Chapter 60: Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is an acquired immunologic disease in which a patient's red blood cells are selectively destroyed or hemolyzed by autoantibodies (auto-Ab) produced by the patient's own immune system

Mack P, Freedman J. Transfus Med Rev 2000;14: 223–233

Etiology

Epidemiology

• Idiopathic AIHA is more common in women than men (2:1) with a peak incidence in the fourth and fifth decades of life. Idiopathic AIHA is not associated with any demonstrable underlying disease

• Secondary causes have been reported in 20–80% of case series

Classification

Warm antibody AIHA

1. Idiopathic or primary type (no recognized underlying disease is present)

2. Secondary type:

   1. Lymphoproliferative disorders (eg, CLL, HD, NHL, and others)

   2. Autoimmune disorders (eg, SLE, RA, ulcerative colitis, Sjögren syndrome)

   3. Infections (eg, EBV, hepatitis C infection)

   4. Tumors (Kaposi sarcoma, various carcinomas, teratoma, ovarian dermoid cyst), thymoma

   5. Immunodeficiency disorders (eg, AIDS, dys- or hypo-gammaglobulinemia)

   6. Posttransplantation (recipients of allogeneic BMT or peripheral blood stem cells; solid organs)

Cold antibody AIHA

1. Idiopathic or primary type (no recognized underlying disease is present)

2. Secondary type (cold agglutinin syndrome):

   1. Infection (eg, Mycoplasma pneumoniae, mononucleosis, CMV, VZV, HIV)

   2. Clinically evident lymphoproliferative disorders (eg, CLL, the lymphomas including Waldenström macroglobulinemia)

   3. Tumors (eg, squamous cell carcinoma of the lung, metastatic adenocarcinomas of the lung and adrenal gland; mixed parotid tumor)

Paroxysmal cold hemoglobinuria (PCH)

1. Idiopathic or primary type (no recognized underlying disease is present)

2. Secondary type

   1. Donath-Landsteiner hemolytic anemia, usually associated with an acute viral syndrome in children (eg, measles, mumps, EBV, CMV, VZV, adenovirus, influenza A, M. pneumoniae, Haemophilus influenzae)

   2. Late-onset or congenital syphilis

Mixed-type AIHA

1. Idiopathic or primary type (no recognized underlying disease is present)

2. Secondary type:

   1. Autoimmune disorders (eg, SLE, lymphoproliferative disorders)

Drug-induced IHA (DIIHA; classified by absence or presence of drug-dependent antibodies)

1. Drug-independent antibodies

   1. “True” autoantibody type: Only antibodies are detectable and does not require the presence of drug for detection (eg, cladribine, fludarabine, levodopa, methyldopa, procainamide)

   2. Antibodies that react like “true” autoantibodies in vitro but found in combination with drug-dependent antibodies (eg, some cephalosporins, streptomycin, teniposide, zomepirac)

2. Drug-dependent antibodies

   1. Antibodies that react with drug-treated (ie, drug-coated) RBCs: Also referred to as “penicillin type,” “drug-adsorption type,” or “hapten type” DIIHA. These agents bind covalently to the RBC membrane, are not easily washed off RBCs, and are inhibited by the in vitro addition of soluble drug (eg, penicillin [PCN] ± PCN derivatives; cephalosporins: cefotetan, cefuroxime, cefotaxime, cefoxitin, cefazolin)

   2. Antibodies that react with RBCs in the presence of soluble drug (when drug, antibody [patient serum] and RBCs are mixed): also referred to as “nonpenicillin type,” “immune complex type,” or “neoantigen type” DIIHA. These agents do not bind covalently to the RBC membrane, are easily washed off RBCs and can activate complement and lead to severe intravascular hemolysis (eg, carboplatin, ceftriaxone, ceftazidime, levofloxacin, cefoxitin, nonsteroidal antiinflammatory drugs, piperacillin-tazobactam, quinine, quinidine)

Laboratory Testing

CBC with differential (review of peripheral blood smear), reticulocyte count, comprehensive metabolic profile with direct bilirubin, lactate dehydrogenase (LDH), haptoglobin, direct/indirect Coombs testing

Additional goal-oriented work-up: infection (eg, mycoplasma, mononucleosis, HIV, syphilis, viral syndromes), plasma/urine Hgb, RBC eluate, serum and urine protein electrophoresis with immunofixation, bone marrow aspiration and biopsy (infiltrative disorder/clarification of cytopenias), Hgb electrophoresis, pregnancy test, autoimmune disease, antiphospholipid antibody syndrome malignancy, CD55/59 for paroxysmal nocturnal hemoglobinuria

Findings indicating hemolysis:

• Elevated: Reticulocyte count (typical cases), LDH, unconjugated bilirubin levels (total bilirubin rarely >5 mg/dL)

• Decreased: Hemoglobin, haptoglobin levels

1°, primary; 2°, secondary; Ab, antibody; APLS, Antiphospholipid syndrome; BM, bone marrow; PCH, paroxysmal cold hemoglobinuria; CNSHA, congenital non-spherocytic hemolytic anemia; PNH, paroxysmal nocturnal hemoglobinuria; RBC, red blood cell; MGUS, monoclonal gammopathy of undetermined significance

Berentsen S et al. Hematology 2007;12:361–370

Gehrs BC, Friedberg RC. Am J Hematol 2002;69:258–271

Gertz MA. Br J Haematol 2007;138:422–429

Jeng MR et al. In: Greer JP et al., eds. Wintrobe's Clinical Hematology. 11th ed. Philadelphia, PA: Lippincott; 2004:1223–1246

Neff AT. In: Greer JP et al., eds. Wintrobe's Clinical Hematology. 11th ed. Philadelphia, PA: Lippincott; 2004:1157–1182

Packman CH. Blood Rev 2008;22:17–31

Petz LD. Blood Rev 2008;22:1–15

Treatment Overview

Comment: The level of clinical evidence supporting the management of AIHA is derived from case reports, case series, and/or expert opinion. Randomized controlled trials of cytotoxic or immunosuppressive agents in AIHA have not been performed

Idiopathic and Secondary Warm Antibody AIHA

1. First-line

   1. Single-agent glucocorticoid therapy

   2. Disease-specific treatments for secondary etiologies^✫ ± glucocorticoids

   3. Discontinue implicated drug if drug-induced

2. Second-line

   1. Splenectomy in surgical candidates who fail to benefit from glucocorticoid therapy

   2. Options in patients not surgical candidates for splenectomy: low-dose glucocorticoids ± danazol; rituximab as a splenectomy sparing procedure

3. Third-line

   1. Immunosuppressive agents (cyclophosphamide and azathioprine)

   2. Danazol

   3. Cyclosporine

   4. Rituximab

   5. Alemtuzumab

   6. High-dose cyclophosphamide

   7. Immune globulin (human) intravenous

   8. Plasmapheresis

   9. Splenic irradiation (reported in CLL)

   10. Mycophenolate mofetil

Cold Antibody AIHA (Cold-Agglutinin Syndrome [CAS])

Idiopathic (Primary) Cold-Agglutinin Syndrome (CAS)

