Hematologic malignancies include a broad and varied range of conditions, including leukemias and lymphomas. An exhaustive review of each disease is beyond the scope of this package. This rotation guide presents key questions and facts about common hematologic malignancies that you may encounter on the wards.
Acute Myeloid Leukemia (AML)
What is the World Health Organization (WHO) classification for AML?
What is the current approach to management?
What are favorable and adverse molecular alterations?
Who is a candidate for allogeneic hematopoietic stem-cell transplantation (HSCT), and when should it be considered? (In first remission? In second remission?)
What are the options for patients who are ineligible for intensive therapy?
What is the prognosis for patients with AML?
What are new potential targets for drug development?
The old FAB (French-American-British) classification of AML that was morphology-based (e.g., M0, M1, M2, M3 AML, etc.) has been replaced by the prognosis-based WHO classification system. This classification system groups AML patients by the presence or absence of critical prognostic indicators, such as cytogenetic abnormalities, presence or absence of marrow dysplasia, and whether or not the leukemia is therapy-related (i.e., related to receipt of prior leukemogenic drugs or radiation therapy). Cases that do not fit into a predefined category are classified as AML-NOS (not otherwise specified), which on subcategorization revert to a morphologic scheme similar to the old FAB classification.
(to obtain the immunophenotype of the malignant cells) is obtained as soon as possible following diagnosis and aids in diagnosis before morphologic or cytogenetic studies are completed.
(“7+3”) consists of a 7-day continuous infusion of cytarabine and three doses of an anthracycline, typically daunorubicin or idarubicin.
Initial morphologic remission
after successful induction chemotherapy does not represent cure; rather, it represents a substantial cytoreduction of malignant cells in the blood and bone marrow, such that a cure might be possible with consolidation therapy. If remission is achieved, consolidation therapy — either high-dose chemotherapy or allogeneic HSCT — is determined by molecular, cytogenetic, and morphologic risk factors.
Patients with favorable cytogenetics — such as t(8;21), t(16;16), or inv(16), or those with prognostically favorable molecular alterations — may be candidates for consolidation with chemotherapy alone. Conversely, patients with unfavorable cytogenetics and molecular aberrations, therapy-related AML, or multilineage dysplasia in their bone marrow are typically consolidated with allogeneic HSCT.
An understanding of supportive care to avoid tumor lysis syndrome is necessary (see the Oncology guide).
See Clinical Pearls & Morning Reports for more about AML.
Acute Lymphoid Leukemia (ALL)
What is the WHO immunohistochemistry classification (B or T cell)?
What are the treatment options?
The definition of ALL is >20% bone-marrow blasts, with no granules, 95% cytochemistry positive for terminal deoxynucleotidyl transferase (TdT).
Multiple approved treatment regimens exist, including combinations of anthracyclines, cyclophosphamide with or without asparaginase, vincristine, and glucocorticoids. Younger adults (<40) should receive asparaginase-containing pediatric regimens.
Central nervous system (CNS) prophylaxis is given with intrathecal methotrexate or cytarabine and courses of high-dose intravenous methotrexate, with or without cranial irradiation.
Postremission regimens are important and consist of a consolidation phase followed by maintenance chemotherapy (approximately 2–3 years).
HSCT is generally reserved for patients with high-risk molecular abnormalities (e.g., mixed lineage leukemia [MLL] or Philadelphia chromosome-positive disease), high-risk clinical features, and patients with relapsed disease.
Specific patient subgroups require variations to standard regimens (e.g., infants, children with predisposing syndromes, patients with Philadelphia chromosome-positive disease, tyrosine kinase inhibitors [TKIs], and T-cell ALL).
Chronic Myeloid Leukemia (CML)
What are the phases of CML, and how is each phase identified?
What therapies are approved for treatment?
CML is a myeloproliferative neoplasm, defined by the BCR-ABL1
fusion t(9,22) (also called the Philadelphia chromosome), which is required for diagnosis.
