Table 5.
Combination therapies for refractory ITP
| References | Arms, n | Medication | Dosing | Cycles | Patients, n | Follow-up | Serious treatment complications | Concomitant tx at baseline | Previous treatment failures | Notes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Reported response | 1 mo | 3 mo | 6 mo | 12 mo | 24 mo | Kidney, % | Liver, % | Thrombosis, % | Infections, % | Other | Rituximab | TPO | ||||||||
| Post–TPO-RA era | ||||||||||||||||||||
| Wang et al117 | 1 | rhTPO | 1 µg/kg SQ, daily for 15 d | 73 | MRR, 38%; TRR, 60% | 0 | 0 | 0 | 0 | 9% visual field defect | Antifibrinolytics | No | No | 1 pt had ICH. MRR, plt > 100 000/µL; TRR, plt > 50 000/µL; OR, increase in plt of 30 000/µL and no bleeding. | ||||||
| Danazol | 200 mg PO, TID | |||||||||||||||||||
| 2 | Danazol | 200 mg PO, TID | 19 | MRR, 8%; TRR, 37% | ||||||||||||||||
| Cui et al118 | 1 | rhTPO | 1 µg/kg SQ daily | 14 d | 19 | Relapse rate: 17.7% at 1 mo, 29.4% at 2 mo, and 29.4% at 3 mo. | Response, 82% | Response, 71% | 0 | 0 | 0 | 0 | No | No | Response, twofold increase in plt, >30 000/µL and no bleeding. Long-term follow-up 3 mo. | |||||
| CSA | 1.5-2 mg/kg PO, BID | 3 mo | ||||||||||||||||||
| 2b | rhTPO | 1 µg/kg SQ, daily | 14 d | 17 | Relapse rate: 50% at 1 mo, 68.8% at 2 mo, and 87.5% at 3 mo. | Response, 50% | Response, 13% | |||||||||||||
| Li et al119 | 1 | CSA | 3 mg/kg PO, BID | 3-6 mo | 45 | SR, 37% (59% in CR group and 9% in PR group); 39% relapsed after stopping tx. | 0 | 0 | 0 | 0 | 11% bleeding | No | No | No | CR, plt > 100 000/µL; PR, plt > 30 000/µL and doubled from baseline; SR, plt > 50 000/µL in follow-up. Mean observation period 18 mo. | |||||
| Prednisone | 10-20 mg PO, daily | |||||||||||||||||||
| 2 | Rapamycin | 6 mg PO, then 2 mg PO, daily | 3-6 mo | 43 | SR, 68% (80% in CR group, 50% in PR group); 24% relapsed after stopping tx. | 0 | 0 | 0 | 0 | 7% bleeding | No | No | 2% | |||||||
| Prednisone | 10-20 mg PO, daily | |||||||||||||||||||
| Choi et al49 | 1 | Dexamethasone | 40 mg PO, days 1-4 | 20 | Response, 60% at 6 mo. Responders had RFS of 92% at 12 mo and 76% at 24 mo. | Response, 55%; CR, 30% | 0 | 0 | 5 | 15% HTN | No | Not clear | Not clear | Response defined by Rodeghiero et al.9 5 pts had secondary ITP; 1 pt had AKI 18 mo after tx due to NSAIDs. | ||||||
| CSA | 2.5-3 mg/kg PO, days 1-28 | |||||||||||||||||||
| Rituximab | 100 mg IV, days 7, 14, 21, and 28 | |||||||||||||||||||
| Zhou et al52 | 1 | Rituximab | 100 mg IV, weekly | 4 wk | 77 | CR, 45%; OR, 79%; SR, 44% | Response, 67% | Response, 44% | Response, 25% | 0 | 26 | 1% MI | No | No | 8% | 1 pt in rituximab/rhTPO group had ICH and died, and 1 pt died from MI with plt count of 26 000/µL. | ||||
| rhTPO | 400 U/kg SQ, initially daily and then weaned depending on plt counts | |||||||||||||||||||
| 2 | Rituximab | 100 mg IV, weekly | 4 wk | 38 | CR, 23%; OR, 71%; SR, 30% | Response, 54% | Response, 30% | Response, 19% | 0 | 0 | 21 | 0% | No | No | 5% | CR, plt > 100 000/µL and no bleeding; PR, plt > 30,000/µL and twofold increase from baseline and no bleeding. | ||||
| Li et al120 | 1 | Rituximab | 100 mg IV, weekly | 4 wk | 14 | CR, 50%; PR, 43%. Median follow-up 17 mo (range, 3-44 mo). | CR, 50%; PR, 43% | CR, 50%; PR, 43% | CR, 43%; PR, 43% | CR, 43%; PR, 43% | CR, 36%; PR, 43% | 0 | 0 | 0 | 7 | 1 pt died from interstitial pneumonitis. 1 pt died from Aspergillus lower respiratory infection and ICH. | No | No | No | CR, plt ≥ 100 000 and no bleeding; response, plt > 30 000/µL and 2 occurrences of increased plt compared with baseline and no bleeding. |
