombocytopenia may respond to both eltrombopag (Overall Response Rate 70%) and romiplostim (Overall Response Rate 82%) with no evidence of serious adverse effects. However, the overall strength of evidence is weak in view of the retrospective nature of the studies, lack of control groups, heterogeneity of data and the potential publication bias.
1
Title: Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. Upendra Mahat MD, Seth J Rotz MD, Rabi Hanna MD. Department of Pediatric Hematology Oncology and BMT Cleveland Clinic Children’s, Cleveland, Ohio.
Corresponding Author: Upendra Mahat MD Department of Pediatric Hematology Oncology and BMT 9500 Euclid Avenue, R-3 Cleveland Ohio 44195 Email: [email protected]
Key words: Thrombopoietin receptor agonists, Eltrombopag, Romiplostim, Prolonged Isolated Thrombocytopenia, Secondary Failure of Platelet Recovery.
2
Abbreviations: HSCT
Hematopoietic Stem Cell Transplant
PIT
Prolonged Isolated Thrombocytopenia
SFPR
Secondary Failure of Platelet Recovery
TPO-R
Thrombopoietin receptor
TPO-RA
Thrombopoietin receptor agonist
Abstract word count: 285 unstructured. Manuscript word count: 3079 Number of tables: 3 Number of figures: 2 Short
running
title:
Thrombopoietin
receptor
thrombocytopenia.
3
agonists
in
prolonged
post-HSCT
Abstract: Prolonged thrombocytopenia after HSCT is a strong risk factor for transplant related mortality and morbidity, and no standard treatment guideline exists. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, increases the platelet production, and are being increasingly used in various conditions with thrombocytopenia. In this review, we present an overview of these TPO-RAs and review their efficacy and safety in prolonged post HSCT thrombocytopenia. Through a systematic literature search, we identified 25 reports describing their use for this indication. Thirteen reports (8 case series and 5 case reports) described the use of eltrombopag in 78 patients with Prolonged Isolated Thrombocytopenia (PIT) and 43 patients with Secondary Failure of Platelet Recovery (SFPR). A consistent and durable response with the rise in platelet counts above 50 x 10 9/L for 7 consecutive days without platelet transfusion was seen in 85 out of 121 patients (Overall Response Rate, ORR 70%). Amongst the responders, 56 were patients with PIT (ORR for PIT of 72%) versus 29 patients with SFPR (ORR for SFPR of 67%). No serious grade 3 or 4 adverse effects were reported. Similarly, 12 reports (6 case series and 6 case reports) described the use of romiplostim in prolonged post HSCT thrombocytopenia (17 patients with PIT and 32 patients with SFPR). Response with the increment of platelet count was described in 40 out of 49 patients (ORR 82%). Amongst the responders, 10 patients had PIT (ORR for PIT of 59%) versus 30 patients had SFPR (ORR for SFPR of 94%). TPO-RAs have an overall favorable response rate for both PIT and SFPR with a reasonable safety profile. However, given the lack of control groups, study heterogeneity, and the potential publication bias, the results should be interpreted with caution.
4
Introduction: Hematopoietic Stem Cell Transplantation (HSCT) is a potentially curative therapy for many malignant and non-malignant conditions. With the improved cellular technologies, increasing use of reduced intensity conditioning and alternative graft sources, and the improved preventive/supportive care, the number, indications and the scope of HSCT is continuously evolving.1 Prolonged thrombocytopenia after HSCT is a strong risk factor for transplant related mortality (TRM).2-5 Platelet count below 100x109/L on day 100 post HSCT has been previously described by multiple reports as a harbinger of increased TRM and decreased overall survival.2,3,5,6 Decreased survival of the post HSCT patients with prolonged thrombocytopenia is often related to the increased incidence of treatment failure, secondary to severe acute and chronic graft versus host disease (GVHD), more often than due to the relapse of underlying disease.3 Aside from the disease recurrence, the etiology behind post HSCT thrombocytopenia is multifactorial, and includes either impaired production (due to poor graft function, infections or drug adverse effects), increased destruction (due to immune mediated processes) or combination of both.7,8 Despite being a common entity with the incidence of over 20% after allogenic HSCT4,9, no common consensus exists for the uniform classification or management of prolonged post HSCT thrombocytopenia. The treatment often consists of platelet transfusion and various other agents used primarily in the treatment of immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) bind to thrombopoietin receptor (TPO-R) and stimulate downstream signaling pathways, leading to the increased platelet production. Eltrombopag and romiplostim are two TPO-RAs, which are being increasingly used in the prolonged and/or refractory thrombocytopenia after HSCT. Here, we present an overview of the
5
biology of thrombopoiesis and the TPO-RAs, and then a detailed report of the use of these agents in the treatment of prolonged thrombocytopenia after HSCT.
