FP Essentials™ 381
Describe the approach to confirming a diagnosis of chronic myelogenous leukemia (CML) or chronic lymphocytic leukemia (CLL).
Cite the first-line treatment for CML.
Summarize the categories of response to CML treatment relevant to follow-up.
Describe the prevention and treatment approach for patients with newly diagnosed CLL.
Distinguish among the diagnostic characteristics of monoclonal gammopathy of undetermined significance, asymptomatic myeloma, and multiple myeloma (MM).
Describe the most effective diagnostic tests to confirm a diagnosis of MM.
Discuss the role of autologous stem cell transplantation in MM treatment.
Summarize an approach to preventing complications in symptomatic patients with MM and lytic lesions.
List common risk factors for non-Hodgkin lymphoma (NHL).
Describe the approach to diagnosis of NHL.
Cite the modalities used for NHL treatment.
Summarize follow-up and surveillance for NHL survivors.
Cite the definition of myelodysplastic syndrome (MDS) and describe the initial screening evaluation.
Describe the 3 characteristics used by the World Health Organization to classify MDS and the 3 characteristics used to determine prognosis.
Summarize management of anemia and iron overload in patients with MDS.
Describe the only effective treatment procedure for patients with MDS.
Key Practice Recommendations
- Prescribe imatinib 400 mg/day as the standard first-line therapy for patients with newly diagnosed chronic myelogenous leukemia.
- Prescribe bisphosphonates as supportive therapy for patients with symptomatic multiple myeloma to reduce pain and to prevent
vertebral fractures and skeletal-related events.
- Offer iron chelation therapy to patients with myelodysplastic syndrome who have received more than 20 to 30 units of red blood
cells (RBCs), for whom ongoing RBC transfusions are anticipated, and for those with serum ferritin levels greater than 2,500
- For patients with myelodysplastic syndrome with low or intermediate-1 International Prognostic Scoring System scores, postpone
hematopoietic stem cell transplantation until evidence of disease progression develops.
- Strength of evidence: SORT B
Source: O’Brien S, Berman E, Borghaei H, et al; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. J Natl Compr Canc Netw. 2009;7(9):984-1023.
- Strength of evidence: SORT A
Source: Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev. 2010;(3):CD003188.
- Strength of evidence: SORT B
Source: Greenberg PL, Attar E, Bennett JM, et al; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: myelodysplastic syndromes. Version 1.2011.
- Strength of evidence: SORT C
Source: Greenberg PL, Attar E, Bennett JM, et al; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: myelodysplastic syndromes. Version 1.2011.
AAFP FP Essentials™ Approved as CME Clinical Content
This activity, FP Essentials™, has been reviewed and is acceptable for up to 60 Prescribed credit(s) by the American Academy of Family Physicians. AAFP accreditation begins June 1, 2010. This activity conforms to the AAFP criteria for evidence-based CME clinical content. Term of approval is for two year(s) from this date with the option of yearly renewal. Each monograph is approved for 5 Prescribed credit(s). Credit may be claimed for 2 years from the date of each monograph.
The evidence-based CME for this activity was based on a current clinical question that identifies gaps in learners’ knowledge, competency and/or performance in medical practice as identified in the current evidence available at the time this activity was approved. Since clinical research is ongoing and new evidence to supporting practice improvement is constant, the AAFP recommends that learners verify sources and review these as well as practice recommendations prior to implementation into practice.
Of all the patients with hematologic malignancies I have treated, I remember best those who died from them. One patient in particular, a dapper retired professor who had an easily identifiable whistle, was a favorite of mine. He was diagnosed with chronic lymphocytic leukemia (CLL) and did well for many years. However, when he developed recurrent pneumonias, I knew trouble was ahead. Despite more aggressive therapy, he never regained his strength or his whistle, and he died within the year. It seems that even with current treatments, survival rates associated with CLL have remained unchanged, yet I can’t help but think that with use of the newer combination therapies he might have suffered less.
I read this edition of FP Essentials™ with great interest. I was heartened by the new chronic leukemia treatments that are improving progression-free survival rates and decreasing the occurrence of severe opportunistic infections. I enjoyed learning more about autologous stem cell transplantation conditioning therapy for multiple myeloma, and was intrigued by the multiple risk factors and prognostic factors for non-Hodgkin lymphoma. Given the increasing recognition of myelodysplastic syndrome, I found the information about the role of cytogenetic analysis for prognostic information and hematopoietic stem cell transplantation for treatment particularly useful. I hope that you find this edition as enlightening as I did.
Mindy A. Smith, MD, MS, Associate Medical Editor
Professor, Department of Family Medicine
Michigan State University College of Human Medicine, East Lansing
Hematologic malignancies account for approximately 10% of new cancer diagnoses and 10% of cancer mortalities in the United States., It is critical for family physicians to recognize the signs and symptoms of these conditions and understand how they are evaluated and treated by oncology subspecialists. This edition of FP Essentials™ will update physicians on recent advances in the diagnosis and treatment of 4 categories of hematologic malignancies: chronic leukemia, multiple myeloma, non-Hodgkin lymphoma, and myelodysplastic syndrome.
Fortunately, many new and effective therapies for these 4 conditions have been developed in recent years, after treatments have lagged decades behind advances made in treating acute leukemias and Hodgkin lymphomas. Familiarity with these therapies, their most common side effects, and the therapeutic dilemmas faced by patients and their families will enhance the quality of collaborative care for patients with these challenging-to-treat conditions.
Chronic Leukemia Management Update
Case 1. Louise, a 57-year-old woman, presents with fatigue and weight loss. On physical examination, splenomegaly and bruising are present.
The white blood cell (WBC) count is elevated at 360,000 cells/mcL; the hemoglobin level and platelet count are normal. The WBC count differential shows 72% neutrophils, 12% bands, 3% metamyelocytes, 3% myelocytes, 2% promyelocytes, 4% basophils, and 4% lymphs. Abdominal ultrasound results confirm splenomegaly.
The blood test results reflect normal maturation of WBCs typically found in the bone marrow, with myelocytes, bands, and segmented neutrophils. You obtain a cytogenetic analysis. The results are positive for Philadelphia chromosome (a translocation between the long arms of chromosomes 9 and 22), and you refer Louise to an oncology subspecialist.
Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) should be suspected in patients who present with fatigue, lethargy, and abdominal discomfort. The main finding on physical examination is usually splenomegaly. Although the platelet count is typically normal, the cells are often dysfunctional, resulting in purpura. The white blood cell (WBC) count is most often between 100,000 cells/mcL and 300,000 cells/mcL; the full spectrum of WBCs is present on peripheral test. A mild basophilia is typically present; anemia and thrombocytopenia are less common.
Identification of reciprocal translocation between chromosomes 9 and 22 confirms the diagnosis. Techniques to test for the Philadelphia, or Ph1, chromosome include conventional cytogenetic analysis, fluorescence in situ hybridization (FISH) analysis, and reverse transcription polymerase chain reaction (PCR). More than 90% of patients with CML exhibit the typical Ph1 chromosome; the majority of these patients are diagnosed using conventional cytogenetic analysis. The Ph1 chromosome causes disease via the protein product of the BCR-ABL genes. This fusion protein exhibits dysregulated tyrosine kinase activity, which can cause leukemogenesis.
Chronic myelogenous leukemia is divided into 3 phases: chronic, accelerated, and blastic transformation. The majority of patients are diagnosed in the chronic phase, which is easily managed. The World Health Organization defines the accelerated phase of CML as including the presence of 1 or more of the following: 10% to 19% blasts in blood or bone marrow, peripheral blood basophils greater than 20%, platelet count less than 100,000/mcL unrelated to therapy, platelet count greater than 1,000,000/mcL and not improving with therapy, progressive splenomegaly or increasing WBC count not improving with therapy, or cytogenetic evolution.
Patients treated with oral chemotherapy and some treated with imatinib (Gleevec) will ultimately develop blastic transformation. This is characterized by increasing blast percentage, large clusters of blasts on bone marrow biopsy, lack of improvement with therapy, and extramedullary disease.
Therapy for CML was revolutionized with the Food and Drug Administration approval of imatinib in 2001. This orally active tyrosine kinase inhibitor has become the standard first-line therapy for patients with newly diagnosed chronic phase CML.Before imatinib, standard therapy consisted of interferon and cytarabine, which was found to be more effective than interferon alone. Initially, imatinib was found to be effective in patients who did not benefit from interferon therapy.
The International Randomized Study of Interferon and STI571 (IRIS) trial showed a marked benefit of imatinib compared with interferon and cytarabine.This crossover trial involved more than 1,000 patients with newly diagnosed CML who were randomized to receive imatinib or interferon plus cytarabine.
Patients who received imatinib as initial therapy for chronic phase CML had event-free and overall survival rates of 89% and 83%, respectively. Of the 318 patients who crossed over to imatinib after receiving interferon plus cytarabine, 82% experienced a complete hematologic response and 56% experienced a major cytogenetic response.
