Aplastic Anemia Home
Navigation Page
New Forum Available

If aplasticcentral has helped you, please help me.

FREE Aplastic Book Preview
 
 

Aplastic Anemia Facts and Statistics

Aplastic anemia and myelodysplastic syndromes can strike any person of any age, of any gender or any race, of any neighborhood anywhere in the world. In the United States, thousands of men, women and children are stricken with these non-contagious and often fatal blood disorders every year. They occur when the bone marrow stops making enough healthy blood cells. In most cases the cause of the diseases is idiopathic (unknown.) The suspected causes are many: radiation, benzene-based compounds, viruses such as hepatitis; environmental toxins; over the counter and prescription medications; street drugs; and other many chemicals too numerous to list.

Aplastic anemia can be traced as far back as 1888 when a famous German pathologist, Dr. Paul Ehrlich, studied the case of a pregnant woman who died of bone marrow failure. It wasn't until 1904 that this disorder was termed aplastic anemia. Because it is not a reportable disease there is no way of knowing of the incidence of the disease. It is estimated that there are 2 new cases per million population (496) each year in the United States, though some doctors feel this number is extremely low. The Aplastic Anemia & MDS International Foundation is one of the only organizations in the world maintaining a voluntary Patient Registry to keep track of patients for statistical analysis.

Myelodysplastic syndromes (MDS) were first described as pre-leukemic conditions in the early 1930's and weren't treated as a separate group of disorders until 1976. Because these also are not reportable diseases, it is very difficult to state the exact incidence. The Aplastic Anemia & MDS International Foundation maintains a voluntary Patient Registry for statistical analysis. It is believed that there are approximately 10,000 to 20,000 new cases each year in the United States with the number increasing each year because of exposure to radiation and other toxins. These are relatively new diseases; therefore the number of diagnosed cases is increasing. The highest incidence is in patients over 60 years of age though people of all ages, including children, are diagnosed with it each year.

Aplastic anemia and myelodysplastic syndromes appear to be more common in Asia than in the United States. A formal epidemiological study was conducted by the National Heart, Lung & Blood Institutes of the National Institutes of Health in Thailand that confirms this to be true for aplastic anemia. It is also suspected that these two diseases are more common in Russia and Vietnam, as well as the countries of Mexico, Africa, India and South America.

Many celebrities have been stricken with aplastic anemia and myelodysplastic syndromes. Madame Curie and Eleanor Roosevelt succumb to aplastic anemia and more recently Carl Sagan and Senator Paul Tsongsas fought myelodysplastic syndromes.

Aplastic anemia has been an intriguing disease not only for the medical community, but for the entertainment industry as well. Best-selling author, Patricia Cornwall included it in her best selling murder mystery "All That Remains." Many television shows have featured Aplastic Anemia patients such as: "ER", "Touched By An Angel", "Sisters", "Bay Watch", "Emergency 911", "Days of Our Lives", "Loving", "General Hospital", "Gideon's Crossing" and "Strange World." In 1934, a black & white movie entitled "Murder on the Blackboard" starring Edna May Oliver and Bruce Cabot featured a man who was poisoned by daily doses of benzene to create 'pernicious anemia of the bones,' or aplastic anemia.

Aplastic Anemia & MDS International Foundation, Inc.
P.O. Box 613 Annapolis, Maryland 21404-0613
800.747.2820 410.867.0242 aamdsoffice@aol.com

Extracts & Statistics from Other Sources

Updated May 8, 2002 Courtesy of Randy Ramage who sadly succumbed due to a virus on March 22, 2002 following BMT .  He found much more optimistic results and made the decision to go forward. 

I told you my Dr. (Dr. Judith Marsh) was on the board of the International BMT registry and the European BMTR and was going to send me info on their BMT success rate records. By the way, noticed you have an artical of hers in your "Current" section under "Walsh". She sent 3 graphs but they are all a bit out of date I feel so didn't scan them and send them off to you. All BMTs are from HLA identical siblings.

The IBMTR graph shows relative survival rates of BMTs comparing with 1976-80 with1981-87 and 1988-92. 1976-80 shows about a 50% survival. 1981-87 shows about a 64% survival. 1988-92 shows about a 69% survival.

The EBMTR shows two comparative graphs. One on immunosuppression therapy and the other on BMTs. The immunosuppression therapy graph compares survival rates between 1981 and 1991 1981 shows about a 59% survival rate 1991 shows about a 75% survival rate The Bone Marrow transplant graph (HLA identical siblings) also compares survival rates between 1981 and 1991 1981 shows about a 55% survival rate 1991 shows about a 78% survival rate

She also sent a more recent graph from the Fred Hutchinson Cancer Research Center comparing 1970-75 with 1976-1988 and with1988-1997. 1970-75 shows about a 50% survival rate up to about 15 years. This then drops off to 45% 1976-88 shows about a 60% survival rate which over 20 years drops off to 65% 1988-97 shows about an 85% survival rate which is maintained for 10 years.

