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Table 1.  

Outcomes Definitions
Primary outcome
 Overall response Achieving a platelet count of ≥30 × 109/L confirmed on ≥2 separate occasions (≥7 d apart), at least a doubling of the baseline platelet count without administration of any other ITP-specific treatment, and the absence of bleeding within 1 y following enrollment.
Secondary outcomes
 Complete response Platelet count ≥100 × 109/L measured on 2 occasions at least 7 d apart and the absence of bleeding within 1 y following enrollment.
 Sustained response Maintenance of a platelet count >30 × 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment of 6 consecutive mo after achievement of response during 1 y following enrollment.
 Remission A durable platelet count >30 × 109/L without bleeding up to 12 mo after enrollment.

Table 1. Definitions of endpoints in the study

Table 2.  

Characteristics ATRA + LD-RTX (n = 112) LD-RTX (n = 56)
Age (y), median (IQR) 46.0 (36.0-55.8) 44.5 (36.0-58.0)
Male, n (%) 59 (52.7) 24 (42.9)
Platelet count (109/L), median (IQR) 17.0 (14.0-21.0) 19.0 (14.0-25.0)
Duration of ITP (mo), median (IQR) 20.0 (15.0-32.8) 20.5 (15.0-27.0)
Previous treatments, n (%)
  Corticosteroids 112 (100.0) 56 (100.0)
  IVIG 20 (17.9) 14 (25.0)
  Vincristine 2 (1.8) 3 (5.4)
  rhTPO 21 (18.8) 8 (14.3)
  Cyclosporin 12 (10.7) 9 (16.1)
  Danazol 21 (18.8) 15 (26.8)
  Azathioprine 4 (3.6) 3 (5.4)
  Mycophenolate mofetil 8 (7.1) 8 (14.3)
  Splenectomy 1 (0.9) 1 (1.8)
  Herbs 7 (6.3) 9 (16.1)
Bleeding score, % (n)
  0 53 (47.3) 31 (55.4)
  1 40 (35.7) 17 (30.4)
  2 11 (9.8) 5 (8.9)
  3 5 (4.5) 2 (3.6)
  4 3 (2.7) 1 (1.8)

Table 2. Baseline characteristics of patients enrolled in the study

rhTPO, recombinant human thrombopoietin.

Table 3.  

  ATRA + LD-RTX LD-RTX Difference between proportions (95% CI)
Participants, n = 112 Proportions Participants, n = 56 Proportions
Primary outcome
 OR 90 0.80 33 0.59 0.22 (0.07-0.36)
Secondary outcomes
 CR 45 0.40 14 0.25 0.15 (0.01-0.30)
 SR 68 0.61 23 0.41 0.20 (0.04-0.35)

Table 3. Responses and outcomes in the ATRA + LD-RTX and LD-RTX groups

Table 4.  

Events ATRA + LD-RTX (n = 112) LD-RTX (n = 56)
Death 1 (0.9) 0 (0.0)
Patients reporting AEs
 Any AEs 79 (70.5) 30 (53.6)
 Any grade 3 to 4 AEs* 4 (3.6) 1 (1.8)
 AE leading to discontinuation of therapy 1 (0.9)† 1 (1.8)‡
AEs occurring in ≥2% of participants overall
 Dry skin 45 (40.2) 0 (0.0)
 Headache or dizziness 21 (18.8) 6 (10.7)
 Fever 16 (14.3) 12 (21.4)
 Upper respiratory infection 4 (3.6) 8 (14.3)
 Urinary tract infection 5 (4.5) 4 (7.1)
 Gastrointestinal infections 2 (1.8) 2 (3.6)
 Muscle/joint pain 2 (1.8) 4 (7.1)
 Rash acneiform 3 (2.7) 3 (5.4)
Any grade 3-4 AEs
 Dry skin 2 (1.8) 0 (0.0)
 Insomnia 2 (1.8) 0 (0.0)
 Mood disorder 0 (0.0) 1 (1.8)

Table 4. Adverse events recorded in the 2 groups

Values are presented as numbers (percentages) of participants experiencing the event at least once.
*Defined as any AE with significant symptoms requiring hospitalization, invasive intervention, transfusion, elective interventional radiological procedure or therapeutic endoscopy or operation, or any life-threatening or disabling AEs which are complicated by acute, life-threatening metabolic or cardiovascular complications or have a need for intensive care, emergent invasive procedure, emergent interventional radiological procedure or therapeutic endoscopy or operation.
†Insomnia.
‡Mood disorder.

CME / ABIM MOC

All-Trans Retinoic Acid Plus Low-Dose Rituximab vs Low-Dose Rituximab in Corticosteroid-Resistant or Relapsed ITP

  • Authors: Yejun Wu, BA; Hui Liu, MD; Qiao-Zhu Zeng, BA; Yi Liu, MD; Jing-Wen Wang, MD; Wen-Sheng Wang, MD; Jia-Feng, MD; He-Bing Zhou, MD; Qiu-Sha Huang, MD; Yun He, MD; Hai-Xia Fu, MD; Xiao-Lu Zhu, MD; Qian Jiang, MD; Hao Jiang, MD; Ying-Jun Chang, MD; Lan-Ping Xu, MD; Xiao-Jun Huang, MD; Xiao-Hui Zhang, MD
  • CME / ABIM MOC Released: 1/20/2022
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 1/20/2023
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Target Audience and Goal Statement

This activity is intended for hematologists, oncologists, internists, and other clinicians caring for patients with immune thrombocytopenia (ITP).

