Age-specific SEER incidence rates, 2007–2011. Data is from the SEER (Surveillance, Epidemiology, and End Results) program.
Multiple myeloma commonly presents with a hypoproliferative anemia, which is present in about 75% of patients at the time of diagnosis. The anemia is typically normocytic, but macrocytosis may be observed in about 10% of patients.[69] The mechanism of anemia can be multifactorial, including impaired hematopoiesis secondary to marrow infiltration by clonal plasma cells and impaired renal function due to direct effects of the monoclonal protein. In addition to anemia, patients with myeloma may develop bony lytic lesions, hypercalcemia, and renal damage from the monoclonal protein.
| Normal range | Diagnosis | 1 month into therapy | 2 months into therapy | 6 months into therapy | |
|---|---|---|---|---|---|
| Serum-free kappa chains | 3.3–19.4 mg/L | 7.2 | 1.6 | 2.5 | 10.8 |
| Serum-free lambda chain | 5.7–26.3 mg/L | 2890 | 564 | 260 | 148 |
| Kappa/lambda ratio | 0.26–1.65 | 0 | 0 | 0.01 | 0.07 |
Given the high prevalence of myeloma in the elderly, a workup for anemia should include an evaluation for monoclonal gammopathy. About 80% of patients with multiple myeloma have clonal plasma cells that secrete the entire immunoglobulin molecule, which consists of both a heavy and light chain, while 20% of patients have cells that produce only the light chain fragment of the immunoglobulin molecule.[69] This can make the diagnosis of myeloma somewhat challenging, as patients with light-chain only secretory myeloma do not present with increased gamma globulins (gamma gap) and cannot be diagnosed easily with serum protein electrophoresis alone.
Although serum protein electrophoresis and immunofixation (SPEP and SIFE) can be used to detect clonal immunoglobulins, they are not sensitive for detecting light-chain only disease, because light chains are rapidly cleared in the urine. In the past, urine studies (urine protein electrophoresis and immunofixation) were required to detect urinary light chains, also known as Bence-Jones proteinuria. The advent of the serum-free kappa and lambda light chain assay, however, has considerably improved the diagnostic ease in detecting patients with light-chain only secretory myeloma and assessing response to therapy.[70] Because myeloma is a clonal disease, the plasma cells secrete only either kappa or lambda restricted immunoglobulin molecules, and an abnormal ratio of kappa to lambda light chains can be seen in the serum at diagnosis. The light chain assay is also a very useful tool to assess burden of disease, as improvement in the kappa/lambda ratio denotes response to therapy.
Another important plasma-cell dyscrasia that is frequently found in the elderly is monoclonal gammopathy of undetermined significance (MGUS). MGUS is an asymptomatic, premalignant clonal plasma cell or lymphoproliferative disorder defined by the presence of a serum M-protein <3 g/dL, bone marrow biopsy demonstrating <10% clonal plasma cells, and the absence of end organ damage. MGUS is not considered a cancer; however, it is a premalignant state. MGUS always precedes the development of multiple myeloma, initially in the form of smoldering myeloma and ultimately in the development of symptomatic myeloma with end-organ damage. However, a majority of elderly patients will never progress to multiple myeloma in their lifetime and will remain in the category of MGUS.
In a predominantly Caucasian population in Olmsted County, Minnesota, the prevalence of MGUS was about 4.6% in those between the ages of 70 and 79 years and rose to 6.6% in those over 80.[71] This prevalence is about two to three times higher in African Americans. Risk stratification is based on quantification of the monoclonal protein, the free light chain ratio, and characteristics of the clonal immunoglobulin molecule. These factors can help define the risk of progression to a symptomatic multiple myeloma. The risk of progression at 20 years can be as high as 58% in high-risk MGUS, 37% in high-intermediate-risk MGUS, 21% in low-intermediate-risk MGUS, and 5% in low-risk MGUS.[72]
A discussion of therapies for myeloma is out of the scope of this chapter, but suffice it to say that myeloma therapy has evolved to include novel agents such as lenalidomide and bortezomib, which in combination can result in >95% response rates in patients with newly diagnosed myeloma.[73] A majority of elderly patients with myeloma are not considered eligible for high-dose chemotherapy and autologous stem-cell transplantation due to their age and comorbidities.
