Sources and Guidelines Referenced

The clinical content in this guide is derived from published evidence-based protocols and established international clinical practice guidelines, including:

• British Society for Haematology (BSH): Guidelines for the Diagnosis and Management of Adult Aplastic Anaemia (Killick et al., 2024).
• European Society for Blood and Marrow Transplantation (EBMT): Severe Aplastic Anemia Working Party Consensus Guidelines (Peffault de Latour et al., 2022).
• National Institutes of Health (NIH): Eltrombopag and Immunosuppressive Therapy Trials (Townsley et al., New England Journal of Medicine, 2017).
• Center for International Blood and Marrow Transplant Research (CIBMTR): Hematopoietic Cell Transplantation Outcomes in Severe Aplastic Anemia Cohort Reports (2022).

Aplastic Anemia Treatment Program: A Comprehensive Patient Guide

1. Definition and Medical Identity

An Aplastic Anemia Treatment Program is a structured hematological protocol designed to restore blood cell production in patients with bone marrow failure. The program combines intensive immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation to eliminate immune-mediated stem cell destruction, promote bone marrow recovery, and re-establish normal red cell, white cell, and platelet counts.

Acquired aplastic anemia is categorized medically as a primary bone marrow failure syndrome (BMFS). In clinical practice, the condition is classified by severity using the modified Camitta criteria into moderate aplastic anemia (MAA), severe aplastic anemia (SAA), and very severe aplastic anemia (VSAA). The primary medical purpose of an integrated treatment program is to interrupt the pathological autoimmune cascade or replace the damaged stem cell niche, thereby reversing life-threatening low blood counts (pancytopenia) and restoring self-sustaining blood generation (hematopoiesis).

2. The Underlying Condition or Need

Aplastic anemia occurs when the immune system mistakenly attacks hematopoietic stem cells inside the bone marrow, causing severe marrow depletion. Without intervention, this hypocellular state leads to progressive pancytopenia, exposing patients to life-threatening infections, severe hemorrhage, and profound anemia. Treatment aims to suppress this immune destruction and stimulate stem cell regeneration.

Under normal physiological conditions, multi-potent hematopoietic stem cells residing within the bone marrow divide and differentiate into three major cell lineages: oxygen-carrying red blood cells (erythrocytes), infection-fighting white blood cells (leukocytes, particularly neutrophils), and blood-clotting cell fragments (platelets or thrombocytes). In aplastic anemia, expanded populations of autoreactive cytotoxic T-lymphocytes release inflammatory signal proteins (cytokines) such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which trigger programmed cell death (apoptosis) in stem cells.

If left untreated, severe aplastic anemia carries a historical mortality rate exceeding 80% within one year of diagnosis, primarily driven by fulminant bacterial or fungal bloodstream infections (sepsis) or fatal intracranial or gastrointestinal bleeding. Modern therapeutic protocols intervene early to halt this destruction before irreversible organ damage or lethal infectious complications occur.

3. How the Treatment Works — Mechanism

An aplastic anemia treatment program works by halting the immune-mediated destruction of bone marrow progenitor cells and stimulating hematopoiesis. Immunosuppressive regimens eradicate autoreactive T-lymphocytes that target stem cells, while stem cell transplantation replaces defective marrow with healthy donor cells. Adjunctive thrombopoietin receptor agonists directly stimulate remaining stem cells to proliferate.

The therapeutic mechanism operates through distinct pathways based on the chosen treatment track:

• Immunosuppressive Therapy (IST): Horse antithymocyte globulin (h-ATG) contains polyclonal antibodies against human T-lymphocytes, causing rapid depletion of circulating and bone marrow-resident autoreactive immune cells. Concurrent administration of cyclosporine (CsA) inhibits calcineurin, suppressing ongoing T-cell activation and interleukin-2 production. The addition of eltrombopag, a small-molecule thrombopoietin receptor agonist (TPO-RA), selectively binds to the c-MPL receptor on residual hematopoietic stem cells, driving cell division and lineage expansion (Townsley et al., NEJM, 2017).
• Allogeneic Stem Cell Transplantation (HSCT): The patient undergoes a pre-transplant conditioning regimen consisting of immunosuppressive chemotherapy (e.g., cyclophosphamide and fludarabine) combined with ATG. This destroys host autoreactive lymphocytes and creates immune tolerance, allowing healthy stem cells collected from a tissue-matched donor to enter (engraft) the patient's bone marrow niches and permanently produce healthy blood cells.