Seeing as how the most recent information was at the Fred Hutchinson Center, I searched the net and found Cyclophosphamide and Antithymocyte Globulin to Condition Patients With Aplastic Anemia for Allogeneic Marrow Transplantations: The Experience in Four Centers which is an October 13th 2000 Report. This gives more current graphs and shows an 88% survival rate using the same standard BMT regimen as is used now on ages between 2 and 59. It can be found at

What I found interesting about this report is that it deals with 93 cases and gives the information on how and when each of the none survivors died. Almost entirely from infections which are named in the report. It also shows the % chance of getting GVHD and at what level ie. Grade 1, 11, 111 or 1V (1V being the most severe). The graphs are also quite good. At the very least the information has made me more determined to avoid sources of infection and follow the Neutropenic (or Clean) Diet. Whether I opt for the BMT or the High dose Cytoxin, the main cause of death is the same...infections that got out of control.

P, 268, ff extracts -  "This is the largest analysis of alternative donor BMT for SAA so far reported. The transplant era 1986-95 was chosen to include cases which were recent enough to reflect current protocals and supportive care but with long enough follow-up to allow meaningful analysis.  ... There was surprisingly little evidence fro an impact of recipient age on survival after alternative donor BMT in this analysis (my note - hang in there you "older types" like me)... The promising results of the Milwaukee Group using T-Cell Depletion require confirmation by other centers.  The probability of 5-year survival after immunosuppressive treatment has improved in the past decade. In a recent study, patients who were treated with a combination of ATG, cyclosporin and granulocyte cologny-stimulating factor (G-CSF) had an 85 % probability of 3-year survival.  

The optimal protocol for alternative donor BMT for SAA cannot be established from this analysis. It is not certain whether limited field irradiation or total body irradiation in pre-transplant preparation reduces graft failure in unrelated donor BMT.  ... At this time, alternative donor BMT is not recommended as a first-line treatment for patinest with SAA who lack an HLA-identical sibling.  Patients who lack an HLA-identical sibling should receive some form of immunosuppression as initial therapy. 

Conclusion

The decision to proceed with alternative donor BMT is complex.  Hematologists are encouraged to discuss cases wutg cebtere specializing in the management of SAA. The correct timing of alternative donor BMT, the upper age limit for recipients and the level of acceptable mismatch have not been defined.  The authors recommend that alternative donor BMT be conisidered within 6 months of the diagnosis of SAA in patients who are less than 30 years of age and have not responded to immunosuppresive therapy. 

1: Acta Haematol 2000;103(1):19-25

Current results of bone marrow transplantation in patients with acquired severe
aplastic anemia. Report of the European Group for Blood and Marrow
transplantation. On behalf of the Working Party on Severe Aplastic Anemia of the
European Group for Blood and Marrow Transplantation.

Bacigalupo A, Oneto R, Bruno B, Socie G, Passweg J, Locasciulli A, Van Lint MT,
Tichelli A, McCann S, Marsh J, Ljungman P, Hows J, Marin P, Schrezenmeier H.

Second Department of Haemotology, Ospedale San Martino, Servizio Radioterapia
IST, Genoa, Italy. apbacigalupo@smartino.ge.it

We have analyzed 2,002 patients grafted in Europe between 1976 and 1998 from an
identical twin (n = 34), from an HLA-identical sibling (n = 1,699) or from an
alternative donor (n = 269), which included unrelated and family mismatched
donors. The proportions of patients surviving in these three groups are,
respectively, 91, 66 and 37%: major causes of failure were acute graft-versus
host disease (GvHD) (11%), infection (12%), pneumonitis (4%), rejection (4%). In
multivariate Cox analysis, factors predicting outcome were patient's age (p <
0.0001), donor type (p < 0.0001), interval between diagnosis and bone marrow
transplantation (BMT) (p < 0.0005), year of BMT (p = 0.0005) and female donor
for a male recipient (p = 0.02). Patients were then divided in two groups
according to the year of BMT: up to or after 1990. The overall death rate
dropped from 43 to 24% (p < 0.00001). Improvements were seen mostly for grafts
from identical siblings (from 54 to 75%, p < 0.0001), and less so for
alternative-donor grafts (from 28 to 35%; p = 0.07). Major changes have occurred
in the BMT protocol: decreasing use of radiotherapy in the conditioning regimen
(from 35 to 24%; p < 0.0001) and increasing use of cyclosporin (with or without
methotrexate) for GvHD prophylaxis (from 70 to 98%; p < 0.0001). In conclusion,
the outcome of allogeneic BMT for patients with severe aplastic anemia has
considerably improved over the past two decades: young patients, grafted early
after diagnosis from an identical sibling, have currently an over 80% chance of
long-term survival. Transplants from twins are very successful as well. The risk
of complications with alternative donor transplants is still high. Copyright
2000 S. Karger AG, Basel

PMID: 10705155 [PubMed - indexed for MEDLINE]

1: Ann Intern Med 1999 Feb 2;130(3):193-201

Comment in:
 Ann Intern Med. 1999 Oct 19;131(8):633-4

Effectiveness of immunosuppressive therapy in older patients with aplastic
anemia. European Group for Blood and Marrow Transplantation Severe Aplastic
Anaemia Working Party.

Tichelli A, Socie G, Henry-Amar M, Marsh J, Passweg J, Schrezenmeier H, McCann
S, Hows J, Ljungman P, Marin P, Raghavachar A, Locasciulli A, Gratwohl A,
Bacigalupo A.

Department Zentrallabor, Kantonsspital Basel, Switzerland.

