Chapter 68: Immune Thrombocytopenia

Idiopathic Thrombocytopenic Purpura (ITP)

ITP is defined as isolated thrombocytopenia with no other clinically apparent associated conditions or causes of thrombocytopenia caused by accelerated destruction as well as impaired production of platelets by antiplatelet autoantibodies

Ballem PJ et al. J Clin Invest 1987;80:33–40

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

George JN et al. Blood 1996;88:3–40

McMillan R. Semin Hematol 2007;44(4 Suppl 5):S3–S11

Epidemiology

Differential Diagnosis

1. Pseudothrombocytopenia (platelet clumping in the presence of EDTA by naturally occurring autoantibodies to normally concealed epitopes on glycoprotein IIb/IIIa)

2. Drug-induced thrombocytopenia (including nonprescription drugs and herbs)

3. Secondary autoimmune thrombocytopenia, for example, CLL, SLE, antiphospholipid antibody syndrome (isolated presence of antinuclear antibodies in a patient with immune thrombocytopenia, without other clinical features of SLE, does not imply a diagnosis of SLE, although some of these patients will eventually develop full-blown SLE)

4. Infectious disorders (HIV, HCV, EBV)

5. Bone marrow failure (myelodysplasia)

6. Congenital/hereditary nonimmune thrombocytopenia

7. Hypersplenism caused by occult liver disease

8. Incidental thrombocytopenia of pregnancy (also termed gestational thrombocytopenia)

9. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome

10. Chronic disseminated intravascular coagulation

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

George JN et al. Ann Intern Med 1998;129:886–890

George JN et al. Blood 1996;88:3–40

Work-up

Objectives are to assess the type, severity, and duration of bleeding, and to exclude other etiologies

1. CBC: Pseudothrombocytopenia from EDTA-dependent platelet agglutination (occurs in ≈ 0.1% of adults) or platelet adherence to neutrophils and monocytes (platelet rosetting) should be ruled out by examination of peripheral smear

2. Peripheral blood smear: Findings consistent with the diagnosis of ITP include thrombocytopenia with normal-sized or slightly larger than normal platelets, and normal red and white blood cell morphology

3. Bone marrow examination: The American Society of Hematology guidelines recommend bone marrow examination as appropriate to establish diagnosis in patients over age 60 years (because of the higher incidence of myelodysplasia), in those with atypical features in peripheral blood smear suggesting an alternative diagnosis, and if not previously performed, in patients considering splenectomy or second-line medical therapies that often cause prolonged immunosuppression or have other significant side effects. Bone marrow biopsy is inappropriate in patients <60 years old, with isolated thrombocytopenia, and no other atypical findings in medical history, clinical examination, and examination of CBC and peripheral blood smear. This view has been supported by several case series

4. HIV and HCV serology: Patients with relevant risk factors should be tested

5. Autoimmune profile: If suggested by history and physical findings (ANA, antiphospholipid antibodies)

If history, physical examination, and examination of CBC and peripheral blood smear are consistent with a diagnosis of ITP and no atypical features are present, no further tests are necessary for diagnosis

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

George JN et al. Blood 1996;88:3–40

Jubelirer SJ, Harpold R. Clin Appl Thromb Hemost 2002;8:73–76

Mak YK et al. Clin Lab Haematol 2000;22:355–358

Westerman DA, Grigg AP. Med J Aust 1999;170:216–217

Classification

Childhood ITP: Usually an acute, self-limited disorder that characteristically resolves within 6 months with only supportive care. Males and females are equally affected, with a peak age at diagnosis of 2–4 years

Adult ITP: Usually a chronic disorder, with insidious onset of symptoms that rarely resolves spontaneously

