Acute myelogenous leukemia is a disease of the elderly. Disease biology and functional status of this patient population contribute to poorer treatment outcomes with standard therapy. Allogeneic hematopoietic stem cell transplantation is associated with an immunologic “graft-versus-tumor” effect. However, transplantation was restricted until recently to younger patients because of prohibitive treatment-related mortality. The development of reduced-intensity preparative regimens and improvements in supportive care now allow older patients with myeloid leukemia a greater opportunity for cure with transplantation. Donor availability, graft-versus-host disease, delayed immune recovery, and the high prevalence of relapsed or refractory disease remain important obstacles to be overcome in the future. Herein, we review the current literature on transplantation for older patients with this myeloid malignancy.
Despite advances in novel therapeutics, supportive care, and postremission therapy, the outcome of high-risk and elderly patients as well as those with relapsed/refractory acute myeloid leukemia (AML) remains poor. There is likely still room for improvement through optimizing conventional chemotherapy.
Through a pharmacy database search we identified all patients with AML treated at Washington University with cladribine-based regimens.
Twenty-four patients were identified that were treated with 2 cladribine-based regimens: CLAG (cladribine [5 mg/m2 days 1-5], cytarabine [2 g/m2 days 1-5] and granulocyte colony-stimulating factor [G-CSF; 300 μg subcutaneously (s.c.) days 0-5]) and CLAM (cladribine [5 mg/m2 days 1-5], cytarabine [2 g/m2 days 1-5], G-CSF [300 mg s.c. days 0-5] and mitoxantrone [10 mg/m2 days 1-3]). Complete responses were achieved in 53% of patients given induction chemotherapy and 44% of those given salvage chemotherapy. The regimens were well tolerated with minimal extramedullary toxicity.
These data suggest that cladrabine-based regimens should be further explored in both the salvage and first-line setting and might offer an attractive backbone on which to add novel therapies.
Mantle cell lymphoma (MCL) exhibits considerable molecular heterogeneity and complexity, and is regarded as one of the most challenging lymphomas to treat. With increased understanding of the pathobiology of MCL, it is proposed that MCL is the result of 3 major converging factors, namely, deregulated cell cycle pathways, defects in DNA damage responses, and dysregulation of cell survival pathways. In the present era of targeted therapies, these biologic insights have resulted in the identification of several novel rational targets for therapeutic intervention in MCL that are undergoing active clinical testing. To date, there is no standard of care in MCL. Several approaches including conventional anthracycline-based therapies and intensive high-dose strategies with and without stem cell transplantation have failed to produce durable remissions for most patients. Moreover, considering the heterogeneity of MCL, it is increasingly being recognized that risk-adapted therapy might be a relevant therapeutic approach in this disease. At the first and second Global Workshops on Mantle Cell Lymphoma, questions addressing advances in the pathobiology of MCL, optimization of existing therapies, assessment of current data with novel therapeutic strategies, and the identification of molecular or phenotypic risk factors for utilization in risk-adapted therapies were discussed and will be summarized herein.
Multiple myeloma (MM) is a neoplastic plasma cell disorder that results in end-organ damage (hypercalcemia, renal insufficiency, anemia, or skeletal lesions). Patients should not be treated unless they have symptomatic (end-organ damage) MM. They should be classified as having high-risk or standard-risk disease. Patients are classified as high risk in the presence of hypodiploidy or deletion of chromosome 13 (del[13]) with conventional cytogenetics, the presence of t(4:14), t(14;16), t(14;20) translocations or del(17p) with fluorescence in situ hybridization. High-risk disease accounts for about 25% of patients with symptomatic MM. If the patient is deemed eligible for an autologous stem cell transplantation (ASCT), 3 or 4 cycles of lenalidomide and low-dose dexamethasone, or bortezomib and dexamethasone, or thalidomide and dexamethasone are reasonable choices. Stem cells should then be collected and one may proceed with an ASCT. If the patient has a complete response or a very good partial response (VGPR), the patient may be followed without maintenance therapy. If the patient has a less than VGPR, a second ASCT is encouraged. If the patient is in the high-risk group, a bortezomib-containing regimen to maximum response followed by 2 additional cycles of therapy is a reasonable approach. Lenalidomide and lowdose dexamethasone is another option for maintenance until progression. If the patient is considered ineligible for an ASCT, then melphalan, prednisone, and thalidomide is suggested for the standard-risk patient, and melphalan, prednisone, and bortezomib (MPV) for the high-risk patient. Treatment of relapsed or refractory MM is covered. The novel therapies—thalidomide, bortezomib, and lenalidomide—have resulted in improved survival rates. The complications of MM are also described. Multiple myeloma is a plasma cell neoplasm that is characterized by a single clone of plasma cells producing a monoclonal protein (M-protein). The malignant proliferation of plasma cells produces skeletal destruction that leads to bone pain and pathologic fractures. The M-protein might lead to renal failure, hyperviscosity syndrome, or through the suppression of uninvolved immunoglobulins, recurrent infections. Anemia and hypercalcemia are common complications.
Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy regimens. The majority of adult patients with Burkitt lymphoma in the United States are over age 40 years. Older patients have historically been underrepresented in published clinical trials of modern intensive therapy, and the outcome of these patients has not been systematically reported. We therefore obtained and analyzed primary data from 14 Burkitt lymphoma treatment series and confirmed that older patients (age > 40 years) are underrepresented in the literature. Historically inferior outcomes of this age subgroup have improved substantially over time. We conclude that (1) modern intensive chemotherapy regimens should remain the standard of care for patients > age 40 with Burkitt lymphoma; (2) selected patients > age 40 now have highly favorable outcomes; and (3) future studies should include formal analysis of this subgroup of patients.
In the highly active antiretroviral therapy era, an increasingly large number of HIV-infected patients are developing non—AIDS-defining cancers (NADCs). As patients survive longer, long-term therapy—related complications take on greater importance. Herein, we describe a patient with AIDS who presented to medical attention with pancytopenia 48 months postchemotherapy with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-EPOCH) for diffuse large B-cell lymphoma. Bone marrow biopsy showed a moderately hypocellular marrow; 51% of the nucleated cells were blasts with myelomonocytic differentiation. Cytogenetic studies revealed an abnormal karyotype with deletion of the long arm of chromosome 11 (11q21) and 2 additional copies of the MLL gene attached to the short arms of chromosome 10 in 80% of the metaphase cells examined. With the diagnosis of therapy-related acute myeloid leukemia (AML) secured, he began induction chemotherapy with idarubicin and cytarabine. Two weeks later, he died of fungal septicemia and multiorgan failure. Through a literature search, we were able to identify 4 additional cases of therapy-related AML in AIDS patients following chemotherapy for lymphomas. The median age of these patients at the time of AML diagnosis was 39 years (range, 33–59 years), the median time from the treatment of lymphoma to AML was 18 months (range, 11–48 months), and the median survival following induction chemotherapy was 4 weeks (range, 2–16 weeks). With many HIV-infected patients surviving alkylator and topoisomerase inhibitor—based treatment and radiation therapy for AIDS-defining cancers and NADCs, long-term follow-up for therapy-related complications assumes greater importance.
Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by the presence of a serum monoclonal immunoglobulin (M-protein) at ≤ 3 g/dL. It is an asymptomatic premalignant disorder that can progress to multiple myeloma and related B-cell disorders. Recent studies have suggested the association of MGUS with enhanced bone loss and debilitating skeletal complications, particularly vertebral compression fractures (VCFs) often leading to back pain. Early identification of MGUS and evaluation of bone status will facilitate prophylactic treatment with bisphosphonates to increase bone density and likely reduce the risk of fractures as well as identify patients with VCFs who might benefit from early surgical intervention. With proper diagnostic and treatment strategies, these patients will experience improved outcomes and quality of life.
Renal impairment is a frequent complication of multiple myeloma (MM) and is associated with significant morbidity and increased early death rate. Bortezomib is active and well tolerated in patients with MM who present or develop renal impairment.
We analyzed 46 consecutive patients who presented with renal impairment in order to evaluate the impact of bortezomib on the improvement of renal function and to identify predictive factors associated with renal response. All patients received bortezomib with dexamethasone with or without other agents.
Renal response was documented in 59% of patients within a median of 11 days (range, 8-41 days). Two of 9 patients who required dialysis became dialysis independent. A complete renal response (CRrenal) was documented in 30% of patients. Toxicities were similar to those seen in myeloma patients without renal failure who were treated with bortezomib-based regimens. Patients with light chain—only myeloma had a higher probability of achieving a renal response, and previously untreated patients had a higher probability for complete resolution of renal impairment, while light chain—only myeloma was independently associated with a shorter time to renal response. The degree of renal impairment was not predictive of the probability for renal response or CRrenal; however, in a subset of patients for whom cystatin C was available, a baseline cystatin C > 2 mg/L or cystatin C calculated estimated glomerular filtration rate < 30 mL/min were associated with a lower probability of CRrenal.
We conclude that bortezomib-based regimens may improve renal function in the majority of myeloma patients with renal impairment.
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