BACKGROUND: Immunosuppressive therapy has been used for successful treatment of
severe aplastic anemia, but little information is available on outcome in older
patients. OBJECTIVE: To evaluate outcome in patients older than 50 years of age
who received immunosuppressive therapy for aplastic anemia. DESIGN:
Retrospective cohort study. SETTING: 56 centers of the European Group for Blood
and Marrow Transplantation (EBMT). PATIENTS: 810 patients with aplastic anemia
reported between 1974 and 1997. Patients were evaluated according to age group:
60 years of age or older (n = 127), 50 to 59 years of age (n = 115), and 20 to
49 years of age (n = 568; reference group). INTERVENTION: Antilymphocyte
globulin, cyclosporine, or both. MEASUREMENTS: Survival, cause of death,
response to treatment, relapse rate, and risk for late complications were
analyzed in all patients and by age group. RESULTS: The 5-year survival rate was
57% (95% CI, 46% to 66%) in patients 50 to 59 years of age and 50% (CI, 39% to
60%) in patients 60 years of age or older compared with 72% (CI, 68% to 76%) in
patients younger than 50 years of age (P < 0.001). Response to therapy, relapse
rate, and risk for clonal complications were similar in all three age groups (P
> 0.2). Age was significantly associated with an increased risk for death
(relative risk compared with patients 20 to 49 years of age, 1.80 [CI, 1.29 to
2.52] for patients 50 to 59 years of age and 2.57 [CI, 1.87 to 3.53] for
patients > or = 60 years of age), mainly because of bleeding or infection (P =
0.02). Response to immunosuppressive therapy in all patients at 12 months was
62% (CI, 58% to 66%); no difference was seen among the age groups in
multivariate analysis (P > 0.2). Sixty-six of the 379 responding patients (17%)
subsequently had relapse. The risk for clonal disorders at 10 years was 20% (CI,
15% to 27%). CONCLUSIONS: Response to immunosuppression in aplastic anemia is
independent of age, but treatment is associated with increased mortality in
older patients.

PMID: 10049197 [PubMed - indexed for MEDLINE]

1: J Clin Oncol 2001 Feb 15;19(4):1152-9

CD6+ donor marrow T-cell depletion as the sole form of graft-versus-host disease
prophylaxis in patients undergoing allogeneic bone marrow transplant from
unrelated donors.

Soiffer RJ, Weller E, Alyea EP, Mauch P, Webb IL, Fisher DC, Freedman AS,
Schlossman RL, Gribben J, Lee S, Anderson KC, Marcus K, Stone RM, Antin JH, Ritz
J.

Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115,
USA. robert_soiffer@dfci.harvard.edu

PURPOSE: The role of donor marrow T-cell depletion (TCD) in preventing
graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic
marrow remains undefined. Because different TCD methodologies differ in the
degree and specificity with which T cells are removed, it is likely that
transplant outcomes would depend on which technique is used. Herein, we report
results in the first 48 recipients of unrelated marrow using CD6+ TCD as the
sole form of GVHD prophylaxis. PATIENTS AND METHODS: Median age of patients was
46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation
consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14
Gy). To facilitate engraftment, patients also received 7.5 Gy (22 points) or 4.5
Gy (26 points) of total lymphoid irradiation (TLI) before admission. No
additional immune suppressive prophylaxis was administered. Granulocyte
colony-stimulating factor was administered daily from day +1 to engraftment.
RESULTS: All 48 patients demonstrated neutrophil engraftment. An absolute
neutrophil count of 500 x 10(6)/L was achieved at a median of 12 days (range, 9
to 23 days). There were no cases of late graft failure. The number of CD34+
cells infused/kg was associated with speed of platelet and neutrophil recovery.
The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in
42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day
100 was 19%. There have been only five relapses. Estimated 2-year survival was
44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50
years of age. In multivariable analysis, age less than 50 years (P =.002),
cytomegalovirus seronegative status (P =.04), and early disease status at bone
marrow transplant (P =.05) were associated with superior survival. CONCLUSION:
CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose
TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis
results in an incidence of GVHD that compares favorably with many adult studies
of unrelated transplantation using unmanipulated marrow and immune-suppressive
medications, especially in light of the median age of our patients (46 years).
Although event-free survival in patients less than 50 years of age is very
encouraging, older patients experience frequent transplantation-related
complications despite TCD.

Publication Types:
Clinical trial

PMID: 11181681 [PubMed - indexed for MEDLINE]

1: Biol Blood Marrow Transplant 2000;6(1):35-43

Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow
transplantation is inferior to other regimens and is associated with decreased
survival and an increased risk of other infections.

Vasconcelles MJ, Bernardo MV, King C, Weller EA, Antin JH.

Department of Adult Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts 02115, USA. michael_vasconcelles@dfci.harvard.edu