The leukemias
Chronic lymphocytic leukemia (CLL) is one of the most commonly encountered leukemias in clinical practice in the elderly. Of an estimated 52,380 cases of leukemia diagnosed annually in the United States, approximately 30% of cases are CLL and 11% are chronic myeloid leukemia (CML).[74] CLL is a B-cell chronic lymphoproliferative neoplasm characterized by progressive accumulation of mature, clonal lymphocytes in the bone marrow and peripheral blood. The natural history of the disease, as defined in the 1970s by Rai and colleagues, can vary widely, with median survival times from diagnosis ranging from >150 months in patients presenting with stage 0 disease (defined by lymphocytosis alone) to only 19 months in patients with stage III and stage IV disease (characterized by the presence of anemia and thrombocytopenia, respectively).[75] The incidence of CLL increases dramatically with age from seven cases per 100,000 person-years in those between 50 and 64 years of age to 20 cases per 100,000 person-years in those between 65 and 74, and 30 cases per 100,000 person-years in those 75 or older.[76]
Anemia itself is not the usual presentation in patients with newly diagnosed CLL, as it can take several years to get to the level of marrow infiltration required to cause disruption of normal hematopoiesis. Thus, hypoproliferative anemia, marked by a low reticulocyte count, is usually seen years after diagnosis. Other mechanisms of anemia include autoimmune hemolysis, which can occur in about 4% of patients with CLL and is commonly seen as a presenting sign of CLL.[77] Autoimmune hemolysis detected in patients with CLL is generally characterized by an elevated reticulocyte count (indicative of a bone marrow responsive to anemia) and the presence of an IgG warm autoantibody, which can often be detected on a direct Coombs test. Other immune phenomena associated with CLL include ITP and pure red cell aplasia (PRCA), which are thought to be the result of immune dysregulation.[78]
The distinction between a hypoproliferative anemia and hemolysis is important, as the treatment can be very different; steroids and the anti-CD20 monocolonal antibody rituximab form the backbone of therapy for autoimmune hemolysis, while targeted or combination chemotherapy aimed at the CLL clone forms the mainstay of treatment for anemia related to dense marrow infiltration by the leukemia. The introduction of new oral agents such as the Bruton’s tyrosine kinase inhibitor ibrutinib have the potential to dramatically alter the natural history of even patients with high-risk CLL who relapse after chemotherapy.[79]
CML is a myeloproliferative neoplasm characterized by unregulated growth of cells in the granulocytic lineage (Table 37.2) and is commonly accompanied by thrombocytosis. Hypoproliferative anemia can be seen in advanced cases of patients presenting in accelerated or blast phase. In contrast to CLL, CML is treated rather than observed, even in asymptomatic patients, with highly effective targeted molecules (tyrosine kinase inhibitors) like imatinib.
| Normal range | Stage 0 CLL | CML | AML | |
|---|---|---|---|---|
| White blood count | 4.5–11 k/cu mm | 33 | 82 | 60 |
| Hemoglobin | 13.9–16.3 g/dL | 15.7 | 14.4 | 8 |
| Platelets | 150–350 k/cu mm | 195 | 895 | 30 |
| Neutrophils | 40%–70% | 18% | 63% | 20% |
| Lymphocytes | 24%–44% | 70% | 5% | 5% |
| Bands, myelocytes, and metamyelocytes | 0%–1% | 0% | 22% | 5% |
| Atypical lymphs | 0%–1% | 8% | 0% | 0% |
| Basophils | 0%–2% | 0% | 7% | 0% |
| Blasts | 0%–1% | 0% | 1% | 70% |
Acute myelogenous leukemia (AML) is characterized by accumulation of undifferentiated myeloid precursors (blasts) in the bone marrow and blood with rapidly progressive anemia and thrombocytopenia. It is responsible for about 36% of newly diagnosed leukemias in the United States.[74] Incidence of AML increases with age, with incidence rates of 10 cases per 100,000 person-years in those aged 65–69, 15 cases per 100,000 person-years in those aged 70–74, and 20 per 100,000 person-years in those aged 75–79.[80] AML is a highly aggressive malignancy that is rapidly fatal when untreated. Treating AML in the elderly is very challenging, as the course of therapy required to “cure” this cancer is very poorly tolerated in the older adult. Biologic rather than chronological age comes into play to select those few elderly able to tolerate the rigors of months of intensive chemotherapy regimens required to induce a remission. AML is incurable with chemotherapy alone in the majority of patients; recent advances in stem-cell transplant technology have made allogeneic transplants accessible to the select fit elderly with minimal comorbidities.[81]
Myeloproliferative neoplasms
Polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF) are all myeloproliferative neoplasms (MPN) that exhibit clonal proliferation and differentiation of mature terminal myeloid cells. PV is unique in its epo-independent expansion of the red cell mass with incidence rates that rise with age – in fact, the highest incidence rate of PV is for men aged 70–79 (24 cases/100,000 persons/year).[82]
Virtually all patients with PV have the V617F mutation (a change of valine to phenylalanine at the 617 position) in the Janus kinase 2 (JAK2) gene.[83] This mutation leads to constitutive tyrosine phosphorylation activity that promotes hypersensitivity to cytokines/growth factors and induces epo-independant erythrocytosis. Approximately half of the patients with ET and PMF also have the JAK2 V617F mutation.
Classic clinical findings in these patients with PV include thrombocytosis, erythrocytosis, leukocytosis/neutrophilia, and thrombocytosis with palpable splenomegaly and symptoms of itching and flushing. They have a significant thrombotic risk that can be reduced by phlebotomy (hematocrit goal of 45% in men and 42% in women), anti-platelet agents, and cytoreductive therapy.[84–86]
ET presents with chronic unexplained thrombocytosis; young patients with ET may be asymptomatic and not require therapy, but patients over the age of 60 are considered high-risk for thrombotic events. The incidence of ET rises with age, with the median age of presentation at 72 years.[87] Patients at high risk of thrombosis may benefit from cytoreductive therapy with hydroxyurea or anagrelide in addition to antiplatelet agents.[88–91]
PMF is the rarest of the three JAK2 mutations associated MPNs; it remains a disease of the elderly, with a median age at presentation of about 67 years.[87] Common signs at presentation include leukocytosis with a neutrophil predominance, tear drop cells on the peripheral blood smear due to marrow fibrosis, and extramedullary hematopoiesis, splenomegaly, pruritus, and macrocytic anemia. Ruxolitinib, a JAK1/JAK2 inhibitor, has shown activity in patients with PMF and can be beneficial in reducing splenomegaly and symptomatology.[92, 93]
Summary
In summary, we have outlined here the approach to anemia and hematological disorders in the elderly, with an emphasis on common causes of anemia and general guidelines for initial therapy.
References
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