4. Types and Variations

Treatment variations for aplastic anemia are categorized into allogeneic stem cell transplantation and non-transplant immunosuppressive therapy. Selection depends on patient age, availability of a human leukocyte antigen matched donor, and underlying medical fitness. Protocols range from matched sibling donor transplants to triple-drug immunosuppressants combining antithymocyte globulin, cyclosporine, and eltrombopag.

Clinicians determine the optimal protocol based on international standards established by the British Society for Haematology (BSH) and the European Society for Blood and Marrow Transplantation (EBMT). The primary protocols are detailed below:

5. Who the Treatment Is For — Indications

An aplastic anemia treatment program is indicated for individuals diagnosed with moderate, severe, or very severe acquired aplastic anemia based on bone marrow cellularity and peripheral blood counts. Eligible patients include those experiencing severe neutropenia, thrombocytopenia, and anemia who possess an HLA-matched donor or require frontline immunosuppressive therapy.

Diagnostic workup must confirm acquired bone marrow failure through specific diagnostic thresholds:

• Severe Aplastic Anemia (SAA): Bone marrow cellularity < 25% (or 25–50% with < 30% residual hematopoietic cells) AND at least two of the following peripheral blood criteria: absolute neutrophil count (ANC) < 0.5 × 10⁹/L, platelet count < 20 × 10⁹/L, or absolute reticulocyte count < 20 × 10⁹/L (or < 60 × 10⁹/L automated).
• Very Severe Aplastic Anemia (VSAA): Meets criteria for SAA but with an ANC < 0.2 × 10⁹/L, placing the patient at extremely high risk for immediate fungal and bacterial infections.
• Moderate Aplastic Anemia (MAA): Hypocellular bone marrow with cytopenias not meeting severe criteria, but causing severe anemia or bleeding symptoms that require regular transfusion support.

6. Who the Treatment Is NOT For — Contraindications

Aplastic anemia treatment is contraindicated in patients with inherited bone marrow failure syndromes requiring altered conditioning, severe active uncontrolled infections, or irreversible organ dysfunction. Additionally, allogeneic stem cell transplantation is contraindicated in patients lacking a suitable donor or those with severe comorbidities unable to tolerate high-dose conditioning chemotherapy.

Contraindications are evaluated carefully prior to treatment initiation:

• Inherited Bone Marrow Failure Syndromes (IBMFS): Conditions such as Fanconi Anemia (FA) or Dyskeratosis Congenita (DC) must be excluded via chromosome breakage analysis (diepoxybutane/mitomycin C testing) or genomic sequencing. Standard conditioning regimens are fatal in FA due to extreme DNA repair hypersensitivity.
• Secondary Myeloid Malignancy: Presence of excessive blast cells (> 5%) or cytogenetic abnormalities characteristic of primary myelodysplastic syndrome (MDS), such as monosomy 7 or complex karyotypes, contraindicates standard IST and requires acute leukemia-style or MDS-specific transplant regimens.
• Severe Irreversible Comorbidities: Advanced cardiac failure (ejection fraction < 40%), severe chronic obstructive pulmonary disease, or end-stage liver disease prohibit high-dose conditioning or intensive immunosuppression.

7. Alternatives and Clinical Comparison

Alternatives to standard aplastic anemia treatment include investigational androgen therapy, isolated growth factor support, or supportive care consisting solely of blood product transfusions and prophylactic antibiotics. However, supportive care does not cure the condition and is reserved for patients ineligible for definitive immunosuppression or stem cell transplantation.

The clinical differences between therapeutic approaches are outlined below:

8. Pre-Treatment Phase

The pre-treatment phase of an aplastic anemia program involves comprehensive clinical evaluation, diagnostic confirmation via bone marrow biopsy, HLA tissue typing, and organ function testing. Patients undergo central venous catheter insertion, infectious disease screening, dental clearance, and fertility preservation counseling before initiating conditioning chemotherapy or immunosuppressive drug protocols.