Pneumocystis carinii pneumonia (PCP) is a life-threatening but preventable
infection that may occur after bone marrow transplantation (BMT). Although
various prophylactic regimens have been used in this setting to prevent active
infection, their efficacy, toxicity profile, and impact on outcomes are poorly
described in this patient group. We undertook a retrospective cohort study in
which we reviewed the records of 451 adult patients who underwent BMT for
hematologic malignancies, aplastic anemia, or myelodysplasia over a 7-year
period at the Brigham and Women's Hospital. Post-BMT PCP prophylaxis consisted
of aerosolized pentamidine (AP) 150 mg every 2 weeks or 300 mg per month,
trimethoprim/sulfamethoxazole (TMP/SMX) 160/800 mg orally b.i.d. 3 times per
week, or dapsone 100 mg orally each day. Prophylaxis was continued for 1 year
post-BMT in all patients when clinically feasible. One hundred twenty-one
patients were unevaluable because of death or relapse <60 days after BMT (n =
89), loss to follow-up upon hospital discharge (n = 20), or other reasons (n =
12). Three eligible patients did not receive any prophylaxis and were not
further evaluated. Of the 327 patients analyzed, 133 underwent autologous BMT, 4
syngeneic BMT, 159 related allogeneic BMT, and 31 unrelated allogeneic BMT.
Graft-versus-host disease prophylaxis in the 190 patients receiving allogeneic
BMT consisted of T-cell depletion with anti-CD5 and complement in 58 patients
and cyclosporine/methotrexate or FK506 with or without steroids in 132 patients.
Eight of 327 (2.4%) documented PCP cases were identified, 0 of 105 in patients
receiving only TMP/SMX. Four cases occurred in patients receiving only AP (4/44,
9.1%; odds ratio [OR] relative to TMP/SMX 23.4, 95% confidence interval [CI]
1.2, 445.2); 1 in patients receiving only dapsone (1/31, 3.2%; OR not
significant); 2 in patients receiving more than 1 prophylactic regimen (2/147
1.4%; OR not significant); and 1 >1 year post-BMT in a patient who was off PCP
prophylaxis. Although the patients receiving only AP had a significantly lower
probability of treatment-related toxicity than those receiving TMP/SMX (OR 0.19
[95% CI 0.04, 0.851), the probability of their acquiring other serious non-PCP
infections was increased (OR 2.2 [95% CI 1.0, 4.6]), and the probability of
their dying by 1 year post-BMT was significantly higher (OR 5.2 [95% CI 2.4,
26.6]), even when adjusted for variables such as type of BMT (autologous versus
allogeneic; high versus low risk) and sex. Although AP is associated with fewer
toxicities, the data show that it is inferior to TMP/SMX in preventing PCP in
the post-BMT setting and is associated with an increased risk of other
infections and a higher mortality at 1 year after BMT.

Publication Types:
Clinical trial

PMID: 10707997 [PubMed - indexed for MEDLINE]

• ·Aplastic anemia and myelodysplastic syndromes are non-contagious blood diseases that can strike regardless of age, gender, race or geographic location. They occur when bone marrow stops making enough healthy blood cells.
• ·Estimates put new cases of aplastic anemia at only 300 per year and of MDS at 20,000 per year. The diseases are too rare to be reported to public health agencies such as the Centers for Disease Control and Prevention. But AA&MDSIF keeps a patient registry database, one of the few sources for statistical information on the diseases.
• ·The most common treatments are transfusions, drugs that suppress the immune system and bone-marrow transplants. While transplants have effected some cures, a bone-marrow match is hard to find; even among relatives, an exact match occurs only about a third of the time.
• ·Many cases have been linked to exposure to toxic chemicals or radiation. Some have a genetic component, and some are the result of the body’s reaction to a virus or infection. In most cases, the cause is unknown.

AA is rare with a worldwide variable annual incidence cited between 2 and 6 cases per million persons. Various studies have been done to determine the prevalence in defined populations. The International Aplastic Anemia and Agranulocytosis Study determined the frequency in Europe and Israel to be 2 cases per million in the early 1980s. Between May, 1984 and April, 1987, a study conducted in France placed that country's annual incidence at 1.5 per million. A geographic variation can be noted: studies conducted in China and Bangkok describe overall annual incidences of 0.74 per hundred thousand and 3.7 per million, respectively. It is undisputed that the disease is more prevalent in the Orient than in the Western world. Age and gender distribution vary with geographic location as well . In the U.S. and Europe, most cases occur in either the 15-24 year age group, or in those > 60 years old. In Bangkok, the greatest number of cases were in the 15-24 year range as well; China, however, reports a peak for women > 50 years and men > 60 years. Men in France have two peaks, one at 15-30 years and a second at > 60 years, while the greatest risk for women was > 60 years old. Males also typically have a more severe course than females. The explanations for the age and gender differences may be some occupational risk, while the geographical variance suggests an environmental influence.

EDITOR: ANNE LeMAISTRE, M.D.

CREATED: 6/24/94, LAST MODIFIED: 4/24/96, UT DPALM MEDIC, copyright 1994-96

apoptosis

<cell biology> Programmed cell death as signalled by the nuclei in normally functioning human and animal cells when age or state of cell health and condition dictates.

An active process requiring metabolic activity by the dying cell, often characterised by cleavage of the DNA into fragments that give a so called laddering pattern on gels.

Cells that die by apoptosis do not usually elicit the inflammatory responses that are associated with necrosis, though the reasons are not clear.

Cancerous cells, however, are unable to experience the normal cell transduction or apoptosis-driven natural cell death process.

See: ced mutant, bcl.

(18 Nov 1997)

December 6, 2000 -- Tisdale & colleagues, Hematology Branch, National Heart, Lung, and Blood Institute, National Institute of Health (NIH), report on randomized trial of high dose cyclophosphamide (Cytoxan) for AA patients in a recent issue of The Lancet. 31 patients were enrolled, 15 assigned cyclophosphamide and 16 were assigned ATG. Both received cyclosporine. The trial was terminated prematurely after 3 early deaths in the cyclophosphamide group. No significant differences at 6 months after treatment in the overall response rate. Author abstract available through PubMed. Tisdale JF, et al. "High-dose cyclophosphamide in severe aplastic anemia: a randomized trial." The Lancet, Nov 4, 2000. Vol 356, no 9241, p 1554.