Treatment Options

The goal of treatment is to achieve a safe platelet count while minimizing side effects of therapy. Achievement of a normal platelet count is not a goal of treatment. In general, observation is recommended for patients with platelet counts ≥30,000/mm³ unless they are undergoing a procedure likely to induce blood loss including surgery, dental extraction, or parturition. Glucocorticoids are considered the initial line of therapy in a patient with a platelet count <30,000/mm³, or a platelet count of 30,000–50,000/mm³ in the presence of clinically important bleeding (or significant risk for it). Splenectomy is recommended for patients with persistent thrombocytopenia despite steroids and for those who require steroids (>5 mg prednisone per day) for prolonged periods (>6 weeks) to maintain safe platelet count levels (≥30,000/mm³), but is considered inappropriate as initial therapy, or if the platelet count is >30,000/mm³. Treatment with rituximab may be considered when splenectomy is considered high risk or if a patient or physician wishes to defer splenectomy, but it should not routinely substitute for splenectomy because the frequency and durability of complete responses with splenectomy are greater than with rituximab. The majority of patients with persistent thrombocytopenia despite prior therapy with glucocorticoids and splenectomy can be managed with watchful observation. When treatment is needed however, it may be chosen from a list of available options, which include traditional immunosuppressive drugs, such as cyclophosphamide and azathioprine, or, more recently, and perhaps with a more favorable risk/benefit profile, rituximab and thrombopoietin receptor agonists, romiplostim and eltrombopag

Emergency Treatment

Hospitalization is required for severe, life-threatening bleeding regardless of the platelet count. Emergency treatment in addition to general supportive care measures, includes:

1. Platelet transfusions (can be given as bolus or continuous infusion)

2. High-dose parenteral glucocorticoids, for example, methylprednisolone 1000 mg/day intravenously in 50–1000 mL 0.9% sodium chloride injection or 5% dextrose injection over at least 30 minutes, daily for 1–3 consecutive days

3. Immune globulin, intravenous (IVIG) 1000 mg/kg (body weight) per dose intravenously. Refer to product-specific recommendations for administration rates (initial, escalation, and maximum rates). Repeat treatment on the following day if the platelet count remains <50,000/mm³ (total dosage/1- to 2-day course = 1000–2000 mg/kg)

4. Other useful measures may include:

Aminocaproic acid oral rinse 5 mL (1.25 g) swish for 30 seconds 4 times per day for gingival bleeding

May be prepared extemporaneously from aminocaproic acid solution for intravenous use or compounded from aminocaproic acid tablets for oral administration

 Local application of fibrin sealant for intractable dental bleeding

 Medroxyprogesterone acetate to control excessive uterine bleeding

These modalities are given either alone or in combination

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

George JN et al. Blood 1996;88:3–40

Regimen: Observation

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

Cortelazzo S et al. Blood 1991;77:31–33

George JN et al. Blood 1996;88:3–40

Provan D, Newland A. Br J Haematol 2002;118:933–944

Vianelli N et al. Haematologica 2001;86:504–509

Efficacy

1. In a consecutive series of 117 patients, no major hemorrhages occurred among 49 patients with platelet counts >30,000/mm³ who did not receive treatment and were followed for a median of 30 months

2. In another consecutive series of 310 patients followed for more than 10 years who generally were treated only if symptomatic or if platelet count <30,000/mm³, none of the patients who were only monitored without active therapy (N = 107) died of bleeding

Toxicity

None

Indications

Patients with platelet counts exceeding 30,000/mm³ unless they are undergoing a procedure likely to induce blood loss including surgery, dental extraction, or parturition

Notes

Patients with low platelet counts (<30,000/mm³) may also be managed only with observation if they have no or minimal bleeding symptoms. This is especially appropriate in an individual patient with platelet count persistently <30,000/mm³ despite treatment, who proves over time that he/she does not bleed and is not at significant risk for major bleeding

Regimen: Glucocorticoids

Ben-Yehuda D et al. Acta Haematol 1994;91:1–6

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

Cheng Y et al. N Engl J Med 2003;349:831–836

George JN et al. Blood 1996;88:3–40

Mazzucconi MG et al. Blood 2007;109:1401–1407

Pizzuto J, Ambriz R. Blood 1984;64:1179–1183

Provan D, Newland A. Br J Haematol 2002;118:933–944

Stasi R et al. Am J Med 1995;98:436–442

Prednisone 1 mg/kg per day (dosage range, 0.5–2 mg/kg per day) orally for not more than 4–6 weeks (usually 2–4 weeks), after which, doses should be slowly tapered to the lowest effective dose, or tapered to discontinuation if an improvement in platelet count was not achieved

• The lowest effective dose may be continued for 4–6 weeks before attempting to slowly taper and discontinue steroids

• Splenectomy should be considered if steroids are required for prolonged periods to maintain safe levels of platelet count

or

Dexamethasone 40 mg per day orally as a single daily dose for 4 consecutive days. This treatment may be repeated 2 more times in 2-week intervals, or given once and repeated only upon relapse