Every candidate undergoes a standardized multi-step pre-treatment workup:

• Bone Marrow Confirmation: Core biopsy and aspirate demonstrating marrow hypocellularity (< 25% space occupied by hematopoietic elements) without fibrosis or abnormal blast cell populations. Cytogenetic analysis (karyotyping and FISH) excludes dysplastic clones.
• HLA Donor Search: High-resolution DNA typing at HLA-A, -B, -C, -DRB1, and -DQB1 loci for the patient and all full siblings. If no sibling match is found, an immediate registry search for matched unrelated donors (MUD) or haploidentical family donors is initiated.
• Infectious Disease Screening: Baseline testing for Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Hepatitis B (HBV), Hepatitis C (HCV), HIV, Herpes Simplex, and Aspergillus antibodies or antigens.
• Vascular Access & Medical Clearance: Surgical placement of a double- or triple-lumen tunneled central venous line (such as a Hickman catheter) to allow concurrent infusion of anti-infectives, blood products, and ATG or stem cells. Pulmonary function tests, echocardiography, and complete dental clearance are mandatory.

9. The Procedure — Step-by-Step Clinical Detail

The treatment procedure involves either a multi-day conditioning regimen followed by intravenous donor stem cell infusion or an intensive multi-day antithymocyte globulin infusion accompanied by daily oral immunosuppressants. Patients remain in specialized protective isolation, receiving continuous cardiovascular monitoring, daily blood count tracking, prophylactic anti-infectives, and transfusion support.

The clinical progression depends on the chosen protocol pathway:

Pathway A: Allogeneic Stem Cell Transplantation Protocol

• Days -6 to -2 (Conditioning Phase): Inpatient administration of conditioning agents. A standard protocol includes cyclophosphamide (50 mg/kg/day IV for 4 days) and fludarabine (30 mg/m²/day IV for 4 days), alongside horse ATG to deplete host T-cells and suppress graft rejection.
• Day -1 (Rest Day): Clearance of chemotherapeutic agents from circulating blood.
• Day 0 (Stem Cell Infusion): Fresh unmanipulated bone marrow or peripheral blood stem cells from the matched donor are processed and infused intravenously via central line over 1 to 4 hours. Anaphylaxis monitoring and continuous pulse oximetry are maintained.
• Days +1 to +28 (Engraftment Monitoring Phase): Daily monitoring for donor cell engraftment (defined as ANC > 0.5 × 10⁹/L for 3 consecutive days). Granulocyte colony-stimulating factor (G-CSF) may be administered per protocol.

Pathway B: Triple Immunosuppressive Therapy Protocol

• Days 1 to 4 (ATG Administration Phase): Horse ATG is administered at 40 mg/kg/day via central venous line as a slow infusion over 8 to 12 hours daily. Prior to each dose, premedication with intravenous methylprednisolone, hydrocortisone, antihistamines, and antipyretics is given to prevent severe allergic reactions.
• Day 1 Onward (Cyclosporine Initiation): Oral cyclosporine is initiated at 5 mg/kg/day in two divided doses, adjusting target trough blood levels between 150–250 ng/mL (or 200–400 ng/mL depending on local assay standards) to maintain immune suppression while limiting kidney toxicity.
• Day 1 to Month 6 (Eltrombopag Therapy): Daily oral eltrombopag is administered at 150 mg daily (adjusted to 75 mg daily for patients of East Asian ancestry per pharmacogenetic dosing guidelines) for 26 consecutive weeks to stimulate stem cell expansion (Killick et al., BSH Guidelines, 2024).

10. Immediate Post-Procedure Period

The immediate post-procedure period covers the first 24 to 48 hours following stem cell infusion or antithymocyte globulin completion. Care focuses on managing acute infusion reactions, monitoring vital signs, administering prophylactic medications for serum sickness, maintaining fluid balance, and sustaining hemoglobin and platelet thresholds through specialized blood component transfusions.

