hematopoietic cells remaining
transfusions of red cells and platelets should be reserved for patients with hemoglobin levels and platelet counts of around 7 g/dL and 10,000/mm3, respectively. Performance of HSCT as rapidly as is feasible minimizes transfusions in patients undergoing histocompatible HSCT. To avoid sensitization to transplant antigens, there should be no transfusions from blood relatives and transfusions should be restricted, if possible, to single unrelated donors to decrease the likelihood of sensitization to donor antigens. In all patients blood products should be leukocyte depleted to reduce the risk of sensitiza-tion and CMV infection. CMV-negative blood products should be used when patients have negative serology for CMV and are potential candidates for HSCT.
Patients receiving chronic red cell transfusion should be followed for evidence of iron overload and chelated appropriately. The use of single donor platelets, when available, is recommended. In females, menses should be suppressed by the use of oral contraceptives. Drugs that impair platelet function, such as aspirin, should be avoided. Intramuscular injections should be given carefully, followed by ice pack application to injection sites.
3. The antifibrinolytic agent epsilon aminocaproic acid (Amicar) can be used to reduce mucosal bleeding in thrombocytopenic patients with good hepatic and renal function. Hematuria is a contraindication to its use. A dose of 100 mg/kg/dose every 6 hours is used. The maximum daily dose is 24 grams. Teeth should be brushed with a cloth or soft toothbrush.
4. Avoid infection. Keep patients out of the hospital as much as possible. Good dental care is important. Rectal temperatures should not be taken, and the rectal areas should be kept clean and free of fissures. If a patient is febrile:
b. Patients with fever and neutropenia should be treated with broad-spectrum antibiotic coverage (Chapter 26). The specific therapy depends on the clinical status of the patient, the presence of indwelling vascular access devices, and knowledge of the local flora pending specific culture results and antibiotic sensitivities. In patients who remain febrile 4-7 days in the face of broad antibacterial coverage, antifungal therapy with amphotericin B should be started empirically. Therapy should be continued until the patient is afebrile and cultures are negative or a specific organism is identified. An appropriate course of therapy is administered if an organism is identified. In the presence of perirectal infection, clindamycin or Flagyl should be added for anaerobic coverage.
5. Maintain hemoglobin level. Prior to any transfusion, perform complete blood group typing to minimize the risk of sensitization to minor blood group antigens and to permit identification of antibodies should they subsequently develop.
6. Patients who were previously treated with immunosuppressive therapy should receive irradiated cellular blood products to prevent complications of GVHD. Patients receiving immunosuppressive therapy should also receive Pneumocystis carinii prophylaxis with trimethoprim and sulfamethoxazole (Bactrim/Septra). No antibacterial prophylaxis should be administered to afebrile, neutropenic patients.
Patients with mild to moderate aplastic anemia should be observed for spontaneous improvement or complete resolution. The treatment of choice for SAA, for patients who have an HLA-matched related donor, is hematopoietic stem cell transplantation. An increasing number of centers are treating moderate aplastic anemia in a fashion similar to SAA.
As soon as the diagnosis of SAA is suspected in children, HLA typing should be performed where potential donors exist. Patients with related histocompatible donors (complete HLA match or a mismatch at a single HLA-A or -B locus) should have an HSCT as soon as possible (complete investigations to exclude FA, paroxysmal nocturnal hemoglobinuria (PNH), or other inherited bone marrow failure syndromes should be carried out) because the risk of transplant-related morbidity and mortality increases with increasing age, an increasing interval from diagnosis to transplant, multiple transfusions, and the occurrence of serious infections.
