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Hematology - Hematologic Malignancies - Fast Facts | NEJM Resident 360

Hematologic malignancies are cancers that affect blood, bone marrow, and lymph nodes. An exhaustive review of all hematologic malignancies is beyond the scope of this guide. We present key facts about the following common hematologic malignancies that you may encounter on the ward as a general medicine resident:

• Myeloid disorders develop in the white blood cells (WBCs) from the myeloid lineage in the bone marrow such as the granulocytes (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], myelodysplastic syndrome [MDS]).

• Lymphoid disorders affect white blood cells known as lymphocytes (e.g., acute lymphoblastic leukemia [ALL], chronic lymphocytic leukemia [CLL], Hodgkin and non-Hodgkin lymphomas, plasma cell dyscrasias such as multiple myeloma).

Workup: In an acute setting, the workup for hematologic malignancies includes:

• Blood tests:

  • to rule out malignant emergencies (CBC with differential, electrolytes and extended lytes including calcium and phosphorus, international normalized ratio [INR], partial thromboplastin time [PTT], fibrinogen, lactate dehydrogenase [LDH], haptoglobin, direct antiglobulin test [DAT], uric acid level, liver enzymes)

  • to confirm the diagnosis (peripheral-blood smear, peripheral-blood and bone-marrow biopsy with samples for flow cytometry, molecular diagnostics, and cytogenetics)

• Lumbar puncture should be considered if the patient has neurologic symptoms.

Myeloid Disorders

Acute Myeloid Leukemia (AML)

AML is caused by increased production of myeloid blasts (immature cells) and is more prevalent in adults than children. AML may occur de novo, secondary to leukemogenic therapy (e.g., radiation therapy or chemotherapy), or after transforming from other myeloproliferative disorders. AML is classified according to the prognosis-based World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia.

Clinical presentation: Patients invariably present with bone-marrow failure due to disruption of natural hematopoiesis by excessive blast formation. Pancytopenia is common, although circulating blasts can cause high white blood cell (WBC) counts. Patients may also present with leukostasis, febrile neutropenia, disseminated intravascular coagulation (DIC), or spontaneous tumor lysis syndrome (TLS).

Diagnosis: The appearance of blasts on the peripheral-blood smear is suggestive of AML, and the diagnosis is confirmed with >20% blasts on bone-marrow biopsy. Flow cytometry can be used to distinguish AML from other acute leukemias; however, the presence of Auer rods is highly associated with myeloid lineage leukemias.

Auer Rods

A 69-year-old man was referred for the evaluation and treatment of neutropenia and anemia. The complete blood count showed a white cell count of 1000 per microliter (reference range, 4800 to 10,800 per microliter), with 10% neutrophils (absolute neutrophil count, 100) and a hemoglobin level of 10.6 g per deciliter (reference range, 14 to 18 g per deciliter). Bone-marrow aspiration revealed 5% blasts and 65% promyelocytes; many promyelocytes had prominent Auer rods (arrows) and mitotic figures.
(Source: Auer Rods. N Engl J Med 2017.)

Management: Chemotherapy is dictated by experts in the field but is dependent on multiple factors, including the disease cytogenetics, mutational profiling, and patient characteristics (i.e., performance status). The goal of treatment is to induce remission, which is often achieved with 7+3 therapy (7 days of cytarabine plus 3 days of an anthracycline, typically daunorubicin or idarubicin). Thereafter, patients may receive consolidation chemotherapy or stem-cell transplantation depending on the disease type.

Chronic Myeloid Leukemia (CML)

CML is caused by increased production of clonal granulocytes (mature cells) with many immature forms (including myelocytes and metamyelocytes) in the circulation. CML is defined by the BCR–ABL1 fusion gene. This abnormal fusion usually results from a reciprocal translocation between chromosomes 9 and 22 that gives rise to an abnormal chromosome 22 (also called the Philadelphia chromosome). CML can transform into acute leukemia (AML or ALL) and can be associated with varied clinical presentations.

Clinical presentation is usually at one of three phases:

• Chronic phase: very high WBC count with left shift of the blood smear and <10% blasts on bone-marrow or peripheral-blood smear. Patients often present with constitutional symptoms, splenomegaly, and complications of cytopenias.

• Accelerated phase: >10% but <20% blasts in the peripheral blood or bone marrow or lack of response to therapy, among other factors.

• Blast phase: ≥20% blasts in the peripheral blood or bone marrow (similar to acute leukemic presentations).

Diagnosis: The diagnosis of CML is confirmed with a cytogenetic analysis of bone-marrow or peripheral-blood cells showing the presence of the BCR–ABL1 gene.

Management: CML cannot be cured without bone-marrow transplantation. Transplantation is considered in patients presenting in an accelerated or blast phase or those with refractory disease. The majority of patients present in the chronic phase, and the foundation of treatment is with an ABL tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, radotinib, ponatinib, and bosutinib). Traditional chemotherapy is also used in select cases.