Five-year follow-up data showed durability of these results.Patients who experienced complete cytogenetic response by 12 months had better overall progression-free survival rates. The most common adverse effects of imatinib were mild and included edema, nausea, muscle cramps, and rashes.
After therapy, close follow-up is warranted. Patients are categorized as exhibiting hematologic response (assessed by a complete blood count [CBC]), cytogenetic response (assessed by bone marrow biopsy with conventional cytogenetic or FISH analysis), or molecular response (assessed by PCR of peripheral blood). At diagnosis, a bone marrow evaluation is performed with conventional cytogenetic and FISH analysis.As follow-up, FISH analysis of the peripheral blood should be obtained every 3 months to assess cytogenetic response.
Treatment goals include normal CBC results by 3 months (complete hematologic response), less than 35% Ph1-positive cells by 12 months (major cytogenetic response), and 0% Ph1-positive cells by 18 months (complete cytogenetic response). If these outcomes are not achieved, alternative therapies should be considered.
Case 1, cont’d. Louise visits the oncology subspecialist, who prescribes hydroxyurea for 1 week to decrease the WBC count, then initiates imatinib 400 mg once daily. Within 2 weeks, the CBC results are normal. In the next few months, Louise undergoes frequent CBC testing to monitor for hematologic response and toxicity. Approximately 1 year after diagnosis, she undergoes a repeat bone marrow analysis with cytogenetic tests. The results show no evidence of Ph1 chromosome-positive cells. Louise is classified as having a complete cytogenetic response.
She continues to take imatinib for more than 4 years. She also undergoes routine fluorescence in situ hybridization analysis of peripheral blood, and the results are negative for the Ph1 chromosome. She experiences mild side effects from imatinib, including diarrhea, edema, and muscle aches, which are treated symptomatically.
When a patient does not benefit from or is intolerant of imatinib, a repeat bone marrow biopsy should be performed. Mutational analysis of BCR-ABL can be helpful because the presence of certain mutations can determine future therapeutic choices. Two new tyrosine kinase inhibitors, dasatinib (Sprycel) and nilotinib (Tasigna), have been approved for patients who do not benefit from or are intolerant of imatinib. Karyotype analysis can help determine the most effective second-line drug.
Allogeneic stem cell transplantation is also a treatment option. The prognosis for each patient depends on several variables: age, interval from diagnosis to transplantation, disease phase, donor-recipient sex match, and donor type (ie, matched related versus matched unrelated).With the advent of imatinib, the optimal timing of transplantation has become less well-defined because more patients with CML experience prolonged benefit from this therapy.
Chronic Lymphocytic Leukemia
Case 2. Susanna is a 66-year-old woman with diabetes and hypertension who presents to your office with fatigue. She denies fever, chills, or night sweats. The physical examination results are negative for lymphadenopathy or splenomegaly. You obtain a complete blood count, which reveals a white blood cell count of 40,000 cells/mcL, with 70% lymphocytes, 25% neutrophils, and 5% monocytes. The peripheral blood test results are notable for lymphocytosis and ruptured or smudge cells. The hemoglobin level and platelet count are normal.
Your local oncology subspecialist recommends obtaining a flow cytometry of peripheral blood, which reveals a monoclonal B-cell process positive for CD5, CD19, CD20, and CD23. The cells are kappa light chain restricted. The zeta chain-associated protein kinase 70 (ZAP-70) level is elevated at 80%; the CD38 test result is negative. Fluorescence in situ hybridization analysis for cytogenetic abnormalities is positive for trisomy 12. Bone marrow biopsy is performed to determine prognosis. The pattern of lymphocytic infiltration is diffuse.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries and accounts for 30% of all leukemias.smudge cells.CLL is a monoclonal lymphocyte condition that causes defective humoral and cellular immunity. Although CLL is often considered an indolent cancer that requires no treatment for more than 10 years, this is the case only for approximately one-third of patients. CLL should be suspected in patients with lymphocytosis with no other obvious etiology. Peripheral blood test results will show lymphocytosis and
Bone marrow aspirate is not required for initial diagnosis but is often obtained if chemotherapy is instituted or cytopenias develop. Cytogenetic and immunologic analysis of abnormal lymphocytes is now possible and can provide information about prognosis.
Flow cytometry can confirm presence of a monoclonal process with typical CD5 positivity of the CLL B cells. The CD5 antigen is typically found on T cells, although it can be found on B cells in healthy patients.B-cell antigens, such as CD19, CD20, CD21, CD23, and CD24, typically are also found. Low levels of surface immunoglobulin are expressed, and only 1 type of light chain is expressed.
Staging for CLL is based on either the Rai staging system or the Binet classification. The Rai system is primarily used in the United States and divides CLL into 5 stages (Table 1). The expected life span is greater than 10 years for patients with stage 0 CLL, 6 to 8 years with stages I to II, and less than 2 years with stages III to IV.
Table 1 Chronic Lymphocytic Leukemia Staging and Prognosis
Chronic Lymphocytic Leukemia Staging and Prognosis
Lymphocytosis in blood or bone marrow
Lymphocytosis and lymphadenopathy
6 to 8 years
Lymphocytosis and enlarged liver and/or spleen with or without lymphadenopathy
6 to 8 years
Lymphocytosis and anemia (hemoglobin level <11 g/dL) with or without enlarged liver, spleen, or lymph nodes
Lymphocytosis and thrombocytopenia (platelet count <100,000/mcL) with or without anemia or enlarged liver, spleen, or lymph nodes
Information from Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219-234.
The patient in Case 2 has stage 0 disease because she only has lymphocytosis. Although the prognosis for this patient is good, early stage disease can progress rapidly in some patients.
Lymphocyte doubling time (LDT) and pattern of bone marrow infiltration have been used to help further determine prognosis in patients with early stage disease. If patients with CLL have an LDT of greater than 12 months, the prognosis is good.The clinical course is typically slower, with a nodular nondiffuse pattern of bone marrow involvement compared with diffuse marrow involvement.
Newer prognostic criteria have been developed, such as the zeta chain-associated protein kinase 70 (ZAP-70), which typically functions as a T-cell receptor enzyme and is not found on B lymphocytes. The presence of elevated levels of ZAP-70 detected by flow cytometry on CLL cells is associated with poor prognosis.
Mutational status of immunoglobulin variable heavy chain (IgVH) genes has also been found to correlate with survival. Unmutated IgVH genes (ie, less than 2% difference in nucleotide sequences compared with germline DNA) found in patients with CLL are associated with shorter life spans.The presence of CD38 is also associated with poor prognosis.
Mutational analysis of the IgVH gene is not readily available in most community hospital settings; however, ZAP-70 results can be easily obtained via flow cytometry. Studies have correlated elevated ZAP-70 level with unmutated IgVH genes and a more aggressive clinical course.,
Cytogenetic studies can help predict prognosis. One study identified 5 major categories of cytogenetic analysis findings.,Normal karyotype, trisomy 12, and 13q deletions were associated with median survival of approximately 10 years. Finding of 17p deletion was associated with 32-month median survival, and 11q deletion was associated with approximately 6.5-year median survival. Mutations of the p53 gene, a tumor suppressor gene located on the short arm of chromosome 17, have been shown to be markers of poor prognosis among patients with CLL.
Case 2, cont’d. Test results for Susanna reveal an elevated ZAP-70 level, a diffuse pattern on bone marrow aspiration, and lymphocyte doubling time of less than 1 year. She also has experienced significant (ie, greater than 10%) weight loss. You discuss the findings with Susanna, and together decide to initiate therapy.
Therapy is indicated when a patient develops constitutional B symptoms that signal disease transformation (eg, fever, chills, night sweats, weight loss) or symptoms related to adenopathy, anemia, or thrombocytopenia. As with the patient in Case 2, LDT should also be considered. Immediate treatment with oral alkylating therapy in asymptomatic patients with early stage CLL has not been shown to be more effective than observation.
Chlorambucil (Leukeran) was considered the standard first-line agent for CLL treatment until fludarabine was found to be associated with higher overall response rates and longer progression-free survival.Overall survival rates were similar. Adverse effects associated with fludarabine include myelosuppression and hemolytic anemia.
Rituximab (Rituxan), a chimeric monoclonal antibody directed against the cell-surface antigen CD20, was found to be effective in CLL treatment.Therefore, investigators combined fludarabine with rituximab. One study reported a 90% response rate (47% complete and 43% partial) with this combination. In this study, 59% of patients had stage I or II disease and 41% had stage III or IV disease. This regimen was associated with a 76% rate of severe neutropenia and a 20% rate of severe infection, including opportunistic infections.
The addition of cyclophosphamide to fludarabine plus rituximab is also effective. Several recent small phase II trials have found benefits of this combination., There has been no reported overall survival benefit with any particular fludarabine-based regimen.