The goal of this activity is to describe the comparative efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in adult patients with corticosteroid-resistant or relapsed ITP, according to a multicenter, prospective, randomized controlled study.

Upon completion of this activity, participants will:

  • Compare responses to of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) vs LD-RTX monotherapy in patients with corticosteroid-resistant or relapsed immune thrombocytopenia (ITP), according to a multicenter prospective, randomized controlled study
  • Compare adverse events with ATRA plus LD-RTX vs LD-RTX monotherapy in patients with corticosteroid-resistant or relapsed ITP, according to a multicenter prospective, randomized controlled study
  • Identify clinical implications of the comparative efficacy and safety of ATRA plus LD-RTX vs LD-RTX monotherapy in patients with corticosteroid-resistant or relapsed ITP, according to a multicenter prospective, randomized controlled study


Disclosures

Medscape, LLC requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated according to Medscape policies. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Yejun Wu, BA

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Yejun Wu, BA, has disclosed no relevant financial relationships.

  • Hui Liu, MD

    Department of Hematology
    Beijing Hospital
    Ministry of Health
    Beijing, China

    Disclosures

    Disclosure: Hui Liu, MD, has disclosed no relevant financial relationships.

  • Qiao-Zhu Zeng, BA

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Qiao-Zhu Zeng, BA, has disclosed no relevant financial relationships.

  • Yi Liu, MD

    Department of Geriatric Hematology
    Chinese PLA General Hospital
    Beijing, China

    Disclosures

    Disclosure: Yi Liu, MD, has disclosed no relevant financial relationships.

  • Jing-Wen Wang, MD

    Department of Hematology
    Beijing Tongren Hospital
    Capital Medical University
    Beijing, China

    Disclosures

    Disclosure: Jing-Wen Wang, MD, has disclosed no relevant financial relationships.

  • Wen-Sheng Wang, MD

    Department of Hematology
    Peking University First Hospital
    Beijing, China

    Disclosures

    Disclosure: Wen-Sheng Wang, MD, has disclosed no relevant financial relationships.

  • Jia-Feng, MD

    Department of Hematology
    Peking University Shenzhen Hospital
    Shenzhen, China

    Disclosures

    Disclosure: Jia-Feng, MD, has disclosed no relevant financial relationships.

  • He-Bing Zhou, MD

    Department of Hematology
    The Affiliated Beijing Luhe Hospital of Capital Medical University
    Beijing, China

    Disclosures

    Disclosure: He-Bing Zhou, MD, has disclosed no relevant financial relationships.

  • Qiu-Sha Huang, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Qiu-Sha Huang, MD, has disclosed no relevant financial relationships.

  • Yun He, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Yun He, MD, has disclosed no relevant financial relationships.

  • Hai-Xia Fu, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Hai-Xia Fu, MD, has disclosed no relevant financial relationships.

  • Xiao-Lu Zhu, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Xiao-Lu Zhu, MD, has disclosed no relevant financial relationships.

  • Qian Jiang, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Qian Jiang, MD, has disclosed no relevant financial relationships.

  • Hao Jiang, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Hao Jiang, MD, has disclosed no relevant financial relationships.

  • Ying-Jun Chang, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Ying-Jun Chang, MD, has disclosed no relevant financial relationships.

  • Lan-Ping Xu, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Lan-Ping Xu, MD, has disclosed no relevant financial relationships.

  • Xiao-Jun Huang, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Xiao-Jun Huang, MD, has disclosed no relevant financial relationships.

  • Xiao-Hui Zhang, MD

    Peking University People’s Hospital
    Peking University Institute of Hematology
    Collaborative Innovation Center of Hematology
    Peking University
    Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation
    National Clinical Research Center for Hematologic Disease
    Beijing, China

    Disclosures

    Disclosure: Xiao-Hui Zhang, MD, has disclosed no relevant financial relationships.

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Editor

  • Jorge A. Di Paola, MD

    Associate Editor
    Blood

    Disclosures

    Disclosure: Jorge A. Di Paola, MD, has disclosed no relevant financial relationships.

CME Reviewer

  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP, has disclosed no relevant financial relationships.


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  • Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

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From Blood
CME / ABIM MOC

All-Trans Retinoic Acid Plus Low-Dose Rituximab vs Low-Dose Rituximab in Corticosteroid-Resistant or Relapsed ITP

Authors: Yejun Wu, BA; Hui Liu, MD; Qiao-Zhu Zeng, BA; Yi Liu, MD; Jing-Wen Wang, MD; Wen-Sheng Wang, MD; Jia-Feng, MD; He-Bing Zhou, MD; Qiu-Sha Huang, MD; Yun He, MD; Hai-Xia Fu, MD; Xiao-Lu Zhu, MD; Qian Jiang, MD; Hao Jiang, MD; Ying-Jun Chang, MD; Lan-Ping Xu, MD; Xiao-Jun Huang, MD; Xiao-Hui Zhang, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME / ABIM MOC Released: 1/20/2022

Valid for credit through: 1/20/2023

processing....