Myelodysplastic Syndrome (MDS)

MDS is an acquired clonal stem-cell disorder resulting in cytopenias and dysmorphic cell precursors due to ineffective hematopoiesis that carries a risk of transformation to acute leukemia.

Clinical presentation: Patients are generally elderly and manifest with a complication of cytopenia or ineffective cell function. Clues in the workup include macrocytosis, hypolobulated neutrophils, and pseudo-Pelger–Huët cells.

Diagnosis: Bone-marrow biopsy with aspirate is necessary to confirm the diagnosis. MDS is defined by dysplasia and <20% blasts. Prognosis is based on the Revised International Prognostic Scoring System for MDS.

Management: The only potentially curative treatment for MDS is allogeneic stem-cell transplantation. Low-risk patients are often treated supportively for cytopenias (e.g., transfusions, erythropoietin, lenalidomide) or with hypomethylating agents (e.g., azacitidine or decitabine), while high-risk patients may receive intensive chemotherapy, allogenic hematopoietic transplantation, targeted therapies or hypomethylating agents.

Clonal Hematopoiesis of Indeterminate Potential (CHIP)

CHIP is defined as acquisition of somaticis mutations that drive clonal expansion, without the presence of cytopenias or dysplasia, and these mutations are associated with increased risk of subsequence myeloid or lymphoid neoplasms. This association is similar to monoclonal gammopathy of undetermined significance and multiple myeloma. Some examples of common CHIP mutations are DNMT3A, TET2, and ASXL1. CHIP has also been found to be associated with increased risk for cardiovascular disease and new data suggest an association with reduced risk for Alzheimer disease.

Lymphoid Disorders

Acute Lymphoblastic Leukemia (ALL)

ALL is caused by increased production of lymphoid blasts (immature cells). ALL is classified according to the WHO classification of tumors system, based on genetic, molecular, and morphologic features.

Clinical presentation: ALL is unique from the other malignancies discussed because it presents more often in childhood (ages 2–5 years) but can present at any age. Presenting symptoms include complications from cytopenias, constitutional symptoms, and splenomegaly with hepatomegaly. Patients with ALL have a higher risk of central nervous system (CNS) involvement and can experience neurologic symptoms.

Diagnosis: The appearance of lymphoblasts on the peripheral-blood smear is suggestive of ALL. The diagnosis is supported by detection of >20% lymphoblasts on bone-marrow biopsy, no visible cytoplasmic granules, and 95% of cells positive for terminal deoxynucleotidyl transferase (TdT). Immunophenotyping and genotypic analysis is also necessary.

Management: Unlike therapy for AML, therapy for ALL is usually prolonged, requiring three phases of chemotherapy (induction, consolidation, and maintenance). Approved regimens include combinations of anthracyclines, cyclophosphamide with or without asparaginase, vincristine, and glucocorticoids. Allogeneic stem-cell transplantation is generally reserved for patients with high-risk molecular abnormalities or clinical features and patients with refractory disease.

Chronic Lymphocytic Leukemia (CLL)

CLL is the most common leukemia in adults and is due to increased production of lymphocytes (mature cells). The stages of CLL are based on clinical characteristics and defined in the Rai (0–4) and Binet (A–C) staging systems. (See Rai and Binet staging systems.)

Clinical presentation: CLL tends to occur in adults older than 50 years with an isolated asymptomatic elevation in WBCs, and in particular, lymphocytes. Patients are usually asymptomatic but may present with signs of anemia, lymphadenopathy, splenomegaly, or cytopenias.

Diagnosis: CLL is diagnosed using peripheral-blood flow cytometry (bone-marrow or lymph node biopsies are not necessary). Smudge cells may be seen on the peripheral-blood smear and are characteristic of this disease.

Management: Therapy is not curative and if patients are asymptomatic, treatment can be delayed even in patients with high lymphocyte counts (leukostasis is uncommon in CLL because the cells are small and fragile). Treatment strategy is determined based on del17p, TP53, and IGHV mutation status. Possible first-line therapies include a BTK inhibitor (ibrutinib, acalbrutinib, zanubrutinib) with or without venetoclax, venetoclax often with rituximab or obinutuzumab, or a chemoimmunotherapy regimen (e.g., fludarabine, cyclophosphamide, and rituximab [FCR] or bendamustine and rituximab). Chemoimmunotherapy (e.g., fludarabine, cyclophosphamide, and rituximab [FCR]) is the standard first-line treatment. Newer therapies can also be used in the treatment of resistant disease.