Biology of Thrombopoiesis: Thrombopoietin as a unique hematopoietic growth factor: Shortly following the identification of v-mpl oncogene from murine myeloproliferative leukemia in 1990, the human homolog, C-MPL gene was successfully cloned from both murine as well as the human sources.10,11 Located on chromosome 1p34.2, C-MPL encodes a protein, CD110, which is a 635-amino acid transmembrane protein, with two extracellular cytokine receptor domains and two intracellular cytokine receptor box motifs. It is constitutively expressed on the hematopoietic progenitor cells, megakaryocytes, and platelets.12 The ligand for C-MPL was subsequently cloned by multiple groups in 1994.13-17 C-MPL ligand, which is encoded by a gene on chromosome 3q27.1, regulates the megakaryocyte proliferation and differentiation both in vivo as well as in vitro.18 With the improved understanding of the biology of thrombopoiesis, the C-MPL ligand has gotten its new and perhaps more appropriate name, the Thrombopoietin (TPO), and the C-MPL receptor, the Thrombopoietin receptor (CD110 or TPOR). Thrombopoietin, a 332 amino acid glycoprotein, is a humoral growth factor produced by liver, kidney, bone marrow stroma and several other tissues.19 Its amino‐ terminal 154 residue receptor binding domain shows homology to erythropoietin20, whereas the carboxyl‐ terminal domain bears no resemblance to any known cytokines, and is important for its structural integrity. Upon binding to its receptor, TPO stimulates cytoplasmic kinases to mediate activation of different signaling pathways, leading to the differentiation and maturation of committed hematopoietic stem cells to megakaryocyte and eventually platelets.21 In contrast to the 6
regulation of other hematopoietic growth factors, the regulation of TPO production is rather unclear and incompletely understood. In general, serum TPO level fluctuates inversely in response to the low blood platelet and marrow megakaryocyte counts.22 TPO production has been thought to be constitutive, and platelets bearing TPO receptors are thought to absorb the hormone and destroy it.23,24 This simple model explains the high endogenous TPO levels in bone marrow failure states such as aplastic anemia, congenital amegakaryocytic thrombocytopenia and post myeloablative chemotherapy, done as the conditioning regimen before HSCT.25-31 However, the normal to low level of TPO found in most patients with ITP is not explained by this hypothesis.28,30,32 Alternative hypothesis is that TPO is regulated by the level of marrow megakaryocyte number and size. In patients with ITP, megakaryocyte numbers are increased and hence the increased absorption of endogenous TPO leads to the decreased TPO levels.33,34 Still, the TPO level seen in many other clinical conditions are less well understood. For instance, the patients with reactive thrombocytosis as well as the thrombocytosis secondary to clonal myeloproliferative disorders (specifically essential thrombocythemia and polycythemia vera) shows higher than expected levels of TPO.35 Over last two decades, our understanding of the site TPO production has gained new and interesting insights. Although the liver is one of the sites of TPO production, patients with various liver diseases have elevated TPO level.36-38 Further investigations in these patients with liver disease have demonstrated the cytokine induced increased TPO production by bone marrow stromal cells 39 as well as by the hepatocytes.40 These variations in TPO regulation seen in various thrombocytopenic states have attributed to the heterogeneity in the treatment pattern seen across these conditions. Targeting Thrombopoietin receptor:
7
With the changing concept of ITP pathophysiology being multi-compartment immunological dysregulation involving both the bone marrow as well as the peripheral circulation and splenic extravascular space41, the ITP treatment paradigm has shifted towards the development of novel therapeutic agents which target TPO-R. These modalities are especially critical in patients, refractory to the conventional therapies. The first attempt to target TPO-R came with the development and extensive study of two such recombinant forms of TPO-RAs, recombinant human TPO (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). These agonists showed excellent initial response. However, many patients were later found to develop paradoxical persistent thrombocytopenia, associated with the production of antibodies cross reactive to endogenous TPO.42-44 Further efforts led to the development of new generations of TPO-RAs which targeted and stimulated these receptors without the production of cross-reactive antibodies. Two such agents, romiplostim and eltrombopag, are currently approved by the United States Food and Drug Administration (US FDA) for the treatment of chronic refractory ITP in adults and children older than 1 year of age. Eltrombopag is also approved for the upfront treatment of severe aplastic anemia along with the standard immunosuppressive therapy (IST).45 Additionally, two newer orally bioavailable small molecules with reportedly better safety profiles (avatrombopag and lusutrombopag) are currently approved in the United States for the use in adult thrombocytopenic patients with liver disease undergoing invasive procedures.46 Furthermore, FDA has recently expanded the approval for avatrombopag for the use in adults with chronic ITP refractory to previous treatment. Although these agents are currently being investigated in other thrombocytopenic states, their use in post HSCT thrombocytopenia has not been described.
