Hematologic Neoplasms

Clonal Stem Cell Disorders

occur when the control mechanism fails and "indolent" clone cells may evolve to more aggressive clone cells

clonal hematopoiesis

increased proliferation of blood cells from an abnormal single HSC

Leukemia

group of hematologic malignancies characterized by the uncontrolled proliferation of leukocytes (white blood cells) in the bone marrow, often spilling into the blood and infiltrating other tissues.

Leukocytosis

WBC count exceeding 11,000 cells/µL in adults. Can be a normal response to acute infection or stress.

Lymphoid

Affects lymphocyte precursors

Myeloid

Affects precursors of other blood cells (e.g., neutrophils, monocytes)

Acute Leukemia

- Rapid onset- Leukocyte development halted at blast phase- Mostly immature (blast) cells in marrow/blood- Without treatment, fatal within weeks to months. Aggressive disease. Requires prompt and intensive treatment

Chronic Leukemia

- Slow progression over months to years- Leukocytes appear more mature- May be asymptomatic for long periods. May require less aggressive or delayed treatment

Acute Myeloid Leukemia (AML)

clonal hematologic malignancy arising from genetic mutations in myeloid hematopoietic stem cells (HSCs). Leads to abnormal proliferation of myeloid blast cells (immature leukocytes) in the bone marrow. Most common acute leukemia in adults and most common cause of death from all leukemias. total WBC count can be low, normal, or high but with a decrease in normal mature cells

Bone marrow failure (due to crowding by leukemic blasts) and Leukemic infiltration of tissues/organs:

AML presents with symptoms related to:

Neutropenia, Anemia, Thrombocytopenia

Symptoms of Bone marrow failure (due to crowding by leukemic blasts)

Hepatosplenomegaly, Bone pain, Gingival hyperplasia, Joint pain or swelling, Skin lesions, Lymphadenopathy and splenomegaly

Symptoms of Leukemic infiltration of tissues/organs

>20% blast cells

% o blast cells in the marrow that is diagnostic of AML

Achieve complete remission (no residual leukemic cells in bone marrow or peripheral blood) via Chemotherapy, HSCT, and treatment of refractory or relapsed AML

Medical Management of AML

Induction Therapy and Consolidation Therapy

Chemotherapy: Two-Phase Treatment

Induction Therapy

Eliminates as many leukemic cells as possible

Cytarabine (high-dose), Daunorubicin, Idarubicin, or Mitoxantrone, ± Etoposide

Common drugs in induction therapy

Neutropenia (ANC may reach zero), Severe thrombocytopenia (<5,000/mm³), Anemia, Risk of infections, bleeding, mucositis. Patients are typically hospitalized for 4-6 weeks

Side effects of Induction Therapy

PRBCs and platelet transfusions, Prompt infection treatment, Growth factors

Supportive Management for Induction Therapy

Consolidation Therapy:

Given after hematologic recovery post-induction. Eliminate minimal residual disease. Often involves cytarabine-based regimens. May be similar to induction but at lower doses. Typically includes multiple treatment cycles

Allogeneic Stem Cell Transplant:

Most common HSCT used in AML. Often done after induction + consolidation. In aggressive cases, may follow induction directly. Potentially curative in CML and is less favored now for CML due to high TKI success, reserved for high-risk or refractory cases

Bleeding, Infection, Tumor Lysis Syndrome (TLS), Myelosuppression from chemo

Complications of AML

Bleeding

Major cause of death in AML (alongside infection). Strongly correlates with severity and duration of thrombocytopenia.

Gastrointestinal (GI) tract, Pulmonary system, Vaginal bleeding, Intracranial hemorrhage

Common bleeding sites in AML

Tumor Lysis Syndrome (TLS)

Caused by massive leukemic cell death from chemotherapy. ↑ Uric acid, ↑ Potassium, ↑ Phosphate, ↓ Calcium due to release of intracellular contents:

Aggressive hydration

Allopurinol or Rasburicase to prevent uric acid crystallization

Prevention/Treatment of TLS

Chronic Myeloid Leukemia (CML)

A myeloproliferative neoplasm arising from a mutation in the myeloid stem cell. Characterized by uncontrolled production of mature and immature granulocytes (especially neutrophils).

