NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-22-005-H01-P
Physician Assistants: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until May 10, 2023. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/91086; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: May 10, 2022; Expiration date: May 10, 2023
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Hematopoietic Growth Factors
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Hematopoietic Growth Factors
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Vivek Roy, MD, Panel Vice Chair
Laura M. Alwan, PharmD, BCOP, Panel Member
Ryan A. Berardi, MSc, Guidelines Layout Specialist, NCCN
Lenora Pluchino, PhD, Oncology Scientist/Medical Writer, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Elizabeth Griffiths, MD, Panel Chair, scientific advisor for AbbVie, Inc., Astex Pharmaceuticals, Bristol-Myers Squibb Company, Celgene Corporation, Genentech, Inc., Novartis Pharmaceuticals Corporation, Taiho Pharmaceuticals Co., Ltd., and Takeda Pharmaceuticals North America, Inc.; grant/research support from Astex Pharmaceuticals, Blueprint Medicines, Bristol-Myers Squibb Company, Celgene Corporation, Celldex Therapeutics, and Genentech, Inc.; consulting fee from Alexion Pharmaceuticals, Inc.
Gary H. Lyman, MD, MPH, FRCP, Panel Member, consulting fees from Merck & Co., Inc., Novartis Pharmaceuticals Corporation, BeyondSpring Inc., G1 Therapeutics, Inc., Kallyope, Samsung Electronics Co., Ltd., and Teva Pharmaceutical Industries Ltd.; honoraria from Bristol-Myers Squibb Company, Partner Therapeutics, Inc., and Seattle Genetics, Inc.; and grant/research support from Amgen Inc.
Victoria Nachar, PharmD, Panel Member, honoraria from Karyopharm Therapeutics and ADC Therapeutics.
Fauzia Riaz, MD, Panel Member, grant/research support from AstraZeneca Pharmaceuticals LP and Genentech, Inc.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; BeiGene; Exact Sciences; Gilead Sciences, Inc.; GlaxoSmithKline; Lantheus Medical Imaging Inc.; Novartis; Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Astellas. This activity is supported by an education grant from Astellas and Seagen Inc. This activity is supported by a medical education grant from Karyopharm® Therapeutics. This activity is supported through an Independent Medical Education grant from Merck & Co., Inc.
Overview
Hematopoietic growth factors are defined by their ability to promote proliferation and differentiation of hematopoietic progenitors into mature blood cells.1 Colony-stimulating factors (CSFs) are hematopoietic growth factors that regulate the growth and differentiation of cells toward the myeloid and erythroid lineages. Myeloid growth factors (MGFs), such as granulocyte CSFs (G-CSFs), are primarily used to reduce the incidence of febrile neutropenia (FN) in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy and to enable safe delivery of planned dose-dense chemotherapy on schedule. Erythropoiesis-stimulating agents (ESAs), including epoetin alfa and darbepoetin alfa, are primarily used to manage cancer-induced anemia and chemotherapy-induced anemia (CIA). Thrombopoietin receptor agonists (TPO-RA), including romiplostim, are a class of platelet growth factors that can be used to manage chemotherapy-induced thrombocytopenia (CIT).2 Management and prevention of FN, CIA, and CIT are integral parts of the supportive care approach for many patients undergoing cancer treatment.
Thrombocytopenia is characterized by a low blood platelet count resulting in decreased blood clotting capability, which puts patients at an increased risk for bleeding. CIT, defined as platelet count <100,000/mcL for 3 to 4 weeks following the last chemotherapy administration and/or resulting in delays in chemotherapy related to thrombocytopenia, can occur as a side effect of myelosuppressive chemotherapy.3–5 Although mild thrombocytopenia does not require treatment or intervention, severe thrombocytopenia (platelet counts <10,000/mcL) can increase the risk for spontaneous bleeding events, and moderate thrombocytopenia (platelet counts <50,000/mcL) can increase the risk of bleeding in patients on systemic anticoagulation. TPO-RAs, such as romiplostim, activate the TPO receptor and can increase the production of platelets.3 Prevention or management of CIT with TPO-RAs could enable the maintenance of relative dose intensity (RDI) of chemotherapy, resulting in improved survival outcomes. Although romiplostim and other TPO-RAs are widely used to treat immune thrombocytopenia, there is currently no FDA-approved treatment for CIT.
The NCCN Guidelines for Hematopoietic Growth Factors are divided into 3 sections outlining the evaluation, prevention, and management of FN, CIT, and CIA, respectively. The purpose of these guidelines is 2-fold: (1) to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies, especially those who are receiving chemotherapy; and (2) to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient’s condition. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT. The most recent full version of these guidelines is available at NCCN.org.