In patients with severe, life-threatening bleeding, such as intracranial hemorrhage:

Methylprednisolone 1000 mg/day, intravenously in 100–250 mL 0.9% sodium chloride or 5% dextrose injection, over at least 30 minutes, daily for 3 consecutive days

Adverse Events

Weight gain, facial swelling, hypertension, hyperglycemia, osteoporosis, cataracts, and mood and behavioral abnormalities^✫

Efficacy

Prednisone:

1. Two randomized studies found equal efficacy between low versus high doses of glucocorticoids (prednisone: 0.5 vs. 1.5 mg/kg per day and 0.25 vs. 1 mg/kg per day)

2. In 1 large study, the incidence of prolonged complete remission was the same for patients treated for 4–6 weeks as for those treated for >3 months

3. About two-thirds to three-fourths of patients initially respond, but long-term remission without maintenance treatment occurs in only 10–30% following cessation of therapy

Dexamethasone:

1. In a consecutive cohort of 125 newly diagnosed adults with ITP, 85% of patients had an initial response; half of those had a sustained platelet count >50,000/mm³ and required no further treatment during 2–5 years of follow-up

2. In another prospective study of 95 patients treated with four 4-day courses of dexamethasone 40 mg/day IV or PO given every 2 weeks, overall response rates after each consecutive cycle was 70%, 76%, 89%, and 86%, respectively

Methylprednisolone:

1. High-dose parenteral glucocorticoids, are reserved for severe, life-threatening bleeding, such as intracranial hemorrhage (see Emergency Treatment)

Indications

Glucocorticoids are considered the initial line of therapy in a patient with

1. Platelet count <30,000/mm³

2. Platelet count 30,000–50,000/mm³ in the presence of clinically important bleeding

Notes

Glucocorticoids are the standard first-line and least-expensive treatment. A short course of dexamethasone may be less toxic and more effective than prolonged prednisone treatment

Regimen: Splenectomy

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

George JN et al. Blood 1996;88:3–40

Kojouri K et al. Blood 2004;104:2623–2634

PizzutoJ, Ambriz R. Blood 1984;64:1179–1183

Schwartz J et al. Am J Hematol 2003;72:94–98

Prior to splenectomy:

1. To enhance operative hemostasis, preoperative immune globulin intravenous, (human) (IVIG) if the platelet count is <20,000/mm³:

    IVIG 1000 mg/kg given as a single dose (total dosage/1-day course = 1000 mg/kg), or

     IVIG 1000 mg/kg per day for 2 consecutive days (total dosage/2-day course = 2000 mg/kg), or

    IVIG 400 mg/kg per day for 5 consecutive days (total dose/5-day course = 2000 mg/kg)

   • Administer intravenously

   • Refer to product-specific labeling for information about preparation (reconstitution and dilution when appropriate), administration rates (initial, escalation, maximum rates), and whether filtration during administration is needed or appropriate

   • If the platelet count remains <50,000/mm³ after a single treatment with IVIG 1000 mg/kg, repeat treatment on the following day

     or

     Prednisone 1 mg/kg per day orally as a single dose for 5–7 consecutive days if the platelet count is <20,000/mm³ (total dosage/5- to 7-day course = 5–7 mg/kg)

     or

     Dexamethasone 40 mg per day orally or intravenously as a single dose for 4 consecutive days if the platelet count is <20,000/mm³ (total dose/4-day course = 160 mg)

2. At least 2 weeks before surgery immunize with:

   • Pneumococcal 13-valent conjugate vaccine,

   • Haemophilus influenzae b (Hib polysaccharide) conjugate vaccine, and

   • Quadrivalent meningococcal (A, C, Y, and W-135) polysaccharide conjugate vaccine

3. Preoperative platelet transfusions are inappropriate if platelet count is >100,000/mm³

Splenectomy can be performed by open laparotomy or laparoscopy, depending on a surgeon's experience

Indications

Recommended in patients with:

1. Platelet counts <10,000/mm³, 6 weeks after initiation of medical therapy

2. Platelet counts <30,000/mm³, 3 months after initiation of medical therapy

Considered inappropriate:

1. As initial therapy

2. If the platelet count is >30,000/mm³

Adverse Events

Laparoscopic splenectomy has less operative mortality and morbidity, as well as more rapid postoperative recovery

Efficacy

Notes

1. The most effective treatment for achieving complete and durable remissions in adults with ITP

2. Consider in patients whose disease:

   • Does not respond to glucocorticoids

   • Recurs after an initial response

   • Requires continued steroid treatment to maintain safe platelet counts

3. Consider above immunizations at the time of initial diagnosis of ITP in an adult patient, because (a) immunizations may not be effective in the face of immunosuppressive therapy, and (b) splenectomy may occasionally need to be performed urgently

Regimen: Accessory Splenectomy

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

Vesely SK et al. Ann Intern Med 2004;140:112–120

Prior to splenectomy:

1. To enhance operative hemostasis, preoperative immune globulin intravenous (human) (IVIG) if the platelet count is <20,000/mm³:

    IVIG 1000 mg/kg given as a single dose (total dosage/1-day course = 1000 mg/kg), or

    IVIG 1000 mg/kg per day for 2 consecutive days (total dosage/2-day course = 2000 mg/kg), or

    IVIG 400 mg/kg per day for 5 consecutive days (total dose/5-day course = 2000 mg/kg)

   • Administer intravenously

   • Refer to product-specific labeling for information about preparation (reconstitution and dilution when appropriate), administration rates (initial, escalation, maximum rates), and whether filtration during administration is needed or appropriate

   • If the platelet count remains <50,000/mm³ after a single treatment with IVIG 1000 mg/kg, repeat treatment on the following day

     or

     Prednisone 1 mg/kg per day orally as a single dose for 5–7 consecutive days if the platelet count is <20,000/mm³ (total dosage/5- to 7-day course = 5–7 mg/kg)

     or

     Dexamethasone 40 mg per day orally or intravenously as a single dose given on 4 consecutive days if the platelet count is <20,000/mm³ (total dose/4-day course = 160 mg)

2. Preoperative platelet transfusions are inappropriate if platelet count is >100,000/mm³

Indications

Many hematologists believe that accessory splenectomy is never indicated. However, in patients who fail to respond to splenectomy or relapse following an initial prolonged response, imaging studies to detect an accessory spleen have been suggested by some

Efficacy

Some case reports have described success with accessory splenectomy. However, these reports are difficult to evaluate and the experience of many hematologists is that accessory splenectomy is not effective

Adverse Events

Laparoscopy may not be appropriate to identify and remove small accessory spleens

Notes

Accessory spleens are present and removed in 15% of ITP patients undergoing splenectomy

Regimen: Immune Globulin Intravenous (Human) (Pooled Normal Human Immunoglobulin)

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

George JN et al. Blood 1996;88:3–40

Godeau B et al. Blood 1993;82:1415–1421

Provan D, Newland A. Br J Haematol 2002;118:933–944

Immune globulin intravenous (human) (IVIG)^✫:

IVIG 400 mg/kg per day for 5 consecutive days (total dose/5-day course = 2000 mg/kg)

or

IVIG 1000 mg/kg per day for 2 consecutive days (total dosage/2-day course = 2000 mg/kg)

or

IVIG 1000 mg/kg given as a single dose (total dosage/1-day course = 1000 mg/kg)

Efficacy

1. Seventy-five percent of patients respond to IVIG by increasing their platelet count

2. Approximately 50% achieve normal platelet counts

3. In almost all patients, the platelet count returns to pretreatment levels in 3–4 weeks

4. Five-day, 2-day, and single doses are equally efficacious

Adverse Events

Indications

1. As a temporary measure to increase platelet count

2. In a patient with a platelet count <50,000/mm³ in the presence of severe bleeding

3. In a patient with a platelet count <30,000/mm³ before splenectomy (or another major operation) to achieve hemostasis during surgery

Notes

The mechanism of action remains largely unknown but is reported to involve Fc receptor blockade on macrophages and monocytes, the presence of antiidiotype antibodies in IVIG that block autoantibody binding to circulating platelets, and immune suppression

IVIG products with high IgA content is contraindicated in persons with IgA deficiency

Regimen: Rh_O(D) Immune Globulin (Human) for Injection (Rh_O(D) IVIG)