Because graft rejection is the major cause of morbidity and mortality in HSCT for SAA, the pretransplantation preparative regimen of cyclophosphamide (Cytoxan) and antithymocyte globulin, ATG (ATGAM/thymoglobulin) with the inclusion of cyclosporin A (CSA [Sandimmune]) in the GVHD prophylaxis regimen is designed to be highly immunosuppressive. Table 6-20 lists the HSCT preparative regime for SAA. Even when an identical twin donor is used, a similar preparatory regimen is recommended. Long-term survival in the range of 90% can be expected with HSCT using histocompatible related donors. The overall risk of unrelated or mismatched related donor transplantation precludes its use as a front-line therapy for SAA at this time. However, as improved HLA typing, preparative regimens, and
Table 6-20. Hematopoietic Stem Cell Transplantation Preparative Regimen for Severe Aplastic Anemia
Day -5 Morning: Cyclophosphamide, 50 mg/kg IV over 1 hour.
Afternoon: ATG, 30 mg/kg IV. First dose of ATG is given over 8 hours; subsequent doses are given over 4 hours.
This is repeated on Day -4 and Day -3.
Day -2 Morning: Cyclophosphamide, 50 mg/kg IV over 1 hour.
Day -1 Rest, cyclosporine A, 10 mg/kg/day PO daily adjusted for serum levels.
Day 0 Marrow infusion
Abbreviation: ATG = antithymocyte globulin.
From Vlachos A, Lipton JM. In: Conn's Current Therapy, WB Saunders Company, 2002, with permission.
GVHD prophylaxis are utilized, HSCT will become available to a wider group of patients with SAA.
Patients unable to undergo HSCT (because no suitable donor is present) should have immunosuppressive therapy based on ATG and CSA, which have become the treatment of choice for these patients. In addition to ATG and CSA corticosteroids, methylprednisolone (Solu-Medrol) or prednisolone (prednisone) is added to prevent serum sickness. GM-CSF (Leukine) or G-CSF (Neupogen) is used to achieve a more rapid increment in the granulocyte count. Short term, the survival using this approach is in the range of 85%.
The regimen of ATG, methylprednisolone, GM-CSF, and CSA treatment for severe aplastic anemia is listed in Table 6-21.
The following criteria are used for exclusion of treatment of patients with immunosuppressive drugs:
1. Serum creatinine, >2 mg%
2. Concurrent pregnancy
3. Sexually active females who refuse contraceptives
4. Patients with concurrent hepatic, renal, cardiac, or metabolic problems of such severity that death is likely to occur within 7-10 days or moribund patients.
Test dose. An intradermal ATG test dose should be carried out prior to ATG treatment. The skin test procedure consists of injection of 0.1 mL of a 1:1000 dilution of ATG in 0.9% sodium chloride solution for injection (5 |ig equine IgG). A control using 0.9% sodium chloride injection is administered on the contralateral side. Allergy is indicated by erythema greater than 5 mm compared to the saline control, developing
Table 6-21. Immunosuppressive Therapy for Severe Aplastic Anemia
1. Antithymocyte globulin: ATGAM antithymocyte globulin (equine) (Pharmacia)
20 mg/kg/day IV once daily, or thymoglobulin (antithymocyte globulin [rabbit], Sang stat) 2.0 mg/kg/day IV once daily days 1 to 8. Diphenhydramine (Benadryl) and Acetominophen (Tylenol) are given as premedication to ATG.
2. Methylprednisolone, 2 mg/kg/day IV days 1 to 8. Divide into 0.5 mg/kg/dose IV every 6 hours.
3. Prednisone taper following an 8-day course of IV methylprednisolone. On days 9 and 10, prednisone, 1.5 mg/kg/day PO to be divided into two equal daily doses. On days 11 and 12, prednisone, 1 mg/kg/day PO to be divided into two equal daily doses. On days 13 and 14, prednisone, 0.5 mg/kg/day PO to be divided into two equal daily doses. On day 15, prednisone, 0.25 mg/kg/day PO to be given in one dose.
4. G-CSF, 5 ^g/kg/day, or GM-CSF, 250 |ig/m2/day SC once daily before bedtime starting on day 5. G-CSF or GM-CSF is to be continued until an absolute neutrophil count of
> 1000/mm3 is reached. G-CSF or GM-CSF should then be tapered.