Management of CIT
Thrombocytopenia is a common side effect of myelosuppressive chemotherapy occurring in approximately 10% to 40% of patients with solid tumors and 40% to 70% of patients with hematologic malignancies.3–5 Clinically significant CIT, which would usually include the development of grade 3 (platelet count <50,000/mcL) or grade 4 (<25,000/mcL) thrombocytopenia, affects approximately 4% (grade 3) and 2% (grade 4) of patients with solid tumors and 16% and 12%, respectively, of patients with hematologic malignancies.5 Gemcitabine‐ and platinum‐based regimens typically carry the highest risk of CIT.3–5 There is currently no FDA-approved agent for the treatment of CIT, which represents an important unmet need. Platelet transfusion offers only temporary improvement in platelet count and is often unreliable and impractical to continue for extended periods.4 Platelet transfusion has the potential to cause transfusion reactions, induce anaphylactic reactions, transmit bacterial infections, and precipitate transfusion-related acute lung injury (TRALI).6 Although complications of platelet transfusion are rare, repeated platelet transfusions increase the risk for these events. Development of CIT often results in treatment delays and dose reductions to allow platelets to recover to the desired count before subsequent administration of chemotherapy.3–5 RDI from CIT-related treatment delays and dose reductions may reduce progression-free survival (PFS) and overall survival (OS).
Romiplostim
TPO is the main growth factor responsible for the stimulation of platelet production. TPO-RA, such as romiplostim, bind to and activate the TPO receptor, thereby increasing the production of platelets.3 Romiplostim is FDA-approved to treat immune thrombocytopenia and is sometimes used off-label to treat CIT. Until recently, studies investigating romiplostim for the management of CIT have been limited to case series and small single-center studies.7–9 A case series of 20 patients with solid tumors and CIT reported that romiplostim treatment improved platelet counts in all patients, allowing for resumption of chemotherapy.9 In a retrospective study of 37 patients with solid tumors and CIT, treatment with romiplostim improved platelet counts in 95% of patients, and 92% were able to resume chemotherapy.8 Another retrospective study of 22 patients with solid tumors demonstrated that romiplostim successfully increased platelet counts and significantly reduced chemotherapy delays and dose reductions due to CIT.7
In a multicenter retrospective analysis of 173 patients (153 with solid tumors, 20 with lymphoma or myeloma), 71% of patients with solid tumors achieved a response to romiplostim, 79% avoided chemotherapy dose reduction or treatment delays, and 89% avoided platelet transfusions.4 Tumor invasion of the bone marrow, prior pelvic irradiation, and prior temozolomide exposure predicted inadequate response to romiplostim in this study. A lower response rate (10%) was seen in patients with nonmyeloid hematologic malignancy and those with bone marrow involvement. In a recent phase II randomized trial comparing romiplostim to untreated observation in patients with solid tumors and CIT, 93% of romiplostim-treated patients experienced correction of their platelet count within 3 weeks compared with 12.5% of control patients (P<.001).3 The mean platelet count after 2 weeks of romiplostim treatment was 141,000/mcL, whereas the mean platelet count in the observation arm was only 57,000/mcL. Eighty-five percent of patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim treatment. These data suggest that romiplostim may manage CIT in patients with solid tumors and that maintenance treatment may permit continuation of chemotherapy in most patients. However, data are limited, especially for romiplostim use in hematologic malignancies.
Additional TPO-RA Agents
Recent data have suggested activity for the TPO-RAs lusutrombopag and eltrombopag for patients with CIT.10–12 Lusutrombopag is currently FDA-approved for management of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a medical or dental procedure, and eltrombopag is approved for patients with chronic immune thrombocytopenia or severe aplastic anemia. The efficacy of lusutrombopag was assessed in an integrated analysis of data from 2 phase III trials that compared lusutrombopag versus placebo in 270 patients with chronic liver disease and hepatocellular carcinoma. Treatment with lusutrombopag reduced the need for platelet transfusions, increased platelet counts for 3 weeks, and reduced the number of bleeding events compared with placebo in patients with hepatocellular carcinoma secondary to chronic liver disease.10 A phase II randomized trial examined the efficacy of eltrombopag in 145 patients with myelodysplastic syndromes or acute myeloid leukemia and severe CIT.12 Patients treated with eltrombopag had significantly lower rates of clinically relevant thrombocytopenia compared with placebo (54% vs 69%; P=.032) and no new safety concerns were noted. A recent phase III trial assessed the efficacy of avatrombopag, a TPO-RA currently FDA-approved for chronic immune thrombocytopenia, in 122 patients with solid tumors and severe CIT (ovarian, bladder, or lung) recruited globally.13 The primary endpoint of the study was the composite percentage of patients who did not need platelet transfusion, chemotherapy dose reductions, or treatment delays of more than 4 days. Avatrombopag-treated patients did have somewhat higher platelet counts and treatment was deemed safe, but this study did not meet its primary endpoint. In totality, although some reports do show promise, outside of a clinical trial setting, insufficient data are available to routinely support use of small molecule TPO-RA for treatment of CIT.