Lymphoma

Lymphoma is caused by increased production of lymphocytes (mature cells). It is clinically differentiated from CLL because the disease affects lymphatic organs (e.g., lymph nodes and spleen) more than peripheral blood. Lymphomas can be subcategorized as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Lymphoma may be associated with infection (e.g., HIV, Epstein–Barr virus, Helicobacter pylori), immunosuppression, or inflammatory disorders.

Clinical presentation:

• HL: The age distribution is typically bimodal with a peak at ages 20 and 40 years. Presenting signs include painless lymphadenopathy, fatigue, and constitutional symptoms (fever, unexplained weight loss, night sweats).

  • often without elevated LDH

• NHL: Presentation varies greatly based on the subtype of disease:

  • indolent (e.g., follicular lymphoma) can be asymptomatic

  • very aggressive (e.g., Burkitt lymphoma) is rapidly progressive

Diagnosis: An excisional biopsy of an affected lymph node is required to make a diagnosis. A core biopsy is acceptable if excisional is not possible. Needle aspiration is inadequate if lymphoma is in the differential diagnosis. Workup must also include imaging, bone-marrow studies, and possible lumbar puncture to help stage disease on the basis of the Ann Arbor staging system. The presence of Reed–Sternberg cells on pathology is pathognomonic for HL.

Reed–Sternberg Cells

(Source: This image was originally published in ASH Image Bank. Girish Venkataraman. Reed Sternberg Cells 2. ASH Image Bank. 2016; 00060570. © The American Society of Hematology.)

Management

• HL: Management of stages I–II includes ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine), sometimes accompanied by radiation therapy.

  • Management of stages III–IV involves six cycles of ABVD, BV-AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine), or escalated BEACOPP chemotherapy (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).

    • Radiation therapy is only used in patients whose positron-emission tomography (PET)/computed tomography (CT) scans remain positive after chemotherapy.

• NHL: Management depends on disease subtype. Subtypes include but are not limited to follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. Staging, molecular biology, and patient characteristics dramatically influence treatment. 

  • Indolent disease is often managed conservatively (watch and wait) while patients are asymptomatic but may require immunotherapy, potentially with chemotherapy, in symptomatic cases.

  • Aggressive lymphomas (e.g., diffuse large B-cell and Burkitt lymphomas) require immediate chemoimmunotherapy.

Multiple Myeloma (MM)

MM is caused by the clonal proliferation of mature B cells known as plasma cells. The spectrum of disease includes monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma, both of which are classified on the basis of monoclonal gammopathy, percentage of plasma cells, and end-organ damage. MGUS is approximately 20 times more common than MM, but patients are asymptomatic and must be monitored due to the risk of progression to MM. Risk of progression is dependent on immunoglobulin isotype, level of paraprotein, and free light-chain ratio.

Diagnosis: The following tables describe diagnostic criteria and staging for MM: 

Diagnostic Criteria for MGUS and Multiple Myeloma

	Monoclonal protein	Bone-marrow plasma cells	End-organ damage
MGUS	<3.0 g/dL	<10%	No
Smoldering or asymptomatic multiple myeloma	≥3.0 g/dL*	≥10%*	No
Multiple myeloma	Any monoclonal protein**	≥10% or presence of extramedullary plasmacytoma	Yes***

*Either serum monoclonal protein ≥3.0 g/dL or bone marrow with ≥10% plasma cells is required for a diagnosis of smoldering myeloma.

**Includes detection by urine protein immunoelectrophoresis (for light-chain MM) and abnormal serum free light chains (for nonsecretory MM)
***Includes hypercalcemia, anemia, renal failure, or lytic bone lesions

(Source: Multiple Myeloma. N Engl J Med 2011.)

New definition: The new definition of active MM from the International Myeloma Foundation is as follows:

Clonal bone marrow plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:

• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

  • Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)

  • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 mol/L (>2mg/dL)

  • Anemia: hemoglobin valure of >20g/L below the lowest limit of normal, or a hemoglobin value <100 g/L

  • Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement

• Any one or more of the following biomarkers of malignancy (MDEs):

  • 60% or greater clonal plasma cells on bone marrow examination

  • Serum involved/uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100 mg/L (a patient’s involved free light chain either kappa or lambda is the one that is above the normal reference range; the uninvolved free light chain is the one that is typically in, or below, the normal range)

  • More than one focal lesion on MRI that is at least 5mm or greater in size.

Management: The following algorithm describes the treatment of newly diagnosed MM.

Current Treatment Algorithms for Newly Diagnosed Myeloma

Approach to the treatment of newly diagnosed myeloma in transplant-eligible (a) and transplant-ineligible (b) patients. VRd, Bortezomib, lenalidomide, dexamethasone; DRd, daratumumab, lenalidomide, dexamethasone; Dara-VRd, daratumumab, bortezomib, lenalidomide, dexamethasone; ASCT, autologous stem cell transplantation.
(Source: Multiple Myeloma Current Treatment Algorithms. Blood Cancer J 2020).

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