May 30, 2000 -- National Institutes of Health, National Heart, Lung and Blood Institute, in Bethesda Maryland, informed us of their new protocol for severe aplastic anemia on presentation, consisting of combined ATG, cyclosporine (for 6 months), and mycophenolate mofetil (for 18 months). It is well tolerated and appears to lead to meaningful clinical responses in at least as high a proportion of cases as does conventional ATG plus CSA. Only 12 patients have been treated to date here. Of note, responses appear to be more rapid and have surprisingly occurred in several patients with "super-severe" disease where neutrophil counts are close to zero.

To find out more about this protocol, call Wanda Zamani at 301-402-0764 or contact be email zamani@nhlbi.nih.gov.

February 1, 2000 -- Screening out damaging leukocytes with leukocyte blood filters is essential to minimized adverse reactions following blood transfusions. Low-level radiation also reduces the amount of lymphocytes in blood, reducing the risk of transfusion-associated graft-versus-host disease. For optimum results, both processes should have been carried out on the blood for your transfusion, but you will need to check this at the time of ordering, and ask the nurse to check again at the bedside. In addition, try for blood that has been leukocyte-filtered before storage, rather than filtered at the bedside. The former is more efficiently filtered. There are no known negative side-effects to blood treated in these ways. A spokesperson at America's Blood Centers stated that insurance companies generally accept the need for these products when fighting aplastic anemia and MDS. Our thanks to AA&MDISF member Bob Carroll for providing this information.

Thank you. Your order has been processed.
IF YOU ORDERED A FULL-TEXT DISEASE REPORT, YOU MUST VIEW OR PRINT YOUR DISEASE REPORT NOW.
If YOU ORDERED A NORD RESOURCE GUIDE OR DISEASE ARTICLE (NOT AVAILABLE ELECTRONICALLY), PLEASE ALLOW 7 to 10 DAYS FOR SHIPMENT.

Anemia, Aplastic

[Synonyms] [ Disorder Subdivisions] [ General Discussion] [Symptoms] [Causes] [Affected Population] [Related Disorders] [Standard Therapies] [Investigational Therapies] [Resources] [References]