5. CSA, 10 mg/kg/day PO initially starting on day 1. Divide into two equal daily doses. Serum drug levels should be monitored as needed with the first level at 72 hours after initiation of therapy. CSA dose to be adjusted to keep serum trough levels between 100 and 300 ng/mL. CSA should be continued until patient is transfusion independent and GM-CSF has been discontinued; then decrease the dose by 2.0 mg/kg every 2 weeks.
Abbreviations: CSA, cyclosporine (formerly cyclosporin A); GM-CSF, granulocyte-macrophage colony-stimulating factor.
Modified from Vlachos A, Lipton JM. In: Conn's Current Therapy. Philadelphia: WB Saunders, 2002.
within the first hour of the skin test. The patient should also be observed for signs and symptoms of systemic allergic reaction. ATG doses are listed in Table 6-21.
• Thrombocytopenia: All patients should receive a daily platelet transfusion on a prophylactic basis to maintain a platelet count of more than 20,000/mm3 (during administration of ATG). Only irradiated and leukocyte-filtered cellular blood products should be used.
• Arthralgia, chills, and fever: Treatment with an antihistamine and a corticosteroid is indicated.
• Chemical phlebitis: A central line (high flow vein) for infusion of ATG should be used and peripheral veins should be avoided.
• Itching and erythema: Treatment with an antihistamine with or without cortico-steroids is indicated.
• Serum sickness: Many patients develop serum sickness approximately 7-10 days following ATG administration. This should be treated by increasing the daily dose of Solu-Medrol until the symptoms abate.
Uncommon adverse reactions to ATG. Dyspnea, chest/back/flank pain, diarrhea, nausea, vomiting, hypertension, herpes simplex infection, stomatitis, laryngospasm, ana-phylaxis, tachycardia, edema, localized infection, malaise, seizures, gastrointestinal bleeding/perforation, thrombophlebitis, lymphadenopathy, hepatosplenomegaly, renal function impairment, liver function abnormalities, myocarditis, and congestive heart failure.
CSA preparations include:
• Neoral oral solution, 100 mg/mL
• Neoral capsule or Sandimmune capsule, 25 mg and 100 mg/capsule.
Oral CSA solution may be mixed with milk, chocolate milk, or orange juice preferably at room temperature. It should be stirred well and drunk at once.
Cyclosporine levels should be performed once a week for the first 2 weeks and then once every 2 weeks for the remainder of the treatment or as necessary to maintain a whole-blood CSA level between 200 and 400 ng/mL. Changes in serum crea-tinine levels are the principal criteria for dose change. An increase in creatinine level of more than 30% above baseline warrants a reduction in the dose of CSA by 2 mg/kg/day each week until the creatinine level has returned to normal. A serum CSA level of less than 100 ng/mL is evidence of inadequate absorption, and a CSA level above 500 ng/mL is considered an excessive dose. If the CSA level is greater than 500 ng/mL, CSA should be discontinued. Levels should be repeated daily or every other day. When the level returns to 200 ng/mL or less, CSA should be resumed at a 20% reduced dose.
Principal side effects of CSA. Renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.
Uncommon side effects of CSA. Significant hyperkalemia, hyperuricemia, hypomag-nesemia, hepatotoxicity, lipemia, central nervous system toxicity, and gynecomastia. An increase of more than 100% in the bilirubin level or of liver enzymes is treated in the same way as an increase of more than 30% in creatinine and warrants a reduction in the dose of CSA by 2 mg/kg/day each week until the bilirubin and/or liver enzymes return to the normal range.
Contraindications to the use of CSA. Hypersensitivity to CSA.
Pharmacokinetic interactions with CSA.