The average age of patients with CLL is 70 years, and therapy does not traditionally begin until the condition progresses to advanced stages. A 6-year follow-up study involved 300 patients with CLL who were treated with cyclophosphamide, fludarabine, and rituximab.It found that patients ages 70 years and older exhibited poorer response to the treatment. The complete response rate among patients older than 60 years was 75%; ages 60 to 70 years, 77%; and age older than 70 years, 51%. The risk of infection decreased over time, and the occurrence of severe opportunistic infections was limited to the first year of remission.
Alemtuzumab (Campath) is a recombinant humanized monoclonal antibody directed against CD52. This cell-surface protein is expressed on most normal and malignant lymphocytes.After alemtuzumab was found to be associated with a 33% response rate in patients with CLL refractory to fludarabine treatment, it was compared directly with chlorambucil in a randomized trial of untreated patients. The study showed an improved overall response rate and longer progression-free survival with alemtuzumab, but found no overall improved survival benefit.
Fifteen percent of patients taking alemtuzumab developed symptomatic cytomegalovirus infections. These patients completed standard antiviral therapy and did not appear to influence the response rate.
One study found a response rate of 96% among 28 patients with CLL who took rituximab with corticosteroids.This treatment offers a relatively nontoxic alternative for elderly symptomatic patients with CLL.
Finally, the combination of pentostatin (Nipent) with cyclophosphamide and rituximab shows promise. One trial found that patients older than 70 years benefited from this regimen as much as younger patients, and with no associated excessive bone marrow toxicity or serious infections.As with other trials, however, patients with deletion of the short arm of chromosome 17 experienced less benefit.
Oncology subspecialists typically do not consider patients with CLL eligible for therapy until the condition has progressed to the advanced stage. The patient in Case 2 is a candidate for several treatment options. Single-agent alkylator therapy; the pentostatin, cyclophosphamide, and rituximab regimen; or rituximab combined with corticosteroids could be considered reasonable options.
At least 50% of patients with CLL die due to an infectious process.Haemophilus influenzae type b vaccine once, and both influenza vaccines annually (http://www.immunize.org/immschedules/immschedule_adult.pdf). Vaccination with live vaccines, such as varicella, should be avoided.Respiratory infections with encapsulated bacteria are common early in the course of CLL and during alkylator therapy. Patients with CLL should receive pneumococcal vaccine every 5 years,
Patients treated with purine analogs, such as fludarabine and pentostatin, and monoclonal agents develop more opportunistic infections, such as Pneumocystis jiroveci pneumonia, aspergillosis, and cytomegalovirus and herpes virus infections. Intravenous gamma globulin use is controversial, and prophylactic antibiotics and antifungals are often used as empiric treatments.
Advances in Multiple Myeloma Management
Case 3. Maxwell is a 68-year-old man presenting with 6 months of back pain and a 4.5-kg (10-lb) weight loss. He has been taking naproxen for pain relief. A compression fracture is seen at T12 on x-ray. Laboratory test results reveal an elevated total protein level of 10 g/dL, serum creatinine level of 1.8 mg/dL, serum calcium level of 11.1 mg/dL, and normocytic anemia. Serum protein electrophoresis results show a monoclonal gamma-globulin spike of 3.5 g/dL. The serum beta-2 microglobulin level is 6.1 mg/L.
Multiple myeloma (MM) is a plasma cell malignancy. Currently, more than 60,000 individuals are diagnosed with MM in the United States each year, and it is the second most common hematologic malignancy.The median age at diagnosis is 70 years, with increasing prevalence with age. The age-adjusted prevalence rate is approximately 2 times greater in blacks compared with whites, and MM is more common in men.
Plasma cells are terminally differentiated B cells that produce immunoglobulins (Igs) to fight infection. MM is a proliferation of monoclonal plasma cells that results in overproduction of Ig (M protein) and light chains (Bence Jones proteins). The typical M protein types in myeloma are IgG (60%); IgA (20%); light chain only (15%); and IgE, IgD, IgM, or nonsecretory (2% or less).
The myeloma cells additionally produce several cytokines and growth factors that increase osteoclastic bone resorption, inhibit osteoblastic bone formation, and promote angiogenesis. These processes result in the end-organ damage that characterizes MM: invasive bone lesions causing pain, pathologic fractures, osteoporosis, and hypercalcemia; bone marrow invasion resulting in anemia and immunodeficiency; light chains that can lead to renal insufficiency, amyloidosis, and peripheral neuropathy; and hyperviscosity from the M protein.
Multiple myeloma is thought to evolve from the premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS).The exact mechanism triggering this transformation is not completely understood. MGUS occurs in 3.2% of the population older than 50 years and is 80 to 100 times more common than MM.
The risk factors for progression of MGUS to MM include an M protein level greater than 1.5 g/dL, presence of non-IgG type M protein, and an abnormal free light-chain ratio. Patients with MGUS and no risk factors have a 5% risk of progression to MM at 20 years; the rate of progression is 58% when all 3 risk factors are present.Regular follow-up and laboratory testing to assess disease progression are warranted; the frequency of follow-up varies depending on risk factors.
Common presenting MM symptoms include bone pain (58%), pathologic fractures (34%), fatigue (32%), weight loss (24%), and recurrent infections.One-third of patients are asymptomatic at the time of diagnosis. These patients are identified through incidental laboratory test result abnormalities, such as elevated total protein level, hypercalcemia, elevated creatinine level, elevated erythrocyte sedimentation rate (ESR), or anemia. Rarer signs and symptoms include plasmacytomas, hyperviscosity syndromes and amyloidosis-related gastrointestinal (GI) symptoms, peripheral neuropathy, or cardiomegaly.
The International Myeloma Working Group developed criteria to define MM, asymptomatic myeloma (smoldering myeloma), and MGUS (Table 2). Symptomatic MM is defined by the presence of M protein in serum or urine, clonal plasma cells in bone marrow, and end-organ damage.
Table 2 Diagnostic Criteria for MGUS, Asymptomatic MM, and MM
Diagnostic Criteria for MGUS, Asymptomatic MM, and MM
Serum monoclonal protein level <3 g/dL; clonal bone marrow plasma cells <10%; and absence of end-organ damage, hypercalcemia, renal insufficiency, anemia, and lytic bone lesions
5% to 58% risk of progression, based on risk factors
Serum monoclonal protein level ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%; absence of end-organ damage, hypercalcemia, renal insufficiency, anemia, and lytic bone lesions
Cumulative probability of progression to symptomatic MM is 73% by 15 years
Greater percentage of plasma cells in bone marrow and greater serum monoclonal protein level predict earlier progression
Serum monoclonal protein >3 g/dL; clonal bone marrow plasma cells >10%; and presence of end-organ damage, hypercalcemia, renal insufficiency, anemia, or lytic bone lesions
Serum beta-2 microglobulin level <3.5 mg/L and serum albumin level ≥3.5 g/dL
Not stage I or III
Serum beta-2 microglobulin level >5.5 mg/L
aThe condition of most patients with MM and renal failure will be categorized as stage III regardless of tumor burden.
MGUS = monoclonal gammopathy of undetermined significance; MM = multiple myeloma.
Information from Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldenström macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc. 2006;81(5):693-703 [Review]. Erratum in Mayo Clin Proc. 2006;81(11):1509; Greipp PR, San Miguel JF, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412-3420. Erratum in J Clin Oncol. 2005;23(25):6281; Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582-2590.
Laboratory screening tests for suspected MM include complete blood count (CBC) with differential, chemistry profile, ESR, and serum and urine protein electrophoresis.The addition of immunofixation to electrophoresis improves the detection of M proteins in patients with myeloma from 82% for serum protein electrophoresis to 93%. The further inclusion of urine protein electrophoresis or serum free light-chain assay brings the detection rate to 97%. Immunofixation also allows for classification of heavy- or light-chain class.
Bone marrow aspiration and trephine biopsy are required to establish the diagnosis of MM. Bone marrow infiltration can be patchy, and multiple aspirations might be needed. Further analyses with metaphase cytogenetic analysis, fluorescence in situ hybridization (FISH), and flow cytometry are used to provide prognostic data. Tumor burden can be estimated with measurement of serum beta-2 microglobulin level.
A skeletal survey is also recommended in the initial evaluation of patients with MM. Recommended views include complete spine, pelvis, skull, humeri, and femurs.Repeat x-rays are indicated to evaluate any new symptomatic areas.
Further imaging with computed tomography (CT) scan and magnetic resonance imaging (MRI) study should be performed in select patients. CT scan is useful for clarifying ambiguous findings and evaluating symptomatic areas that appear without pathologic lesions on x-rays. MRI study is the test of choice when spinal cord compression is suspected. CT scan and MRI study can be used to evaluate soft-tissue lesions and can provide complementary information. Bone scans and dual energy x-ray absorptiometry scans have no role in the management of MM.
Case 3, cont’d. You diagnose Maxwell with International Staging System stage III multiple myeloma, which is high risk. He declines autologous stem cell transplantation and elects to undergo chemotherapy.
