NEW YORK CITY—The latest options for preventing and treating tumor lysis syndrome (TLS), thrombocytopenia, and anemia in caring for patients with hematologic malignancies were reviewed and updated here at the National Comprehensive Cancer Network (NCCN) Annual Congress on Hematologic Malignancies.
All those conditions are key challenges in supportive care, but fortunately there are several strategies available for managing each of these conditions, said the meeting's chair, Andrew D. Zelenetz, MD, PhD, Chief of the Lymphoma Service in the Division of Hematology/Oncology at Memorial Sloan-?Kettering Cancer Center.
Myron S. Czuczman, MD, Chief of the Lymphoma/Myeloma Section at Roswell Park Cancer Institute, called tumor lysis syndrome “one of the few true oncologic emergencies that are potentially fatal that we face as oncologists.”
To manage the condition, “remember one word—prevention,” said Dr. Czuczman, adding that awareness of the patient's risk factors and identifying high-risk patients early are key.
Risk factors include the start of cytotoxic therapy, tumors with high proliferation rates, bulky tumors and those highly sensitive to treatment, a high number of circulating tumor cells (25,000 and over), and increased levels of lactate dehydrogenase (LDH).
If patients have preexisting hyperuricemia, decreased urine flow, dehydration, renal failure, or insufficiency, “you better be worried that they are at a much higher risk of developing TLS,” Dr. Czuczman said. Other predisposing risk factors are taking supplements with potassium or phosphorus, medications toxic to the kidneys, and potassium-sparing diuretics.
Using aggressive prophylactic strategies to avert clinical manifestations of TLS and close monitoring of electrolytes are also critical—“Once you see tumor lysis syndrome developing, jump on it fast and start treating it,” he added.
To help monitor patients, oncologists should test renal function, serum electrolytes, and LDH, uric acid, and phosphorus levels, and perform EKGs in some patients, and dialysis may also be necessary.
Patients with TLS should be managed with intravenous hydration of about 3 L/day, said Dr. Czuczman. While alkalinization of the urine is something that oncologists often do for adult patients, it remains somewhat controversial in the literature, he said. Patients also need to maintain a urine output of more than 100 cc/hour, and forced diuresis may also be necessary.
Hyperkalemia is usually the first electrolyte imbalance that oncologists will observe and can be potentially life threatening, he said.
In addition to using aggressive hydration, oncologists generally treat patients with hypertonic glucose and intravenous insulin, and calcium gluconate, sodium polystyrene sulfonate, loop diuretics, and dialysis are also used.
Hyperuricemia usually develops 24 to 48 hours after the start of cancer therapy, Dr. Czuczman continued. Management usually includes hydration, and dialysis may be needed if the condition is severe.
Agents to treat hyperuricemia include allopurinol, which blocks the conversion of xanthine and hypoxanthine to uric acid, and rasburicase, which catalyzes oxidation of uric acid into an inactive and soluble metabolite easily excreted by the kidneys.
Allopurinol reduces uric acid levels by more than half with a mean response of five days, he said, adding that when used prophylactically, allopurinol decreases uric acid about 93% of the time. However, the drug only inhibits formation of new uric acid. It can also reduce the clearance of purine-based chemotherapy agents used to treat leukemia and is associated with reduced clearance of methotrexate. Patients may also have hypersensitivity reactions.
Rasburicase is FDA-approved for the initial management of plasma uric acid levels in high-risk pediatric patients and is being evaluated in clinical trials for treatment of adult patients, said Dr. Czuczman.
One advantage of rasburicase is that oncologists can start cytotoxic therapy four hours after the first dose of the drug. It also reduces existing plasma uric acid, and alkalinization of urine is not required.
However, patients with G6PD deficiency may be at risk of hemolysis if they take rasburicase, he said. The drug also has a black box warning for risk of anaphylaxis, and methemoglobinemia and hypoxemia may occur.
Hyperphosphatemia ?& Hypocalcemia
Hyperphosphatemia can also occur about one to two days after treatment starts and precipitates calcium into renal tubules leading to hypocalcemia.
Management includes treatment with aluminum hydroxide or carbonate or sevelamer carbonate. Hemodialysis may be needed for severe or refractory cases, Dr. Czuczman noted.
Hypocalcemia usually resolves once hyperphosphatemia is controlled; and if patients are symptomatic, calcium gluconate may be given intravenously along with EKG monitoring.
Managing platelets is another challenge oncologists may encounter when treating patients with hematologic malignancies and thrombocytopenia.
The goals are to decrease active bleeding and the risk of bleeding during procedures and to provide bleeding prophylaxis, said another speaker, David J. Kuter, DPhil, MD, Chief of Hematology at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School. “Overall, platelet transfusions are, were, and probably will be the standard therapy for treating acute thrombocytopenia.” Based on the available literature, a platelet count lower than 10,000 per microliter appears to be a trigger for platelet transfusion for most patients.
However, whether prophylactic platelet transfusion is necessary remains to be seen, he said. For example, results of the PLADO (Prophylactic PLAtelet Dose) study presented at last year's ASH Annual Meeting by Sherrill J. Slichter, MD, of Puget Sound Blood Center in Seattle and colleagues concluded that therapeutic platelet transfusion was safe and reduced platelet transfusion numbers and that routine prophylactic transfusion was not necessary.
Whether there is a minimal platelet dose necessary for hemostasis when treating patients with thrombocytopenia is also being evaluated, and Dr. Kuter said that based on the results of the PLADO study, a lower dose than what is typically used may be appropriate, and that the full report of the ASH abstract is now accepted for publication in the New England Journal of Medicine.