Patients can be in a chronic, accelerated, or blastic phase.
The treatments that are approved for patients with CML are imatinib, nilotinib, and dasatinib.
Compared with imatinib, the second-generation TKIs nilotinib and dasatinib produce significantly higher rates of major molecular response (MMR) and complete cytogenetic response (CCyR) and lower rates of disease progression.
Resistance can often develop to these agents by amplification or mutation of BCR-ABL1
Nilotinib, dasatinib, bosutinib, and ponatinib are approved for resistant disease.
Ponatinib is the only TKI that is effective in patients with the T315I
mutation, but it is toxic to arteries.
Allogeneic HSCT should be considered for patients in accelerated or blastic phase (if donors are available) and may be considered in patients who relapse, have refractory disease, or are intolerant to TKIs. HSCT is the only curative therapy.
Chronic Lymphocytic Leukemia (CLL)
What are the clinical and prognostic features of CLL?
How is CLL staged?
What is the standard first-line treatment?
CLL tends to have a natural history measured in years, and the main threat to life is marrow replacement and subsequent cytopenias and infections.
Clinical features and associated manifestations of CLL include autoimmune hemolytic anemia, thrombocytopenia, hypogammaglobulinemia, and Richter syndrome (aggressive transformation).
The stages of CLL are delineated in the Rai (0–4 based on risk stage) and Binet (A–C based on clinical characteristics) systems. (See Rai and Binet staging.)
Key prognostic features include cytogenetic risk factors (11q and 17p deletion) and other factors (unmutated IGVH
gene, CD38, ZAP70).
Standard therapy is not curative, and patients should be observed unless there is an indication for treatment (e.g., symptoms or advanced stage).
Chemoimmunotherapy is the standard first-line treatment (e.g., fludarabine, cyclophosphamide and rituximab [FCR]). Recent developments include novel therapies combined with chemotherapy, and the antibodies against the B-cell surface antigen CD20, obinutuzumab and ofatumumab, have been found to have significant efficacy in CLL. For resistant CLL, two newer targeted drugs — ibrutinib (targeting Bruton tyrosine kinase) and idelalisib (phosphoinositide 3-kinase) — have demonstrated efficacy. Patients with 17p deletion respond poorly to standard regimens, but ibrutinib can be effective.
Myelodysplastic Syndrome (MDS)
Who is at risk for developing MDS?
How does prognosis differ between primary and secondary MDS?
What are important cytogenetic markers for diagnosis and management?
What management options are available?
What are treatment goals and additional supportive care options?
How is response to treatment defined?
What is the WHO classification for MDS?
What are the cytopenias associated with MDS?
MDS is an acquired clonal stem-cell disorder resulting in cytopenias and dysmorphic cell precursors that carries a risk of transformation to leukemia.
MDS manifests with signs and symptoms of cytopenias due to bone-marrow dysfunction.
Dysplastic features on a peripheral smear (e.g., pseudo-Pelger–Huët anomaly or neutrophil hyposegmentation) and bone marrow with >10% dysplasia, often with blasts, suggest the diagnosis.
Cytogenetic abnormalities may affect management; patients with chromosome 5q deletion alone are responsive to lenalidomide. Various molecular abnormalities have prognostic significance.
Treatment depends on a patient’s risk stratification:
Low- and intermediate-risk patients
receive mostly supportive care.
Intermediate-high– and high-risk patients
receive chemotherapy with hypomethylating agents (azacitidine or decitabine) and are considered for HSCT (in high-risk patients aged >55).
See Clinical Pearls & Morning Reports for more on MDS classification and treatment goals.
What are the clinical manifestations of multiple myeloma?
How does management of multiple myeloma change in the setting of renal failure?
How is multiple myeloma diagnosed, and what are its stages?
When is treatment indicated, and what does it entail?
Who is eligible for transplantation, and what is the risk stratification?
How is disease response evaluated?
The following tables describe diagnostic criteria, evaluation, staging, and management of multiple myeloma:
(Source: Multiple Myeloma, N Engl J Med 2011.)