1. First-line:

   1. Avoidance of cold; wearing warm clothing

2. Second-line or later (approaches that have produced responses in small groups of patients with CAS):

   1. Glucocorticoids (generally less effective than in warm Ab AIHA)

   2. Cytotoxic drugs (eg, chlorambucil)

   3. Plasma exchange

   4. Splenectomy in IgM (not IgG) CAS

   5. Rituximab

   6. High-dose cyclophosphamide

   7. Plasmapheresis

Secondary Cold-Agglutinin Syndrome (CAS)

1. First-line:

   1. Treat the underlying cause where identifiable

   2. Provide supportive care (spontaneous remissions of secondary AIHA have been observed in patients with infectious mononucleosis and Mycoplasma pneumoniae infections)

   3. Keep patient warm if the cold reactive antibodies demonstrate a high thermal amplitude

2. Second-line or later:

   1. Glucocorticoids

   2. Rituximab

   3. Plasmapheresis

Paroxysmal Cold Hemoglobinuria (PCH)

1. First-line

   1. Symptomatic therapy; transfusion support as indicated for brisk hemolysis; avoidance of cold; wearing warm clothing

   2. Corticosteroids are often added, but efficacy is difficult to evaluate because of transient nature of the hemolysis

   3. Plasmapheresis if PCH is life-threatening

   4. Treatment of syphilis if present

Mixed-Type Antibody AIHA

1. First-line

   1. Single-agent glucocorticoid therapy

   2. Disease-specific treatments for secondary etiologies ± glucocorticoids

2. Second-line

   1. Splenectomy in surgical candidates who fail to benefit from glucocorticoid therapy

   2. High-dose cyclophosphamide

   3. Rituximab

Drug-Induced Immune Hemolytic Anemia

1. First-line:

   1. Discontinuation of the suspected or causative agent is indicated

   2. Supportive care (also, see section on Purine Analog-Induced AIHA)

2. Second-line:

   1. Glucocorticoids if hemolysis is severe

Notes: Transfusion of RBCs in patients with symptomatic life-threatening AIHA is potentially indicated at any point along the disease or treatment continuum. The early collaboration of the treating physician with their blood bank or transfusion service is strongly recommended

Regimen: Prednisone

American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001;44:1496–1503

Gehrs BC, Friedberg RC. Am J Hematol 2002;69:258–271

Hemolytic anemia resulting from warm-reacting antibodies. In: Lichtman MA et al. eds. Williams Manual of Hematology. 8th ed. New York, NY: McGraw Hill Medical; 2011:115–120

Murphy S, LoBuglio AF. Semin Hematol 1976;13:323–334

Petz LD. Curr Opin Hematol 2001;8:411–416

Petz LD, Garratty G. Blood transfusions in autoimmune hemolytic anemia. In: Petz LD, Garratty G, eds. Immune Hemolytic Anemias. 2nd ed. New York, NY: Churchill Livingstone; 2004:375–400

Petz LD, Garratty G. Management of autoimmune hemolytic anemias. In: Petz LD, Garratty G eds. Immune Hemolytic Anemias. 2nd ed. New York, NY: Churchill Livingstone; 2004:401–405

Rosse WF. Autoimmune hemolytic anemia. In: Handin RI, Lux SE, Stossel TP, eds. Blood: Principles and Practice in Hematology. Philadelphia, PA: JB Lippincott; 2005:1859–1885

Prednisone 1–1.5 mg/kg (≈40–60 mg) per day, or 0.5–0.75 mg/kg (≈20–30 mg) twice daily, orally, continually for a minimum of 3–4 weeks before assessing efficacy

Supportive care:

Add a proton pump inhibitor during prednisone therapy

Calcium 400–600 mg elemental Ca per day; administer orally, continually, plus

Vitamin D₃ 800 units (calciferol or cholecalciferol 20 mcg) per day or an activated form of vitamin D; administer orally, continually. Supplementation is recommended for patients beginning or receiving prednisone (or prednisone equivalent ≥5 mg/day) for ≥3 months (American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001). Monitor for hypercalcemia and hypercalciuria, especially if activated forms of vitamin D are used. Patients receiving prolonged glucocorticoid therapy should be assessed for hypogonadism, and if present, corrected if possible. Also see Chapter 44: Indications for Bisphosphonates in the Hematology Oncology Setting

Folic acid 1 mg/day; administer orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Titration of prednisone in responding patients:

Murphy S, LoBuglio AF. Semin Hematol 1976;13:323–334

• Once Hgb is ≥10 g/dL, taper prednisone by 10–15 mg/week to a dose of 20–30 mg/day. This can usually be accomplished in 4–6 weeks

• If Hgb persists ≥10 g/dL, follow with a gradual reduction in 5-mg decrements to a dose of 10 mg/day over a period of 3 months

• If Hgb persists ≥10 g/dL, withdraw all therapy by slowly decreasing the dose over another 3-month period

or

Rosse WF. Autoimmune hemolytic anemia. In: Handin RI, Lux SE, Stossel TP, eds. Blood: Principles and Practice in Hematology. Philadelphia, PA: JB Lippincott; 2005:1859–1885

• Once Hgb is ≥10 g/dL, taper prednisone rapidly at first by 20 mg/day (0.3 mg/kg/day) each week to a dose of 20 mg/day. This can usually be accomplished in 2–3 weeks. The dose is then maintained for approximately 1 month to see if remission continues, then

• If Hgb persists ≥10 g/dL, switch to an alternating-day regimen over 2 months. In the first month, reduce the dose to 20 mg/dose every second day alternating with 10 mg/dose every second day. In the second month, reduce the dose to 20 mg/dose every second day, then

• If Hgb persists ≥10 g/dL, reduce the dose to 10 mg/dose every second day over the next month, then

• If Hgb persists ≥10 g/dL, reduce the dose to 5 mg/dose every second day over the next month, then

• If Hgb persists ≥10 g/dL, withdraw all therapy over another few months

Notes:

If the DAT is (+), a dose of 10 mg/every second day is maintained so long as remission continues

If at any point during dose reduction exacerbation of hemolysis occurs, increase the dose to the previous level and maintain that level. If the dose exceeds 20 mg (0.3 mg/kg) every second day, consider other therapeutic options

Indications

Initial therapy in:

• Patients with warm-antibody AIHA with clinically important signs and symptoms of anemia if there are no contraindications for its use

• Patients with mixed AIHA

Second-line therapy in others

Efficacy

Expert Opinion

Consider splenectomy, or if the patient is not a candidate for splenectomy, other immunosuppressive therapy if:

1. Response is not achieved after 3 weeks of prednisone treatment

2. Contraindications to prednisone therapy exist

3. Patient experiences intolerable side-effects

4. Prednisone doses of ≥15 mg/day are required to maintain a Hgb ≥10 g/dL

Toxicity

Dose Modifications

Note: Administer prednisone 0.6 mg/kg per day to patients who are older than age 70 years, immobilized or osteoporotic patients, and in a setting of active infection or other mitigating conditions

Prednisone tapering schedule for patients with AIHA who have achieved remission (based on the experience of the authors in the following reference):

