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A Multicenter Study of Romiplostim for Chemotherapy-Induced Thrombocytopenia in Solid Tumors and Hematologic Malignancies

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A Multicenter Study of Romiplostim for Chemotherapy-Induced Thrombocytopenia in Solid Tumors and Hematologic Malignancies ARTICLE Platelet Biology & its Disorders A multicenter study of romiplostim for Ferrata Storti Foundation chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies Hanny Al-Samkari,1,2 Aric D. Parnes,2,3,4 Katayoon Goodarzi,1,2 James I. Weitzman,2,5 Jean M. Connors2,3,4 and David J. Kuter1,2 1Division of Hematology Oncology, Massachusetts General Hospital, Boston, MA; 2Harvard Medical School, Boston, MA; 3Hematology Division, Brigham and Women’s Haematologica 2021 Hospital, Boston, MA; 4Department of Medical Oncology, Dana-Farber Cancer Institute, Volume 106(4):1148-1157 Boston, MA and 5Division of Hematology Oncology, Newton-Wellesley Hospital, Newton, MA, USA ABSTRACT hemotherapy-induced thrombocytopenia (CIT) frequently compli- cates cancer treatment causing chemotherapy treatment delays, dose Creductions, and discontinuation. There is no US Food and Drug Administration (FDA)-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional romi- plostim treatment pathways at four US centers. The primary outcome was achievement of a romiplostim response (median on-romiplostim platelet 9 9 count ≥75x10 /L and ≥30x10 /L above baseline). Secondary outcomes includ- 9 ed time to platelet count ≥100x10 /L and rates of the following: platelet count <100×109/L, platelet count <75x109/L, platelet count <50x109/L, thrombocytosis, chemotherapy dose reduction/treatment delay, platelet transfusion, bleeding, and thromboembolism. Multivariable regression was used to identify predictors of romiplostim non-response and compare week- ly dosing with intracycle/intermittent dosing. A total of 173 patients (153 solid tumor, 20 lymphoma or myeloma) were treated, with 170 (98%) receiving a median of four (range: 1-36) additional chemotherapy cycles on romiplostim. Romiplostim was effective in solid tumor patients: 71% of patients achieved a romiplostim response, 79% avoided chemotherapy dose reductions/treatment delays, and 89% avoided platelet transfusions. Median Correspondence: per-patient platelet count on romiplostim was significantly higher than base- HANNY AL-SAMKARI line (116x109/L vs. 60x109/L; P<0.001). Bone marrow (BM) tumor invasion, [email protected] prior pelvic irradiation, and prior temozolomide exposure predicted romi- plostim non-response. Bleeding rates were lower than historical CIT cohorts Received: March 5, 2020. and thrombosis rates were not elevated. Weekly dosing was superior to intracycle dosing with higher response rates and less chemotherapy dose Accepted: May 27, 2020. reductions/treatment delays/bleeding; intracycle dosing had an incidence Pre-published: June 4, 2020. rate ratio (IRR) for dose reduction/treatment delay of 3.00 (95%CI: 1.30- 6.91; P=0.010) and an IRR for bleeding of 4.84 (95%CI: 1.18-19.89, P=0.029) compared with weekly dosing. Blunted response (10% response rate) was https://doi.org/10.3324/haematol.2020.251900 seen in non-myeloid hematologic malignancy patients with BM involve- ment. In conclusion, romiplostim was safe and effective for CIT in most ©2021 Ferrata Storti Foundation solid tumor patients. Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Introduction Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- Thrombocytopenia is frequent in cancer patients, usually due to myelosuppres- poses is subject to the following conditions: 1 https://creativecommons.org/licenses/by-nc/4.0/legalcode, sive chemotherapy, tumor infiltration of the bone marrow (BM), or infection. sect. 3. Reproducing and sharing published material for com- Chemotherapy-induced thrombocytopenia (CIT) is a common complication of mercial purposes is not allowed without permission in writing cytotoxic chemotherapy and many targeted therapies, occurring in approximately from the publisher. 15-25% of patients receiving platinum, taxane, and/or gemcitabine-based regimens.2 Currently there is no US Food and Drug Administration (FDA)-approved agent for CIT management. Platelet transfusion offers only temporary, unreliable 1148 haematologica | 2021; 106(4) Multicenter study of romiplostim for CIT improvement that is often impractical or impossible to Institutional romiplostim chemotherapy-induced continue for extended periods. Therefore, chemotherapy thrombocytopenia pathways: weekly versus intracycle dose reductions and treatment delays are the current stan- dosing dard of care for the management of CIT, allowing platelet Patients qualified to enter their institutional romiplostim CIT count to recover to the desired count for subsequent pathway after persistent thrombocytopenia (platelet count administration of cancer-directed treatment. Reduced rel- <100x109/L) at least 3 weeks from the date of last chemotherapy ative dose intensity (RDI) that results from CIT-related administration or after a delay in chemotherapy regimen initia- treatment delays and dose reductions may reduce progres- tion ≥1 week due to thrombocytopenia. For solid tumor sion-free survival (PFS) and overall survival (OS).3,4 patients, two institutions utilized a weekly romiplostim CIT Conversely, management or prevention of CIT with pathway in which romiplostim was administered weekly irre- thrombopoietic agents may maintain RDI and improve spective of timing of chemotherapy administration and two uti- OS, particularly in curable malignancies.5-8 Bleeding in lized an intracycle romiplostim CIT pathway in which romi- CIT has major consequences for patient outcomes; plostim was administered primarily on chemotherapy off- patients with CIT who develop major bleeding have been weeks, on average twice per month (see Figure 1 for dosing shown to have substantially lower OS.4 pathways). Regardless of pathway, platelet counts were Thrombopoietin receptor agonists (TPO-RA) have been obtained weekly. All hematologic malignancy patients were developed and approved for use in immune treated at institutions that employed the weekly romiplostim thrombocytopenia (ITP),9 aplastic anemia,10 hepatitis treatment pathway. C-associated thrombocytopenia,11 and perioperative thrombocytopenia.12-14 Romiplostim is a weekly subcuta- Effectiveness and safety measures neously-administered TPO-RA currently approved to The primary outcome was achievement of a romiplostim treat ITP. Maximal doses of romiplostim are considerably response, defined as a median on-romiplostim platelet count 9 9 more potent in raising the platelet count than the oral ≥75x10 /L and at least 30x10 /L higher than the pretreatment small molecule TPO-RA in healthy subjects and possibly baseline. Median on-romiplostim platelet counts were used in all in ITP,15-17 making this an ideal agent for investigation into analyses comparing individual patient baseline platelet count to myelosuppressive thrombocytopenias such as CIT. To individual patient on-romiplostim platelet count. As romiplostim date, studies of romiplostim to manage CIT have been response is a measure of effectiveness over the entire duration of limited to case series and small single-center studies.18-21 romiplostim treatment, the time from romiplostim initiation to 9 These studies suggest that romiplostim is effective in rais- first achievement of platelet count ≥100x10 /L was also evaluated. ing the platelet count in patients with solid tumors. Because there is no universally accepted platelet count threshold Predictors of romiplostim non-response, optimal dosing that defines CIT recurrence, incidence rates of all measured regimens, and use in non-myeloid hematologic malignan- platelet counts below thresholds of 50x109/L, 75x109/L, and cies (lymphoma and myeloma) have not been evaluated. 100x109/L were also evaluated. Similarly, thrombocytosis was Clinical outcomes data more relevant than simple platelet defined as >400x109/L and incidence rates were evaluated. count measurements, such as resumption of treatment Other clinical outcomes included rates of chemotherapy without further chemotherapy dose reductions or treat- intensity reduction (dose reduction or treatment delay) specifi- ment delays, bleeding, or thrombosis, are limited. The cally for thrombocytopenia and rates of platelet transfusion, safety of TPO-RA in cancer patients is a concern, as TPO- bleeding, and arterial or venous thromboembolic events. RA carry an associated risk for venous thromboembolism Patients treated with romiplostim for CIT but not able to (VTE), which could add to the baseline risk associated resume chemotherapy were included in analyses of bleeding, with malignancy. VTE, and platelet count outcomes while on romiplostim treat- The present study aims to address these questions and ment but not analyses of chemotherapy intensity reduction or evaluate romiplostim to manage CIT in a large cohort of platelet transfusion. both solid tumor and hematologic malignancy patients treated at four affiliated US academic cancer centers. Predictors of romiplostim non-response Institutional pathways guided administration of romi- Predictors of failure to achieve a romiplostim response plostim at each center. Management of CIT remains an (referred to hereafter as “predictors of romiplostim non- off-label use of romiplostim. response”) were evaluated using a multivariable logistic model (see Online Supplementary Methods for
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