Prognosis of patients with MM traditionally has been determined through the Durie-Salmon staging system, which assesses tumor mass based on hemoglobin level, calcium level, M protein production, IgG and IgA peaks, Bence Jones protein level, and presence of lytic bone lesions.Table 2).This staging system has been replaced by the International Staging System, which uses 2 variables: serum beta-2 microglobulin and serum albumin levels (
Further risk stratification of myeloma is determined through evaluation of genetic markers. The Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) uses plasma cell FISH analysis, metaphase cytogenetic analysis, and plasma cell labeling index to evaluate for specific genetic abnormalities.Patients are then classified as high risk (25% of patients) or standard risk (75%) depending on the abnormalities present. Risk class is then used to select a treatment regimen, with high-risk patients receiving more aggressive therapy.
Patients with MM traditionally have been treated with alkylating agents and dexamethasone. With recent major advances in treatment, the overall 5-year survival rate has increased from 26% to 40% over the past 30 years.The regular use of autologous stem cell transplantation (ASCT) has contributed greatly to improved survival rates and has become a significant component of therapy for eligible patients.
Autologous Stem Cell Transplantation
Autologous stem cell transplantation is associated with higher rates of complete response and improvement in overall survival rates; there is a 1% to 2% treatment-associated mortality rate.Criteria for ASCT eligibility vary among treatment centers but are typically determined by age, functional capacities, and comorbidities. Survival rates are comparable between patients who receive ASCT at the time of progression and those who receive it earlier, although early transplantation is recommended because of the possibility that patients will no longer be candidates later in the disease course.
Myeloablative doses of melphalan (Alkeran) are used for ASCT conditioning therapy, which is high-dose chemotherapy administered as a precursor to stem cell transplantation. Tandem ASCT, a preplanned repetition of the initial high-dose chemotherapy/stem cell infusion, has been shown to be beneficial in patients who do not achieve an adequate partial response with initial conditioning therapy.
Immunomodulatory and Proteasome Inhibitor Drugs
In the past decade, 2 newer drug classes—immunomodulatory drugs and proteasome inhibitors—have significantly improved response rates compared with traditional therapy for MM. These drugs are used for initial therapy and recurrence.
Thalidomide (Thalomid), an immunomodulatory drug thought to inhibit angiogenesis, was the first of the novel therapies for MM to come into use. Thalidomide was first shown to be effective as monotherapy for MM in 1999.Subsequent trials showed improved response rates when combined with traditional therapy compared with traditional therapy alone.
The rate of deep venous thrombosis (DVT) is increased with use of thalidomide; concomitant dexamethasone use increases this risk. Aspirin is recommended for DVT prophylaxis in patients taking thalidomide combined with low-dose dexamethasone.Prophylactic-dose low-molecular-weight heparin or full anticoagulation with warfarin is needed when high-dose dexamethasone is combined with thalidomide. Additional adverse effects include hypothyroidism, bradycardia, syncope, peripheral neuropathy, sedation, rash, constipation, and fatigue.
Lenalidomide (Revlimid) became the second immunomodulatory drug approved for use in the treatment of MM in 2006.For MM treatment, it is approved for use in combination with dexamethasone. A less toxic analog of thalidomide, lenalidomide has been associated with high response rates with fewer adverse effects than thalidomide. DVT remains a common complication with lenalidomide and dexamethasone combination therapy, and the same DVT prophylaxis used with thalidomide is recommended. Additional adverse effects include cytopenias, fatigue, and rash.
Bortezomib (Velcade) is a proteasome inhibitor approved for use in MM treatment in 2003. Proteasomes function in cellular metabolism and regulation by degrading proteins. By inhibiting proteasome function, bortezomib leads to cellular apoptosis.Bortezomib has been shown to be extremely effective in improving response rate, median time to progression, and 1-year survival, and is now used in combination therapies. Peripheral neuropathy occurs in 45% of patients taking bortezomib and frequently can be severe. Other common adverse effects include cytopenia, fatigue, fever, and GI side effects.
Response to Treatment
The International Myeloma Working Group released standardized response criteria for MM in 2006.These criteria are for use in clinical trials and to guide some treatment decisions. Many of the same tests used in establishing the diagnosis of MM are used in determining response, with emphasis placed on changes in M protein levels measured by electrophoresis and immunofixation.
The various response categories for treated MM include stringent complete response, complete response, very good partial response, partial response, stable disease, and progressive disease. Very good partial response, a commonly used category denoting substantial tumor reduction, is a clinically significant stage used in post-ASCT evaluation. It is defined as a serum or urine M protein level detectable with immunofixation but not with electrophoresis, or a decrease of serum M protein level by greater than 90% with the urine M protein level less than 100 mg/24 hours.
Disease progression is identified by any of these criteria: an increase of 25% or more from the baseline levels of serum or urine M protein; increase in free light chain level or bone marrow plasma cell percentage; development of hypercalcemia; development of new bone lesions or new soft tissue plasmacytomas.
Approach to Treatment
Initial therapy for MM should be initiated in patients with symptomatic disease. Early treatment is not indicated in patients with smoldering myeloma because it has not been shown to be beneficial. The therapeutic goals for initial therapy should be to rapidly control disease, reverse disease-related complications, decrease early mortality risk with minimal toxicity, and allow for collection of stem cells when ASCT is a therapeutic option.
For patients for whom ASCT is an option, those with standard-risk myeloma should be treated with a lenalidomide- or bortezomib-containing regimen. There is a low threshold for adding the other agent if there is a poor initial response. Patients with high-risk myeloma should be treated with a bortezomib-containing regimen. Patients who are not candidates for ASCT should be treated with melphalan-prednisone-thalidomide or melphalan-prednisone-bortezomib. Frail older patients can be treated with melphalan-prednisone because of increased toxicities associated with novel therapies.
Maintenance therapy is currently recommended only after ASCT.Patients with standard-risk MM who experience limited benefit and who opt not to undergo tandem ASCT usually benefit from thalidomide maintenance therapy. Lenalidomide can be administered as maintenance therapy in patients with high-risk MM until time of disease progression. The standard use of maintenance drugs has not been established for patients who are ineligible for ASCT.
Multiple myeloma is a disease characterized by recurrences. The treatment for recurrent myeloma is individualized, with consideration given to prior treatments, timing of recurrence, age, and clinical circumstances. As the disease progresses, the use of palliative care in accordance with the wishes of the patient and family is essential.
Complications of Treatment
Case 3, cont’d. Maxwell begins treatment with melphalan-prednisone-thalidomide. Intravenous pamidronate and narcotic analgesics are started for management of hypercalcemia and bone pain.
Pain control is a significant component of MM management. Family physicians should assess pain at every visit and should be comfortable with the use of opiates. Use of nonsteroidal anti-inflammatory drugs should be avoided in patients with MM because of the increased risk of renal insufficiency.
Bisphosphonates have been shown to decrease the number of skeletal events in patients with MM. Their mechanism of action is to inhibit osteoclasts, which have increased activity in myeloma. They are currently recommended for use in patients with MM and lytic bone lesions on skeletal survey or those with osteoporosis or osteopenia.
Intravenous infusions of pamidronate and zoledronic acid are approved for use in patients with MM; however, there is growing evidence for use of pamidronate because of a lower incidence of osteonecrosis of the jaw. Monthly treatment should be continued for 2 years, at which time further treatment can be considered.
Osteonecrosis of the jaw is a painful condition associated with bisphosphonate use, especially after dental procedures. It is recommended that patients undergo dental procedures before starting therapy. Patients taking bisphosphonates should pursue regular preventive dental care and discontinue use of bisphosphonates 1 month before any planned dental procedure.
Bone lesions can require localized treatment to reduce pain and prevent further complications. Fractures from long-bone lesions are treated with surgical fixation, and local radiation can be used to manage refractory pain.Patients with vertebral lesions can achieve adequate pain relief with percutaneous vertebroplasty (ie, injection of bone cement into the vertebra) and kyphoplasty (ie, re-expansion of the collapsed vertebra with a balloon before injection of methyl methacrylate). Spinal cord compression is treated with corticosteroids and radiation therapy; occasionally, surgical decompression is needed to manage spinal instability.
Infection control is a critical consideration for patients with MM. Immunization should be offered for influenza, pneumococcus, and Haemophilus influenzae type b, although response to immunization can be suboptimal.
Prophylactic antibiotic treatment is often used in conjunction with chemotherapeutic agents. Trimethoprim-sulfamethoxazole can be administered during the first 2 months of therapy with standard alkylating agents.Use of acyclovir (Zovirax) is recommended with bortezomib therapy because of an increased incidence of herpes zoster.
All patients with MM who present with febrile illness should be started on broad-spectrum antibiotics. Because of the prevalence of renal insufficiency among these patients, aminoglycosides should be used with caution. Patients with recurrent infections might benefit from administration of intravenous immunoglobulin.
Anemia is common at initial presentation and can recur with disease progression. Anemia typically improves with initial chemotherapy. Erythropoietin can be used in patients who do not respond to chemotherapy.Transfusion and erythropoietin should be considered for symptomatic patients; however, use of erythropoietic agents is associated with higher DVT risk in patients receiving thalidomide or lenalidomide. Additionally, family physicians should remain alert for other etiologies of anemia in these patients.
