**5.5 Second line treatment**

Until recently, splenectomy was the most common second line option for the treatment of refractory chronic ITP. The use of the anti-CD20 monoclonal antibody, rituximab, as a B-cell depletion therapy has gained tremendous popularity as a spleen saving treatment modality. Rituximab can be used alone or in combination with dexamethasone. However, the complete durable response rate is not as high as splenectomy( Schweizer et al. 2007). Relapsed patients can benefit from re-treatment with rituximab. Long-term immunosuppression and progressive multifocal encephalopathy remains potential serious complications with rituximab use.

### **5.6 The role of splenectomy:**

Splenectomy still remains the most effective second line option and offers the highest rate of durable complete remissions. Splenectomy has been shown to lead to durable response in 60% to 70% of patients (Kumar et al. 2002). However, with the introduction of a number of novel treatments, some clinicians recommend delaying splenectomy until later in the course of the illness. Despite the reduced morbidity and mortality with laparoscopic splenectomy in the hands of experienced surgeons, prophylactic appropriate vaccination, and use of antibiotics promptly in the event of febrile illness in post-splenectomy patients; still fewer patients are opting for splenectomy.

#### **5.7 Therapeutic options after splenectomy failure**

Treatment of patients with refractory ITP following splenectomy is challenging. While many drugs are available, no one treatment is widely accepted (McMillan & Durette, 2004). Intensive treatment should be reserved for patients with persistently low platelet counts in the presence of bleeding. Figure 2 shows an algorithm for managing ITP patients at different severities of disease. Other important considerations in the management of chronic ITP include the time to onset of efficacy, duration of benefit, and whether patients are able to maintain a response off therapy or if continued, the drug dosage necessary to maintain safe platelet counts.

Several immunosuppressive agents alone or in combination have shown some efficacy, including azathioprine (Quiquandon et al 1990), danazol, cyclophosphamide,

Once the diagnosis of persistent or chronic ITP is established and the need for the treatment is determined, underlying infection must be ruled out. Traditional modalities, such as steroids and immunosuppression, could be detrimental in the presence of infection. Intermittent courses of steroids and IVIG are used along with other immunosuppressive modalities. The most commonly used regimens are prednisone at a dose of 1 mg/kg per day orally. The popularity of pulse dosing of high-dose dexamethasone is rising (40 mg/day for 4 days) due to the convenience of short duration of treatment (Cheng et al., 2003). The reported success rate with pulse dexamethasone in chronic ITP is conflicting, and longlasting durable responses are generally not expected. Intravenous immunoglobulins (dose 1- 2gm/kg) can also be used if there is a need to increase platelet count rapidly. Other alternative option is anti-D therapy. It is only recommended in Rh-positive and nonsplenectomized patients. Intermittent anti-D therapy can be used on a long-term basis but

Until recently, splenectomy was the most common second line option for the treatment of refractory chronic ITP. The use of the anti-CD20 monoclonal antibody, rituximab, as a B-cell depletion therapy has gained tremendous popularity as a spleen saving treatment modality. Rituximab can be used alone or in combination with dexamethasone. However, the complete durable response rate is not as high as splenectomy( Schweizer et al. 2007). Relapsed patients can benefit from re-treatment with rituximab. Long-term immunosuppression and progressive multifocal encephalopathy remains potential serious

Splenectomy still remains the most effective second line option and offers the highest rate of durable complete remissions. Splenectomy has been shown to lead to durable response in 60% to 70% of patients (Kumar et al. 2002). However, with the introduction of a number of novel treatments, some clinicians recommend delaying splenectomy until later in the course of the illness. Despite the reduced morbidity and mortality with laparoscopic splenectomy in the hands of experienced surgeons, prophylactic appropriate vaccination, and use of antibiotics promptly in the event of febrile illness in post-splenectomy patients; still fewer

Treatment of patients with refractory ITP following splenectomy is challenging. While many drugs are available, no one treatment is widely accepted (McMillan & Durette, 2004). Intensive treatment should be reserved for patients with persistently low platelet counts in the presence of bleeding. Figure 2 shows an algorithm for managing ITP patients at different severities of disease. Other important considerations in the management of chronic ITP include the time to onset of efficacy, duration of benefit, and whether patients are able to maintain a response off therapy or if continued, the drug dosage necessary to maintain safe

Several immunosuppressive agents alone or in combination have shown some efficacy, including azathioprine (Quiquandon et al 1990), danazol, cyclophosphamide,

the potential risk of severe hemolysis should be taken into consideration.

**5.4 Initial treatment of chronic ITP:** 

**5.5 Second line treatment** 

complications with rituximab use.

patients are opting for splenectomy.

platelet counts.

**5.7 Therapeutic options after splenectomy failure** 

**5.6 The role of splenectomy:** 

mycophenylate mofetil (Hou et al. 2003), cyclosporine (Emilia et al. 2001), and vinca alkaloids. Another factor to consider when choosing an agent is patient preference for an oral agent administered daily, or an intravenous agent administered intermittently in an infusion clinic. Hematopoietic stem cell transplantation is used very rarely to treat ITP that has proven to be very refractory to treatment.

Fig. 2. Algorithm For the Management of Chronic ITP: "Individualize, individualize, and individualize"

Our better understanding of the immunopathogenesis has lead to the development of many novel therapies in the management of chronic ITP. Thrombopoietin receptor agonists (TRAs), which bind and activate the thrombopoietin (TPO) receptor to stimulate platelet production, have opened a new door in the management of chronic refractory ITP. Romiplastin (TPO peptide mimetic) and eltrombopag (nonpeptide TPO mimetic) are two recently approved agents for the treatment of refractory ITP (Burzynski, 2009). These agents have the advantage compared to recombinant TPO agonists of not causing the development of antibodies. The response rate of these agents ranges somewhere between 37% and 50%. To date, the clinical experience with these novel agents for a relatively benign disease is limited. Despite showing a favorable safety profile to date, these agents may have potential long-term side effects, such as thrombosis and myelofibrosis.

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