Thursday, June 8, 2023
| 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
| 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.
| 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
| 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.
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.
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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.
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.