Hypercalcemia should be treated with rehydration. Patients with mild cases might require only oral rehydration, whereas patients with more severe cases require intravenous hydration.All patients should be started on bisphosphonates.
Renal insufficiency is common, and reversible etiologies such as hypercalcemia, dehydration, and drug-induced nephrotoxicity should be suspected.Consultation with a nephrology subspecialist is indicated if symptoms do not improve, and dialysis or plasma exchange therapy might be indicated.
Advances in Non-Hodgkin Lymphoma Management
Case 4. Kent, a 40-year-old man with a history of AIDS related to intravenous drug abuse, presents to the emergency department with a gradually worsening headache associated with vomiting over the past month. Magnetic resonance imaging study of the brain with and without gadolinium contrast reveals a solitary enhancing mass in the right frontal lobe.
Lymphomas are a heterogeneous group of lymphoproliferative malignant diseases that account for 4% of cancers diagnosed annually in the United States.Lymphomas are the fifth most common type of cancer and the fifth leading cause of cancer mortalities.
Hodgkin lymphoma (also called Hodgkin disease) and non-Hodgkin lymphoma (NHL) begin in the lymphatic tissue and can spread to other organs. Hodgkin lymphoma, which typically begins as a painless enlargement of the lymph nodes, tends to spread in a more predictable pattern than NHL. Hodgkin lymphoma is marked by the presence of Reed-Sternberg cells and accounts for only 10% of lymphomas.With 65,980 new cases and 19,500 mortalities in 2009, NHL is the most common hematologic cancer and has the second fastest-growing incidence among cancers in the United States.
There are more than 50 different types of lymphoma, including subtypes. The World Health Organization classification system differentiates between lymphomas of B-cell, T-cell, and natural killer (NK)-cell neoplasm origins and whether they are derived from precursor or mature lymphocytes.Further subclassification is based on histology, immunophenotype, and cytogenetic and molecular characteristics. Treatment and prognosis vary by type and stage at diagnosis.
This section focuses on the 6 most common types of NHL, which account for 80% of all NHL: diffuse large B-cell lymphoma (31%), follicular lymphoma (22%), small lymphocytic lymphoma (6%), mantle cell lymphoma (MCL) (6%), peripheral T-cell lymphoma (6%), and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) (5%).Treatment strategies are also influenced by whether the type of NHL tends to be indolent or aggressive.
Chronic infection, immunosuppression, environmental stressors, and certain hereditary traits have been linked with certain types of lymphomas. In these situations, chronic stimulation of the immune system can lead to dysregulation of different kinds of cells. Chronic infections, such as with Epstein-Barr virus, have been associated with Hodgkin lymphoma. Posttransplant lymphoproliferative disorder has been linked with endemic Burkitt lymphoma. Adult T-cell leukemia/lymphoma is seen with human T-lymphotropic virus 1 infection.
Treatment of Helicobacter pylori infection can lead to regression of early stage gastric MALT lymphoma. Autoimmune diseases, including rheumatoid arthritis and Sjögren syndrome, are associated with diffuse large B-cell lymphoma and some marginal zone lymphomas. Enteropathy-associated T-cell lymphoma has been linked to celiac disease.
Environmental stressors associated with development of lymphoma include ionizing radiation such as sunlight, agricultural pesticides, and dark hair dyes manufactured before 1980. Patients with HIV infection and those undergoing immunosuppressive treatment after organ transplantation are at an increased risk of developing lymphoma. Although no specific genetic tests are available, all first-degree family members of probands with NHL are at increased risk.
Signs and Symptoms
Manifestations differ depending on the sites involved and whether the lymphoma is indolent or aggressive. Aggressive lymphomas can manifest as a rapidly growing mass and are more likely to include the classic B symptoms of fever greater than 38°C (100.4°F), weight loss greater than 10% of body weight in the past 6 months, and drenching night sweats.
Patients with indolent lymphomas can have asymptomatic slow-growing lymphadenopathy, hepatomegaly, and cytopenias. The lymphadenopathy can wax and wane and might not be identifiable until compression of structures, such as the ureter, orbit, or spinal cord, occurs.
Symptoms of T-cell lymphomas include fatigue, rash, fever, ascites, effusions, and those related to the central nervous system (CNS), bone, or gastrointestinal (GI) tract. Manifestations of the low-grade B-cell lymphomas (eg, follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma) are complicated because all can transform into high-grade diffuse large B-cell lymphoma.
The standard of care in the initial diagnosis of lymphoma is excisional biopsy. This ensures that all of the morphologic, immunophenotypic, and genetic data needed to make an accurate diagnosis are obtained. Fine-needle aspiration can be more cost-effective when evaluating recurrence, but should not replace excisional biopsy for initial diagnosis.
Complete blood count with examination of the blood for circulating lymphoma cells; liver function tests; and measurement of lactate dehydrogenase level, which indicates tumor mass, should all be obtained at the time of diagnosis. To identify patients at increased risk of tumor lysis syndrome, measurement of serum uric acid, potassium, calcium, and phosphorous levels can be helpful.
Bone marrow biopsy should be obtained to determine the lymphoma type and percentage of cellularity. The presence of a paraprotein on serum protein electrophoresis can indicate bone marrow involvement in small lymphocytic lymphoma and marginal zone lymphoma. Newer molecular and cytogenetic studies, including DNA microarray analysis technologies (eg, testing for bcl-2 and bcl-6 on blood or bone marrow), are being tested to improve diagnostic accuracy.
Case 4, cont’d. Kent undergoes Toxoplasma titer testing. The result is negative for infection. A brain biopsy reveals a large B-cell lymphoma. Evaluation and slit-lamp examination of cerebrospinal fluid and bone marrow, and computed tomography scan of the chest, abdomen, and pelvis all show negative results.
The Ann Arbor staging system, which was first developed to stage Hodgkin lymphoma, is also used to stage NHL and is based on the extent of involvement of nodal groups.Stage I involves a single lymph node region or lymphoid structure, such as the spleen or thymus. Stage II involves 2 or more lymph node regions on the same side of the diaphragm. Stage III involves lymph node groups above and below the diaphragm. Stage IV involves 1 or more extranodal sites with or without regional lymph node involvement, along with distant nodal involvement. Typically, stage I or II disease responds to local radiation alone, whereas stage III or IV disease requires systemic treatment.
Stage does not always correlate well with prognosis; some widespread indolent lymphomas are not always associated with poor prognosis. In addition, certain poor prognostic factors (eg, involvement of bone marrow or the CNS) are not considered in staging.
Factors associated with poor prognosis are listed in Table 3. The International Prognostic Index was developed to help convey information about prognosis to patients and to aid in the interpretation of clinical trials.
Table 3 5 Prognostic Risk Factors From the International Prognostic Index for Aggressive NHL
5 Prognostic Risk Factors From the International Prognostic Index for Aggressive NHL
Age (≤60 years versus >60 years)
Serum lactate dehydrogenase level (normal versus elevated)
Performance status (ie, patient response to tumor) (0 or 1 versus 2 or more)
Tumor stage (stage I or II versus stage III or IV)
Extranodal disease sites (1 or fewer versus more than 1)
NHL = non-Hodgkin lymphoma.
Information from The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987-994.
Treatments for NHL depend on the type and stage of disease. Treatment ranges from observation in indolent lymphoma to local radiation therapy in localized disease and various combinations of chemotherapy with and without radiation therapy in more widespread disease.
Monoclonal antibodies bind to surface molecules that are involved in the growth, differentiation, proliferation, and activation of B cells.Antibodies can induce antitumor activity; and, to minimize toxicity, ideal target antigens are present on malignant cells, but to a much lesser degree or not at all on normal cells.
Rituximab, the first monoclonal antibody to be approved by the Food and Drug Administration (FDA), is a chimeric human-mouse immunoglobulin G1 kappa monoclonal antibody that binds to CD20.Adverse effects include infusion reactions, but these are rarely severe or life threatening. Treatment with rituximab depletes B cells but infectious complications are rare. Improved survival rates in patients with follicular lymphoma and diffuse large B-cell lymphoma have been shown with the addition of rituximab to chemotherapy regimens.
One study found that rituximab resistance occurred in 50% of patients with recurrent CD20-positive follicular lymphomas, and 60% of those previously treated with rituximab did not benefit from retreatment.Several new anti-CD20 antibodies are in development to decrease adverse effects and improve effectiveness through humanization of the molecule. Optimal therapy duration and whether maintenance therapy during disease remission is of benefit are still unknown.
In radioimmunotherapy, radioisotopes conjugated with monoclonal antibodies deliver radiation directly to the cancerous cells, sparing normal uninvolved tissue. The radioisotopes Y-ibritumomab tiuxetan and I-tositumomab, which both target CD20, decay within the tumor, delivering total-body radiation continuously at a declining rate over days to months. Lymphomas are ideal targets for radioimmunotherapy because they are sensitive to radiation in a dose-dependent manner. The main adverse effects are myelosuppression and treatment-induced myelodysplastic syndrome.
