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 | ||||||||
| Pre–TPO-RA era | ||||||||||||||||||||
| Figueroa et al44 | 1 | Cyclophosphamide | 400-650 mg/m2 IV, days 1 and 8 | 3-8 | 10 | CR, 60% (>4, 9, 11, 30, 53, and 126 mo); PR, 20% (>2, >9 mo) | CR, 70%; PR, 20% | CR, 70%; PR, 10% | CR, 60%; PR, 10% | CR, 40%; PR, 0% | CR, 40%; PR, 0% | 0 | 0 | 10 | 0 | Nausea, alopecia, acne, malaise | No | No | No | 2 pts have secondary ITP. ∼10 y follow-up. 2 pts had NR and died of ICH 2 mo later. |
| Prednisone | 40 mg/m2 PO, days 1 and 14 | |||||||||||||||||||
| Vincristine | 2 mg IV, days 1 and 8 | |||||||||||||||||||
| Procarbazine or etoposide | 100 mg/m2 PO, days 1 and 14 or 100 mg/m2 IV, days 14-16 | |||||||||||||||||||
| Choudhry et al113 | 1 | Vinblastine | 4 mg/m2 IV, weekly and then monthly | 8 mo | 16 | CR, 38%; PR, 25% after induction | CR, 38%;PR, 25% | CR, 19%; PR, 6% | 0 | 0 | 0 | 0 | No | No | No | 1 pt had ICH. CR, plt > 150 000; PR, less than twofold increase in plt and >50 000/µL. | ||||
| Danazol | 2-3 mg/kg PO, daily | Remission in 25% during f/u (6-10 mo) | ||||||||||||||||||
| McMillan45 | 1 | Cyclophosphamide | 400-650 mg/m2 IV, days 1 and 8 | 3-8 | 12 | CR 42%; PR 8% | CR, 58%; PR, 17% | CR, 58%; PR, 8% | CR, 50%; PR, 8% | CR, 50%; PR, 8% | CR, 50%; PR, 0% | 0 | 0 | 0 | 0 | Nausea, alopecia, acne, malaise | No | No | No | Follow-up of Figueroa et al.4 3 pts had ICH. CR, plt > 140 000/µL; PR, plt < 50 000/µL. |
| Prednisone | 40 mg/m2 PO, days 1, and 14 | |||||||||||||||||||
| Vincristine | 2 mg IV, days 1 and 8 | |||||||||||||||||||
| Procarbazine, or | 100 mg/m2 PO, days 1 and 14 | |||||||||||||||||||
| Etoposide | 100 mg/m2 IV, days 14-16 | |||||||||||||||||||
| Kappers-Klunne and van’t Veer114 | 1 | Cyclosporine tapered by 50 mg/d every 2 wk | 3 mg/kg PO, BID | >4 wk | 10 | CR, 30%; PR, 20% | CR, 30%; PR, 20% | CR, 30%; PR, 20% | CR, 20%; PR, 10% | CR, 20%; PR, 0% | CR, 20%; PR, 0% | 30% HTN; severe muscle pain, HA, nausea, gum hyperplasia. | CR, plt > 110 000/µL for 12 wk; PR, plt > 40 000/µL for 8 wk. 1 pt required longer CSA to retain CR. | |||||||
| Dosing below 3 mg/kg PO, BID | ||||||||||||||||||||
| 2 | CSA | 2.5 mg/kg PO BID | <4.5 mo | 10 | CR, 20% (>2 y, >4 y); PR, 40% | CR, 20%; PR, 40% | CR, 20% | CR, 20% | 10 | |||||||||||
| Prednisone | 0.4 mg/kg/d | Unclear length of follow-up | ||||||||||||||||||
| Williams & Boxer115 | 1 | Vincristine | 1.5 mg/m2 IV, weekly | 2-4 doses | 10 | 80% had PR or CR. Treated pts have been off therapy for a median of 13 mo. | CR, 70%; PR, 0% | CR, 70%; PR, 10% | CR, 70%; PR, 10% | CR, 50%; PR, 10% | CR, 20%; PR, 0% | 0 | 0 | 0 | 30% peripheral neuropathy, 30% constipation, 30% jaw pain, 20% alopecia, 40% nausea | Many pts on concomitant tx | No | No | 40% Evans syndrome.CR, normal plt after cessation of CSA; PR, plt 80 000-120 000/µL for ≥3 mo while off CSA. | |