Rosse WF, Schrier SL. Treatment of autoimmune hemolytic anemia: warm agglutinins. In: Mentzer WC, Landaw SA, eds. 2012 UpToDate, Version 19.3: January 2012:1–15 (accessed 1.30.12)

1. After a Hgb of >10 g/dL is achieved, maintain the prednisone dose at 60 mg/day for 1 week, then

2. Rapidly taper the prednisone dose to 20 mg/day over a period of 2 weeks. Maintain this dose for 1 month, then

3. If remission persists, gradually reduce the dose on alternate days to 10 mg/day. Maintain this regimen for 1 month

4. If remission persists, omit the dose on alternate days while maintaining the dose at 20 mg every other day

5. If remission persists, reduce the dose to 10 mg/day on alternate days. Tapering of glucocorticoids should be continued as long as the hemoglobin and haptoglobin levels remain improved and stable, LDH levels stay low, and the absolute reticulocyte count remains <100,000/mm³

6. Glucocorticoids can be stopped when there is normalization of the hemoglobin, haptoglobin, LDH, and absolute reticulocyte count, although the Coombs test may remain positive. The patient should be monitored for recurrence for a number of months following cessation of treatment

Notes:

If, at any time during the above prednisone tapering schedule, the remission is not maintained, other measures (eg, cytotoxic therapy or splenectomy), must be instituted. The authors state that this approach is also warranted in patients with AIHA who do not respond to prednisone after 2–3 weeks of therapy

Splenectomy

ActHIB Haemophilus b conjugate vaccine (tetanus toxoid conjugate) for intramuscular injection; product label, November 2009. Sanofi Pasteur, Inc. Swiftwater, PA

Akpek G et al. Am J Hematol 1999;61:98–102

Bowdler AJ. Semin Hematol 1976;13:335–348

Coon WW. Arch Surg 1985;120:625–628

Hemolytic anemia resulting from warm-reacting antibodies. In: Lichtman MA et al., eds. Williams Manual of Hematology. 8th Ed. New York, NY: McGraw Hill Medical; 2011:115–120

Katkhouda N et al. Ann Surg 1998;228:568–578

Menactra (meningococcal [groups A, C, Y, and W-135]) polysaccharide diphtheria toxoid conjugate vaccine for intramuscular injection; product label, March 2011. Sanofi Pasteur, Inc., Swiftwater, PA

Menomune-A/C/Y/W-135 (meningococcal polysaccharide vaccine, groups A, C, Y and W-135 combined) Suspension for subcutaneous injection; product label, January 2009. Sanofi Pasteur, Inc. Swiftwater, PA

Menveo (meningococcal [groups A, C, Y and W-1350] oligosaccharide diphtheria CRM₁₉₇ conjugate vaccine) solution for intramuscular injection; product label, March 2011. Novartis Vaccine and Diagnostics S.r.l., Bellaria-Rosia 53018, Sovicille (SI), Italy

Petz LD, Garratty G. Management of autoimmune hemolytic anemias. In: Petz LD, Garratty G, eds. Immune Hemolytic Anemias. 2nd ed. New York, NY: Churchill Livingstone; 2004:401–458

PNEUMOVAX 23 (pneumococcal vaccine polyvalent) sterile, liquid vaccine for intramuscular or subcutaneous injection; product label, Oct 2011. Merck & Co., Whitehouse Station, NJ,

Open or laparoscopic splenectomy depending on the surgeon's experience or patient requirements

Prior to splenectomy administer:

Pneumococcal vaccine: Pneumovax 0.5 mL; administer by intramuscular or subcutaneous injection in deltoid muscle or lateral mid-thigh

Haemophilus influenzae type b vaccine (Hib) 0.5 mL; administer by intramuscular injection only

Meningococcal vaccine:

   Menactra 0.5 mL; administer by intramuscular injection only in deltoid muscle, or

   Menomune 0.5 mL; administer by subcutaneous injection

Supportive care:

Folic acid 1 mg/day; administer orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Efficacy

Notes

1. Annual influenza vaccination is also recommended in asplenic patients

2. Patient education should include instruction as to early signs of potential OPSI and emphasis to seek early medical attention when present

3. For guidance on the prevention and treatment of OPSI and the use of vaccines in persons with altered immunocompetence see: BMJ 1996;312:430–434, Special Populations: patients with anatomical or functional asplenia. In: American College of Physicians Guide to Adult Immunization, 4th ed. American College of Physicians, 2011:87 (immunization.acponline.org accessed 2.12.12)

Indications

Recommended as second-line therapy in surgical candidates with AIHA who:

1. Do not benefit adequately from glucocorticoid therapy

2. Benefit initially from glucocorticoid therapy but suffer a relapse on taper

3. Require unacceptably high maintenance glucocorticoid doses (eg, >10–20 mg/day of prednisone) or have intractable side effects to glucocorticoid therapy

Note: Although considered ineffective in cold-agglutinin syndrome (CAS), a few cases of atypical CAS with hemolysins reactive at 37°C (98.6°F) and responsive to splenectomy have been reported (Petz LD, Garratty G. Management of autoimmune hemolytic anemias. 2004)

Toxicity (Complications)

1. Overwhelming postsplenectomy infection (OPSI):

   1. Incidence: Children <15 years (0.13–8.1%) vs. adults (0.28–1.9%), but may occur at any age

   2. Risk factors: Young age, history of hematologic disorders

   3. Timing: Most infections occur within 2 years after splenectomy; 42% reported within 5 years

   4. Mortality: 50–70% in older studies with >50% of deaths within the first 48 hours after hospitalization

2. Thrombocytosis

3. Deep venous thrombosis (reported to be increased in myeloproliferative disorders postsplenectomy)

4. Pseudohyperkalemia

Regimen: Rituximab

Bussone G et al. Am J Hematol 2009;84:153–157

D'Arena G et al. Am J Hematol 2006;81:598–602

D'Arena G et al. Eur J Haematol 2007;79:53–58

Gupta N et al. Leukemia 2002;16:2092–2095

Narat S et al. Haematologica 2005;90:1273–1274

Petz LD, Garratty G. Blood transfusions in autoimmune hemolytic anemia. In: Petz LD, Garratty G, eds. Immune Hemolytic Anemias. 2nd ed. New York, NY: Churchill Livingstone; 2004:375–400

Rituxan (rituximab) injection for intravenous use; product label, April 2011. Genentech Inc., South San Francisco, CA Wood AM. Am J Health Syst Pharm 2001;58:215–232

Premedication for rituximab:

Acetaminophen 650–1000 mg; administer orally, plus

Diphenhydramine 25–50 mg; administer orally or intravenously, 30–60 minutes before starting rituximab

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

Notes on rituximab administration:

• Infuse 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 administration at 100 mg/hour, and increase by 100 mg/hour every 30 minutes as tolerated, to a maximum rate of 400 mg/hour

• Interrupt rituximab administration for fever, chills, edema, congestion of the head and neck mucosa, hypotension, and other serious adverse events. Resume rituximab administration at a 50% reduction in rate after adverse events abate. Treat with IV diphenhydramine + acetaminophen, oxygen with bronchodilators, sodium chloride injection intravenously, and/or epinephrine subcutaneously as appropriate for managing hypersensitivity reactions

Supportive care:

Folic acid 1 mg/day; administer orally to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Indications

Off-label use in the following adults with AIHA:

1. Patients with idiopathic or secondary AIHA with warm, cold, or mixed warm-cold hemolysins

2. Patients with persistent disease after immunosuppressive therapies

Alone (52%) or in combination (48%) with glucocorticoids, single or multiagent chemotherapy (lymphoproliferative disorders [LPD]), or IVIG

Efficacy (N = 71) and Toxicity

Regimen: Alemtuzumab

Campath (alemtuzumab) injection for intravenous use; product label, August 2009. Genzyme Corporation, Cambridge, MA

Karlsson C et al. Leukemia 2007;21:511–514

Laurenti L et al. Leukemia 2007;21:1819–1821

Willis F et al. Br J Haematol 2001;114:891–898

Premedication for alemtuzumab:

Acetaminophen 500–1000 mg; administer orally 30 minutes before each dose and each dose escalation, plus

Diphenhydramine 50 mg; administer intravenously, 30–60 minutes before starting alemtuzumab and during escalation, then change to oral administration after escalation

Alemtuzumab dose escalation schedule:

Alemtuzumab 3 mg/day; administer intravenously diluted in 100 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 2 hours, daily until infusion-related adverse effects are grade ≤2, then:

Alemtuzumab 10 mg/day; administer intravenously diluted in 100 mL 0.9% NS or D5W over 2 hours, daily until tolerated (eg, infusion-related toxicities grade ≤2), then:

Alemtuzumab 30 mg/dose; administer intravenously diluted in 100 mL 0.9% NS or D5W over 2 hours as a maintenance dose (see below)

Alemtuzumab maintenance schedule:

Alemtuzumab 30 mg/dose; administer intravenously in 100 mL 0.9% NS or D5W over 2 hours as maintenance dose on alternate days for 3 doses per week (eg, Monday, Wednesday, Friday) not to exceed 90 mg/week

Notes on alemtuzumab administration:

If alemtuzumab is withheld for ≥7 days during treatment, restart with the dose-escalation schedule (this can usually be accomplished in 3–7 days)

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 HIGH

 Antimicrobial primary prophylaxis is recommended:

• Antibacterial—P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)

• Antifungal—recommended

• Antiviral—anti-herpes antivirals (eg, acyclovir or equivalent)

• Continue antimicrobial prophylaxis for a minimum of 2 months after completing alemtuzumab or until the CD4+ count is ≥200 cells/mmn³, whichever occurs later

See Chapter 47 for more information

Folic acid 1 mg/day orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Indications

Off-label use has been reported in the following settings in adults with AIHA:

1. Patients with idiopathic or secondary AIHA with warm, cold, or mixed warm-cold hemolysins

2. Patients with persistent AIHA after immunosuppressive therapies

3. Alone or in combination with glucocorticoids (at lowest possible dose and tapered off when feasible)

Note: The FDA-approved indication for alemtuzumab is single-agent therapy for B-cell CLL

Efficacy (N = 12) and Toxicity

Toxicity

Notes

The treatment experience with alemtuzumab for AIHA is limited. Rare reports of treatment-related hemolysis have been reported with this agent: Galimberti S. J Immunother 2004;27:389–393; Wierda WG et al. Blood (Proc Am Soc Hematol) 2006;108:[abstract 2839a]

Therapy Monitoring

1. CBC with differential count weekly or more frequently if worsening neutropenia, anemia, and/or thrombocytopenia

2. Hold therapy for grade 3 or 4 infusion reactions (pyrexia, chills/rigors, nausea, hypotension, urticaria, dyspnea, rash, emesis, and bronchospasm

3. Discontinue alemtuzumab for any autoimmune thrombocytopenia or for worsening of baseline AIHA (if alemtuzumab is used for the treatment of AIHA)

4. Assess PCR for CMV at 6 weeks following initiation of alemtuzumab therapy

5. Irradiate blood products if they are required during therapy

6. Avoid live vaccine administration in patients who have recently received alemtuzumab

Regimen for Purine Analog-Induced Autoimmune Hemolytic Anemia

Dearden C et al. Blood 2008;111:1820–1826

Johnson S et al. Lancet 1996;347:1432–1438

Leporrier M et al. Blood 2001;98:2319–2325

Robak T, Kasznicki M. Leukemia 2002;16:1015–1027

Steurer M et al. Cancer Treat Rev 2006;32:377–389

Epidemiology

Notes

1. For patients treated with FC, the percent of DAT (+) patients decreased after treatment and increased with F monotherapy

2. Multivariate analysis showed that a pretreatment (+) DAT was associated with more advanced stage and ↑ β₂-microglobulin

3. The DAT result had an independent association with the development of AIHA: Risk of AIHA in a patient with a (+) DAT was 1:3; >90% of patients with a (−) DAT did not develop AIHA

4. Patients receiving chlorambucil or F alone were 3-fold more likely to develop AIHA than FC-treated patients

5. AIHA development was associated with older age, advanced stage, (+) DAT, and treatment modality

Purine Analog Rechallenge

In patients with purine analog-induced AIHA, there is published experience suggesting an increased risk of recurrent AIHA with purine analog rechallenge. A selection of this experience is outlined below:

1. Seven of 8 CLL patients with prior fludarabine-induced AIHA subsequently rechallenged with fludarabine developed recurrent AIHA of whom 3 died (Weiss RB et al. J Clin Oncol 1998;16:1885–1889)

2. Among 12 cases of fludarabine-induced AIHA observed among 52 patients with CLL, 6/8 patients rechallenged with fludarabine developed recurrent AIHA of whom 2 died (1 from hemolysis) (Myint H et al. Br J Haematol 1995;91:341–344)

3. Four (10%) relapsed CLL patients who were treated previously with cladribine developed a first-episode AIHA event after retreatment with cladribine (1 with cladribine alone, 2 with cladribine + prednisone, and 1 with cladribine + cyclophosphamide + mitoxantrone; “CMC” regimen) (Robak T et al. Eur J Haematol 2002;69:27–36)

Treatment

No prospective, randomized, controlled trials have been reported assessing the treatment of purine analog-induced AIHA in patients with CLL or other lymphoproliferative disorders. A recommended approach for the management and treatment of purine analog-induced AIHA, in lieu of more definitive evidenced-based guidance, is outlined below:

1. Discontinue purine analog treatment at the diagnosis of AIHA

2. Initiate corticosteroid therapy (see the section on prednisone for the treatment of AIHA)

3. If the AIHA is poorly responsive to initial corticosteroid therapy:

   1. Consider the use of an agent with a lower risk of associated myelosuppression (eg, cyclosporine or azathioprine; see pertinent sections in this chapter), or

   2. Consider alternative chemotherapy for the underlying lymphoproliferative disorder (eg, R-CVP or R-CHOP for CD20+ B-CLL based on Expert Opinion), or

   3. Consider the use of single-agent rituximab (see the section on rituximab for the treatment of AIHA and the “RCD” regimen for B-CLL)

   4. If the above measures fail to achieve remission of the AIHA or if the patient is intolerant to or declines the above measures, splenectomy should be considered