Radioimmunotherapy has been effective in patients with recurrent and refractory low-grade NHL, with response rates of up to 50% to 75%.Promising results have also been found among patients with MCL and aggressive diffuse large cell disease. Radiation safety issues, along with economic issues and the need for specialized treatment centers, have limited the use of this treatment strategy.
Immunomodulating Drugs and Other Novel Treatments
Lenalidomide is an immunomodulatory drug in the same class as thalidomide. It has been used in the treatment of myelodysplastic syndrome and multiple myeloma. Lenalidomide inhibits prosurvival factors to induce apoptosis, inhibits pro-inflammatory cytokines, and enhances T-cell and NK-cell killing of tumor cells.Neutropenia and thrombocytopenia are the major adverse effects. Several studies of lenalidomide have shown clinical response of patients with diffuse large B-cell lymphoma, follicular lymphoma, MCL, and transformed NHL. Optimal treatment and combination treatment regimens are under investigation.
Treatment of Specific Types of Non-Hodgkin Lymphoma
Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma is the most common and one of the most aggressive forms of NHL. Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone with the addition of rituximab (R-CHOP) is the standard of care in diffuse large B-cell lymphoma.
Early-stage nonbulky disease is treated with 3 to 4 cycles of R-CHOP and consolidative involved field radiotherapy (IFRT) or 6 cycles of R-CHOP without radiation therapy.rescue the patient. This is known as high-dose therapy with autologous stem cell rescue.Bulky early-stage disease is treated similarly to advanced disease, with 6 cycles of R-CHOP. Typically, second-line chemotherapy is administered first for refractory disease, then stem cells are mobilized and high-dose chemotherapy is administered; finally, the banked stem cells are administered to
The most common low-grade NHL, follicular lymphoma, has an indolent course that typically waxes and wanes over several years. If detected early, when still localized, likelihood of survival has been shown to improve greatly with local IFRT. One study found that 20% to 60% of patients treated with IFRT were disease free at 10 years.The addition of chemotherapy to radiation therapy in localized disease has not been shown to improve overall survival rates.
Most of these lymphomas are not detected until they are widespread and are typically deemed untreatable.Patients must have symptomatic or aggressive disease to be eligible for treatment. Watchful waiting, which can delay the need for systemic therapy for 2 to 3 years after initial diagnosis, is recommended for patients with asymptomatic disease.
Young patients who are eligible for treatment should undergo chemotherapy with rituximab. Autologous stem cell transplantation and radioimmunotherapy can be used if standard therapy is ineffective.Higher survival rates have been found among patients with recurrent follicular lymphoma with rituximab maintenance therapy. However, the optimal schedule of therapy and potential for long-term toxicity are unknown.
Small Lymphocytic Lymphoma
Small lymphocytic lymphoma (SLL) is low grade and is the extramedullary form of chronic lymphocytic leukemia. As with follicular lymphomas, conservative treatment with rituximab and a purine analog (eg, fludarabine) is typically used first.The monoclonal antibody alemtuzumab (Campath), which targets CD52, can be considered as alternative to rituximab and fludarabine. Patients with recurrent SLL can be treated with anthracyclines, anthracenediones, or allogeneic stem cell transplantation. The incidence of SLL increases with age, so therapy is often limited by infectious complications and comorbidities.
Mantle Cell Lymphoma
Although MCL can remain indolent for many years with little treatment, most MCL is aggressive. The overall survival rate associated with MCL (ie, 3 to 5 years) is the lowest among the B-cell lymphomas.Conventional chemotherapy, such as R-CHOP, is rarely completely effective but can lead to remissions of up to 1 to 2 years. Treatment of patients with recurrent disease with high-dose chemotherapy and autologous stem cell transplantation can result in 5-year disease-free survival rates of 40% to 65%. Bortezomib is approved for treatment of patients with recurrent MCL.
Peripheral T-Cell Lymphoma
Treatment of peripheral T-cell lymphoma is complicated by the fact that there are 15 different subtypes, some of which are indolent and some of which are aggressive. The rarity of this lymphoma also makes it difficult to study.Initially, peripheral T-cell lymphoma was treated in the same manner as diffuse large B-cell lymphoma, with combination chemotherapy such as CHOP, with response rates of 50% to 60% and long-term survival of 10% to 30%.
Treatment with other combined chemotherapy regimens, immunotherapy, histone deacetylase inhibitors and folate antagonists, or high-dose chemotherapy with stem cell transplantation have not resulted in significant improvements in response or survival rates. Other novel approaches, including use of monoclonal antibodies and targeted kinase inhibitors, are being studied. No general consensus exists regarding the treatment of peripheral T-cell lymphoma, and patients should be encouraged to participate in clinical trials to help improve treatments for this type of NHL.
Extranodal Marginal Zone B-Cell Lymphoma, MALT Type
Mucosa-associated lymphoid tissue lymphoma is an indolent form of marginal zone lymphoma that arises in extranodal B cells. Most low-grade MALT lymphomas occur in the GI tract, but they can also be found in the ocular adnexa, salivary glands, thyroid, lung, thymus, and breast as the result of an immune stimulus, such as a chronic infection or autoimmune process. In 85% to 90% of cases, H pylori infection is associated with gastric MALT lymphoma, and treatment with antibiotics can lead to remission. Five-year survival rates among patients with this lymphoma are greater than 80% regardless of the type of treatment.
When patients with gastric MALT lymphoma do not improve with antibiotics, other options include gastrectomy, local radiotherapy, chemotherapy (chlorambucil or cyclophosphamide), and monoclonal antibody therapy. Treatment of nongastric MALT lymphoma varies by location, but in general MALT lymphomas are treatable with local radiation therapy. Systemic chemotherapy is reserved for palliation in advanced disease. The average expected life span for patients with MALT lymphoma is 5 years.
Case 4, cont’d. Kent begins high-dose methotrexate-based treatment for the B-cell lymphoma, as well as highly active antiretroviral therapy. This is followed by whole-brain radiation with a complete response.
Prophylaxis for Central Nervous System Involvement in Non-Hodgkin Lymphoma
Central nervous system involvement at the time of presentation, as the site of recurrence, or as part of progressive disease, can occur in 5% of patients with NHL.The CNS is the site of first recurrence after complete remission in 50% of patients. Neurologic symptoms indicating CNS involvement include altered mental status, cranial nerve abnormalities, spinal cord dysfunction, motor or sensory deficits, and headaches.
Because CNS involvement is associated with poor prognosis (median survival 2 to 6 months) and the focus of treatment after CNS involvement is primarily palliative, strategies to reduce NHL recurrence through local radiation or systemic chemotherapy with or without intrathecal chemotherapy are being studied.Risk of CNS involvement is low in patients with indolent NHL (2.8%), so routine prophylaxis is not recommended. In patients with Burkitt NHL or lymphoblastic NHL, risk of CNS involvement has been shown to be up to 25%. Prophylaxis is routinely recommended for these patients.
Presence of high-grade lymphomas that involve the bone marrow, skeleton, testicles, breasts, orbits, and paranasal sinuses also warrants consideration of prophylaxis, although definite proof of prevention of CNS involvement is limited. Patients with aggressive NHL with at least 4 of the 5 risk factors for CNS involvement (Table 4) qualify for prophylaxis. High-dose intravenous methotrexate is typically administered in combination with intrathecal methotrexate for prophylaxis. A short course of intrathecal prophylaxis is typically administered with AIDS-related lymphomas.
Table 4 Risk Factors and Indicators for Central Nervous System Prophylaxis for NHL Recurrence
Risk Factors and Indicators for Central Nervous System Prophylaxis for NHL Recurrence
Elevated serum lactate dehydrogenase level
Serum albumin level <35 g/L
Age <60 years
Retroperitoneal lymph node involvement
Involvement of more than 1 extranodal site
NHL = non-Hodgkin lymphoma.
Information from Hollender A, Kvaloy S, Nome O, et al. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol. 2002; 13(7):1099-1107.
Non-Hodgkin Lymphoma and HIV Infection
Impaired cellular immunity, such as occurs in HIV infection, can lead to neoplasms, and patients with HIV infection or AIDS are at much greater risk of developing NHL than the general population.Diffuse large B-cell lymphoma, Burkitt NHL, and CNS NHL are considered AIDS-defining malignancies. Non-Hodgkin lymphoma is the leading cause of cancer-related death in US patients with AIDS.
The use of highly active antiretroviral therapy (HAART) has led to declines of 40% to 80% in the rate of NHL among these patients when compared with the pre-HAART era.Use of HAART with or after chemotherapy in patients with NHL has led to rates of remission and survival similar to those among patients without HIV infection.