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

Gaines AR. Blood 2000;95:2523–2529

George JN et al. Am J Hematol 2003;74:161–169

Scaradavou A et al. Blood 1997;89:2689–2700

Rh_O(D) IVIG 50–75 mcg/kg^✫; administer ONLY by the intravenous route over 3–5 minutes (1 μg = 5 IU Rho(D) IVIG)

Notes:

• For patients with ITP it is recommended that before deciding to treat patients with Rho (D) IVIG the following be obtained: blood type, CBC, reticulocyte count, DAT, and dipstick urinalysis

• Administer Rho (D) IVIG only after confirming a patient is Rho (D)-positive

• An initial dose may be administered in two divided doses given on separate days

• Other treatments MUST be used in patients with evidence of hemolysis or patients at risk of hemolysis

   In patients with a hemoglobin level less than 8 g/dL, alternative treatments should be used due to the risk of increasing the severity of anemia

• The frequency and dose used should be administered based on a patient's clinical response by assessing platelet counts, red cell counts, hemoglobin, and reticulocyte levels

• Rho (D) IVIG is commercially available in a liquid formulation appropriate for intravenous administration without further dilution, or it may be diluted in 0.9% sodium chloride injection

Indications

Rho (D) IVIG is used to transiently elevate the platelet count in Rho (D)+ patients who have a spleen

Efficacy

In a single-institution experience, 70% of adult patients with ITP patients increased platelet count by ≥20,000/mm³ within 2 days. In half of those patients, the response lasted 3 weeks or more

Adverse Events

1. The only clinically important adverse effect is alloimmune hemolysis. All Rho (D)+ patients develop a positive direct antiglobulin test after treatment, accompanied by a transient (1–2 weeks) decrease in hemoglobin concentration of approximately 0.5–2 g/dL

2. Severe intravascular hemolysis with DIC and acute renal failure has been reported as an adverse effect of Rho (D) IVIG

Notes

The mechanism of action is opsonization of Rho (D)+ red blood cells that are preferentially removed by the spleen, thus sparing autoantibody coated platelets through Fc receptor blockade

Regimen: Cyclophosphamide, Azathioprine Mycophenolate Mofetil

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

George JN et al. Blood 1996;88:3–40

George JN et al. Semin Hematol 2000;37:290–298

Hou M et al. Eur J Haematol 2003;70:353–357

McMillan R. Ann Intern Med 1997;126:307–314

Provan D et al. Am J Hematol 2006;81:19–25

Quiquandon I et al. Br J Haematol 1990;74:223–228

Vesely SK et al. Ann Intern Med 2004;140:112–120

Cyclophosphamide 1–2 mg/kg per day (maximum dose = 150 mg/day), orally in the morning, continually if a response occurs (total dosage/week = 7–14 mg/kg; maximum dose/week = 1050 mg)

Encourage patients to increase their consumption of nonalcoholic fluid (64–80 ounces [1900–2400 mL]) to prevent developing hemorrhagic cystitis

or

Azathioprine 1–2 mg/kg per day (maximum dose = 150 mg/day), orally, continually if a response occurs (total dosage/week = 7–14 mg/kg; maximum dose/week = 1050 mg)

or

Mycophenolate mofetil 750–1000 mg/dose orally twice daily for a minimum of 12 weeks (total dose/day = 1500–2000 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential with cyclophosphamide is LOW

Emetogenic potential with azathioprine and mycophenolate mofetil is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Therapy Monitoring

Monitor CBC and leukocyte differential serially—initially at least weekly, then every other week

Notes

1. With cyclophosphamide, adjust dose to induce mild neutropenia

2. If no response occurs, discontinue after 3–4 months. If a response occurs, continue until maximum platelet count is achieved, then taper slowly and discontinue

Indications

Patients with persistent thrombocytopenia despite prior therapy with glucocorticoids and a prior splenectomy

Efficacy

1. Each can induce complete remission in approximately 15–20% and partial remission in another 30–50% of patients after glucocorticoids and splenectomy have failed

2. Responses may occur slowly over few months. Therefore, treatment should continue up to 4 months before being considered a failure