Copyright (C) 1986, 1987, 1988, 1990, 1991, 1992, 1993, 1995, 1996, 1997, 1998, 1999 National Organization for Rare Disorders, Inc. **IMPORTANT** It is possible that the main title of the report (Aplastic Anemia) is not the name you expected. Please check the SYNONYMS listing to find the alternate name(s) and disorder subdivision(s) covered by this report. Synonyms   Aregenerative Anemia Erythroblastophthisis Hemorrhagica Aleukia Hypoplastic Anemia Panmyelopathy Panmyelophthisis Progressive Hypoerythemia Refractory Anemia Toxic Paralytic Anemia Disorder Subdivisions:   Information on the following diseases can be found in the Related Disorders section of this report: Fanconi's Anemia Dyskeratosis Congenita Anemias, Other General Discussion   **REMINDER** The information contained in the Rare Disease Database is provided for educational purposes only. It should not be used for diagnostic or treatment purposes. If you wish to obtain more detailed information about this disorder, please contact your personal physician and/or the agencies listed in the "Resources" section this report. Aplastic Anemia is a rare bone marrow disorder characterized by decreased function of the bone marrow that results in abnormally low levels of all the cellular elements of the blood (pancytopenia). In some cases, the disorder may affect primarily single cell lines (i.e., red blood cells, white cells, or platelets). The initial symptoms may include increasing weakness, fatigue, recurrent or persistent infections, and/or bleeding. In about 50 percent of cases, the exact cause is not known. In some cases, certain toxic agents (e.g., inorganic arsenic) or drugs (e.g., phenylbutazone, choramphenicol, etc.) may cause Aplastic Anemia. . Symptoms   The symptoms of Aplastic Anemia may begin suddenly, but in most cases they appear gradually. The initial symptoms of Aplastic Anemia may include increasing weakness, fatigue, recurrent or persistent infections, and/or lethargy. Physical activity may be followed by headache and/or difficulty breathing. An individual with this disorder may get frequent bacterial infections and/or be sicker than is normal for that particular infection. Nosebleeds and/or bleeding under the skin are also common. The symptoms of Aplastic Anemia are dependent on the extent of the reduced number of all blood cells (pancytopenia) or the type of blood cell(s) that are affected. . Causes   In about 50 percent of cases of Aplastic Anemia, the disease has no apparent cause. Certain toxic agents that may cause the disorder include inorganic arsenic and certain drugs such as phenylbutazone, chloramphenicol, other antibiotics, azathioprine, carbamazepine, carbonic anhydrase inhibitors, dapsone, ethosuximide, gluthethimide, gold compounds, penicillamine, pentoxifylline, probenecid, quinacrine, sulfonamides, sulfonylureas, trimethadione, and anticonvulsants. High doses of radiation may also cause marrow failure but this is not usually classified as aplastic anemia. The symptoms of Aplastic Anemia are the result of the loss of primitive cells (stem cells) in the bone marrow that are the precursors (forerunners) of more mature blood cells. A majority of cases of aplastic anemia appear to be caused by activation of the immune system with secondary damage to the marrow. Affected Population   Aplastic Anemia is a rare bone marrow disorder that affects males and females in equal numbers. This disorder affects approximately 1.5 to 2 in 1,000,000 people in the United States; approximately 500 to 1,000 new cases are reported each year. Acquired Aplastic Anemia affects children slightly less frequently than adults. However, children may also develop the disease from the less frequent inherited causes of bone marrow failure. Related Disorders   Symptoms of the following disorders can be similar to those of Aplastic Anemia. Comparisons may be useful for a differential diagnosis: Fanconi's Anemia is an inherited disorder characterized by abnormalities of the heart, kidneys, skeleton, and other body systems. Failure of the bone marrow to produce adequate blood cells and platelets may develop at any age but most frequently occurs at the end of the first decade of life. The initial symptoms of Fanconi's Anemia may be easy bruising and unexplained nosebleeds (epistaxis). Fanconi's Anemia is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Fanconi's Anemia" as your search term in the Rare Disease Database.) Dyskeratosis Congenita is a rare disorder characterized by darkening and/or unusual absence of skin color (hyper/hypopigmentation), abnormal changes in the nails (dystrophy), and progressive degenerative changes of the mucous membranes (leukoplakia) that line the anus, urethra, lips, mouth, and/or eyes. This disorder may be inherited or occur sporadically. (For more information on this disorder, choose "Dyskeratosis Congenita" as your search term in the Rare Disease Database.) Other types of anemias include: Megaloblastic Anemia, Warm Antibody Hemolytic Anemia, Cold Antibody Hemolytic Anemia, Acquired Autoimmune Hemolytic Anemia, Pernicious Anemia, Folic Acid Deficiency Anemia, Blackfan- Diamond Anemia, Hereditary Nonspherocytic Hemolytic Anemia, Hereditary Spherocytic Hemolytic Anemia, and Sickle Cell Anemia. (For information on other types of Anemias, choose "Anemia" as your search term in the Rare Disease Database.) Other diseases with symptoms of failure of the bone marrow to produce sufficient blood cells may also occur in renal failure, liver diseases, endocrine abnormalities, late-stage malignancies (particularly with metastasis to the bone marrow), chronic infections, and certain hereditary diseases. . Standard Therapies   When Aplastic Anemia is thought to be caused by exposure to chemicals or drugs, the toxic source must be removed or eliminated. If a drug is known to cause Aplastic Anemia (e.g., certain anticonvulsants), the prescribing physician will require affected individuals to take periodic blood tests so the drug can be discontinued if there are signs of bone marrow suppression. Since individuals affected by a severe form of Aplastic Anemia are susceptible to recurring infections, they should seek medical attention with any illness accompanied by a fever. The most effective initial treatment for aplastic anemia depends upon the patient’s age. For patients less than 30 years of age, the most effective treatment for Aplastic Anemia is bone marrow transplant from a matched related donor. An affected individual’s closest relatives should be tissue-typed. In 20 to 30 percent of patients, a brother or sister of the individual may be a compatible donor. Blood transfusions before a transplant should be done only if absolutely necessary since they lower the chances of successful transplantation. If a bone marrow transplant is a possibility, then the affected individual's family members should not be used for blood transfusions. Aspirin and other drugs that may cause platelet dysfunction should be avoided. In patients 30 years of age or older, initial treatment with immunosuppressive drugs is the treatment of choice. A combination of drugs that suppress the immune system (e.g. antilymphocyte globulin, prednisone, and cyclosporin) may result in an improvement of bone marrow function in 70 to 80 percent of individuals with Aplastic Anemia. The use of granulocyte colony stimulating factors (GCSF or GMCSF) may decrease infectious complications while the patient begins to respond to immune suppression. Responses to immune suppressive drugs are usually not as complete or as long lasting as responses to bone marrow transplantation. Investigational Therapies   A phase III clinical study is underway to determine the long-term safety and effectiveness of cyclophosphamide (cytoxan) for the treatment of Aplastic Anemia. High doses of the drug are administered over four days, followed by either three months of cyclosporine or no cyclosporine. More studies are needed to determine the long-term safety and effectiveness of this drug regimen for the treatment of Aplastic Anemia. For more information, contact: Marlene & Stewart Greenbaum Cancer Center University of Maryland 22 South Greene Street Baltimore, MD 21201 Attn: Meyer Heyman, M.D. (410) 328-2594 High-dose cyclophosphamide and G-CSF (granulocyte-colony stimulating factor) are being studied for the treatment of Aplastic Anemia. Newly diagnosed and previously treated individuals with severe Aplastic Anemia (who are not candidates for bone marrow transplantation) may be eligible for this study. For more information, contact: Johns Hopkins Oncology Center 600 North Wolfe Street Baltimore, MD 21287 Robert Brodsky, M.D. (410) 614-2809 or Richard Jones, M.D. (410) 955-2815 The orphan drug Etiocholanedione is being studied for the treatment of Aplastic