1. Diagnostic Approach and Overview of Pancytopenias
Andrew J Seier, MD
PGY-1

2. Types Bone marrow infiltration/destruction Bone marrow aplasia
Infections: tuberculosis, fungi (e.g. disseminated histoplasmosis, visceral leishmaniasis)
Bone marrow aplasia
B12/folate deficiency, medications (e.g. methotrexate, cyclophosphamide, colchicine, azathioprine, ganciclovir, etc.), immune destruction, aplastic anemia, infection (HIV, viral hepatitis, parvovirus B19)
Alcohol consumption, benzene exposure
Blood cell sequestration/destruction
Hypersplenism (e.g. from cirrhosis, lymphoma, autoimmune disease),
DIC, TTP, myelodysplastic syndrome
Crohn disease may impair absorption of iron, folate, and vitamin B12; induce an inflammatory state that exacerbates anemia; require partial bowel resection that affects absorption of nutrients and calories; and require treatment with myelosuppressive agents.
History (e.g. other medical conditions) is critical.
Visceral leishmaniasis seen in some soldiers returning from Afghanistan and Iraq

3. The Importance of Physical Exam
Lymphadenopathy
Associated with hematologic malignancies, autoimmune and infectious diseases
Hepatomegaly, splenomegaly, stigmata of liver disease
Liver disease as a cause of hypersplenism/sequestration
Infectious causes
Rashes
related to drug reactions, rheumatologic disorders, infections, and malignancies
Oral lesions
Thrush suggests immune compromise
Oral ulcers may be seen in SLE, Crohn’s
Presence of both splenomegaly and lymphadenopathy may suggest an underlying hematologic malignancy (eg, lymphoma, leukemia), infectious disease, or autoimmune disorder
Abnormalities of liver function without stigmata of chronic liver disease or splenomegaly may be associated with infectious diseases (eg, acute viral hepatitis), medications, autoimmune disorders, or hemophagocytic lymphohistiocytosis as potential causes of pancytopenia.

4. Initial Evaluation CBC with diff Peripheral smear
Reticulocyte count (absolute < 20,000 suggests hypoproliferation)
PT/INR, aPTT
CMP, LDH, uric acid
Type & screen

5. Bone Marrow Biopsy Helpful Not helpful Acute leukemias Aplastic anemia
Multiple myeloma
Not helpful
Medication-induced
Recent use of hematopoietic growth factors
Peripheral destruction, sequestration
Medication-induced or peripheral destruction/sequestration: can do bone marrow biopsy if still required, but should wait 1-2 weeks observing blood counts along the way.

6. Pancytopenic Emergencies
ANC < 1000, newly-diagnosed or with evidence of infection
Symptomatic anemia (e.g. myocardial ischemia, hypotension)
Thrombocytopenia < 10,000 (or < 50,000 with active bleeding)
DIC, TTP, HUS, or other MAHA with schistocytes and elevated LDH
Acute leukemia (e.g. with DIC or tumor lysis syndrome)
Associated metabolic abnormalities
Delirium, dehydration, abdominal pain: hypercalcemia (multiple myeloma, adult T-cell leukemia/lymphoma)
Acute renal failure (e.g. with elevated uric acid in tumor lysis syndrome
If none of the above are present, CBC is stable and near normal, and the patient is asymptomatic, referral is non-urgent

7. Autoimmune Causes RA, Felty’s syndrome SLE Sarcoidosis
Associated conditions
Pernicious anemia
Thyroid disease (severe hypothyroid, thyrotoxicosis)
some of the treatments for these illnesses (eg, gold salts, cytotoxic agents) may exacerbate the cytopenias
Consider alternative agents if these are the cause, manage associated conditions.