8
The binding of TPO-RA causes the conformational change in TPO-R, and the activation of various downstream signaling pathways including JAK2/STAT5, PI3K/AKT and ERK, ultimately leading to increased platelet production.47,48 Romiplostim is a peptibody, which binds to the extracellular domain, which is also the binding site for endogenous TPO. It is administered as subcutaneous injection. On the other hand, eltrombopag is an orally-active nonpeptide small molecule that binds to the transmembrane domain (TMD) of the TPO-R, which mechanistically makes it an attractive drug in conditions with elevated endogenous TPO level, such as severe aplastic anemia and various other bone morrow failure syndromes. Additionally, the eltrombopag appears to exert more stimulatory effects at the earlier stages of megakaryopoiesis whereas the romiplostim mostly stimulates mature megakaryocytic precursors.49 Although our experience with these two agents for last 10 years has shown safe and promising results, some theoretical concerns for serious long-term risks, particularly bone marrow fibrosis, thromboembolism and clonal evolution exist. Based on the current evidence, it does not seem that TPO-RA induce substantial fibrosis, and even those patients who develop increased reticulin and collagen will regress during or after the discontinuation of TPO-RA treatment.50,51 Similarly, the available evidence has not shown definitive correlation between the use of these agents and the risk of clonal evolution and malignancy.45,52 In spite of the evidence of increased risk of thrombosis in some patients treated with TPO-RAs, most available data on the risk of thrombosis are based on the retrospective and registry studies.46 Furthermore, specific adverse effects such as cataract and transaminitis are seen more frequently with eltrombopag, whereas the development of neutralizing antibodies and the injection site pain are seen with romiplostim.46
9
Prolonged
thrombocytopenia
after
Hematopoietic
Stem
Cell
Transplantation:
Thrombocytopenia is a common complication after HSCT, which often has multifactorial etiologies including poor graft function, GVHD, drugs, infections, and microangiopathy. The prolonged thrombocytopenia after HSCT, which is an independent adverse prognostic factor for transplant related mortality and overall survival, has not been systematically investigated.2,4,53 Apropos, no definitive guideline exists for the classification and management of patients with prolonged post HSCT thrombocytopenia. The existing literature categorizes these patients into the following two types according to the timelines of their presentation (as graphically depicted in Figure 1)
1. Prolonged Isolated Thrombocytopenia (PIT): is often defined as the platelet (PLT) count <20 x 109/L or platelet transfusion dependence for more than 60 days (although some reports describe >90 days) after HSCT, despite the engraftment of all other peripheral blood cell lines. PIT can be attributed to either a) delayed platelet engraftment (often defined as persistent severe thrombocytopenia with platelet count <20 x 109/L beyond 35 days after HSCT 54, b) primary graft failure (failure to achieve initial engraftment by day 28 after HSCT 55
or c) poor graft function (usually defined as persistent thrombocytopenia (platelet count
≤20 x 109/L) with neutropenia (ANC ≤0.5 x 109/L) and/or hemoglobin <7 g/dL for at least 3 consecutive days by 28 days after HSCT with transfusion dependence associated with hypoplastic-aplastic BM and complete donor chimerism without the concurrent GVHD or disease relapse.56 2. Secondary Failure of Platelet Recovery (SFPR): is the thrombocytopenia which subsequently develops after the initial platelet engraftment and is not due to graft rejection or
10
relapse. SFPR is defined as the decline of platelet counts below 20 x 109/L for 7 consecutive days or requiring transfusion support after achieving sustained platelet counts ≥50 x 109/L without transfusions for 7 consecutive days after HSCT.9 It is estimated to occur in as much as 20-40% of patients undergoing allogeneic HSCT.57,58 Although the exact etiology and mechanism of SFPR is not clearly understood, multiple factors have been reported to increase the risk of developing SFPR such as unrelated donor, grade II-IV GVHD, GVHD prophylaxis (especially combination of methotrexate with cyclosporine and prednisone compared to cyclosporine and prednisone alone59), renal or liver dysfunction, conditioning regimen with a combination of busulfan, cyclophosphamide and total-body irradiation, stem cell dose, infections (especially CMV, EBV and other opportunistic viral and bacterial infections), T-cell depletion and the use of ganciclovir or valganciclovir. 57,58,60
Use of thrombopoietin receptor agonists in post HSCT thrombocytopenia: We conducted a detailed systematic search of the databases PubMed, Embase, Ovid Medline, Cochrane and google scholar with the key search words “Prolonged Isolated Thrombocytopenia”, “delayed platelet recovery”, “Secondary Failure of Platelet Recovery”, “post HSCT thrombocytopenia”, “thrombopoietin receptor agonists”, “eltrombopag” and “romiplostim” with the aim of identifying all reports describing the characteristics and the outcomes of patients with post HSCT thrombocytopenia who were treated with TPO-RAs, eltrombopag or romiplostim. We also selected additional relevant articles listed in the references of the identified articles. Evidence available only as abstract form was excluded. Individual reports were reviewed in entirety to extract the data on the study characteristics and the outcomes. The schematic summary of the result of literature search is presented in Figure 2.
11
1. Eltrombopag use in prolonged post HSCT thrombocytopenia: We identified 13 reports (8 case series and 5 case reports), as detailed in Table 1, describing the use of eltrombopag for prolonged thrombocytopenia after HSCT.31,56,61-71 These reports included a total of 121 patients of varying age, with the median age of 48 years (Range: 10-70 years). Patients underwent
HSCT for wide range of conditions, which included 75
patients with leukemia, 14 patients with lymphoma, 27 patients with bone marrow failure, 4 patients with multiple myeloma, and 1 patient with Gaucher syndrome. One hundred and eleven out of 121 patients underwent allogenic transplants from various donor sources (54 haplo, 22 matched unrelated donor, 10 matched related donor, 25 unspecified source), whereas 10 patients underwent autologous transplantation. Seventy-eight patients developed PIT either due to primary graft failure or poor graft function. Forty-three patients initially engrafted, and subsequently developed thrombocytopenia due to SFPR. Eltrombopag was initiated at a median of 171.5 days after HSCT. Wide variability existed in the dosages (range 12.5 mg daily to 150 mg daily). Most of the studies reported initiating treatment within the lower dose range, and escalating the dose based on the response to treatment. Patients were treated for variable duration ranging from 2 weeks to 1 year depending on the severity of thrombocytopenia and the response to treatment. Most of the studies included small number of patients treated at a single center; and did not include the control group for comparison. Although there was no consistent measure of response to therapy across the studies, most of the studies measured response as either time to platelet transfusion independence or time to platelet count consistently above 50 x 10 9/L for 7 consecutive days without the need for platelet transfusion. Consistent and durable response with the rise of platelet count was seen in 85 out of 121 patients (Overall Response Rate ORR of
12
70%). Amongst the responders, stable platelet count with transfusion independence was reported following the discontinuation of eltrombopag after different time periods. However, few reports described a small number of patients, who had subsequent decline in the platelet count after the discontinuation of eltrombopag. These patients were mostly treated by switching to romiplostim.66,67 Re-introduction of eltrombopag to successfully maintain platelet count was described in one patient.63 In the intragroup comparison amongst the responders, 56 were patients with PIT (ORR for PIT of 72%) versus 29 patients with SFPR (ORR for SFPR of 67%). None of the reports described any serious grade 3 or 4 adverse effects.