The role of the family physician in the follow-up of patients treated for NHL includes monitoring for recurrence, monitoring for secondary malignancies, and helping to manage the other consequences of treatment. To monitor for recurrence, these patients should undergo a complete physical examination every 3 to 6 months for up to 5 years, depending on whether the NHL was indolent or aggressive.
Secondary malignancies develop at a higher rate in survivors of NHL and most commonly occur in the lung, breast, or colon, or as leukemia. If the patient received radiation treatment before age 25 years, the risk of secondary malignancy is greater.Although there is an increased risk of heart failure and stroke with doxorubicin-based chemotherapy, it has been shown that patients treated for NHL have no greater risk of coronary artery disease than the general population.
Advances in Myelodysplastic Syndrome Management
Case 5. Mrs Francis is a 75-year-old woman who presents with fatigue, pallor, and petechiae. A complete blood count reveals anemia (hemoglobin level 9.5 g/dL) and thrombocytopenia (platelet count 51,000/mcL). Serum iron, total iron-binding capacity, ferritin, B12, and folate levels are normal. The serum erythropoietin level is low (200 IU/L).
Myelodysplastic syndrome (MDS) is a family of hematogenous conditions characterized by peripheral blood cytopenias, hypercellular dysplastic-appearing bone marrow, and progression to acute myelogenous leukemia (AML). The incidence increases with age, and the typical patient is diagnosed between ages 70 and 75 years.The incidence of MDS in the United States is 3.3/100,000 and is highest in men, non-Hispanics, and whites. The strongest risk factor for developing MDS is advanced age, and 80% to 90% of MDS cases are primary or de novo.
Secondary MDS is primarily the result of exposure to radiation therapy or certain chemicals. Chemotherapy drugs, such as alkylating agents and topoisomerase inhibitors, have been implicated, and the latency period is typically 5 to 10 years between exposure and diagnosis.Reported odds ratios for developing MDS as a result of environmental exposures are 4.55 for agricultural chemical exposure, 2.05 for solvent exposure, 1.45 for cigarette smoking, and 3.22 for cigarette smokers exposed to agricultural chemicals or solvents.
Signs and symptoms of anemia (eg, fatigue, exercise intolerance, pallor) are common at presentation. Easy bleeding and bruising or infectious complications can also be present at the time of initial diagnosis.The anemia is most often macrocytic, with median hemoglobin level of 9.1 g/dL. The differential diagnosis of MDS includes other causes of macrocytic anemia, such as vitamin B12 and folate deficiencies, alcohol consumption, thyroid conditions, copper deficiency, HIV infection, or macrocytosis-inducing drug exposure (eg, valproic acid, zidovudine, hydroxyurea, folate antagonists).
Initial evaluation should include complete blood count (CBC), serum ferritin level, total iron-binding capacity, serum iron level, reticulocyte counts, vitamin B12 levels, red blood cell (RBC) folate level, and thyroid-stimulating hormone level.Normocytic or microcytic anemia is less often seen in patients with concomitant hemoglobinopathies or severe iron deficiency.
At presentation, patients with MDS typically have a median platelet count of approximately 100,000/mcL, and 30% to 45% are thrombocytopenic.The presenting median absolute neutrophil count has been found to be 1,780/mcL, and 40% of patients with MDS are neutropenic; 26% have blasts present in peripheral blood test results. Bone marrow aspiration and biopsy, including cytogenetic testing and iron staining, should be performed for patients with persistent unexplained cytopenia.
The bone marrow in patients with MDS is typically hypercellular with megaloblastoid changes, atypical megakaryocytes, erythroid hyperplasia, and defective maturation in the myeloid series; some patients have increased blasts or ringed sideroblasts.Typically, at least 200 bone marrow cells and 20 megakaryocytes are examined, and at least 10% of these should be dysplastic to confirm diagnosis.
Cytogenetic testing of bone marrow cells is essential and provides valuable prognostic information. Conventional cytogenetic assays involve light microscopy of chromosomes that are extracted from dividing cells, arrested in metaphase with colchicine, and then Giemsa stained.
Approximately half of all patients with primary MDS have 1 karyotypic abnormality or more. The most common chromosomal abnormalities are loss of the long arm of chromosome 5, trisomy of chromosome 8, loss of chromosome 7, or loss of the long arm of chromosome 20.If standard karyotyping is unsuccessful, fluorescence in situ hybridization techniques should be used.
The World Health Organization (WHO) classification of MDS uses various peripheral blood cytopenias, bone marrow morphologies, and cytogenetic characteristics of MDS to describe 7 different conditions (Table 5)., The term myeloid refers to cells from the granulocytic, monocytic/macrophage, erythroid, megakaryocytic, or mast cell lineages. Ringed sideroblasts are late erythroid precursor cells with abnormal accumulations of iron in mitochondria that line the periphery of the nucleus. Auer rods are distinctive azurophilic rods resulting from the coalescence of primary cytoplasm granules in myeloid blast cells.
Table 5 WHO Classification of MDS
WHO Classification of MDS
|Condition||Peripheral Blood Findings||Bone Marrow Findings|
Unicytopenia or bicytopenia
Refractory anemia with ringed sideroblasts
≥15% of erythroid precursors are ringed sideroblasts
Refractory cytopenia with multilineage dysplasia
Dysplasia in ≥10% of cells in ≥2 myeloid lineages (neutrophil and/or erythroid precursors and/or megakaryocytes)
Refractory anemia with excess blasts-1
Unilineage or multilineage dysplasia
Refractory anemia with excess blasts-2
Unilineage or multilineage dysplasia
Unequivocal dysplasia in <10% of cells in 1 or more myeloid lineages when accompanied by cytogenetic abnormality considered presumptive evidence for MDS diagnosis
MDS associated with isolated del(5q)
Normal to increased megakaryocytes with hypolobated nuclei
MDS = myelodysplastic syndrome; WHO = World Health Organization.
Information from Bennett JM. A comparative review of classification systems in myelodysplastic syndromes (MDS). Semin Oncol. 2005;32(4 Suppl 5):S3-S10; Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100(7):2292-2302 [Review].
The WHO classification of MDS has assisted in more accurately predicting patient outcomes and selection of optimal treatment and management strategies.Refractory anemia is the most common classification of patients with recently diagnosed MDS in the United States.
The International Prognostic Scoring System (IPSS) for evaluating prognosis in patients with MDS was devised in 1997 after evaluation of multiple clinical variables in 816 patients with primary MDS.Table 6).Mortality has been found to correlate closely with evolution of MDS into AML, and univariate analysis has shown that myeloblast percentage, cytogenetic status, and number of cytopenias are highly discriminant (
Table 6 International Prognostic Scoring System for MDS
International Prognostic Scoring System for MDS
|Prognostic Variable||IPSS Score|
Bone marrow blasts
5% to 10%
11% to 20%
21% to 30%
aCytopenias are defined as hemoglobin level <10 g/dL, absolute neutrophil count <1,500/mcL, and platelet count <100,000/mcL.
IPSS = International Prognostic Scoring System; MDS = myelodysplastic syndrome.
Scores by risk group: 0, low; 0.5 to 1.0, intermediate-1; 1.5 to 2.0, intermediate-2; 2.5 or greater, high.
Adapted from Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating the prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-2088. Erratum in Blood. 1998;91(3):1100.
Karyotypes associated with a good prognosis are normal, -Y, del(5q), and del(20q), whereas those associated with the poorest prognosis are complex (ie, 3 or more abnormalities) or chromosome 7 abnormalities. All other abnormalities were shown to be associated with an intermediate prognosis.
Four prognostic categories were derived from the IPSS, with a median range of survival from 5.7 years for the low-risk group to 0.4 years for the high-risk group (Table 7). Transfusion dependency and age older than 60 years are also associated with poorer prognosis.,
International Prognostic Scoring System Clinical Outcomes for MDS
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As an example, using Tables 6 and 7, a patient with 11% to 20% blasts (1.5 points), a good karyotype (0 points), and 2 cytopenias (0.5 points) has an IPSS score of 2.0. An IPSS score of 2.0 places the patient in the intermediate-2 risk group with a median survival of 1.2 years. Within 1.1 years, 25% of these patients will progress to AML.
Case 5, cont’d. Bone marrow analysis results for Mrs Francis reveal no blasts, no Auer rods, 5% ringed sideroblasts, and 10% dysplastic megakaryocytes. Cytogenetic test results show no del(5q) abnormalities but presence of del(13q) abnormality. Mrs Francis is diagnosed with myelodysplastic syndrome that is classified as refractory anemia with an International Prognostic Scoring System risk group of intermediate-1.
The course of MDS is variable. The condition is thought to be incurable without bone marrow transplantation. However, most patients with MDS are not good candidates for transplantation, and many are best managed with observation alone.,For example, frail elderly patients with MDS in the low or intermediate-1 IPSS risk groups can be considered for serial CBC monitoring to document an indolent course.