4. Among patients with a history of purine analog-induced AIHA, close monitoring is recommended with any subsequent treatment

Notes

Recurrent AIHA has been observed in a patient with CLL previously treated with fludarabine who, upon progression of disease, received chlorambucil 10 mg/day and developed rapid-onset hemolytic anemia (day 9). Despite the use of steroid therapy, the patient's Hgb fell further and the patient died (Orchard J et al. Br J Haematol 1998;102:1107–1113)

Regimen for Refractory Autoimmune Hemolytic Anemia: High-Dose Cyclophosphamide

Brodsky RA et al. Ann Intern Med 2001;135:477–483

Moyo VM et al. Blood 2002;100:704–706

High-dose cyclophosphamide 50 mg/kg (ideal body weight) per day; administer intravenously in 100–1000 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 60 minutes, for 4 consecutive days, days 1–4 (total dosage/4-day course = 200 mg/kg ideal body weight)

Mesna 10 mg/kg per dose; administer intravenously, diluted within the range of 1–20 mg mesna/mL in 0.9% NS or D5W over 15 minutes starting at the same time as cyclophosphamide with repeated doses at 3, 6, and 8 hours after cyclophosphamide administration begun, for 4 doses/day on 4 consecutive days, days 1–4 (total dosage/day = 40 mg/kg; total dosage/4-day course = 160 mg/kg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days 1–4 is HIGH. Potential for delayed symptoms

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL, by subcutaneous injection for 1 dose

• Begin use on day 10 (6 days after completing cyclophosphamide)

• Continue filgrastim beyond the ANC nadir until ANC recovers to ≥1000/mm³

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

• Antibacterial—consider fluoroquinolone prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)

• Antifungal—recommended

• Antiviral—antiherpes antivirals (eg, acyclovir)

See Chapter 47 for more information

Folic acid 1 mg/day, orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Dose Modifications

No dose modification. Treatment criteria: (a) age ≤70 years, (b) cardiac ejection fraction >40%, (c) serum creatinine <2.5 mg/dL (<221 μmol/L), and (d) FVC/FEV/CO diffusion capacity at least 50% of predicted

Indications

High-dose cyclophosphamide with mesna and filgrastim support has been reported in a limited number of patients with severe refractory AIHA, defined as a need for transfusions and steroids >10 mg (prednisone)/day despite 2 therapies for idiopathic AIHA and at least 1 treatment for secondary AIHA

Clinical features of the enrolled patients included:

Severe refractory AIHA (6, idiopathic; 3, secondary): warm Ab AIHA (N = 7), CAD (N = 1), mixed AIHA (N = 1). Median pretreatment Hgb: 6.7 g/dL (range: 5–10 g/dL). Median number of prior regimens = 3

Efficacy (N = 9)

Toxicity (N = 9)

Notes

Benefits of therapy versus risks should be assessed

Use only by clinicians and medical centers with active experience in the use of “transplant doses” of cyclophosphamide and with the availability of appropriate ancillary clinical support and personnel

Red Blood Cell Transfusion

Branch DR, Petz LD. Transfusion 1999;39:6–10

Buetens OW, Ness PM. Curr Opin Hematol 2003;10:429–433

Petz LD. Blood transfusion in acquired hemolytic anemia. In: Petz LD, Swisher SN, Kleinman S, Spence RK, Strauss RG, eds. Clinical Practice of Transfusion Medicine. 3rd ed. New York, NY: Churchill Livingstone;1996:469–499

Petz LD. Hematology 2002 (American Society of Hematology Educational Program) 449–454

Petz LD. Transfusion 2003;43:1503–1507

Petz LD, Garratty G. Blood transfusions in autoimmune hemolytic anemia. In: Petz LD, Garratty G, eds. Immune Hemolytic Anemias. 2nd ed. New York, NY: Churchill Livingstone; 2004:375–400

Rosenfield RE, Jagathambal. Semin Hematol 1976;13:311–321

RBC infusion: Volume and rate considerations:

Volume: The optimal volume of RBCs to be infused depends on the clinical setting. In general, the aim is to supply just enough RBCs to treat or prevent hypoxemia while avoiding overtransfusion

Rate: Administer RBCs slowly with a total volume not to exceed 1 mL/kg per hour

Monitoring considerations:

Hgb/Hct: In the setting of acute, life-threatening AIHA, the Hgb/Hct should be monitored at 2-hour intervals; at least every 12–24 hours in individuals less acutely ill

Volume status: During and following transfusion, assessments should be performed for the presence of congestive heart failure (CHF) or volume overload. Particular caution is advised for the development of fluid overload in the elderly and in patients with reduced cardiac reserve. Diuretic therapy should be used as clinically indicated

Other considerations:

Cold agglutinin syndrome: The patient should be dressed warmly and be in a warm environment

Indications

Recommended in patients who are acutely ill with signs and symptoms compatible with acute hemolysis or in patients with progressive anemia where severe levels of hemolysis (eg, Hgb <5–6 g/dL) may probably be reached

General guidelines based on Hgb values and the probability of significant physiologic impairment:

Petz LD. Blood transfusion in acquired hemolytic anemia. In: Petz LD, Swisher SN, Kleinman S, Spence RK, Strauss RG, eds. Clinical Practice of Transfusion Medicine. 3rd ed. New York, NY: Churchill Livingstone; 1996:469–499

Note: The decision to transfuse should ultimately be guided by clinical assessments performed in individual patients

Efficacy

Not available. Goal of therapy is to stabilize red cell mass and reverse symptoms of acute anemia

Toxicity

Potential complications relevant to patients with AIHA may include:

1. Volume overload and congestive heart failure with attempts to raise the hematocrit too quickly

2. Acute hemolytic transfusion reactions

3. Development of alloimmunization

4. Posttransfusion hemoglobinemia or hemoglobinuria, particularly with large volumes of RBCs with ongoing auto-Ab production

5. Diffuse intravascular coagulation (DIC)

6. Thromboembolism

7. Death

Blood Product Selection

Note: Hemoglobin-based oxygen carriers (RBC Substitutes) have not received FDA approval for any indication

Warm Ab AIHA:

1. Most severe hemolytic transfusion reactions are caused by anti-A or anti-B antibodies. While a broadly reactive auto-Ab will make all units incompatible, with standard blood-banking techniques the ABO type can usually be identified permitting identical or compatible ABO type blood for transfusion

2. The blood bank should assess for alloantibodies (allo-Abs) that may be present from prior transfusion during the previous 3 months or pregnancy that may be masked by the presence of an auto-Ab. Allo-Abs have been reported to be present in 12–40% of patients with warm Ab AIHA. Allo-Abs have been reported in 209/647 (32%) of sera from patients with AIHA. Failure to identify the presence of allo-Abs may lead to worsening of the hemolysis, falsely increasing the perceived severity of AIHA following transfusion. The more common allo-Ab target antigens may include: C, E, c, e, K, Fy^✫, Fy^†, Jk^✫, Jk^†, S, and s

Cold agglutinin syndrome:

1. Compatibility testing should be done at 37°C (98.6°F). If testing cannot be performed strictly at this temperature, then it is recommended that 1 or 2 autoadsorptions be performed. Although high-titer cold agglutinins will not be completely removed with this maneuver, reactions that occur at 37°C (98.6°F) are likely to be eliminated