Advance Events

Cyclophosphamide

Dose-related marrow suppression

Teratogenicity

Infertility

Alopecia

Hemorrhagic cystitis

A risk for development of AML

Azathioprine

Reversible leukopenia

Small risk of developing malignancy

Teratogenicity

Mycophenolate mofetil

Headache

Diarrhea

Constipation

Nausea, vomiting

Myelosuppression

Hypertension

Peripheral edema

Regimen: Cyclosporine

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

Choudhary DR et al. Haematologica 2008;93(online):e61–e62

McMillan R. Ann Intern Med 1997;126:307–314

Vesely SK et al. Ann Intern Med 2004;140:112–120

Cyclosporine 1.25–2.5 mg/kg per dose, orally every 12 hours, continually if a response occurs (total dosage/day = 2.5–5 mg/kg)

Note: Cyclosporine is marketed as capsules for oral administration and in a microemulsion formulation. The formulations are not bioequivalent and cannot be interchanged

Cyclosporine may be given in combination with:

Prednisone 0.5–2 mg/kg per day, orally for not more than 4–6 weeks (usually 2–4 weeks), after which, doses should be slowly tapered to the lowest effective dose, or tapered to discontinuation if an improvement in platelet count was not achieved

• The lowest effective dose may be continued for 4–6 weeks before attempting to slowly taper and discontinue steroids

Supportive Care

Not emetogenic

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Indications

Patients with persistent thrombocytopenia despite prior therapy with glucocorticoids and a prior splenectomy

Efficacy

Cyclosporine has been reported to induce rates of remissions comparable to azathioprine and cyclophosphamide with complete remission in 15–20% and partial remission in another 30–50% of patients

Responses occur slowly over few months. Treatment should continue up to 4 months before being considered a failure

Therapy Monitoring

Measure serum creatinine, LFTs and serum trough cyclosporine concentrations weekly for 1 month, then monthly or every 2 months^✫. Adjust cyclosporine dose as needed in increments or decrements of 0.5–0.75 mg/kg per day

Adverse Events

Regimen: Vinca Alkaloids

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003;120:574–596

George JN et al. Blood 1996;88:3–40

George JN et al. Semin Hematol 2000;37:290–298

Vesely SK et al. Ann Intern Med 2004;140:112–120

Vincristine 1–2 mg by intravenous injection over 1–3 minutes, once per week for 4–6 weeks (total dosage/week = 1–2 mg)

or

Vinblastine 5–10 mg by intravenous injection over 1–3 minutes, once per week for 4–6 weeks (total dosage/week = 5–10 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Prophylaxis for decreased bowel motility

Give a bowel regimen to prevent constipation based initially on stool softeners

Note: Institute prophylaxis from the beginning of treatment, particularly when vincristine is used

Adverse Events

Indications

Patients with persistent thrombocytopenia despite prior therapy with glucocorticoids and a prior splenectomy

Efficacy

1. Either vincristine or vinblastine may produce a transient increase in platelet count, usually lasting 1–3 weeks, in approximately 50% of patients with persistent thrombocytopenia after splenectomy

2. Sustained responses are observed in less than 10% of patients

3. Results are comparable with both drugs

Therapy Monitoring

1. Baseline and periodic neurologic examination: monitor for the onset and development of neurologic adverse effects

2. Weekly: CBC and leukocyte differential counts

3. Baseline serum LFTs and bilirubin, repeated at least every other week

Note

Vincristine should be discontinued after 4–6 weeks or after dose-related peripheral neuropathy occurs, whichever is earlier

Regimen: Rituximab

Arnold DM et al. Ann Intern Med 2007;146:25–33

[British Committee for Standards in Haematology General Haematology Task Force] Br J Haematol 2003; 120:574–596

Godeau B et al. Blood 2008;112:999–1004

Premedication: Primary prophylaxis with Acetaminophen 650–1000 mg, and diphenhydramine 50–100 mg orally 30 minutes to 1 hour before rituximab administration to mitigate infusion reactions

Rituximab 375 mg/m² intravenously in 0.9% sodium chloride injection or 5% dextrose injection, diluted to a concentration within the range of 1–4 mg/mL, once weekly for 4 weeks (total dosage/4-week course = 1500 mg/m²)

Infusion rate:

• Initially, at 50 mg/hour. If hypersensitivity or infusion reactions do not occur during the first 30 minutes, increase the rate by 50 mg/hour every 30 minutes as tolerated, to a maximum rate of 400 mg/hour