Symptomatic anemia is most often treated with erythropoiesis-stimulating agents and blood transfusions. Thus far, patients with MDS have not been found to experience shorter survival times with use of erythropoiesis-stimulating agents, as has been seen in patients with solid malignancies. Patients in the low and intermediate-1 IPSS risk groups with less than 5% myeloblasts and those with low serum erythropoietin levels (less than or equal to 500 IU/L) have shown the greatest response to erythropoiesis-stimulating agents.
Epoetin alfa or darbepoetin alfa (Aranesp) is used for at least 8 weeks before consideration of eicosapentaenoic acid (EPA) use.Refractory anemia with ringed sideroblasts often responds poorly to EPA alone; the response can be markedly enhanced by adding synergistic treatment with granulocyte colony-stimulating factor (Neupogen). The target hemoglobin level during EPA use in patients with MDS is less than or equal to 12 g/dL.
Transfusions should be performed in symptomatic patients only. In general, these should be performed between hemoglobin level thresholds of 8 to 10 g/dL, depending on the cardiopulmonary and anticipated chemotherapy situation of each patient.Some oncology subspecialists recommend no single hemoglobin level cutoff. Leukocyte-reduced RBC transfusions are preferable, and irradiated RBCs are recommended for directed-donor transfusions and transfused products for potential stem cell transplantation patients.
Iron overload is a potentially serious complication in patients who receive more than 20 to 30 units of RBC transfusions.When plasma iron exceeds the binding capacity of transferrin, it catalyzes toxic free-radical reactions. Patients with long-term RBC transfusion needs should undergo regular ferritin level testing and be monitored for heart, liver, and pancreas organ dysfunction. T2-weighted magnetic resonance imaging study is increasingly used to measure liver and myocardial iron concentrations. Iron overload-associated cardiac and hepatic dysfunction have been documented retrospectively in patients with MDS and iron overload.
Studies of patients with MDS who are at low or intermediate risk have shown prolonged survival times with iron chelation therapy.,National Comprehensive Cancer Network (NCCN) guidelines recommend chelation therapy for patients in IPSS low and intermediate-1 risk groups who are expected to survive for several years with ongoing transfusion requirements, who have undergone more than 20 to 30 units of RBC transfusion, and have a ferritin level greater than 2,500 ng/mL. Other oncology subspecialists use a ferritin threshold of 1,000 ng/mL.
Deferoxamine (Desferal) is a parenteral iron chelator that requires overnight subcutaneous infusions 5 to 7 nights/week, thus limiting its practicality. Deferasirox (Exjade) is an oral chelator recently approved by the Food and Drug Administration (FDA) that can be used to lower ferritin levels in patients with MDS at doses of 20 to 30 mg/kg per day.
Diarrhea is the most common adverse effect, which is often lactase deficiency-related, and can be managed with lactase, avoidance of dairy foods, and antidiarrheal agents. Drug-associated rash often resolves without dosage adjustment, but more serious adverse effects on renal function (serum creatinine level greater than 33% above baseline) and liver function (elevated serum transaminase levels) can require dosage reduction or discontinuation. Auditory and ophthalmologic toxicity should be monitored by pretherapy and annual hearing and vision tests.
There are now low-intensity FDA-approved chemotherapy agents for use in patients with MDS who are transfusion-dependent or who do not benefit from EPA. Hypomethylating agents deplete nuclear DNA methyltransferase and disrupt DNA repair complexes.
Azacitidine (Vidaza) and decitabine (Dacogen) have been shown to induce hematologic response and decrease the rate of progression to AML.,, Azacitidine should be administered subcutaneously once daily for 7 days every 28 days, and decitabine should be administered intravenously for 3 days every 6 weeks. Myelosuppression is the major side effect. A minimum of 4 to 6 cycles of therapy should be used before treatment is considered ineffective.
Immunosuppressive Agents and Immunomodulators.
Immunosuppressive agents can destroy lymphocytes that attack the myeloid precursors in some patients with MDS.,Antithymocyte globulin (Atgam) with or without cyclosporine has been found to restore hematopoiesis for a subgroup of patients with low or intermediate-1 IPSS risk scores, who are younger than 60 years, have hypocellular marrows, or who are HLA-DR15 or paroxysmal nocturnal hemoglobinuria clone-positive.
The immunomodulatory drug lenalidomide has been shown to enhance erythropoietin-receptor signaling and decrease need for transfusions in up to 67% of patients with del(5q) and 26% of patients with non-del(5q).,,Among patients with del(5q), lenalidomide has been shown to induce complete cytoplasmic response in nearly half of patients. It is considered first-line therapy for this 5% subpopulation of patients with MDS. Lenalidomide is associated with less sedation and neurotoxicity than thalidomide but is associated with significant neutropenia, thrombocytopenia, and renal dysfunction.
Neutropenia and Thrombocytopenia Management
Neither granulocyte colony-stimulating factor nor granulocyte-monocyte colony-stimulating factor is used to manage routine infections or as prophylaxis in MDS. These factors can be useful in management of recurrent or resistant bacterial infections in severely neutropenic patients.
Prophylactic antibiotics in patients with MDS and neutropenia are controversial, and resistance, drug interactions, and expected duration of severe neutropenia should be considered. The NCCN has published guidelines on the prevention and treatment of cancer-related infections in patients with MDS. (Available with a free subscription at http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf.)
There are no FDA-approved agents for stimulating megakaryocytes in patients with MDS, although several thrombopoietic agents are under investigation. Chronic bleeding remains a serious issue in patients with MDS. Platelet transfusions for acute bleeding provide only short-term treatment. Prophylactic platelet transfusions are offered by some centers when the platelet count is less than 10,000/mcL., Aminocaproic acid (Amicar) might be considered for management of severe bleeding refractory to platelet transfusions.
Case 5, cont’d. After 4 months of asymptomatic anemia and no bleeding complications, Mrs Francis requires a first transfusion for fatigue, tachycardia, and a hemoglobin level of 8 g/dL. Epoetin alfa is begun at 40,000 units 2 times/week.
She averages 1, then eventually 2 red blood cell (RBC) transfusions/month within 12 months and a platelet transfusion for a lower gastrointestinal bleed when the platelet count is 15,000/mcL. At a cumulative count of 20 units of total RBC transfusions, chelation therapy is initiated with oral deferasirox.
Despite increasing the epoetin alfa dosage, the transfusion requirement for Mrs Francis increases and azacytidine is started. The transfusion requirement then decreases to 1 unit/month for 6 months.
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT) remains the only effective long-term treatment for MDS, as all of the previously discussed therapies eventually become ineffective. However, only 5% of patients with MDS are eligible for HSCT because of advanced comorbidity.
Because patients in low or intermediate-1 IPSS risk groups often survive several years with symptoms controlled by erythropoietic agents and transfusions, HSCT is typically postponed until evidence of disease progression develops.However, the prognosis for patients in the IPSS intermediate-2 and high-risk groups is so poor that HSCT should be considered immediately on diagnosis.
Standard myoablative conditioning therapy is recommended for patients ages 60 years and younger and those with greater blast burden, whereas less toxic reduced-intensity conditioning is recommended for older patients and those with fewer than 10% marrow blasts., A transplant-related mortality rate of 20% to 30% is comparable in patients with MDS regardless of sibling-donor or volunteer-donor use.,, Patients in IPSS low-risk groups who undergo HSCT have been found to have an average 80% 5-year survival rate, whereas patients with 5% to 20% marrow blasts have an average 25% 5-year overall survival rate.
Pediatric Myelodysplastic Syndrome
The median age of MDS presentation is 7 years in children.The incidence of MDS secondary to prior chemotherapy or radiation in children is 7% to 18% of pediatric MDS cases. Del(5q), which is common in adults with MDS, is rare in children. Monosomy 7 is the most common chromosomal abnormality in pediatric MDS.
Refractory cytopenias are the most common subtype of pediatric MDS.Children are more likely to present with thrombocytopenia and neutropenia than with anemia, as is more typical in adult patients. Children with refractory cytopenias typically present with symptoms of pancytopenia, including fatigue, bruising, and infection. Twenty percent are asymptomatic. Monosomy 7 is associated with a rapid progression and poor prognosis.
Children with refractory cytopenias and normal karyotype should be observed closely over time and can experience stable symptoms over many years. Transfusion dependence and frequent neutropenic infections can occur. The treatment of choice for children with refractory cytopenias and monosomy 7, or children with normal karyotype and severe disease, is HSCT.
Primary MDS with a greater blast count can be difficult to distinguish from de novo AML. Typical features of MDS include a blast count less than 20% and monosomy 7. Features of AML include a blast count greater than 30%, organomegaly, leukocytosis, and specific chromosomal changes.Treatment of high-grade MDS consists of allogenic HSCT, which resolves the MDS in approximately 50% of cases.
Myelodysplastic syndrome secondary to chemotherapy or radiation therapy occurs in children and adults. Treatment-related MDS can manifest as refractory cytopenia, MDS with a greater blast count, or as a syndrome that resembles chronic myelomonocytic leukemia. The prognosis is worse for these patients than it is for those with primary MDS, but HSCT can improve likelihood of survival.,
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