Prolonged Posthematopoietic Cell Transplant Thrombocytopenia
Prolonged thrombocytopenia following hematopoietic cell transplant (HCT; defined as a platelet count <100 × 109/L on day +100 post-HCT) affects approximately 20% of allogeneic HCT recipients and is a strong predictor of transplant-related morbidity and mortality.14 The etiology of prolonged post-HCT thrombocytopenia is multifactorial and includes impaired platelet production due to poor graft function, infection, or adverse drug effects, as well as increased platelet destruction due to immune-mediated processes. Decreased survival of patients with prolonged post-HCT thrombocytopenia is often related to the increased incidence of treatment failure secondary to severe acute or chronic graft-versus-host disease, and less commonly due to relapse of underlying disease. There is no consensus on the management of prolonged post-HCT thrombocytopenia.14
Several studies have examined the efficacy of TPO-RAs in patients with prolonged thrombocytopenia following HCT, including those with secondary failure of platelet recovery.14–16 An extensive systematic review of 37 case reports suggests that patients with prolonged post-HSCT thrombocytopenia may respond to either eltrombopag (overall response rate [ORR], 70%) or romiplostim (ORR, 82%), with no evidence of serious adverse effects. However, the strength of the evidence is weak due to the retrospective nature of the studies, lack of control groups, and heterogeneity of the data.14 In a retrospective analysis of 32 patients with prolonged post-HSCT thrombocytopenia, 66% achieved overall recovery and 44% achieved complete recovery when treated with eltrombopag.15 Patients who responded to eltrombopag also received fewer platelet transfusions than nonresponders (median, 11 vs 95 units; P<.001). After a median follow-up of 364 days, the OS was 100% for responders and 37% for nonresponders (P<.001). In a phase II randomized trial of 60 patients with prolonged post-HCT thrombocytopenia, a significantly higher proportion of patients in the eltrombopag arm achieved a platelet count of ≥50,000/mcL compared with the placebo arm (21% vs 0%; P=.046).16 However, OS, PFS, relapse rate, and nonrelapse mortality were similar in the 2 arms. These data suggest that TPO-RAs can promote platelet recovery and reduce platelet transfusion in patients with prolonged post-HCT thrombocytopenia, but more robust data are needed.
NCCN Guidelines Recommendations
Because there are currently no FDA-approved treatment options and no clinical practice guidelines for the management of CIT, the NCCN Hematopoietic Growth Factors Panel felt it was important to develop this content to fulfill an unmet clinical need. Following a brief initial discussion, the panel decided to add a new section on the management of thrombocytopenia to guide clinical use of TPO-RA in patients with cancer (see TGF-1 and TGF-2, pages 438 and 439, respectively). To reduce overtreatment of CIT, the panel decided that patients with suspected CIT should first be evaluated and treated accordingly for other potential causes of thrombocytopenia, such as nutritional deficiencies, medications/supplements that suppress platelet production, infections (including viral reactivation), immune thrombocytopenia, heparin-induced cthrombocytopenia, radiation-induced myelosuppression, hematologic malignancy, consumption of platelets secondary to blood loss, and thrombotic microangiopathies, among other etiologies. The panel recommends performing a CBC with differential and blood smear for morphologic evaluation, including evaluation for platelet clumping and other cytopenias, during patient assessment.
If there is no other cause of thrombocytopenia identified and CIT is diagnosed, the panel considers several treatment options as appropriate: platelet transfusion per AABB (formerly the American Association of Blood Banks) guidelines, chemotherapy dose reduction or change in regimen, enrollment in a clinical trial of TPO-RAs, or off-label treatment with romiplostim following a full discussion of the potential benefits and harms. Several members of the panel emphasized that the primary purpose of using TPO-RAs for treatment of CIT is to maintain dose schedule and intensity of chemotherapy when such benefit is thought to outweigh the potential risks. The panel expressed concern regarding the safety of TPO-RA in patients with cancer, because TPO-RAs carry an associated risk for venous thromboembolism (VTE), which could add to the baseline risk already associated with malignancy.3,4,8,9 In a phase II trial, 10.2% of patients developed VTE within the first year of romiplostim treatment. Therefore, the panel advises that caution is warranted and indicates that patients receiving TPO-RAs should be closely monitored for potential complications, including VTE. To enhance safety and patient monitoring, the panel encourages participation in clinical trials whenever possible in patients for whom a TPO-RA is being considered for management of CIT.