During this critical inpatient window, clinical management involves:

• Managing Infusion Reactions: ATG can trigger cytokine release syndrome, causing fever, rigors, hypotension, or bronchospasm. Continuous monitoring of blood pressure, oxygen saturation, and cardiac rhythm is enforced during and for 48 hours post-infusion.
• Serum Sickness Prophylaxis: Patients completing horse ATG receive an ongoing course of oral or intravenous corticosteroids (e.g., prednisone 1 mg/kg/day) tapering over 14 days to prevent serum sickness—an immune-complex reaction characterized by fever, joint pain (arthralgia), generalized skin rash, and proteinuria occurring 7 to 14 days after ATG exposure.
• Supportive Transfusion Support: Continuous maintenance of peripheral blood thresholds using irradiated, leukoreduced blood products. Transfusions are administered to keep hemoglobin > 7.0–8.0 g/dL and platelets > 10–20 × 10⁹/L to prevent spontaneous internal hemorrhage.

11. Recovery — Short and Long Term

Recovery from aplastic anemia treatment spans several months to years, depending on whether the patient underwent transplantation or immunosuppressive therapy. Neutrophil recovery typically occurs within three to four weeks, while full immune reconstitution and platelet stabilization take six to twelve months, requiring ongoing outpatient blood monitoring and antimicrobial prophylaxis.

The recovery timeline proceeds through distinct clinical milestones:

• Phase 1: Acute Recovery (Weeks 1–4): Inpatient HEPA-filtered isolation continues until neutrophil counts recover above 0.5 × 10⁹/L. Prophylactic broad-spectrum antibacterial, antifungal (e.g., posaconazole or fluconazole), and antiviral (e.g., acyclovir) coverage is maintained.
• Phase 2: Early Outpatient Recovery (Months 1–3): Outpatient visits twice weekly for blood count evaluation, kidney function testing, and therapeutic drug monitoring of cyclosporine levels. Patients remain on PCP/PNEUMOCYSTIS prophylaxis (trimethoprim-sulfamethoxazole or pentamidine).
• Phase 3: Intermediate Reconstitution (Months 3–6): Gradual tapering of steroids and monitoring for delayed response to IST or chronic graft-versus-host disease (cGvHD) post-transplant. Eltrombopag is discontinued at 6 months if hematological response is achieved.
• Phase 4: Long-Term Maintenance (Months 6–24): Cyclosporine is slowly tapered over a 6 to 12-month period once stable blood counts are achieved. Repeat bone marrow biopsies are performed at month 6 and month 12 to verify marrow cellularity and cytogenetic stability.

12. Risks, Side Effects, and Complications

Risks associated with aplastic anemia treatment include severe neutropenic infection, organ toxicity, graft-versus-host disease, serum sickness, graft failure, and secondary clonal evolution. Complications range from mild allergic reactions to life-threatening sepsis, requiring rigorous infection control, therapeutic drug monitoring, and immediate clinical intervention upon detection of adverse symptoms.

The risk severity matrix summarizes clinical complications, frequencies, and management strategies:

Long-term safety studies highlight that while stem cell transplantation carries higher early treatment-related mortality (10–15% within 100 days), long-term survivors experience low rates of disease recurrence. Conversely, immunosuppressive therapy has low early mortality (< 5%), but carries a persistent lifetime risk of relapse (20–30%) or secondary transformation into myelodysplastic syndrome or acute myeloid leukemia (Peffault de Latour et al., EBMT Guidelines, 2022).

13. Lifestyle and Behavioural Considerations

Lifestyle considerations during aplastic anemia recovery center on strict infection prevention, dietary modification, and physical protection. Patients must follow a low-microbial diet, avoid public places during neutropenic phases, refrain from contact sports due to bleeding risks, maintain meticulous oral hygiene, and adhere strictly to prescribed immunosuppressive medication regimens.

Patient behavioral modifications are divided into risk-mitigation domains:

• Infection Risk Mitigation: Avoid crowded public indoor spaces, wearing fit-tested N95 respirators during unavoidable medical travel. Strict hand hygiene and avoiding exposure to standing water, garden soil, unpasteurized dairy, or raw meats (neutropenic dietary precautions).
• Bleeding Precautions: Refraining from contact sports, high-impact exercise, and heavy lifting while platelet counts remain under 50 × 10⁹/L. Soft-bristled toothbrushes and electric shavers must replace hard toothbrushes and safety razors.
• Sun Protection & Nephroprotection: Patients taking cyclosporine require daily broad-spectrum sunblock due to heightened skin cancer risks, and must maintain aggressive fluid intake (2–3 liters daily) while avoiding non-steroidal anti-inflammatory drugs (NSAIDs) to protect renal function.