2. Romiplostim use in prolonged post HSCT thrombocytopenia:
We identified 12 reports, as detailed in Table 2, describing the use of romiplostim in prolonged thrombocytopenia after HSCT.72-83 These reports included a total of 49 patients of varying age, with the median age of 48 years (range 3-68 years). Forty-eight patients underwent allogenic HSCT for wide range of conditions, which included 29 patients with leukemia, 6 patients with various types of lymphomas, 9 patients with bone marrow failure and 4 patients with other conditions (1 primary immunodeficiency, 1 X-linked adrenoleukodystrophy, 1 Xlinked chronic granulomatous disease and 1 neuroblastoma). The remaining one patient underwent consolidation with autologous HSCT for AML and HIV, due to the unavailability of matched donor. Graft sources in the allogenic HSCT were matched unrelated donor (MUD) in 27 patients, matched related donor (MSD) in 14 patients and haploidentical in 7 patients. Umbilical cord blood (UCB) was used as the graft source in 6 patients. A total of 17 patients developed PIT either due to primary graft failure or poor graft function, whereas 32 patients were diagnosed as SFPR. Romiplostim was initiated at the median of 85 days (range 27-365 days) after HSCT at a 13
minimum starting dose of 1 mcg/kg/dose subcutaneously. In majority of the studies, the dose was gradually escalated weekly to the maximum weekly dose of 10 mcg/kg/dose until the platelet response was achieved. Patients were treated for variable duration ranging from 2 weeks to 1 year depending on the severity of thrombocytopenia and the response to treatment. Most of the studies described response to treatment as the platelet count consistently above 50 x 10 9/L for 7 consecutive days without platelet transfusion. Forty out of 49 patients (ORR 82%) responded to romiplostim after a median of 31.5 days (14-126 days) of initiation of treatment. Amongst the responders, 10 patients had PIT (ORR for PIT of 59%) versus 30 patients had SFPR (ORR for SFPR of 94%). Most of the patients who responded to romiplostim were successfully titrated off the treatment at variable time period with the durable transfusion independence. One report described a patient who developed recurrent thrombocytopenia after the discontinuation of therapy.83 The patient was successfully treated with the re-initiation of romiplostim. None of the reports described any serious grade 3 or 4 adverse effects or any thromboembolic events or evidence of new bone marrow fibrosis. As with the eltrombopag studies, all these studies were retrospective, included small sample size and lacked the control group for the comparison of drug effect. Nonetheless, the response to romiplostim appeared robust with no indication of serious adverse effects.
Conclusion and future directions: The prolonged thrombocytopenia after HSCT is a common entity with a complex and often multifactorial etiology. It is considered a bad prognostic factor for transplant related morbidity and mortality. Aside from the platelet transfusion, no common consensus guidelines exist for the management of prolonged post HSCT thrombocytopenia. In view of their efficacy
14
and safety, TPO-RAs, eltrombopag and romiplostim, are being increasingly utilized as a new avenue of treatment in various thrombocytopenic conditions aside from ITP. Post HSCT thrombocytopenia is one of these attractive targets, which could potentially benefit from these agents. Existing reports, as described above, are retrospective case series and case reports, published from single center experience describing the small number of patients. Although the majority of these reports describe the measurable response to TPO-RAs treatment with the reduction in platelet transfusion requirement, the overall strength of their quality is weak. In view of their retrospective nature, small sample size, lack of controls and the non-randomized treatment pattern, these results should be critically analyzed before making a clinical treatment decision. In addition, the publication bias towards the successful treatment outcomes are likely to exist. Although the lack of matched control groups limits our ability to make a comparative analysis, the response to eltrombopag appeared similar in post HSCT thrombocytopenia due to PIT compared to SFPR, whereas the patients with SFPR had seemingly higher ORR to romiplostim than patients with PIT. These studies do not suggest any report of serious adverse effects, at least in short term. Currently there are multiple ongoing clinical trials evaluating the efficacy and safety of these agents for this indication (as listed in Table 3). Results from these trials should provide better insight in the treatment of these patients with prolonged post HSCT thrombocytopenia. Additionally, measuring the levels of endogenous TPO and the other cytokines in post HSCT thrombocytopenia (PIT and SFPR) merits further investigation, and perhaps will provide important insight on the future therapeutic development. Newer TPO-RAs (avatrombopag and lusutrombopag) appear safe and attractive agents, but needs further investigation for the use in prolonged post HSCT thrombocytopenia.
15
Conflict of interest: In this report, we discuss the use of medications which currently do not have US FDA approval for the discussed indication. We have no conflict of interest to disclose.