Management of Multiple Myeloma
(Source: Multiple Myeloma, N Engl J Med 2011.)
Novel agents are standard of care, and eligible patients should be offered stem-cell transplant (SCT) after initial therapy.
See Clinical Pearls & Morning Reports for more on multiple myeloma.
What is the prognosis?
How are typical variants classified?
What are the stages?
What are the complications of therapy?
Hodgkin’s lymphoma is a highly curable subtype of lymphoma with well-defined histology and staging. Patients typically present with lymphadenopathy and constitutional symptoms (fever, unexplained weight loss, night sweats).
The presence of Reed–Sternberg cells in biopsy specimens is pathognomonic.
(Source: Reed–Sternberg-Cell Leukemia and Lactic Acidosis — Unusual Manifestations of Hodgkin’s Disease, N Engl J Med 1964.)
WHO histologic classification is used to classify typical variants:
nodular sclerosis (the most common)
nodular lymphocyte-predominant type
Detailed imaging with CT or positron emission tomography (PET) is required for staging, using the Ann Arbor staging system with Cotswold’s modification.
Management of stages I–II includes ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine), usually without radiation therapy.
Management of stages III–IV involves six cycles of ABVD, or escalated BEACOPP chemotherapy (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).
Late complications of therapy include secondary cancers, cardiac disease (such as heart failure from diminished function), pulmonary toxicity, and hypothyroidism (particularly in patients who receive radiation therapy).
Novel risk-adaptive approaches are being tested wherein patients who respond rapidly (visualized by PET) can receive less therapy and those with persistent disease receive more-intense therapy.
Patients with relapsed or refractory disease receive salvage chemotherapy. Chemosensitive patients are treated with autologous stem-cell transplantation (SCT). Novel agents include brentuximab for relapsed and refractory disease and programmed cell death protein 1 (PD-1) inhibitors.
See Clinical Pearls & Morning Reports for more about the risks for secondary complications and management of Hodgkin’s lymphoma in special situations (e.g., HIV and pregnancy).
Non-Hodgkin’s Lymphoma (NHL)
What are the most common types?
What is the presentation?
What infections are related to NHL?
NHL includes many different subtypes that range from indolent to very aggressive. The most common are diffuse large-B-cell lymphoma and follicular lymphoma.
Aggressive lymphomas often manifest with systemic B symptoms of fever, night sweats, and weight loss; a rapidly growing mass; and extranodal involvement.
Examples of aggressive lymphomas include diffuse large-B-cell lymphoma, Burkitt lymphoma, and adult T-cell leukemia–lymphoma.
More indolent lymphomas typically present with lymphadenopathy, hepato- or splenomegaly, or cytopenias.
Examples of indolent lymphomas include follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma.
Many subtypes are related to infections, including those caused by Epstein–Barr virus (Burkitt lymphoma), Helicobacter pylori
(mucosa-associated lymphoid tissue [MALT] lymphoma), HIV (Burkitt lymphoma and diffuse large-B-cell lymphoma), human T-cell lymphotropic virus (adult T-cell leukemia–lymphoma), and Kaposi sarcoma–associated herpes virus (primary effusion lymphoma).
Patients with NHL can present with oncologic emergencies, including spinal cord compression, pericardial tamponade, hypercalcemia, superior vena cava (SVC) syndrome, hyperleukocytosis, acute airway obstruction, tumor lysis syndrome, hyperviscosity syndrome, and intestinal obstruction, severe autoimmune hemolytic anemia. (See the Oncology rotation guide for more on management of oncologic emergencies.)
includes complete history and physical examination (with attention to all potentially involved lymphoid sites), imaging (CT alone or often CT and PET for determining the stage of disease), and tissue or lymph-node excisional biopsy (needle aspiration is inadequate for lymphoma diagnosis).
depends highly on subtype and aggressiveness but usually consists of a combination chemotherapy and immunotherapy.