| rhTPO | 300 µg/kg/d | 14 d | ||||||||||||||||||
| Mahévas et al50 | 1 | Supportive: IVIG, CSA, or no treatment | 12 | NR | 0% | 0% | 24 | 40 infection, 3 sepsis | No | Yes | Yes | Response, plt > 100 000/µL or >30 000/µL and doubled from baseline. Pts crossed over from 1 group to the other. No. of pts here represents total no. of pts treated in a specific arm. 7 patients had ICH, 2 pts had HSCT, and 5 pts died. | ||||||||
| 2 | Immunosuppressants | 14 | Response, 7% | 0% | 0% | |||||||||||||||
| 3 | TPO + immunosuppressants | 10 | Response, 70% with median follow-up of 15 mo. At end of follow-up, response was 30% (median, 84 mo). | |||||||||||||||||
| 4 | TPO and supportive IVIG/CSA | 5 | NR | 0% | 0% | |||||||||||||||
| Gudbrandsdottir et al53 | 1 | CSA/MMF, TPO, and IVIG | 18 | 72% (CR + PR) | 0 | 6 HTN | Duration of combination treatment, min 1 mo (mean, 5 mo) | |||||||||||||
| Feng et al54 | 1 | Danazol | 200 mg PO, BID | 16 wk | 45 | OR, 82% (CR, 38%); 24% relapsed | Response, 47% | Response, 62% | 0 | 0 | 0 | 2% serious bleeding, 64% dry skin, 20% HA, 20% GI disorders, 7% HTN | 36% | 7% | 9% | PR, plt > 30 000/µL and at least doubled from baseline; CR, plt > 100 000/µL and no bleeding, without rescue medication at 12-mo follow-up. | ||||
| ATRA | 10 mg PO, BID | |||||||||||||||||||
| 2 | Danazol | 200 mg PO, BID | 48 | OR, 44% (CR, 8%); 43% relapsed | Response, 15% | Response, 25% | 0 | 2 | 0 | 8% serious bleeding, 6% dry skin, 17% HA, 19% GI disorders, 6% HTN. | 35% | 6% | 10% | |||||||
| Wang et al121 | 1 | Rituximab | 100 mg IV, weekly | 4 wk | 79 | CR, 33%; PR, 25%; MR, 14% | 3 | 3 | 1% | 10% dizziness/HA, 15% vomiting | CR, plt > 100 000/µL for 2 mo and no bleeding; PR, plt > 50 000/µL for 2 mo and no bleeding; minimal effective, plt > 20 000/µL for 2 mo and improved bleeding. | |||||||||
| 2 | Cyclophosphamide | 0.8 g IV weekly; 2 mg/kg/d PO | 3 mo | 86 | CR, 13%; PR, 36%; MR, 13% | 6 | 6 | 3% | 14% dizziness/HA, 17% vomiting | |||||||||||
| 3 | Rituximab | 100 mg IV, weekly. | 4 wk | 84 | CR, 58%; PR, 17%; MR, 7% | 1 | 1 | 0% | 6% dizziness/HA, 7% vomiting | |||||||||||
| Cyclophosphamide | 0.8 g IV weekly, 2 mg/kg/d PO | 3 mo | ||||||||||||||||||
Long-term follow-up may be low because patients relapsed or because of the small number of patients at the specific time point.
AKI, acute kidney injury; ATRA, all-trans retinoic acid; BID, twice a day; CSA, cyclosporine A; DDR, double the standard dose rituximab; f/u, follow-up; GI, gastrointestinal; HA, headache; HSCT, hematopoietic stem cell transplant; HSV, herpes simplex virus; HTN, hypertension; ICH, intracranial hemorrhage; MI, myocardial infarction; min, minimum; MMF, mycophenolate mofetil; MRR, major response rate; NSAID, nonsteroidal anti-inflammatory drug; OR, overall response; plt, platelets; PO, by mouth; pt/pts, patient/patients; R-CVP, rituximab, cyclophosphamide, vincristine, and prednisone; RFS, relapse-free survival; rhTPO, recombinant human TPO; SQ, subcutaneous; SR, sustained response; TID, 3 times a day; TRR, total response rate; tx, treatment; UTI, urinary tract infection.
*
With the addition of immunosuppressive therapy.