1. Carbamazepine, phenobarbital, phenytoin, rifampin: Decreases half-life and blood levels of CSA.
2. Sulfamethazine/trimethoprim IV: Decreases serum levels of CSA.
3. Erythromycin, fluconazole, ketoconazole, nifedipine: Increases blood levels of CSA.
4. Imipenem-cilastatin: Increases blood levels of CSA and central nervous system toxicity.
5. Methylprednisolone (high dose), prednisolone: Increases plasma levels of CSA.
6. Metoclopramide (Reglan): Increases absorption and increases plasma levels of CSA.
Pharmacologic interactions with CSA.
1. Aminoglycosides, amphotericin B, nonsteroidal anti-inflammatory drugs, trimethoprim/sulfamethoxazole: Nephrotoxicity.
2. Melphalan, quinolones: Nephrotoxicity.
3. Methylprednisolone: Convulsions.
4. Azathioprine, corticosteroids, cyclophosphamide: Increases immunosuppression, infections, malignancy.
5. Verapamil: Increases immunosuppression.
6. Digoxin: Elevates digoxin level with toxicity.
7. Nondepolarizing muscle relaxants: Prolongs neuromuscular blockade. Hematopoietic growth factors
The addition of human recombinant G-CSF or GM-CSF to a regimen of ATG, cyclosporine, and corticosteroids provides improved protection from infectious complications by stimulating granulopoiesis. The regimen we recommend uses GM-CSF and G-CSF interchangeably.
Although the short-term outcome with immunosuppressive therapy is comparable to that obtained with HLA-matched related HSCT, the decision to choose HSCT for younger patients who have a histocompatible donor is based on the result of long-term follow-up. Although there is some late mortality, due to chronic GVHD and therapy-related cancer, in patients undergoing HSCT for SAA, the survival curves are relatively flat. Improved GVHD prophylaxis and safer preparative regimens should further improve these results. In contrast, the risk of clonal hematopoietic disorders such as MDS, AML, and PNH is unacceptably high relative to both the short- and long-term risks of HSCT. Those undergoing immunomodulation must be closely followed for the development of clonal disorders. In terms of unrelated or poorly matched related donor HSCT, current risks favor the use of immunomod-ulatory therapy in those patients with SAA who cannot receive a matched related HSCT.
For the patient who fails HSCT, has a partial response (ANC >500/mm3, but still is red cell and platelet transfusion dependent), or relapses following immunomodula-tory therapy, management choices include alternative donor HSCT or further immunosuppressive therapy. These choices are under evaluation.
Children and teenagers for whom a fully HLA-matched unrelated donor, determined by high-resolution typing, exists are good candidates for an alternative donor HSCT. A delay in transplantation, along with the associated risk of infection and additional transfusions attendant to a second course of immune therapy, seems unwarranted in this setting. For older patients and those without a good alternative donor, preliminary data suggest that high-dose cyclophosphamide may be more effective than a second course of ATG/CSA/G-CSF. Androgens and alternative cytokines are being evaluated and should be considered experimental.
Complete remission in severe aplastic anemia after high-dose cyclophosphamide therapy without bone marrow transplantation has been reported. The use of highdose cyclophosphamide is controversial due to considerable toxicity reported by some investigators. The rationale for the use of high-dose cyclophosphamide is as follows:
1. The majority of patients with severe aplastic anemia lack an HLA-identical sibling for treatment with bone marrow transplantation.
2. Although the majority (80%) of children with severe aplastic anemia benefit from the use of treatment with ATG and cyclosporine, many do not attain completely normal counts and some patients treated successfully with immuno-suppressive therapy either relapse or develop late clonal diseases such as paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome, or acute leukemia.
3. After preparation with cyclophosphamide, most allografts persist indefinitely; however, in several cases, a complete autologous reconstitution of hematopoiesis has occurred.
4. Patients with very severe aplastic anemia (i.e., severe aplastic anemia patients with an absolute neutrophil count of less than 200/mm3 at diagnosis) respond to immunosuppressive therapy, but have greater morbidity and mortality due to the profound neutropenia.