14. How Outcomes Are Measured

Outcomes in an aplastic anemia treatment program are measured by hematological response criteria, including complete or partial restoration of peripheral blood counts and freedom from transfusion dependency. Long-term success is evaluated through five-year overall survival, event-free survival, absence of relapse, and lack of secondary clonal evolution to myeloid malignancies.

Standard clinical response criteria established by international registries evaluate success at 3, 6, and 12 months post-treatment:

• Complete Response (CR): Hemoglobin normal for age/gender, absolute neutrophil count > 1.5 × 10⁹/L, platelet count > 150 × 10⁹/L, and complete independence from blood product transfusions.
• Partial Response (PR): Blood counts no longer meet criteria for severe aplastic anemia; transfusion independence achieved for both red blood cells and platelets, with ANC > 0.5 × 10⁹/L.
• Non-Response (NR): Persistent blood counts meeting SAA criteria, continuing transfusion dependency, or failure to achieve PR threshold by 6 months.

Five-year overall survival (OS) for young patients receiving matched sibling donor stem cell transplants exceeds 85% to 90%. For patients undergoing triple immunosuppressive therapy, overall response rates (CR + PR) range between 70% and 80% at 6 months (Townsley et al., NEJM, 2017).

15. Recent Advances and Current Standard of Care

Recent advances in aplastic anemia management include adding thrombopoietin receptor agonists to frontline immunosuppressive regimens and developing haploidentical stem cell transplantation using post-transplant cyclophosphamide. Modern conditioning protocols have significantly reduced treatment-related mortality, improved engraftment rates, and expanded successful donor options for patients without matched sibling donors.

The standard of care has evolved through key innovations over the last decade:

• Frontline Eltrombopag Triplet Therapy: Incorporating eltrombopag directly into frontline ATG and cyclosporine therapy increases the overall response rate at 6 months from ~60% to over 80%, with higher rates of complete hematological restoration compared to dual IST alone.
• Haploidentical Transplants with Post-Transplant Cyclophosphamide (PTCy): The introduction of high-dose post-transplant cyclophosphamide eliminates donor-reactive T-cells after stem cell infusion. This innovation allows patients lacking a full HLA match to safely undergo transplant using half-matched family donors (parents, children, siblings) with survival rates approaching fully matched transplants.
• Reduced-Intensity Conditioning (RIC): Tailored conditioning protocols incorporating fludarabine and low-dose cyclophosphamide have lowered transplant-related toxicities, allowing older adults (aged 40–65 years) to undergo curative transplantation safely.

16. Common Myths and Misconceptions

Common myths regarding aplastic anemia treatment often stem from confusion between aplastic anemia and nutrition-based anemias or leukemia. Disproving these misconceptions requires clear clinical evidence regarding the autoimmune nature of bone marrow failure, the necessity of definitive therapy over dietary changes, and the true mechanisms of stem cell transplantation.

Myth: Aplastic anemia can be cured by iron supplements, vitamin B12, or dietary modifications.
Reality: Aplastic anemia is a non-nutritional autoimmune bone marrow destruction. Supplemental iron or vitamins cannot restore immune-mediated stem cell loss and may cause iron overload toxicity in patients receiving blood transfusions.

Myth: Immunosuppressive therapy cures aplastic anemia permanently in all patients.
Reality: While IST induces blood count recovery in 70-80% of patients, approximately 20-30% experience disease relapse when immunosuppressants are tapered, and 10-15% may develop long-term clonal evolution requiring transplantation (BSH Guidelines, 2024).

Myth: Blood transfusions cure aplastic anemia over time.
Reality: Transfusions are supportive treatments that temporarily restore red cells and platelets. They do not stimulate the bone marrow or stop autoimmune destruction, and frequent transfusions lead to iron overload and immune sensitization against donor tissues.

Myth: Stem cell transplantation is only considered as a last resort when all medications fail.
Reality: For young patients (< 40–50 years) with severe aplastic anemia who have an HLA-identical sibling, allogeneic stem cell transplantation is the definitive frontline treatment of choice, yielding five-year survival rates above 90%.

Myth: Bone marrow donation for transplantation involves removing parts of the donor's spine.
Reality: Stem cell collection involves either harvesting bone marrow fluid from the posterior pelvic bone under general anesthesia or collecting peripheral blood stem cells via automated blood filtration (apheresis). Spinal cord tissue is never touched.