• Subsequently, if previous administration was well tolerated, start at 100 mg/hour, and increase by 100 mg/hour every 30 minutes as tolerated, to a maximum rate of 400 mg/hour

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

• Antibacterial—not indicated

• Antifungal—not indicated

• Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Adverse Events

Black Box Warnings (excerpts)

1. Severe infusion reactions, including urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactoid events

2. Patients with preexisting cardiac or pulmonary conditions and those who experienced prior cardiopulmonary adverse reactions may be at increased risk for an adverse outcome from severe infusion reactions

3. Severe, including fatal, mucocutaneous reactions, including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis, with onset from 1–13 weeks after receiving rituximab

4. JC virus infection resulting in progressive multifocal leukoencephalopathy may occur in rituximab treated patients with autoimmune diseases and may result in death; most cases diagnosed within 12 months after a last treatment with rituximab

Hepatitis B reactivation with fulminant hepatic failure and death have been reported among chronic carriers of HBV

Therapy Monitoring

Weekly CBC and leukocyte differential counts during treatment, and periodically thereafter

Note: Avoid primary or booster vaccination with live vaccines before and during rituximab treatment

Indications

Patients with persistent thrombocytopenia despite prior therapy with glucocorticoids and a prior splenectomy

Notes

Optimal dose and schedule of rituximab in treatment of ITP is not determined

Efficacy

1. A systematic review of 19 reports of rituximab in ITP, including 313 patients, nearly all of whom had previously received glucocorticoids, and half had also undergone splenectomy, reported 62.5% overall response rate (platelet count >50,000/mm³). None of the included trials were controlled

2. In a recent prospective phase II trial of 60 patients with chronic ITP and platelet count <30,000/mm³, who were candidates of splenectomy, 4 weekly treatments of rituximab were able to safely defer splenectomy among 24 (40%) patients for 2 years

Regimen: Thrombopoietin Receptor Agonists Romiplostim and Eltrombopag Olamine

Bussel JB et al. N Engl J Med 2006;355:1672–1681

Bussel JB et al. N Engl J Med 2007;357:2237–2247

Kuter DJ et al. Lancet 2008;371:395–403

PROMACTA (eltrombopag) tablets, for oral use, product labeling dated 12/2011. GlaxoSmithKline, Research Triangle Park, NC

Nplate (romiplostim) for subcutaneous injection, product labeling dated 12/2011. Amgen Inc., Thousand Oaks, CA

Romiplostim dosing guidelines:

• Target a platelet count ≥50,000/mm³ (a different platelet count target may be chosen for individual patients)

• Start 1 mcg/kg (actual body weight) once weekly as a subcutaneous injection, and check platelet count weekly

  • If platelet count <10,000/mm³, give 2 mcg/kg every week

  • If platelet count 11,000–50,000/mm³, give 2 mcg/kg every 2 weeks

• Once platelet count is in the desired target range (50,000–200,000/mm³ in clinical trials)

  • Continue same dose weekly

  • Increase dosage by 1 mcg/kg every week to a maximum dosage of 10 mcg/kg per wk if platelet count drops to <10,000/mm³

  • Increase by an additional 1 mcg/kg to a maximum dosage of 10 mcg/kg per wk after 2 consecutive weeks of platelet counts from 11,000–50,000/mm³

  • Decrease by 1 mcg/kg after 2 consecutive weeks of platelet counts between 201,000–400,000/mm³

  • Withhold if platelet count is >400,000/mm³. Resume treatment after platelet count is <200,000/mm³, and reduce subsequent doses by 1 mcg/kg

• DO NOT exceed the maximum weekly dose of 10 mcg/kg

 Discontinue romiplostim if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the maximum dosage of 10 mcg/kg per day

Do not shake romiplostim vials during reconstitution

Eltrombopag olamine dosing guidelines:

• Use the lowest dose of eltrombopag needed to achieve and maintain a platelet count ≥50,000/mm³ as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response

• Do not use eltrombopag in an attempt to normalize platelet counts

• In clinical studies, platelet counts generally increased within 1–2 weeks after starting eltrombopag and decreased within 1–2 weeks after discontinuing eltrombopag

Treatment Modifications

Adverse Events

Romiplostim

• Commonly (mild to moderate): Headache, dizziness, fatigue, insomnia, arthralgia, myalgia, pain in extremity, back pain, abdominal pain, nausea, diarrhea