Anemia. More studies are needed to determine the long-term safety and effectiveness of this drug for the treatment of Aplastic Anemia. For more information, contact the sponsor: SuperGen, Inc. 3158 Des Plaines Avenue, Suite 10 Des Plaines, IL 60018 Early studies are underway to test the use of the steroid hormone etiocholanedione (ED) for treatment of Aplastic Anemia. More studies are needed to determine the long-term safety and effectiveness of this drug for the treatment of Aplastic Anemia. For more information, contact: University of Texas-Houston Medical School 6431 Fannin PO Box 20708 Houston, TX 77225 (713) 792-5450 Attn: Harinda S. Juneja, M.D. The National Institutes of Health is conducting a laboratory study regarding the incidence of Aplastic Anemia after infection. For more information, contact: National Institutes of Health National Heart, Lung & Blood Institute Building 10-7, Room C103 Bethesda, MD 20892 (301) 496-5093 Attn: Neal S. Young, M.D. Laboratory studies are being conducted on blood and marrow to determine the cause or origin (etiology) of Aplastic Anemia. For more information, contact: Dana Farber Cancer Institute Pediatric-Hematology/Oncology 44 Binney Street Boston, MA 02115 (617) 632-4932 Attn: Eva Guinan, M.D. Dr. Gary Pekoe is conducting a phase I clinical trial of RII Retinamide for the treatment of refractory aplastic anemia. More studies are needed to determine the long-term safety and effectiveness of this treatment. For more information, contact: Gary Pekoe, M.D. Long Beach VA Hospital 5901 E Seventh St Long Beach, CA 90822 (800) 321-2466 The Children's Hospital of Pittsburgh is conducting a randomized clinical trial comparing the use of immunosuppression (ATG and cyclosporine) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to an investigational hematopoietic cytokine immunosuppressor (PIXY321) for the treatment of acquired severe Aplastic Anemia. Individuals who are eligible to participate in this study must be between one and 21 years of age and previously untreated. For more information, contact: Jeffrey Hord, M.D. Children's Hospital of Pittsburgh 3520 Fifth Ave Pittsburgh, PA 15213 (412) 692-5055 A phase III clinical trial is underway to compare the use of cylcophosphamide versus cylcophosphamide in combination with antithymocyte globulin in affected individuals receiving bone marrow transplantations from an HLA-identical sibling. For more information, contact: Jakob R. Passweg. M.D. International Bone Marow Transplant Registry 8701 Watertown Plank Road P.O. Box 26509 Milwaukee, WI 53226 (414) 456-8325 Physicians at Indiana University Medical Center are conducting a Phase II clinical trial of subcutaneously administered interleukin-2 in individuals with Myelodysplastic Syndrome. Eligible individuals must be over the age of 18 years. For more information, contact: Micheal S. Gordon, M.D. Indiana University Medical Center 535 Barnhill Drive, Route 473 Indianapolis, IN 46202-5289 (317) 274-7119 The Hematology Branch at the National Institutes of Health/National Heart, Lung and Blood Institute (NHLBI) is conducting clinical research studies on Aplastic Anemia. The purpose of one of the studies is to compare the use of antithymocyte globulin combined with cyclosporine versus high dose cylclophosphmide combined with cyclosporine as a treatment for Aplastic Anemia. Affected individuals that are eligible for this study must be 18 years of age or older. Another study is being conducted on the use of antithymocyte globulin and cyclosporine in children with Aplastic Anemia (less than 18 years of age). For more information, individuals may contact: Wanda Zamani NIH/Hematology Branch, National Heart, Lung and Blood Institute (NHLBI) Website: http://www.nhlbi.nih.gov/nhlbi/seekpat/hematol.htm e-mail: zamaniwe@gwgate.nhlbi.nih.gov Tel: (301) 402-0764 Fax: (301) 402-3088 For more information, physicians may contact: Dr. Neal Young, Chief of the Hematology Branch or Dr. John Barrett, Chief of the Bone Marrow Transplant Unit NIH/Hematology Branch, National Heart, Lung and Blood Institute (NHLBI) Website: http://www.nhlbi.nih.gov/nhlbi/seekpat/hematol.htm Tel: (301) 496-5093 Fax: (301) 496-8396 A phase III clinical trial of antithromocyte globulin, cyclosporine, corticosteroid, and GCSF with or without stem cell factor is being subported by the biotechnology company, Amgen. For information on the study and participating centers contact: J. Wade Lovelace Amgen, Inc. One Amgen Center Drive Thousand Oaks, CA 91320 Tel: (805) 447-1192 Fax: (805) 480-1330 E-mail: wadel@amgen.com NORD does not promote, endorse, or encourage participation in any specific medical research study. This information is presented to further scientific understanding that could lead to the prevention, treatment, and/or cure of rare disorders. NORD recommends that anyone interested in participating in a clinical research program seek the advice or counsel of his or her own personal physician(s). This disease entry is based upon medical information available through December 1999. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder. Resources   This information was provided by the National Organization for Rare Disorders, P.O. Box 8923, New Fairfield, CT 06812-8923, phone: (203) 746-6518, web site: www.rarediseases.org, e-mail: orphan@rarediseases.org. For more information on Anemia, Aplastic, please contact: Aplastic Anemia & MDS International Foundation, Inc. P.O. Box 613 Annapolis, MD 21404--0613 e-mail: aamdsoffice@aol.com Home Page: http://www.aamds-international.org NIH/National Heart, Lung and Blood Institute 31 Center Drive MSC 2480 Building 31A Rm 4A16 Bethesda, MD 20892--2480 (301) 592-8573 e-mail: nhlbiinfo@rover.nhlbi.nih.gov Home Page: http://www.nhlbi.nih.gov/ Aplastic Anemia Association of Canada 22 Aikenhead Road Etobicoke Ontario, M9R- 2Z3 Canada (416) 235-0468 e-mail: aplastic@enterprise.ca Home Page: http://www.aplastic.ualberta.ca NIH/Hematology Branch, National Heart, Lung and Blood Institute (NHLBI) (301) 402-0764 e-mail: zamaniw@nhlbi.nih.gov Home Page: http://www.nhlbi.nih.gov/nhlbi/seekpat/hematol.htm References   Bennett JC & Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:831-37. Isselbacher KJ, ed. Harrison’s Principles of Internal Medicine. 14th ed. McGraw-Hill, Inc.; 1998:672-75. Stein, JH ed. Internal Medicine. 4th ed. Mosby-Year Book, Inc.; 1994:873-77. Berkow R & Beers M, Eds. The Merck Manual. 17th ed. Merck Research Laboratories; 1999:862-63. Behrman RE, ed. Nelson Textbook of Pediatrics. 15th Ed. W.B. Saunders Company; 1996:599, 1414-15. Hoffman R, et all, ed. Hematology Basic Principles and Practice. 2nd Ed. Churchill-Livingstone, Inc.; 1995:299-349. Frank MM, et al, eds. Samter’s Immunologic Diseases. 5th Ed. Little, Brown and Company; 1995:1478-81. Tichelli A, et al., Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. European group for blood and marrow transplantation severe aplastic anemia working party. Ann Intern Med. 1999;130:193-201. Sagmeister A, et al., A restrictive platelet transfusion policy allowing long-term support of outpatients with severe aplastic anemia. Blood. 1999;93:3124-6. Marsh J, et al., Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia. A report from the European blood and marrow transplant (EMBT) severe aplastic anemia working party. Blood. 1999;93:2191-5. Young NS, et al., The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997;336:1365-72. Kiem Y, et al., Hepatitis-associated aplastic anemia. N Engl J Med. 1997;337:424-5. Margolis D, et al., Urelated donor bone marrow transplantation to treat severe aplastic anemia in children and young adults. British J Haemaology. 1996;94:65-72. Issaragrisil S, Brief Report: Transplantation of cord-blood stem cells into a patient with severe thalassemia. N Engl J Med. 1995;332:367-69. Naser SD, et al., The use of colony-stimulating factors in primary hematologic disorders. Cancer. 1992;70:921-7. Frickhofen N, et al., Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group. N Engl J Med. 1991;324:1297-304. The National Organization for Rare Disorders (NORD) web site, its databases, and the contents thereof are copyrighted by NORD. No part of the NORD web site, databases, or the contents may be copied in any way, including but not limited to the following: electronically downloading, storing in a retrieval system, or redistributing for any commercial purposes without the express written permission of NORD. Permission is hereby granted to print one hard copy of the information on an individual disease for your personal use, provided that such content is in no way modified, and that credit for the source (NORD) and NORD’s copyright notice are included on the printed copy. Any other electronic reproduction or other printed versions are strictly prohibited.