| Methylprednisone | 100 mg/m2 IV, weekly | 2-4 doses | ||||||||||||||||||
| CSA | 5 mg/kg PO, BID | 3-6 mo | ||||||||||||||||||
| Boruchov et al47 | Acute | IVIG | 1 g/kg IV | 17 | 66% responded to acute IV therapy. | 0 | 0 | 6; plt very low at the time. | 0 | No | No | No | Increase in plt to >30 000/µL to a total count > 50 000/µL | |||||||
| Anti-D | ||||||||||||||||||||
| Vincristine | 0.03 mg/kg IV | |||||||||||||||||||
| Vinblastine | 10 mg IV | |||||||||||||||||||
| Maintenance | Danazol | 10 mg/kg PO | 18 | Response, 65% at 2 mo and 71% at 4 mo (did not start immunosuppressive therapy in 8 pts with HIV) | 65% (11/17) | 0 | 0 | 0 | 0 | 6% ileus | No | No | No | |||||||
| Azathioprine | 2-2.5 mg/kg PO | |||||||||||||||||||
| Hasan et al46 | 1 | Second-dose rituximab* | 375 mg/m2 IV, weekly ×4 weeks | 4 wk | 20 | None with benefit over standard-dose rituximab; 38% responded to R-CVP but short duration; 63% responded to DDR, 4 pts with longer response compared with initial treatment. No pt with NR to initial rituximab responded to DDR. | CR, 50%; PR, 20% | CR, 45%; PR, 20% | CR, 40%; PR, 5% | CR, 5%; PR, 0% | 0 | 0 | 0 | 0 | 13% allergy | No | Yes | No | CR, plt > 150 000/µL for ≥3 mo; PR, plt > 50 000/µL for ≥3 mo. | |
| 2 | Rituximab | 375 mg/m2 IV, weeks 1, 2, 5, and 8 | 4 infusions | 8 | CR 38% PR 0% | CR 38% PR 0% | CR 13% PR 0% | CR 0% PR 0% | No | Yes | No | |||||||||
| Cyclophosphamide | 750 mg/m2 IV, every 4 wk | 3 | ||||||||||||||||||
| Vincristine | 1.4 mg/m2 IV, every 4 wk | 3 | ||||||||||||||||||
| Prednisone | 100 mg PO, days 1-5, every 4 wk | 3 | ||||||||||||||||||
| 3 | DDR | 750 mg/m2 IV, weekly | 4 wk | 8 | CR, 50%; PR, 13% | CR, 50%; PR, 13% | CR. 38%; PR, 13% | CR, 0%; PR, 0% | No | Yes | No | |||||||||
| Arnold et al48 | 1 | Azathioprine | 2 mg/kg/d | 19 | CR, 11%; PR, 63% in a median of 24 mo of follow-up (11.5-46.8 mo); 57% relapsed. | 0 | 0 | 0 | 32 | 16%, gum hypertrophy and tremors. | No | No | No | Response: more than twofold and plt > 30 000/µL for 4 wk. Infections reported to be unrelated to tx. | ||||||
| CSA | 2 mg/kg/d | |||||||||||||||||||
| MMF | 1-2 g/d | |||||||||||||||||||
| Gómez-Almaguer et al116 | 1 | Rituximab | 100 mg IV, weekly | 4 wk | 11 | 45% achieved CR, 55% achieved PR. Median duration of CR was 46 wk. | CR, 27%; PR, 73% | CR, 36%;PR, 64% | CR, 36%; PR, 55% | CR, 18%; PR, 27% | PR, 0%; CR, 0% | 0 | 0 | 0 | 18%, HSV; 36%, UTI |
9% died from unclear cause | Patients should have Evans syndrome. CR, plt > 150 000/µL; PR, plt > 50 000/µL on 2 consecutive occasions. | |||
| Alemtuzumab | 10 mg SQ, days 1-3 | |||||||||||||||||||
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.