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Figure/Table legends: Figure 1: Graphic depiction of the post HSCT thrombocytopenia in relation to different post HSCT complications. PIT is defined as the platelet counts < 20 × 109/L or dependence on platelet transfusions >60 days after HSCT whereas SFPR refers to the decline in platelet count to < 20 × 109/L for 7 consecutive days, or a requirement for transfusion support after achieving a sustained platelet count ≥ 50 × 109/L without transfusions for 7 consecutive days post-HSCT (GVHD, Graft-versus-Host Disease, SOS, Sinusoidal Obstruction Syndrome, PIT, Prolonged Isolated Thrombocytopenia, SFPR, Secondary Failure of Platelet Recovery, HSC: Hematopoietic Stem Cells)
Figure 2: Graphic summary of the result of literature search of TPO-RAs use in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. 21
(PIT: Prolonged Isolated Thrombocytopenia, SFPR: Secondary Failure of Platelet Recovery, ORR overall response rate)
Table 1: Use of Eltrombopag in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. Table 2: Use of Romiplostim in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. Table 3: Currently active clinical trials using TPO-RAs (eltrombopag and romiplostim) in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation.
22
Stud De y sig n
N Age (yrs, median and range)
Dis ease
HSCT type
TCP type
Fu et Ca al. se 2019 ser ies
3 28 (128 54)
AM L14 AL L-
Haplo-38
PIT 23(DPE8, PoGF15), SFPR-15
Ti m e to E p a g fr o m H S C T (d a ys , m e di a n, ra n g e) 1 7 9 (7 423
Max daily dose, (mg, maximum, range)
D ur ati on of tre at m en t (m ed ia n, ra ng e)
Response to Epag
Time to PLT> 50 x109/ L (medi an, range)
Adve rse effec ts
100 (25100)
O ve ral l:
24 responders (63.2%) PLT transfusion independence rate 63.2%, >=50 x 10 9/L rate 52.3%
32 (7127) days
None
17 SA A-1 MD S-6
Rive ra et al. 2018
Ca se ser ies
1 56 (254 69)
AL L-2, AM L-4 MD S-2, MP N-2 SA A1, NH L-3
5 2 9)
Haplo-7 MRD-3 MUD-4
PIT-3, SFPR-11
N 150 (50R 150) (f ro m o ns et of T C P 2, 24
64 (1 419 5) da ys 77 (2 419 4) da ys in res po nd ers 91 (820 6 ) da ys in res po nd ers an
8 out of 14 patients (57%) showed PLT recovery ≥50 × 109/L.
No grad e 3/4 adve rse effec ts. 42% (6/14 ) grad e 1-2 AEs
11 5 5 d a ys )
Yuan Ca et al. se 2019 ser ies
Raut et al Ca 2014 se ser ies
1 56 (363 70)
1 29.5 2 (18-57)
AM L/M DS9, AL L-2, HD1, SA A-1 AM L-2 SA A-1 MM -3 Ly mph oma -6
AlloHSCT (graft source NR)
PIT-6 (PEF>+1 00 days) SFPR-7
8 1 (3 63 0 0)
Starting dose 25-50. Max dose not reported.
2 Allo (AML-1, SAA-1), 10- Auto SCT (MM-3, lymphoma6-, AML-1)
PIT
2 1 (1 76 0)
25-50
25
d 21 (993 ) in no nres po nd ers N R
29 (1 311 4) da ys
ORR 62% (8/13) No difference between pt with normal vs decreased BM megakaryocyte (67% vs 60%)
33 (1168) days
None
Gradual increase in PLT
NR
None
Tana ka et al 2016
Ca se ser ies
1 53(192 63)
Tang Ca et al se 2018 ser ies
1 34 (212 53)
Mar otta et al 2019
1 48.5 2 (26-67)
Ca se ser ies
7 AM L, MD S-2, TA LL/ Ly1, LL 1, FL 1 AL L-4, AM L-3, MP AL1, SA A3, MF1 AM L-5, MD S-2, MM -1, CM L-1,
MSD-3 URD-9
PIT-5 SFPR-7
1 6 8 (6 31 7 8 5)
12.5-50
11 6 da ys (4 927 3)
CI of PLT recovery (>50 x 10 9/L) 71% in SFPR and 60% in PIT
54 (14195) days
None
Allo HSCT
PIT (PoGF)
1 7 5 (6 51 1 8 0)
25-75
8 (223 ) we ek s
ORR 83.3%, Complete response (trilineage 66.7%)
29 (1049) days
None
Haplo-8, MUD-2, MRD-2
PIT (PoGF)
7 9 (4 23 6 7)
50-150
10 7 (2 815 5) da ys
Hematologic response in 7 pts with complete response in 6 pts.