Myth: Patients can stop taking cyclosporine as soon as their blood counts normalize.
Reality: Premature discontinuation of cyclosporine leads to high rates of autoimmune relapse. Medication must be continued for at least 6 to 12 months after achieving maximum response and tapered slowly under hematological supervision.

17. Frequently Asked Questions

What is the primary difference between immunosuppressive therapy and stem cell transplantation?

Immunosuppressive therapy uses medications like antithymocyte globulin and cyclosporine to stop your immune system from destroying bone marrow stem cells, allowing your own marrow to recover. Stem cell transplantation uses chemotherapy to clear out your immune system and replaces your damaged marrow with healthy stem cells from a matched donor.

How long will I need to stay in the hospital during treatment?

Patients receiving immunosuppressive therapy typically spend 7 to 14 days in the hospital for ATG administration, allergy prophylaxis, and fluid monitoring. Patients undergoing allogeneic stem cell transplantation require an inpatient hospital stay of 3 to 6 weeks to complete conditioning chemotherapy, stem cell infusion, and acute engraftment monitoring in protective isolation.

Why is horse ATG preferred over rabbit ATG for aplastic anemia?

Clinical trials show that horse ATG achieves higher response rates and superior overall survival compared to rabbit ATG when used as frontline therapy for severe aplastic anemia. Rabbit ATG causes more intense and prolonged immune suppression, which increases infection risks without improving bone marrow recovery rates.

What is serum sickness and how is it managed?

Serum sickness is an immune reaction to animal proteins in ATG, causing fever, joint pain, muscle aches, and skin rash 7 to 14 days after infusion. It is managed and prevented using a planned 14-day tapering course of corticosteroid medications like prednisone alongside antihistamines.

Can aplastic anemia recur after successful treatment?

Yes. Approximately 20% to 30% of patients treated with immunosuppressive therapy experience a disease relapse, often during or after cyclosporine tapering. Relapse is rare following successful stem cell transplantation once full donor cellular engraftment is permanently established.

Is fertility preserved during aplastic anemia treatment?

Immunosuppressive therapy with ATG, cyclosporine, and eltrombopag does not typically impair fertility. However, stem cell transplantation conditioning protocols use high-dose chemotherapy, which carries significant risks of temporary or permanent infertility. Sperm banking or oocyte cryopreservation should be discussed before starting transplant conditioning.

How often will I need bone marrow biopsies after treatment?

Bone marrow aspirates and core biopsies are performed at 3, 6, and 12 months post-treatment, and annually thereafter for 5 years. These biopsies confirm rising marrow cellularity, verify healthy cell maturation, and screen for cytogenetic changes associated with clonal evolution.

What is clonal evolution in aplastic anemia?

Clonal evolution refers to the development of new chromosomal abnormalities in bone marrow cells over time, potentially transforming aplastic anemia into myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). It occurs in 10-15% of patients treated with IST, requiring ongoing long-term marrow monitoring.

Why must I follow a neutropenic diet during recovery?

When your absolute neutrophil count drops below 0.5 × 10⁹/L, your body cannot effectively fight foodborne bacteria and fungi. A neutropenic diet excludes raw meats, unpasteurized dairy, uncooked seafood, and unwashed raw produce to prevent life-threatening gastrointestinal bacterial infections.

How is an HLA donor found if I do not have a matched sibling?

If no full sibling is an HLA match, clinicians search international bone marrow donor registries for a 10/10 matched unrelated donor (MUD). If no fully matched donor is available, half-matched family members can serve as donors using specialized haploidentical transplant protocols.

What blood count levels indicate severe aplastic anemia?

Severe aplastic anemia is diagnosed when bone marrow cellularity is under 25% and at least two of these peripheral blood limits are met: absolute neutrophil count under 0.5 × 10⁹/L, platelet count under 20 × 10⁹/L, or absolute reticulocyte count under 20 × 10⁹/L.

When can I return to work or normal physical activity?

Most patients can resume light daily activities within 3 months of immunosuppressive therapy or 6 months post-transplant. Returning to full-time work, school, or exercise depends on blood count recovery, infection risks, and medication side effects, usually taking 6 to 12 months total.