2. The specificity of cold agglutinins is often anti-I. Providing I antigen-negative blood may not be practical because of its rarity and may not be beneficial

3. There is controversy among experts as to the worth of blood warming in this setting. In patients with severe CAS or PCH, blood warming has been advocated. When an inline blood warmer is used, the temperature should be carefully regulated at body temperature to avoid RBC injury that can result in lethal in vivo hemolysis. Guidelines for the use of blood-warming devices have been published by the American Association of Blood Banks (AuBuchon, JP. Guidelines for the Use of Blood Warming Devices. Bethesda, MD: American Association of Blood Banks; 2001)

Paroxysmal cold hemoglobinuria:

1. The use of p or p^k RBCs (lacking the P antigen) is not practical because of its rarity and availability only from rare donor files. In this setting, transfusion of common P types should be provided

Notes

Initial communication between the clinician and the blood bank:

At the first indication that RBC transfusion may be required, the clinician should contact the blood bank or transfusion service. This communication should include:

1. An indication of the urgency for transfusion

2. An inquiry into the compatibility testing procedures used by the blood bank to assess the safety of the selected RBCs for transfusion, and

3. Clinical information that may help in assessing the risk of alloimmunization (eg, history of pregnancy, prior blood transfusion; particularly, during the past 3 months)

What the clinician should expect from the blood bank-transfusion service:

1. Notification of the diagnosis of AIHA made during compatibility testing for a requested transfusion

2. Information about the compatibility test procedures performed

3. RBCs selected for transfusion after excluding the presence of alloantibodies (eg, by adsorption techniques or by extended phenotype)

4. Assurances that the transfused cells are unlikely to cause an acute hemolytic transfusion reaction even though the RBCs cannot be expected to survive normally because of the autoantibody

Plasmapheresis

Silva VA et al. J Clin Apher 1994;9:120–123

von Baeyer H. Ther Apher Dial 2003;7:127–140

Protocol for plasmapheresis alone:

Plasma exchange (PEX) and albumin human (HA) for IgM (IgA) Ab-mediated hemolysis and for IgG 1,2,4-mediated hemolysis

Daily PEX/HA at 1–1.5 times the plasma volume until hemolysis is controlled and transfusions are no longer required

Indications

von Baeyer H. Ther Apher Dial 2003;7:127–140

Therapeutic plasmapheresis in AIHA has been advocated under 2 conditions:

1. As an emergency bridging measure to eliminate auto-Abs until immunosuppressive therapy becomes effective

2. As therapy after failure of immunosuppressive therapy and splenectomy in an attempt to treat relapsing hemolysis

Efficacy (N = 20)

Notes

The American Association of Blood Banks and the American Society of Apheresis have assigned a Category III indication to plasmapheresis for AIHA, citing there is “insufficient data to determine the effectiveness of apheresis in which the results of clinical trials may be conflicting or in some circumstances where efficacy has been based on uncontrolled anecdotal reports.” (Smith JW et al. Transfusion 2003;43:820–822)

Toxicity

Potential side effects to plasmapheresis include:

1. Complications associated with central venous catheter

2. Type I allergic hypersensitivity reactions

Regimen for Refractory Warm Antibody Autoimmune Hemolytic Anemia: Immunosuppressive Therapy Azathioprine or Cyclophosphamide

American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001;44:1496–1503

Corley CC Jr et al. Am J Med 1966;41:404–412

Habibi B et al. Am J Med 1974;56:61–69

Hitzig WH, Massimo L. Blood 1966;28:840–850

Murphy S, LoBuglio AF. Semin Hematol 1976;13:323–334

Petz LD. Curr Opin Hematol 2001;8:411–416

Petz LD, Garratty G. Management of autoimmune hemolytic anemias. In: Petz LD, Garratty G, eds. Immune Hemolytic Anemias. 2nd ed. New York, NY: Churchill Livingstone; 2004:401–458

Rosse W et al. Challenges in managing autoimmune diseases. In: American Society of Hematology Educational Program 1997;92–94

Worrledge S. Immune hemolytic anemias. In: Hardesty RM, Weatherall DJ, eds. Blood and Its Disorders. Oxford, UK: Blackwell Scientific; 1982:479–513

Azathioprine 2 mg/kg per day; administer orally, continually (total dosage/week = 14 mg/kg), or

Azathioprine 75–200 mg/day; administer orally, continually (total dose/week = 525–1400 mg)

Note: Adjust therapy to maintain “slight thrombocytopenia or leukopenia.” See Dose Modifications below

or

Azathioprine 80 mg/m² per day; administer orally, continually (total dosage/week = 560 mg/m²), plus

Prednisone 60 mg/day; administer orally, continually (total dose/week = 420 mg)

or

Cyclophosphamide 60 mg/m² per day; administer orally, continually (total dosage/week = 420 mg/m²), plus

Prednisone 60 mg/day; administer orally, continually (total dose/week = 420 mg)

Guidelines for tapering prednisone:

30 mg/day for 1 week; 20 mg/day for 1 week; 15 mg/day for 4 weeks; 10 mg/day for 4 weeks; 5 mg/day for 4 weeks; 5 mg every other day for 4 weeks; discontinue

Guidelines for tapering azathioprine, after 6 months of therapy:

60 mg/m² per day for 4 weeks; 35 mg/m² per day for 4 weeks; 15 mg/m² per day for 4 weeks; 25 mg every other day for 4 weeks; 25 mg twice weekly; discontinue

Guidelines for tapering cyclophosphamide after 6 months of therapy:

45 mg/m² per day for 4 weeks; 30 mg/m² per day for 4 weeks; 15 mg/m² per day for 4 weeks; 25 mg every other day for 4 weeks; 25 mg twice weekly; discontinue

Supportive Care

Antiemetic prophylaxis

Emetogenic potential with cyclophosphamide is MODERATE

Prednisone and azathioprine are 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

Steroid-associated gastritis:

Add a proton pump inhibitor during prednisone use to prevent gastritis and duodenitis

Calcium and vitamin D supplementation in patients receiving long-term low- to medium-dose glucocorticoid therapy and who have normal levels of gonadal hormones (American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001;44:1496–1503). See Chapter 44, Indications for Bisphosphonates in the Hematology-Oncology Setting

Folic acid 1 mg/day; administer orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Indications

Consider immunosuppressive therapy in patients with warm Ab AIHA who:

• Do not benefit from glucocorticoids

• Require unacceptable maintenance doses of glucocorticoids

• Are poor surgical candidates for splenectomy

• Experience a relapse following splenectomy

Efficacy

Toxicity

Potential side effects include:

1. Myelosuppression

2. Anemia

3. Thrombocytopenia

4. Infection

5. Renal and hepatic function abnormalities

6. Nausea and vomiting

7. Alopecia

8. Sterility

9. Secondary malignancies

10. Urinary tract hemorrhagic (cyclophosphamide)

11. SIADH (cyclophosphamide)

Therapy Monitoring

CBC with differential: Weekly during the first month, and weekly for a month after any dose increase. Otherwise, every 2 weeks until counts stabilize, and then, monthly