The panel also discussed the management of patients with thrombocytopenia post-HCT. After careful consideration, it was decided that patients with post-HCT thrombocytopenia should first be evaluated for the other potential causes of thrombocytopenia mentioned earlier, as well as for primary or secondary graft failure, graft-versus-host disease, relapse of hematologic malignancy, and transplant-associated thrombotic microangiopathy. The panel then recommends that patients with primary or secondary failure of platelet recovery without another clear underlying cause be considered for platelet transfusion per AABB guidelines or participation in a clinical trial of TPO-RA.
The romiplostim dosing strategy suggested by the panel includes weekly dosing beginning at 2 to 4 mcg/kg, increased no more than 1 to 2 mcg/kg per week, to target platelet count of 100,000 to 150,000/mcL.3,4 Target platelet goals for CIT suggested by the panel are somewhat higher than the FDA guidance for other thrombocytopenic conditions (generally >50,000/mcL) due to the anticipated decrease associated with chemotherapy treatment; such recommendations are derived from the small number of series reported for this indication.3,4,7–9 The maximum dose is 10 mcg/kg weekly per prescribing information. This strategy is supported by data suggesting that weekly dosing was superior to intracycle dosing, with higher response rates and less chemotherapy dose reductions/treatment delays/bleeding.4
Summary
These NCCN Guidelines Insights highlight important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors. The panel recently developed a new section for the inclusion of TPO-RA and other treatment options in the management of patients with CIT. The incorporation of TPO-RA into the NCCN Guidelines represents an opportunity to ensure the receipt of high-quality supportive care for patients with cancer and CIT. Since there is currently no FDA-approved treatment for CIT, clinicians must make decisions regarding the appropriate incorporation of TPO-RA into clinical practice. Increased education and awareness of the available treatment options, including TPO-RA, will help to ensure the acceptance and use of these agents in supportive oncology care for patients with CIT.
References
- 2.↑
Zhang X, Chuai Y, Nie W, et al. Thrombopoietin receptor agonists for prevention and treatment of chemotherapy-induced thrombocytopenia in patients with solid tumours. Cochrane Database Syst Rev 2017;11:CD012035.
- 3.↑
Soff GA, Miao Y, Bendheim G, et al. Romiplostim treatment of chemotherapy-induced thrombocytopenia. J Clin Oncol 2019;37:2892–2898.
- 4.↑
Al-Samkari H, Parnes AD, Goodarzi K, et al. A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies. Haematologica 2021;106:1148–1157.
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Shaw JL, Nielson CM, Park JK, et al. The incidence of thrombocytopenia in adult patients receiving chemotherapy for solid tumors or hematologic malignancies. Eur J Haematol 2021;106:662–672.
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Al-Samkari H, Marshall AL, Goodarzi K, et al. The use of romiplostim in treating chemotherapy-induced thrombocytopenia in patients with solid tumors. Haematologica 2018;103:e169–172.
- 8.↑
Miao J, Leblebjian H, Scullion B, et al. A single center experience with romiplostim for the management of chemotherapy-induced thrombocytopenia. Am J Hematol 2018;93:E86–E88.
- 9.↑
Parameswaran R, Lunning M, Mantha S, et al. Romiplostim for management of chemotherapy-induced thrombocytopenia. Support Care Cancer 2014;22:1217–1222.
- 10.↑
Alkhouri N, Imawari M, Izumi N, et al. Lusutrombopag is safe and efficacious for treatment of thrombocytopenia in patients with and without hepatocellular carcinoma. Clin Gastroenterol Hepatol 2020;18: 2600–2608.e1.
- 11.↑
Meng F, Chen X, Yu S, et al. Safety and efficacy of eltrombopag and romiplostim in myelodysplastic syndromes: a systematic review and meta-analysis. Front Oncol 2020;10:582686.
- 12.↑
Mittelman M, Platzbecker U, Afanasyev B, et al. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. Lancet Haematol 2018;5:e34–43.
- 13.↑
Al-Samkari H, Kolb-Sielecki J, Safina SZ, et al. Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo- controlled, phase 3 trial. Lancet Haematol 2022;9:e179–189.
- 14.↑
Mahat U, Rotz SJ, Hanna R. Use of thrombopoietin receptor agonists in prolonged thrombocytopenia after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2020;26:e65–73.
- 15.↑
Gao F, Zhou X, Shi J, et al. Eltrombopag treatment promotes platelet recovery and reduces platelet transfusion for patients with post-transplantation thrombocytopenia. Ann Hematol 2020;99:2679–2687.
- 16.↑
Ahmed S, Bashir Q, Bassett R, et al. Eltrombopag for post-transplantation thrombocytopenia: results of phase II randomized, double-blind, placebo-controlled trial. Transplant Cell Ther 2021;27:430.e431–430.e7.
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2022.
All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