8. Hypoproliferative Causes
Aplastic anemia
B12, folate, or copper deficiency
Suppression from alcohol or viral infections
Myelodysplastic syndrome
Certain malignancies
Hairy cell leukemia
T-cell large granular lymphocyte leukemia
Copper deficiency may be due to zinc overload

9. Neoplastic Causes Acute leukemias Myelodysplastic syndrome
Often see circulating blasts
Myelodysplastic syndrome
Often see dysplastic leukocytes
Myelofibrosis
Tear drop cells (dacrocytes), nucleated RBCs, early WBCs

10. Overview and Treatment of Myelodysplastic Syndromes

11. Description
A group of hematopoietic stem cell disorders characterized by
Ineffective, dysplastic hematopoiesis
Risk of transformation to acute leukemia
Quantitative and qualitative defects in production of red blood cells, platelets, and granulocytes
Develops like other cancers, from stepwise acquisition of oncogenic mutations

12. Epidemiology 10,000-30,0000 cases per year in the United States
Most common in older adults, median age at diagnosis 65 years or older
Associated with certain exposures: benzene, radiation, tobacco, chemotherapy drugs
Certain connective tissue disorders associated
Behçet’s, Sjögren’s, IBD, polymyalgia rheumatica, relapsing polychondritis
No causal link established

13. Presentation Hepatomegaly, splenomegaly, lymphadenopathy uncommon
Infection
Usually bacterial, often skin infections
Non-infectious cutaneous manifestations
Sweet syndrome (acute febrile neutrophilic dermatosis: uncommon, but much greater frequency than in general population)
Myeloid sarcoma (extra-medullary AML)
Pancytopenia with inappropriately low reticulocyte response
Sweet syndrome (acute febrile neutrophilic dermatosis), when complicating the course of MDS, may herald transformation to acute leukemia

14. Peripheral Smear Findings
RBCs
Normocytic or macrocytic
Ovalomacrocytes most common, can also see dacrocytes, stomatocytes, or acanthocytes
Basophilic stippling, Howell-Jolly bodies, and megaloblastoid nucleated red cells

15. Peripheral Smear Findings (cont.)
WBCs: most commonly seen finding are the pseudo-Pelger- Huet abnormality and reduced granulation

16. Pre-treatment Evaluation: Scoring
●Low/very low IPSS-R – Patients with a very low (≤1.5 points) or low (>1.5 to 3 points) IPSS-R score are primarily treated with supportive care or low intensity therapies such as azacitidine or decitabine or immunosuppressive therapy.
●High/very high risk IPSS-R – Patients with a high (>4.5 to 6 points) or very high (>6 points) IPSS-R score with a good performance status are primarily treated with high intensity combination chemotherapy or allogeneic HCT in an attempt to alter the disease course.
●Intermediate IPSS-R – For patients with an intermediate (>3 to 4.5 points) IPSS-R score, either low intensity therapy or high intensity therapy is acceptable, and management choices should be informed by the degree of symptoms, medical fitness, and goals of care, which should be established in discussions between the patient and clinician. Some medically fit patients may select intensive treatment with the goal of long-term survival and possible cure. Others may select lower intensity approaches with the goal of prolonging survival, alleviating symptoms, or improving the quality of life without an expectation of long-term disease control.
●Supportive care is an important adjunct to the management of all patients with MDS. (See "Management of the hematologic complications of myelodysplastic syndromes".)

17. Treatment Modalities High-intensity
Allogeneic hematopoietic cell transplant
Combination chemotherapy, such as daunorubicin and cytarabine
Low-intensity (improves symptoms, not curative)
Hematopoietic growth factors (epoetin alfa, eltrombopag, GM- CSF)
Azacitidine/decitabine (hypomethylating agents)
Immunosuppresive therapy
Lenalidomide
Supportive care
Antibiotics PRN
RBC and platelet transfusions PRN

18. Prognosis Highly dependent on underlying cytogenetics
Intermediate-, high-, or very high-risk patients can receive high-intensity therapy, which can be curative
With older age, other medical comorbidities, often supportive care is the best option
High- to very-high risk groups have survival measured in months with supportive care

19. End