On this basis, patients with severe aplastic anemia who lack an HLA-identical sibling donor have been treated by some clinicians on high-dose cyclophosphamide as a single course. Table 6-22 lists the high-dose cyclophosphamide therapy regimen for severe aplastic anemia.
Long-Term Sequelae and Outcomes for Severe Aplastic Anemia
Table 6-23 lists the long-term sequelae following treatment of aplastic anemia. Outcomes for both immunosuppressive therapy and HSCT have improved considerably.
1. Survival rates of greater than 80% have been realized with both immunosup-pressive therapy or stem cell transplantation. Stem cell transplantation is curative for most patients.
Table 6-22. High-Dose Cyclophosphamide Therapy for Severe Aplastic Anemia
1. Cyclophosphamide,a 45 mg/kg/day IV x 4 days
2. Mesna (Mesnex),a 360 mg/m2/dose IV with cyclophosphamide, as a 3-hourly infusion after cyclophosphamide, and as bolus at hours 6, 9, and 12 hours following cyclophosphamide
3. GM-CSF, 250 |ig/M2/day SC starting 24 hours after fourth dose of cyclophosphamide and to continue until absolute neutrophil count >1000/mm3
Abbreviation: GM-CSF, granulocyte-macrophage colony-stimulating factor. aNot FDA approved for this indication.
From Vlachos A, Lipton JM. In: Conn's Current Therapy. Philadelphia: WB Saunders, 2002, with permission.
Table 6-23. Long-Term Sequelae Following Treatment of Aplastic Anemia"
Type of therapy and incidence of complications
Immunosuppressive Bone marrow Sequelae therapy (%) transplantation (%)
10-Year cumulative cancer incidence 18.8 3.1
10-Year cumulative myelodysplastic syndrome 9.6 0.0
10-Year cumulative acute leukemia (AL) 6.6 0.25
10-Year cumulative solid tumor (ST) incidence 2.2 2.9
Conclusion: Survivors of aplastic anemia are at high risk of developing late malignancies. Incidence of MDS and AL is higher in patients treated with immunosuppressive therapies; however, the incidence of ST is the same in both transplantation and immunosuppressive treated patients.
aReport of European Bone Marrow Transplantation Working Party on severe aplastic anemia.
2. Immunosuppressive therapy improves hematopoiesis and achieves transfusion independence in the majority of patients, but the time to response is long, hematopoietic response may be partial, and relapses are relatively common.
3. Clonal hematopoietic disorders including PNH, myelodysplasia, and leukemia may develop in up to 10% of patients treated with immunosuppressive therapy (1ST). An analysis of 1765 patients with acquired aplastic anemia treated with either sibling transplant (n = 583) or 1ST (n = 1182) produced the following results:
a. Matched sibling donor HSCT is always superior in young patients (<20 years of age) at any neutrophil count.
b. Immunosuppression is superior in older patients (41-50 years) with a neutrophil count greater than 0.5 x 109/L.
c. For the 21- to 40-years-of-age group, the differences are less clear.
d. In all age groups there is a higher percentage of late failures for the immuno-suppression-treated patients.
e. The difference in survival between patients treated with HSCT and immuno-suppression is not linear, but increases with time. For the younger group of patients, a 10% advantage in favor of HSCT at 1 year became a 19% advantage at 5 years.
f. There is a higher risk of late death in patients treated with immunosuppres-sive therapy due to complications, including relapse and evolution to clonal disorders.
The European Bone Marrow Transplantation Working Party compared the rate of secondary malignancies following HSCT and IST. Forty-two malignancies developed in 860 patients receiving IST, compared to 9 in 748 patients who underwent HSCT. In this study, acute leukemia and myelodysplasia were seen exclusively in IST-treated patients, whereas the incidence of solid tumors was similar in the two groups of patients.