Notes

1. The rapid withdrawal of immunosuppressive agents may lead to a rebound phenomenon of hyperimmune responsiveness

2. If glucocorticoids have produced an incomplete remission before the initiation of immunosuppressive therapy, they should be continued until signs of clinical improvement

Treatment Modifications

Adjust azathioprine and cyclophosphamide therapy to maintain a “slight degree of marrow suppression” manifested as mild thrombocytopenia or leukopenia

Although “slight degree of marrow suppression” was not further defined in these studies, consider using National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 toxicity as reasonable benchmarks; that is:

 WBC: 3000/mm³ to the lower limit of normal

 ANC: ≥1500/mm³ to <2000/mm³

 Platelets: ≥75,000/mm³ to the lower limit of normal

 Hemoglobin: 10 g/dL to the lower limit of normal

Regimen for Refractory Warm Antibody Autoimmune Hemolytic Anemia: Danazol

Ahn YS et al. Ann Intern Med 1985;102:298–301

DANAZOL capsules, USP, product label, revised April 2009, Barr Laboratories, Inc., Pomona, NY

Pignon J-M et al. Br J Haematol 1993;83:343–345

Danazol 200 mg/dose; administer orally 3–4 times/day, continually (total daily dose = 600–800 mg)

Notes:

Danazol is usually added initially to medications previously employed for AIHA (eg, prednisone), or is given concomitantly with prednisone 1 mg/kg per day

If a hematologic remission (HR) is attained, glucocorticoids are tapered to a minimal requirement or discontinued. If a HR is maintained for >1 months without prednisone, danazol is gradually tapered to 200–400 mg/day, and this dose is continued indefinitely as long as there is no clinically important toxicity and Hgb remains >10 g/dL

Supportive Care

Antiemetic prophylaxis

Emetogenic potential with danazol is MINIMAL

See Chapter 39 for antiemetic recommendations

Note: Emetic symptoms may occur in association with benign intracranial hypertension, a rare adverse event associated with danazol use

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

Steroid-associated gastritis:

Add a proton pump inhibitor during prednisone use to prevent gastritis and duodenitis

Calcium and vitamin D supplementation in patients receiving long-term low- to medium-dose glucocorticoid therapy and who have normal levels of gonadal hormones (American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001;44:1496–503). See Chapter 44, Indications for Bisphosphonates in the Hematology-Oncology Setting

Folic acid 1 mg/day; administer orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Contraindications: Undiagnosed abnormal genital bleeding, pregnancy, breast feeding, porphyria, “markedly impaired” hepatic, renal, or cardiac function

Indications

Patients with 1° (primary) or 2° (secondary) warm antibody AIHA:

1. In refractory disease despite prior therapy with glucocorticoids, splenectomy, and immunosuppressive therapy

2. Less frequently as initial therapy with prednisone

Efficacy

Toxicity (Potential)

1. Virilization with facial hair growth, hair loss, and menstrual irregularities

2. Nervousness

3. Cushingoid features; glucose intolerance in patients with diabetes mellitus

4. Muscle cramps and myalgia

5. Elevations of LFTs

6. Fluid retention

7. Thromboembolism

8. Allergic skin reactions

9. Benign intracranial hypertension

Therapy Monitoring

1. Monitoring of LFTs at baseline and at least monthly or earlier as clinically indicated

2. Assessment for virilization since some signs may not be reversible

Treatment Modifications

Regimen for Refractory Warm Antibody Autoimmune Hemolytic Anemia: Cyclosporine

Emilia G et al. Br J Haematol 1996;93:341–344

Hershko C et al. Br J Haematol 1990;76:436–437

Starting dosage:

Cyclosporine 2.5 mg/kg per dose; administer orally twice daily for 6 days (total dosage/day = 5 mg/kg) or

Cyclosporine 2–3 mg/kg per dose; administer orally twice daily for 6 days (total dosage/day = 4–6 mg/kg)

Maintenance dosage:

Cyclosporine 1.5 mg/kg per dose adjusted to maintain a serum cyclosporine concentration between 200–400 ng/mL

Alternate Schedule

Starting dosage:

Cyclosporine 1.25 mg/kg per dose; administer orally twice daily, continually (total dosage/week = 17.5 mg/kg)

Maintenance dosage:

If no response, increase cyclosporine by 0.25 mg/kg per dose (0.5 mg/kg·day) increments every 2 weeks to a maximum of 2 mg/kg per dose (4 mg/kg·day; maximum total dosage/week = 28 mg/kg)

Note: Dosages vary with indication and AIHA is not an approved indication. Dosages and schedules for autoimmune diseases often fall within a broad range of 0.5–4 mg/kg per dose, administered orally every 12 hours. Generally, treatment is initiated at a low dosage and is titrated to the least dose that achieves a desired therapeutic effect

After that effect or a maximal response is achieved, an attempt should be made to gradually decrease the dose with the goal of discontinuing therapy

Supportive Care

Antiemetic prophylaxis

NOT indicated

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

Folic acid 1 mg/day, orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

AHFS Drug Information 2004:3625–3639

Emilia G et al. Br J Haematol 1996;93:341–344

Hershko C et al. Br J Haematol 1990;76:436–437

Indications

Cyclosporine has been administered in limited numbers of patients with refractory AIHA alone or in the setting of Evans syndrome

Efficacy

Toxicity

Treatment Modifications

Therapy Monitoring

1. Baseline: Serum creatinine (similar results on 2 occasions), BUN, CBC with differential, magnesium, potassium, uric acid, liver function tests, lipoproteins

   Note: Serum lipoproteins are recommended because levels may increase modestly during therapy

2. First 3 months: Serum creatinine, BUN and other baseline lab measurements plus BP every 2 weeks; thereafter, stable patients monitored monthly

   Note: Measure serum creatinine with initiation of new NSAID therapy or if a concomitantly used NSAID is increased in dose

3. Cyclosporine levels: Weekly for 2–3 months and then once per month. Increase monitoring frequency when potentially interacting drugs are introduced and withdrawn

   Note: The type of cyclosporine assay used to monitor blood levels is important. Recommended trough levels for the cyclosporine parent compound depends on the type of assay used (HPLC vs. RIA vs. fluorescence polarization immunoassay) and vary by whole blood versus serum/plasma. Target levels are based on cyclosporine monitoring strategies in the transplant setting

   Note: Monitor drug–drug interactions that may alter renal function and either increase or decrease cyclosporine concentrations

Notes

Every 10 months (if ongoing use is required), discontinue cyclosporine for 2 weeks to evaluate for persistence of response

Cyclosporine levels correlating with AIHA response have not been systematically reported

Cyclosporine should only be used for therapeutic applications other than transplantation only by clinicians experienced in immunosuppressive therapy

Management of patients, during initiation or any change in, cyclosporine therapy should be performed in facilities equipped with adequate laboratory/supportive medical equipment and staffed with adequate medical personnel

Regimen for Refractory Warm Antibody Autoimmune Hemolytic Anemia: Immune Globulin Intravenous (Human) (IVIG)