Chromosome 22 (BCR gene) & Chromosome 9 (ABL gene) = BCR-ABL fusion gene → Philadelphia chromosome

CML can be caused by reciprocal translocation between

abnormal tyrosine kinase, leading to unregulated cell proliferation.

BCR-ABL codes for

Chronic phase, Accelerated Phase, Blast Crisis

Phases of CML

Chronic Phase

Most patients are asymptomatic. Diagnosed incidentally by a CBC showing leukocytosis. Mild symptoms if any. Disease is stable, and complications are rare.

Accelerated Phase

Progressive worsening of blood counts. New chromosomal abnormalities may emerge. Symptoms may develop: Fatigue, Anemia, Splenomegaly, Dyspnea, Bone pain, Fever without infection, Weight loss

Blast Crisis (Blast Phase)

Transformation to a disease that resembles Acute Myeloid Leukemia (AML).

Severe leukocytosis: WBC count > 100,000/mm³. Lymphadenopathy (uncommon, but if present, indicates poor prognosis)

Achieving remission (ideally molecular remission), Prolonging the chronic phase, Preventing progression to accelerated phase or blast crisis. Not curable in most older adults.

Medical Management of CML

Tyrosine Kinase Inhibitors (TKIs)

First-Line Treatment for CML. target the BCR-ABL fusion gene (Philadelphia chromosome). inhibits leukemic cell proliferation → promotes remission at molecular and cytogenetic levels. significantly increase survival and are now standard of care for CML. Are oral agents, often taken lifelong and at home.

Imatinib, Dasatinib, Nilotinib

First-Line TKIs

Second-Line TKIs

used when patients are resistant or intolerant to first-line TKIs:

Bosutinib and Ponatinib (used in TKI-resistant mutations like T315I mutation)

Second-Line TKIs

Corticosteroids, Antiseizure drugs (e.g., phenytoin, carbamazepine), Antacids, St. John's Wort

Decreases TKI efficacy

Grapefruit juice, Azole antifungals (e.g., ketoconazole, clotrimazole), Clarithromycin and other macrolides

Increases TKI levels (risk of toxicity):

Polycythemia Vera (Primary Polycythemia)

A chronic myeloproliferative disorder characterized by overproduction of erythrocytes, leukocytes, and platelets, with erythrocytosis being predominant. One of the Philadelphia chromosome-negative myeloproliferative disorders. ↑ Hct & Hgb, ↑ uric acid, hypercellular bone marrow. ↓ or normal serum EPO. Peripheral smear may show large, abnormally shaped RBCs. Splenomegaly is common

JAK2 gene mutation

Most patients with Polycythemia Vera exhibit what gene mutation which leads to uncontrolled hematopoiesis

Masked Polycythemia Vera

Patients with JAK2 mutation but who don't meet full diagnostic criteria. More likely to progress to myelofibrosis or acute myeloid leukemia (AML)

Thrombotic Events

Most Common Cause of Death of polycythemia vera

Reduce thrombotic risk without increasing bleeding, Prevent progression to myelofibrosis or AML, Relieve symptoms (e.g., pruritus, splenomegaly)

Medical Management of Polycythemia Vera

Phlebotomy

Mainstay therapy of polycythemia vera. Reduces hematocrit < 45% and removes 500 mL of blood weekly (initially). Induces iron deficiency, slowing RBC production

Low-Dose Aspirin

Recommended for all PV patients. Reduces vascular thrombosis risk. Withheld temporarily during active bleeding

Cytoreductive Therapy

Used to control blood cell counts, especially in High-risk patients and Low-risk patients with: Splenomegaly, Progressive leukocytosis/thrombocytosis, Poor phlebotomy tolerance, Symptoms or progression to AML/myelofibrosis

Hydroxyurea (Hydroxycarbamide), Interferon-α, Ruxolitinib. Less commonly used: Busulfan, Pipobroman, Anagrelide

Cytoreductive Agents

Hydroxyurea (Hydroxycarbamide)