The natural history of moderate aplastic anemia is uncertain and clinical experience varies widely. For this reason, it is generally thought that these patients should be treated initially with supportive therapy with very close follow-up. Those patients who progress to develop severe aplastic anemia and/or significant and severe thrombocytopenia and bleeding, serious infections, or a chronic red blood transfusion requirement should be treated with the same treatment options as described for severe aplastic anemia.
SIDEROBLASTIC ANEMIAS (MITOCHONDRIAL DISEASES WITH BONE MARROW FAILURE SYNDROMES)
The sideroblastic anemias are a heterogeneous group of mitochondrial disorders characterized by:
• Anemia that may be normocytic, normochromic or microcytic, and hypochromic except in Pearson syndrome, which is characterized by macrocytic anemia probably due to fetal-like erythropoiesis
• Ineffective erythropoiesis (i.e., erythroid hyperplasia in bone marrow despite anemia)
• Presence of iron-loaded normoblasts demonstrated as ring sideroblasts (greater than 10% of erythroid precursor) by Pearls' Prussian blue stain (This stain serves as a surrogate technique for electron microscopy or energy dispersive x-ray analysis used for the demonstration of iron-loaded mitochondria in nor-moblasts.)
• Mild to moderate hemolysis due to peripheral red blood cell destruction of unknown etiology
The sideroblastic anemias can arise from the primary or secondary defects of mitochondria. In congenital sideroblastic anemias, iron rings are predominantly seen in late normoblasts (i.e., orthochromatic and polychromatophilic normoblasts), whereas they are seen in earlier erythroid cells (i.e., basophilic normoblasts) in the acquired form. Table 6-24 shows a classification of the sideroblastic anemias.
Table 6-24. Classification of Sideroblastic Anemias
I. Primary mitochondrial defects (i.e., involving 2.7 to 7.767 kb deletional lesion of mitochondrial DNA)
A. Pearson syndrome (refractory sideroblastic anemia with vacuolization of bone marrow precursors and exocrine pancreatic dysfunction) characterized by:
Refractory aregenerative macrocytic sideroblastic anemia; thrombocytopenia and neutropenia less significant Increased fetal hemoglobin
Vacuolization of marrow precursors (erythroid and granulocytic series)
Low birth weight
Exocrine pancreatic dysfunction
Hepatic failure, chronic diarrhea
Severe lactic acidosis
Renal tubular dysfunction
No reported disease in siblings
B. Expanded Pearson syndrome:
Pearson syndrome with Kearns-Sayre syndrome (myopathy, pigmentary retinopathy, cardiac conduction defects, ophthalmoplegia). A mother of a patient with Pearson syndrome has been described to have Kearns-Sayre syndrome.
C. Wolfram syndrome, also known by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) (Chapter 4 pages 64-65).
Table 6-24. (Continued)
II. Secondary involvement of mitochondria
A. Congenital sideroblastic anemia due to mutations of nuclear DNA
1. X-linked recessive defect due to point mutation in the gene for erythroid-specific 8-aminolevulinic acid synthase (ALA-S2)
2. Autosomal dominant sideroblastic anemia
3. Autosomal recessive sideroblastic anemia
B. Acquired sideroblastic anemias
1. Drugs and toxins:
Chloramphenicol—inhibits mitochondrial protein necessary for normal electron transfer and energy generation Isoniazid—inhibits ALA-S Cycloserine—inhibits ALA-S
Lead—inhibits ALA-S, ferrochelatase, 8-aminolevulinic acid dehydratase Ethanol—inhibits multiple aspects of mitochondrial function
2. Sideroblastic anemia of myelodysplastic syndromes:
In some patients with refractory anemia with ringed sideroblasts (RARS), heteroplastic mutations of mitochondrial DNA affecting subunit 1 of cytochrome C oxidase
3. Sideroblastic anemias of systemic (rheumatoid arthritis, polyarteritis nodosa), metabolic (pyridoxine responsive anemia), and malignant disorders (leukemia, carcinoma)
4. Idiopathic sideroblastic anemias
5. Pyridoxine—responsive anemia
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