NR
1 pt with iron overl oad devel oped skin
26
Li et Ca al. se 2019 ser ies
Reid Ca et al se 2012 rep ort
IMF -1, SA A1, AL L-1 3 12.4(11 SA .4-15.6) A-2 Gau cher dise ase1 2 42-63 AM L-2
Ca 1 55 Fuji se mi et rep al ort 2015 Dyb a et al 2016
Ca 1 56 se rep ort
Foll icul ar lym pho ma Acu te undi ffer
hype rpig ment ation .
MUD-2, Haplo-1
PIT-1 SFPR-2
MUD-1 Auto HSCT-1
PIT
Allo-HSCT
PIT
PB MUD Mismatched (6/8) x2
PIT (PoGF)
27
7 9 (5 01 5 6) 2 8 0 (1 4 04 2 0) 4 4 3
50
40 (2 269 ) da ys 6 we ek s
CR-2 NR-1
P1-7 P2-62 P3NR
None
Transfusion independent within 2 weeks. PLT remained at 20-40 x 109/L
Not reache d
None
NR
N R
PLT to normal
NR
NR
3 4 3
50
N R
Quick improvement in counts. Transfusion independent in several wks.
Severa None l weeks
50
Ali Ca 1 10 et al se 2017 rep ort
enti ated leuk emi a SA A
MSD
SFPR
3 0 9
25-75
10 .7 m on ths 1 ye ar
PLT to normal
26 weeks
None
Mast Ca 1 26 AM MSD PIT 7 50 Increase of trilineage 72 None er et se L (PoGF) 2 days al rep 2018 ort Note: N number of patients, pts patients, HSCT hematopoietic stem cell transplant, TCP thrombocytopenia, Epag eltrombopag, MUD matched unrelated donor, MRD Matched related donor, Allo allogenic, UCB umbilical cord blood, PIT Prolonged Isolated Thrombocytopenia, DPE delayed platelet engraftment, SFPR Secondary Failure of Platelet Recovery, PoGF poor graft function, PFE primary engraftment failure, NR not reported, PLT platelet, SAA severe aplastic anemia, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MDS myelodysplastic syndrome. MF myelofibrosis, MM multiple myeloma, CML chronic myeloid leukemia, MPN myeloproliferative neoplasm, HD Hodgkin disease, NHL Non Hodgkin lymphoma, FL Follicular lymphoma, IMF inherited marrow failure, MPAL mixed phenotype acute leukemia
28
Study, De N Age year of sig (yrs, public n median, ation range)
Hartra nft et al 2017
Ca se ser ies
13
48 (1768)
Diag H nosis SC T ty pe
AML -5, CML -2, CLL1ALL -1, NHL 1, MDS -1, NB-1, BL-1
M U D7 M R D6
TCP type
SFPR-9 PIT-4
Time from HSCT to RPM (days, median, range)
R P M do se, (m cg /k g, m ax im u m, ra ng e)
No. of RPM dosage s (media n, range)
Response
91 (21-208) for SFPR pts. NR for PIT pts.
10 (110 )
Respon ders 17 (3-60) Non respond ers 6 (112)
Response in 7 out of 13 patients (54%). Median survival in responder vs non responder: 753 days vs 266 days (p: 0.0375)
29
Time to PLT>50 x109/ L (median, range)
A d v er se ef fe ct s
35 (14-56) days in responders
N on e
Ca
8
53 (1667)
7
57(2 5-60)
Battip se aglia ser et al ies 2015
Ca
Calmet se tes et ser al ies 2011
Maxim ova et al 2014
Ca se ser ies
7
11 (813)
AML -5, MDS -1, NHL1, 1 TAL L/Ly
Ha plo -5 M R D1 M U D2 AML M -2, R NHL- D2, 2, ALL- M 1, U MDS D-1, 4 SAA- U 1 CB -1 ALL- M 3, U AML D-1 3 SAA- M 1 R PID-1 DFanco 3 ni-1 Ha plo -1
SFPR-5 PIT3(PEF/BK hemorrhagi c cystitis)
72.5 (42-381)
10 (110 )
10 (532)
PLT recovery with median of 2 dosages in SFPR. Median time to HC recovery on 3 pts was 44 days (9-106) after median of 4 injections.