First-line agent for high-risk PV. Suppresses bone marrow. Reduces thrombotic events. Side effects: myelosuppression

Interferon-α

Used in younger patients (<60 years), Pregnancy, Hydroxyurea intolerance. Reduces splenomegaly, Reduces pruritus, Prevents thrombosis. Side effects: Flu-like symptoms, Depression, High cost

Ruxolitinib

A JAK2 inhibitor. For patients resistant or intolerant to hydroxyurea and not candidates for interferon-α. Reduces splenomegaly, Alleviates symptoms, Improves quality of life. Side effects: Dose-dependent anemia and thrombocytopenia

Busulfan, Pipobroman, Anagrelide

Effective but higher risk of leukemic transformation. Significant side effects. Reserved for refractory patients and those with limited life expectancy

Lymphoma

are neoplasms of cells of lymphoid origin. These tumors usually start in lymph nodes but can involve lymphoid tissue in the spleen, GI tract (e.g., the wall of the stomach), liver, or bone marrow. They are often classified according to the degree of cell differentiation and the origin of the predominant malignant cell.

Hodgkin lymphoma and NHL.

Lymphomas are broadly classified into two categories:

Hodgkin Lymphoma

A rare but highly curable malignant lymphoma characterized by the presence of Reed-Sternberg (RS) cells. Begins in a single lymph node and spreads through contiguous lymphatic pathways. ↑ ESR, ↑ Serum copper level, ↓ Skin test reactivity - reflects impaired cell-mediated immunity E.g., anergy to Candida, mumps, ↑ Risk for infections, particularly herpes zoster

Reed-Sternberg (RS) cells

Diagnostic hallmark of Hodgkin Lymphoma. Gigantic, multinucleated B-cell derived malignant cells. Characteristically appear like an "owl's eye" under the microscope

Nodular Sclerosis (NSCHL), Mixed Cellularity (MCCHL), Lymphocyte-Depleted (LDCHL), Lymphocyte-Rich (LRCHL)

WHO Subtypes of Hodgkin Lymphoma

Nodular Sclerosis (NSCHL)

Most common (~70%) and often seen in young adults. The Lymph node contains fibrous (sclerotic) tissue. ~40% have B symptoms. Is highly curable

Mixed Cellularity (MCCHL)

2nd most common (~20-25%). Affects older adults and males. Strong association with HIV. Frequent B symptoms

Lymphocyte-Depleted (LDCHL)

Rare, aggressive form, Lymph nodes contain many RS cells, few lymphocytes. Common B symptoms. Poorer prognosis

Lymphocyte-Rich (LRCHL)

Uncommon. Lymph nodes show many lymphocytes and RS cells. Rare B symptoms. Favorable prognosis

Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

Not considered a classical HL subtype. Few RS cells, instead contains "popcorn" cells (a variant of B-cells). Presents with peripheral adenopathy. Minimal lymph node involvement. Can relapse or transform into aggressive Non-Hodgkin Lymphoma (NHL)

B Symptoms

Systemic Symptoms Indicative of Advanced Disease. Fever, Drenching night sweats, Unintentional weight loss >10% in 6 months. Painless, firm lymphadenopathy, usually unilateral (Most common early sign)

erythrocyte sedimentation rate (ESR)

speed at which erythrocytes settle out of plasma. marker of inflammation and disease activity

Excisional lymph node biopsy:

Confirmatory Diagnostic Test for HL. Identifies Reed-Sternberg cells

Doxorubicin (Adriamycin), Bleomycin, Vinblastine, Dacarbazine

Chemotherapy agents: ABVD. Used during Early-Stage Disease (Stage I-II)

Doxorubicin, Vinblastine, Mechlorethamine, Etoposide, Vincristine, Bleomycin, Prednisone

Chemotherapy agents: Stanford V. Used during Early-Stage Disease (Stage I-II)

Standard chemotherapy: ABVD with additional cycles

Advanced-Stage Disease (Stage III-IV or B symptoms)

Monoclonal antibodies (MoAbs): e.g., Brentuximab, Everolimus and Checkpoint inhibitors: e.g., Nivolumab, Pembrolizumab