The PLADO study is a three-arm prospective, randomized trial, giving patients with thrombocytopenia one of three doses of platelets to prevent bleeding: a medium dose (2.2×1011 platelets/m2), which corresponds to the current standard transfusion dose of six pooled platelet concentrates or one apheresis unit; a low dose (1.1×1011 platelets/m2) or three pooled platelet concentrates or half an apheresis unit; or a high dose (4.4×1011 platelets/m2) or 12 pooled platelet concentrates or two apheresis units.
The primary endpoint of the study was what percentage of patients experienced at least one episode of bleeding that was at least Grade 2. In the low-, medium-, and high-dose groups, the bleeding rate was about 70%. Therefore, said Dr. Kuter, the study demonstrates that a low-dose or three pooled platelet concentrates have the same benefit as the standard dose of six. “This is probably going to change our practice in the coming year or so,” he predicted.
Thrombopoietic Growth Factors
Between 1998 and 2001, researchers developed a second generation of thrombopoietic growth factors because first-generation molecules worked only in some patients treated with chemotherapy and didn't work in those receiving myeloablative therapy, Dr. Kuter explained. The result was the development of thrombopoeitin (TPO) peptide mimetics, TPO nonpeptide mimetics, and TPO agonist antibodies.
Romiplostim is an Fc-peptide fusion protein and TPO mimetic peptide that stimulates platelet response and is commercially available for the treatment of adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP).
Eltrombopag is a TPO receptor agonist that stimulates megakaryocyte proliferation and differentiation, increases platelet counts, and is commercially available for the treatment of thrombocytopenia in patients with chronic immune ITP.
Unfortunately, though, no data have been made public on the impact of these drugs on chemotherapy-induced thrombocytopenia, Dr. Kuter said. “We're going to have to wait until the next ASCO Annual Meeting to have any data. My speculation is that both molecules will work as the first generation did.”
However, the drugs have been shown to be effective in hepatitis C and myelodysplastic syndrome patients in addition to those with chronic ITP, he noted, concluding that while thrombopoietic growth factors can increase platelet counts and could become standard prophylaxis for some oncology patients, this requires further study.
While management of anemia is another important aspect of cancer care, there is controversy about whether blood transfusions or erythropoietin-stimulating agents (ESAs) are the best treatment options, said Eric H. Kraut, MD, Professor of Medicine and Director of Benign Hematology at Ohio State University.
In recent years, of course, some safety concerns about ESAs have come to light, and the risks and benefits of erythropoietins have to be weighed against those of blood transfusions.
Dr. Kraut cited a 2007 review article in The Lancet (2007;370:415-426) noting that most reactions to blood transfusions are acute, but not that common, and include urticaria or other cutaneous reactions, red blood cell alloimmunization, mistransfusion, hemolytic reaction, fatal hemolysis, and transfusion-related acute lung injury. Other drawbacks include acute and chronic infection and iron overload.
The benefits of transfusions include rapid improvement in hemoglobin and a reduction of fatigue. The benefits of ESAs include a sustained increase in hemoglobin, possible improvement in quality of life, and avoidance of transfusion risks, Dr. Kraut continued.
Moreover, after evaluating multiple clinical studies, a 2008 FDA advisory panel concluded that 50% of patients on chemotherapy require blood transfusions compared with only 20% to 25% of patients taking ESAs while on chemotherapy.
Among the risks of ESAs are thromboembolic complications, Dr. Kraut said, pointing to a study last year in JAMA (2008;914-024) where the authors extracted the rates of venous thromboembolic events from 51 trials of 13,611 patients and found the relative risk of this complication to be 1.57.
In addition, a 2008 review of eight trials of cancer patients receiving darbepoetin or epoetin showed that the drugs resulted in increased mortality and tumor progression in patients with a variety of malignancies and a target hemoglobin of 12 g/dL (JAMA 2008;299:914-924). Concomitant treatment included radiotherapy, palliative radiotherapy, chemotherapy, or no treatment.
Additionally, the ESA Individual Pa tient Data Meta-Analysis Collaborative Group (Lancet 2009;373:1532-1542) evaluated the original data of 13,933 patients in 53 randomized studies, most of breast cancer and lung cancer, evaluating ESAs plus RBC transfusion vs RBC transfusion alone. The researchers also analyzed patients who received chemotherapy and those who did not.
The risk of death was found to increase by a factor of 1.17 for patients receiving ESAs without chemotherapy and by 1.10 for those receiving ESAs with chemotherapy.
Overall, noted Dr. Kraut, recent NCCN, FDA, ASCO, ASH, and CMS guidelines state that ESAs are not indicated for patients with nontreatment-related anemia and solid tumor cancer or in those individuals with myelosuppressive chemo therapy-induced anemia when the goal is cure. Individual evaluation is needed when myelosuppressive chemotherapy is given with noncurative intent. Oncologists should also carefully consider whether to use ESAs in patients with breast, head and neck, cervical, and non-small cell lung cancers, Dr. Kraut said.
Many of the studies on which guidelines were based administered ESA when hemoglobin was between 12 and 14 g/dL, and the risks in these patients are not clear. No safety data are available on ESA dosing when hemoglobin is between 10 and 12 g/dL, but the goal is to avoid transfusion. Most advisory groups note that ESA therapy is not indicated if hemoglobin is higher than10 g/dL, he noted, and physicians should also always consider the risk of thromboembolic disease.