• Progression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in clinical trials with romiplostim. Romiplostim is not indicated for the treatment of thrombocytopenia caused by myelodysplastic syndromes or any cause of thrombocytopenia other than chronic ITP

• Romiplostim should be used with caution in patients with ITP and chronic liver disease

Eltrombopag olamine

• Commonly (mild to moderate): Nausea, vomiting, myalgia, paresthesia

• Eltrombopag has also been reported to cause hepatotoxicity and development or worsening of cataracts

Black Box Warnings for Eltrombopag Olamine

Eltrombopag may cause hepatotoxicity

1. Measure serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to initiating eltrombopag olamine, every 2 weeks during the dose adjustment phase, and monthly after a stable dose is established. If bilirubin is increased, perform fractionation

2. Evaluate abnormal serum LFTs with repeated testing within 3–5 days. If the abnormalities are confirmed, monitor serum LFTs weekly until abnormalities resolve, stabilize, or return to baseline levels

3. Discontinue eltrombopag olamine if serum ALT concentrations increase to ≥3× the upper limit of normal range and are:

   • Progressive, or

   • Persistent for ≥4 weeks, or

   • Accompanied by increased direct bilirubin, or

   • Accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation

4. Reinitiating treatment with eltrombopag olamine is not recommended. If the potential benefit for reinitiating treatment is considered to outweigh the risk for hepatotoxicity, then cautiously reintroduce eltrombopag and measure serum liver tests weekly during the dose adjustment phase. If liver tests abnormalities persist, worsen, or recur, then permanently discontinue eltrombopag

Serious adverse events for both agents

1. Bone marrow reticulin deposition: Detection of peripheral smear abnormalities necessitates a bone marrow examination. If increased reticulin deposition is observed, discontinue treatment

2. Worsening thrombocytopenia after discontinuation of treatment (not caused by anti-TPO antibodies)

Although both romiplostim and eltrombopag olamine may increase the platelet count to levels greater than normal, no increased incidence of thromboembolic events has been reported in clinical trials

Both romiplostim and eltrombopag olamine have been subject to requirements of Risk Evaluation and Mitigations Strategy (REMS) programs. Prescribers are advised to consult the U.S. Food and Drug Administration Approved Risk Evaluation and Mitigation Strategies website at www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm or product manufacturers' websites for information about current REMS requirements

Efficacy

Both agents have been effective in randomized controlled clinical trials for increasing platelet counts in patients both before and after splenectomy. Both agents have been shown to increase platelet counts in patients in whom multiple previous therapies had failed

Therapy Monitoring

Romiplostim

• Obtain weekly CBCs and platelet counts during dose adjustment phases, monthly thereafter while patients are receiving romiplostim, and weekly for at least 2 weeks after discontinuing romiplostim. Consider alternative treatments for worsening thrombocytopenia

  Note: Hyporesponsiveness or failure to maintain a platelet response with romiplostim should prompt a search for causative factors, including neutralizing antibodies to romiplostim

  Product labeling provides information about submitting blood samples to Amgen, Inc., for analysis of antibody formation to romiplostim and thrombopoietin (TPO)

Eltrombopag olamine

• Baseline ocular examination, and periodically thereafter, particularly if visual change are noted during ongoing treatment

• Serum AST, ALT, and bilirubin prior to initiating eltrombopag olamine, every 2 weeks during the dose adjustment phase, and monthly after a stable dose is established (see Adverse Effects section for eltrombopag olamine [above])

• Weekly CBCs with differential leukocyte counts during dose adjustment phases until a stable platelet count has been achieved then monthly thereafter, and weekly for at least 4 weeks after discontinuing eltrombopag olamine

Notes

Both of these recently approved agents act by increasing production, mediated by stimulation of the thrombopoietin receptor

Romiplostim is a novel thrombopoiesis-stimulating protein, with no sequence homology with endogenous thrombopoietin (TPO). It consists of 2 identical single-chain subunits, each consisting of human IgG₁-kappa Fc domain, covalently linked to a TPO receptor-binding peptide (a “peptibody”)

Eltrombopag is a nonpeptide, small molecule, thrombopoietin receptor agonist

In clinical trials, development of anti-TPO antibodies with neutralizing capability have not been reported with either agent