Anderson D et al. Transfus Med Rev 2007;21 (No. 2, Suppl 1): S9–S56

Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep 1999;48:518–521

Flores G et al. Am J Hematol 1993;44:237–242

Go RS, Call TG. Mayo Clin Proc 2000;75:83–85

Ratko TA et al. JAMA 1995;273:1865–1870

Hydration prior to immune globulin intravenous (human) (IVIG):

Ensure patients are not dehydrated before IVIG administration. Dehydration is a risk factor for renal failure. Patients who are well hydrated do not need additional hydration

Note: Patients at an increased risk for developing acute renal failure include those with any degree of preexisting renal dysfunction, diabetes, volume depletion, sepsis, paraproteinemia, age >65 years, and those receiving concomitant nephrotoxic drugs. The risk for renal impairment and thrombotic events associated with IVIG also correlate with administration rate, IgG product sucrose content, and product osmolality. The best recommendation is not to exceed the administration recommendations published in product labeling

Immune globulin intravenous (human) 0.4–0.5 g/kg per day; administer intravenously (consult product labeling for appropriate administration rates), daily for 2–5 days

Note: For sucrose-containing products, do not exceed a maximum infusion rate of 3 mg sucrose/kg (patient's body weight) per minute

Supportive Care

Folic acid 1 mg/day; administer orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Indications

Ratko TA et al. JAMA 1995;273:1865–1870

A University Hospital Consortium Expert panel on IVIG and AIHA found that:

1. IVIG may have a role in patients with warm-type AIHA that does not respond to glucocorticoids

2. Evidence does not exist for the routine use of IVIG in AIHA

Efficacy

Treatment Modifications

Toxicity

Side effects with a frequency of 1–10%:

Infusion reactions^✫

Back or chest pain or tightness

Malaise and myalgia

Nausea and vomiting

Headache

Fever and chills

Renal damage^†

Side effects with a frequency of <1%:

Thrombosis (myocardial infarct, stroke, spinal cord ischemia)

Aseptic meningitis syndrome, with doses ≥2 g/kg

Therapy Monitoring

1. Prior to IVIG: BUN and serum creatinine

2. Daily during IVIG administration: BUN, serum creatinine, weight, and urine output monitoring

Notes

The National Advisory Committee on Blood and Blood Products of Canada and Canadian Blood Services convened a panel of experts on the use of intravenous immunoglobulin (IVIG) for the treatment of hematologic conditions as a basis for recommendations to Provincial Health Ministries (data reviewed from 1982–2004). The following recommendations were made relative to the use of IVIG for AIHA:

• IVIG is not recommended for routine use in either the acute or chronic treatment of AIHA

• IVIG may be considered among treatment options for severe life-threatening AIHA

(Anderson D et al. Transfus Med Rev 2007)

Regimen for Refractory Warm Antibody Autoimmune Hemolytic Anemia: Mycophenolate Mofetil (MMF)

CellCept (mycophenolate mofetil) product label, February 2010. Genentech USA, Inc., South San Francisco, CA

Howard J et al. Br J Haematol 2002;117:712–715

Zimmer-Molsberger B et al. Lancet 1997;350:1003–1004

Starting dose:

Mycophenolate mofetil 1000 mg/day; administer orally as a single dose, or 500 mg twice daily, continually, or

Mycophenolate mofetil 1000 mg/day; administer intravenously reconstituted and diluted with 5% dextrose injection (D5W) to a concentration of 6 mg/mL, over at least 2 hours daily, continually (total dose/week = 7000 mg)

Maintenance dose after 2 weeks:

Mycophenolate mofetil 1000 mg/dose; administer orally twice daily, continually

or

Mycophenolate mofetil 1000 mg/dose; administer intravenously reconstituted and diluted with D5W to a concentration of 6 mg/mL, over at least 2 hours twice daily, continually (total dose/week = 14,000 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL to MODERATE

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—Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)

• Antifungal—not indicated

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

See Chapter 47 for more information

Folic acid 1 mg/day, orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Efficacy (N = 6)

Toxicity

Treatment Modifications

Indications

MMF has been administered off-label to limited numbers of patients with 1° (primary) or 2° (secondary) AIHA treated with prior immunosuppressive regimens, including glucocorticoids ± splenectomy. Medications administered concomitantly with MMF have included prednisolone, cyclosporine, and IVIG

Therapy Monitoring

1. CBC with differential: Weekly during the first month, twice monthly during the second and third month, and then monthly, thereafter, for the first year

2. Periodic history and physical examination and performance of comprehensive metabolic profile as indicated

Notes

1. MMF use is recommended for clinicians who are experienced in renal, hepatic, or cardiac transplantation and in the management of immunosuppressive therapy

2. Patients receiving MMF should be instructed to report immediately any evidence of infection, gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), change in neurological status, shortness of breath, unexpected bruising, bleeding, or any other manifestation of bone marrow suppression

Regimen for (Idiopathic Cold-Agglutinin) Autoimmune Hemolytic Anemia: Cytotoxic Therapy Chlorambucil

Hippe E et al. Blood 1970;35:68–72

Leukeran (chlorambucil) tablets, product label, November 2006. GlaxoSmithKline, Research Triangle Park, NC

Petz LD. Blood Rev 2008;22:1–15

Petz LD, Garratty G. Blood transfusion in autoimmune hemolytic anemias. In: Petz LD, Garratty G, eds. Immune Hemolytic Anemias. 2nd ed. New York, NY: Churchill Livingstone; 2004:375–400

Chlorambucil 2–4 mg/day, orally, continually, as a starting dose (total dose/week = 14–28 mg)

Notes:

• Increase dose in 2-mg increments every 2 months until a favorable response or dose-limiting toxicity occurs

• With achievement of a favorable response, additional options include intermittent treatment as required or maintenance therapy

• Although doses as high as 8–20 mg/day may be reached, with continued therapy these may have to be reduced to doses as low as 2 mg/day

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

Folic acid 1 mg/day, orally, continually, to prevent depletion of folate stores and megaloblastic anemia resulting from chronic hemolysis

Toxicity

Potential side effects include:

1. Leukopenia

2. Thrombocytopenia

3. Infection

4. Oral ulcers

5. Hypersensitivity and fever

6. Hepatotoxicity

7. Infertility

8. Seizures

9. Gastrointestinal toxicity

10. Interstitial pneumonitis

11. Secondary malignancy

12. Fetal harm (contraception recommended)

Therapy Monitoring

CBC with differential: Twice per week during the first 3–6 weeks of therapy or after a dose adjustment then weekly until counts stabilize and then every 2 weeks

Notes

The intermittent use of chlorambucil has been reported to be beneficial in limited numbers of patients with seasonal precipitation of symptomatic idiopathic CAS where the occupational environment required cold weather exposure. These reports predated clinical experience with agents such as rituximab

Indications

Patients with idiopathic cold agglutinin syndrome producing symptomatic anemia, Raynaud phenomena or cold-intolerance (off-label use)

Efficacy (N = 15)

(Petz LD, Garratty G. Immune Hemolytic Anemias. 2nd ed. 2004)

Improvement with therapy: 67% (10/15)^✫

(Hippe E et al. Blood 1970)

Case series of 4 patients with idiopathic cold agglutinin syndrome:

Treatment Modifications