 

Lancet 2000 Nov 4;356(9241):1554-9

Related Articles, Books, LinkOut

Comment in:

• Lancet. 2000 Nov 4;356(9241):1536-7

High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial.

Tisdale JF, Dunn DE, Geller N, Plante M, Nunez O, Dunbar CE, Barrett AJ, Walsh TJ, Rosenfeld SJ, Young NS.

Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. johntis@intra.niddk.nih.gov

BACKGROUND: High-dose cyclophosphamide has been proposed as an alternative immunosuppressive agent for treatment of severe aplastic anaemia, with a response rate similar to that with regimens containing antithymocyte globulin (ATG) but neither relapse nor clonal haematological complications. We undertook a phase III, prospective, randomised trial to compare response rates to immunosuppression with either high-dose cyclophosphamide plus cyclosporin or conventional immunosuppression with ATG plus cyclosporin in previously untreated patients. METHODS: Between June, 1997, and March, 2000, 31 patients were enrolled. 15 were assigned cyclophosphamide (1 h intravenous infusion of 50 mg/kg daily for 4 days) and 16 were assigned ATG (40 mg/kg daily for 4 days); both groups received cyclosporin, initially at 12 mg/kg daily with adjustment to maintain concentrations at 200-400 microg/L, for 6 months. The primary endpoint was haematological response (no longer meeting criteria for severe aplastic anaemia). The trial was terminated prematurely after three early deaths in the cyclophosphamide group. Analyses were by intention to treat. FINDINGS: Median follow-up was 21.9 months (range 1-33). There was excess morbidity in the cyclophosphamide group (invasive fungal infections, four cyclophosphamide vs no ATG patients; p=0.043) as well as excess early mortality (three deaths within the first 3 months cyclophosphamide vs no ATG patients; p=0.101). There was no significant difference at 6 months after treatment in the overall response rates among evaluable patients (six of 13 [46%] cyclophosphamide vs nine of 12 [75%] ATG). INTERPRETATION: A longer period of observation will be necessary to assess the secondary endpoints of relapse and late clonal complications as well as disease-free and overall survival. However, cyclophosphamide seems a dangerous choice for treatment of this disorder, given the good results achievable with standard therapy.

Publication Types:

• Clinical trial
• Randomized controlled trial

PMID: 11075769 [PubMed - indexed for MEDLINE]