Abstract and Introduction

Abstract

The study aimed to compare the efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) patients. Recruited patients were randomized at a ratio of 2:1 into 2 groups: 112 patients received LD-RTX plus ATRA, and 56 patients received LD-RTX monotherapy. Overall response (OR), defined as achieving a platelet count of ≥30 × 109/L confirmed on ≥2 separate occasions (≥7 days apart), at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding within 1 year after enrollment, was observed in more patients in the LD-RTX plus ATRA group (80%) than in the LD-RTX monotherapy group (59%) (between-group difference, 0.22; 95% CI, 0.07-0.36). Sustained response (SR), defined as maintenance of a platelet count >30 × 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment for 6 consecutive months after achievement of OR during 1 year following enrollment, was achieved by 68 (61%) patients in the combination group and 23 (41%) patients in the monotherapy group (between-group difference, 0.20; 95% CI, 0.04-0.35). The 2 most common adverse events (AEs) for the combination group were dry skin and headache or dizziness. Our findings demonstrated that ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a promising treatment option for corticosteroid-resistant or relapsed adult ITP. This study is registered at www.clinicaltrials.gov as #NCT03304288.

Introduction

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased platelet destruction and insufficient platelet production.[1-4] Corticosteroids and IV immunoglobulin (IVIg) are first-line treatments.[5,6] Approximately one-third of ITP patients fail to achieve a response; in addition, most patients who respond to first-line treatment relapse and require further second-line therapies.[5,6] However, the optimal second-line treatment remains uncertain.[6]

Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody that exerts its treatment effects through the rapid depletion of CD20-positive B lymphocytes and modulation of T cells,[7,8] has been frequently used in ITP treatment.[5,6] There is not yet a gold standard regimen of RTX. Schedules have been proposed, including the standard dose (SD) (375 mg/m[2] weekly for 4 administrations) and low dose (LD) (100 mg flat dose weekly for 4 administrations). Previous studies using SD-RTX demonstrated an overall response (OR) of nearly 60% and a sustained response (SR) of 30% to 40%.[9-11] A meta-analysis of 9 studies on LD-RTX in ITP revealed a comparable OR with SD-RTX.[12] Moreover, LD-RTX usually means significantly reduced expenditure (10 000 to 40 000 USD per 4-infusion course) and easier administration than SD-RTX.[12,13] These advantages indicate that LD-RTX might be a promising treatment option for ITP. However, the reported median time to response (TTR) of monotherapy of LD-RTX was 30 days, significantly longer than that of SD-RTX (10.5 days).[10] A lower SR of LD-RTX compared with SD-RTX was also revealed.[10] Moreover, another study reported that for patients with corticosteroid-resistant or relapsed ITP, no difference between SD-RTX and placebo in OR and treatment failure rate was observed within 78 weeks in the treatment, indicating that a general recommendation for the use of SD-RTX monotherapy in corticosteroid-resistant or relapsed ITP could not be supported.[14] It was indicated that increased doses of RTX might maintain the concentration and prolong the elimination of B cells according to the pharmacokinetic data of RTX.[15,16] Additional doses of RTX were demonstrated to improve the efficacy of rheumatoid arthritis and lymphoma treatment.[17-19]

All-trans retinoic acid (ATRA), a key metabolite of vitamin A, is involved in cell proliferation and differentiation.[20,21] Our preliminary studies indicated the efficacy of ATRA in the ITP model due to its effects on inducing megakaryocyte (MK) differentiation and maturation, as well as its immunomodulatory effects.[22-25] We previously conducted a multicenter, randomized trial demonstrating that the combination of ATRA (10 mg twice daily) and danazol (200 mg twice daily) achieved an improvement in overall response (82% vs 44%; odds ratio [OdR] 5.95, 95% CI 2.29 to 15.43) and 12-month remission (62% vs 25%; OdR 4.94, 95% CI 2.03 to 12.02) compared with danazol monotherapy (200 mg twice daily).[26] Dai et al also evaluated immunomodulatory therapy with ATRA (10 mg 3 times daily) and prednisone (10 mg twice daily) in 35 patients with chronic ITP, reporting an OR of 54.3%.[27]

Since RTX and ATRA share disparate mechanisms in treating ITP, a combination of LD-RTX (with 2 additional doses) and ATRA may work synergistically based on a “double-hit” mechanism targeting both platelet production and destruction, which may overcome the long TTR and improve the SR rate of LD-RTX. Therefore, our study aimed to determine the efficacy and safety of ATRA plus LD-RTX compared with LD-RTX monotherapy in patients with corticosteroid-resistant or relapsed ITP.