SFPR
7-61 (27)
10 (110 )
NR
TCP corrected in all patients
7
4
SFPR (4 viral infection, 2 immune, 1 both)
85 (62-104)
30
6 of 7 achieved PLT transfusion independence in second week of treatment
SFPR-2 wks HC pts-44 days to HC recovery
54(24-84) days
4 weeks
N on e
N on e
N on e
Ca
5
39 (3541)
ALL3, AML -1 SAA1
3
57(3 6-62)
HL, Ha AML, plo MF -1 M U D2
Lancm se an et ser al ies 2018
Ca
Poon se et al ser 2013 ies
dU SFPR-2 CB PFE-3 -4 M SD -1
SFPR-1, PIT-2
59 (38-396)
8 (18)
10 (617)
Yes-4 No-1 (response is PLT >50 x109/ L for 7 days)
34.5 (1458) amongst responders
361(166-480)
10 (110 )
NR
All 3 responded
126(72127)
31
4no ne 1fo ca l 01 + fi br os is on B M B x N on e; B M bx af te r R x di d no
Ca
1
3
XL CGD
1 year
5 (15)
NR (6 months total treatme nt)
Sustained increase in PLT
3 weeks
Ca 1 se rep ort
5
Fanco U SFPR ni CB anemi a
117
10
4 (d+117149)
By D+130, PLT >25 x109/L
? by Day +149 (32 days)
N on e
Ca 1 se rep ort
59
CLL
M U D
SFPR
202
10
11
No
No response
N on e
Ca 1 se rep ort
58
AML (HIV +)
Au to
PGF
80
Yes
31 days N (>20x109/L) on e
4
X linke d
M U D
SFPR
~83
37 21 5 mc g we ekl y 3 4
Yes
~ 4 weeks
Buchbi se nder et rep al ort 2007 Buchbi nder et al 2015 DeRe mer et al 2013 Ganga tharan et al 2011
Beck Ca et al se rep
1
M U D
SFPR
t sh o w fi br os is N R
32
N on e
2010 ort
Bollag Ca 1 et al se 2012 rep
48
adren oleuk odyst rophy CML
M SFPR SD -1
NR
6
NR
PLT increased.
~3 weeks
ort
Note: N=number of patients, HSCT hematopoietic stem cell transplant, MUD unrelated donor, MRD Matched related donor, Allo: allogenic, Auto: autologous, UCB umbilical cord blood, PIT prolonged isolated thrombocytopenia, SFPR secondary failure of platelet recovery, PoGF poor graft function, NR: not reported, PLT: platelet, SAA: severe aplastic anemia, HC: Hemorrhagic cystitis.
33
N on e
ClinicalTrials.g ov identifier
Phase
Status
Title
NCT01791101
2
Recru iting
Eltrombopag in Patients with Delayed Post Transplant Thrombocytopenia
NCT01000051
2 (single group randomized)
Comp leted
Eltrombopag for Post-HSCT Thrombocytopenia
1/2
Comp leted
Using ROMIPLOSTINE for Persistent Thrombocytopenia with Transfusion-dependent Patients Who Received Allogeneic Hematopoietic Stem Cell.
2
Activ e, not recrui ting
Eltrombopag Olamine 34 in Increasing Platelet Counts in Patients Undergoing Transplant
NCT01980030
NCT01927731
Sponsors Gruppo Italiano Malattie EMatolo giche dell'Adul to, Italy M.D. Anderso n Cancer Center Novartis Pharmac euticals (collabor ator) Assistan ce Publique Hôpitaux de Paris M.D. Anderso n Cancer Center NCI (collabor ator)
Condition
Age inclusion
Thromboc ytopenia
18 years and older.
Thromboc ytopenia
18 years and older.
Thromboc ytopenia
18 years and older.
Thromboc ytopenia
18 Years and older
NCT02046291
1
Activ e, not recrui ting
NCT03515096
3
Recru iting
Safety of Romiplostim (Nplate®) Following UCBT
Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
35
Masonic Cancer Center, Universit y of Minnesot a Shenzhe n Second People's Hospital, China
Thromboc ytopenia
18 Years and older
Thromboc ytopenia
18 Years and older
36
37