Treatment options for Relapsed or Refractory HL

Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

Chemotherapy agents: CHOP. Used during Stage IB-IIB of NLPHL. Often combined with Rituximab

Cyclophosphamide, Vincristine, Prednisone

Chemotherapy agents: CVP. Used during Stage IB-IIB of NLPHL. Often combined with Rituximab

Non-Hodgkin Lymphomas

A heterogeneous group of lymphoid cancers involving malignant transformation of lymphocytes. Arises from a single clone of lymphoid cells (usually B cells), but cells can vary in morphology. Lacks Reed-Sternberg cells, Involves widespread and unpredictable lymphatic and extranodal infiltration, Often involves multiple lymph node regions and may present outside lymphoid tissue

Indolent (Slow-Growing) Lymphomas

These lymphomas grow slowly and often present with minimal symptoms. They may not require immediate treatment unless symptomatic but can eventually transform into aggressive types.

Cutaneous T-cell lymphoma (CTCL)

Primarily affects the skin; includes mycosis fungoides and Sézary syndrome.

Follicular lymphoma

Most common indolent NHL; arises from B cells in germinal centers. Often widespread at diagnosis.

Gastric MALT (Mucosa-Associated Lymphoid Tissue)

Associated with chronic H. pylori infection; arises in the stomach lining.

Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)

Involves IgM overproduction, leading to hyperviscosity symptoms.

Marginal zone B-cell lymphoma

Often extranodal (e.g., salivary glands, thyroid); includes MALT.

Small-cell lymphocytic lymphoma (SLL)

Closely related to CLL; typically involves lymph nodes and marrow, not blood.

Aggressive (Fast-Growing) Lymphomas

These lymphomas grow rapidly, require prompt treatment, and may be curable with appropriate therapy.

Anaplastic large cell lymphoma (ALCL)

T-cell origin; can be ALK-positive (better prognosis) or ALK-negative.

AIDS-associated lymphoma

Highly aggressive; includes DLBCL, Burkitt; linked to immunodeficiency.

Burkitt lymphoma

Very fast-growing; often associated with EBV; common in children and in immunocompromised individuals.

Diffuse large B-cell lymphoma (DLBCL)

Most common aggressive NHL; high response to R-CHOP therapy.

Mantle cell lymphoma

Often presents late; considered aggressive with variable response to therapy.

Peripheral T-cell lymphoma

Heterogeneous group; poor prognosis; includes several rare and difficult-to-treat subtypes.

Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine) Prednisone

What combination therapy is the mainstay for NHL

ICE regimen (Ifosfamide, Carboplatin, Etoposide)

Chemotherapy options for Relapsed or Refractory NHL

TLS, Hep B reactivation, Progressive Multifocal Leukoencephalopathy (PML)

Potential Complications of Treatment of NHL

Tumor Lysis Syndrome (TLS)

Occurs 12-72 hours after chemotherapy. Seen in bulky/aggressive lymphomas (e.g., DLBCL, Burkitt's). Manifestations: Hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, AKI. Prevention: IV fluids, allopurinol, rasburicase

Hepatitis B Reactivation

Risk ↑ with rituximab-based regimens. Can occur even in seronegative patients. Prophylaxis: Antivirals like lamivudine or entecavir

Progressive Multifocal Leukoencephalopathy (PML)

Rare, 90% fatal. Seen in severely immunosuppressed patients. Symptoms: Confusion, ataxia, visual/speech issues. No effective treatment

Cutaneous T-cell lymphoma (CTCL), Follicular lymphoma, Gastric MALT (Mucosa-Associated Lymphoid Tissue), Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia), Marginal zone B-cell lymphoma, Small-cell lymphocytic lymphoma (SLL)

Indolent (Slow-Growing) Lymphomas:

Anaplastic large cell lymphoma (ALCL), AIDS-associated lymphoma, Burkitt lymphoma, Diffuse large B-cell lymphoma (DLBCL)Mantle cell lymphoma, Peripheral T-cell lymphoma

Aggressive (Fast-Growing) Lymphomas: