Introduction

For hematologists, treatment of anemia remains an important area of expertise. The availability of erythrocyte stimulating proteins (ESPs) such as epoetin alfa (Procrit®) and darbepoetin alfa (Aranesp®) have transformed the treatment of chemotherapy-induced anemia (CIA) from one of observation or transfusion to one of active intervention. Over the past decade, a series of studies have clearly correlated improvement in quality of life with improvement in hemoglobin levels for anemic cancer patients. Broader uses of ESPs are now expanding to anemia of cancer and even nonmalignant-related anemia. The 45th Annual American Society of Hematology meeting held December 6-9, 2003 devoted considerable attention to exploration of various aspects of the consequences of anemia and its treatment.

Erythrocyte Stimulating Proteins

There is little effective therapy for patients with anemia complicating myelodysplastic syndrome, (MDS) although small series have reported improvement in anemia after treatment with growth factors. Jadersten, et. al¹ reported long term outcome on 129 patients treated with Procrit + G-CSF in Nordic Group studies between 1990 - 1999. The majority had low risk MDS: 30 refractory anemia, 41 refractory anemia with ringed sideroblasts and 58 refractory anemia with excess blasts, mostly International Prognostic Scoring System (IPSS) low or low/intermediate. With a median follow up of 30 months, the overall erythroid response rate was 39% with 22% complete remission and 17% partial remission. The median duration of response was 23 months. Responses were more durable in the RA/RARS group (28 months) compared to RAEB (12 months) (p=0.04). There was no increased progression to AML when the treated group was compared to an untreated group of patients matched for IPSS. Effective maintenance doses of EPO range considerably from 5,000 to 50,000 units (median 30,000 units) weekly. These long-term results are important and allow us to offer selected patients a treatment strategy with a real chance of success without negative effect on long-term outcome.

Patients with cancer not receiving chemotherapy appear to benefit from ESP treatment in single arm phase II trials. Preliminary results of a randomized trial comparing Aranesp® to supportive care in this patient population were reported by Charu et al.² Anemic patients with a median hemoglobin of 10.2 gm/dl were randomized in a 4:1 fashion to receive Aranesp® or observation. Aranesp® at 3 mcg/kg every two weeks increased the hemoglobin by 2.1 gm/dl vs. 0.3 gm/dl in untreated subjects, with coincident reduction in transfusions (10% vs. 30%) and substantial reduction in fatigue. This study is ongoing as are explorations of other drugs and schedules for treatment of the anemia of cancer.

Another group of patients deserving further evaluation are those with mild anemia, defined as hemoglobin of 10-12 gm/dl. Longitudinal studies have shown that maximal quality of life benefits are achieved when hemoglobin is brought to near normal levels. New National Comprehensive Cancer Network (NCCN) guidelines also recommend target hemoglobin of 11-12 gm/dl. Straus and colleagues,³ randomized patients with hematologic malignancies receiving chemotherapy to early treatment with Procrit® when hemoglobin was 10-12 gm/dl, or to delayed treatment, waiting until the hemoglobin was <9 gm/dl. Results are shown in table 1.

Table 1.

Early treated patients had improved QOL, as evidenced by an improvement over late treated patients on FACT-AN and linear analog scales which were clinically significant. Moreover, early patients had significantly less days in bed (52% vs. 3.1%) (p=0.017) and restricted activity days (41.6% vs. 12.6%) (p=0.042). This study confirms the multiple benefits of treating patients as soon as anemia appears, rather than delaying therapy.

Other uses of ESPs in hematologic malignancies were also presented at ASH. In an M.D. Anderson study, 60% of CML patients in chronic phase treated with Gleevec® developed anemia, which was severe in 9% of the population. Response to Gleevec® was not influenced by the development of anemia. Of anemic patients, 101 (43%) received Procrit at a starting dose of 40,000 units per week. Hematologic response of >2 gm/dl rise was documented in 69% of patients who had previously failed Interferon and 77% of patients previously untreated. Procrit® is effective in treating Gleevec® induced anemia in CML.

Aranesp® was studied in the treatment of post-allogeneic stem cell transplant (SCT) induced anemia.⁵ Thirteen anemic patients post-allo SCT with a mean hemoglobin of 10.7 gm/dl were treated with q2wk Aranesp®. All had a hematologic response with a median rise of 4.4 gm/dl at 65 days after initiation of treatment. Interestingly, three patients with prior Procrit® treatment also responded. Aranesp® should be considered for anemic patients after allo-SCT. A different approach utilizing early treatment with G-CSF and Procrit® after autotransplant with peripheral blood stem cells (PBSC) was reported by Olivieri, et al.⁶ Starting Procrit 10,000 units per day + G-CSF 5 mcg/kg day +1 was compared to starting G-CSF only beginning day +5. Every clinical parameter examined, including time to engraftment of neutrophils, time to engraftment of platelets, days in the hospital, days of IV antibiotics and costs, was significantly better for the early Procrit® plus G-CSF group. Packed red blood cell transfusions were almost abolished in the early growth factor group, median 0 (range 0-6) vs. the later G-CSF group median 2 (range 0-8). Early use of growth factors after high-dose chemotherapy and autologous SCT is associated with improved engraftment kinetics and superior clinical outcome.

One of the most important practical issues is how well Procrit® and Aranesp® perform in the most common usage of these drugs, chemotherapy induced anemia (CIA). A retrospective medication use evaluation in hospital outpatient in community settings was reported by Boccia et al.⁷ Over 3,000 chart records were abstracted including 1,444 patients treated with Aranesp® only and 1,341 patients treated with Procrit® only. The most common starting dosages were 200 mcg q2 weeks for Aranesp® and 40,000 weekly for Procrit®. The mean (range) changes in hemoglobin concentration after 12 weeks were similar, 1.0 gm/dl (0.9 - 1.1) for Aranesp® and 1.1 gm/dl (1.0-1.2) for Procrit®. Lower rates of dose escalation (22-23%) than occur in the clinical trial setting were noted and may account for the less robust hemoglobin rise compared to the trial reports.

The first data from a prospective head-to-head trial of Procrit® vs. Aranesp® were reported by Schwartzberg, et al.⁸ This preliminary analysis included 210 patients, 105 per arm, of 300 patients ultimately enrolled with breast, ovarian or non-small cell lung cancer receiving chemotherapy and anemia with hemoglobin <11 gm/dl. Baseline demographics and clinical characteristics were well balanced between the arms. Results are shown in table 2.

Table 2.

Hb response = >2 gm/dl rise in hemoglobin from baseline

Hemato response = >2 gm/dl rise in hemoglobin or hemoglobin >12 gm/dl

These data were calculated by ITT and by evaluating only those with available data. No difference in the incidence or the severity of adverse events was observed between treatment groups. This early prospective and retrospective data suggests similar efficacy of weekly Procrit® and every 2-week Aranesp® with the latter offering greater patient convenience.

Correlating Anemia and Quality of Life

The M.D. Anderson Symptom Inventory (MDASI), a 19 question list of core symptoms and symptom interference with life activities was evaluated in an open label trial of Aranesp to assess relationships between hemoglobin change and symptom burden.⁹ There was a 22% improvement in the MDASI fatigue score for baseline to week 13 using available data. Change in fatigue scores improved proportionally to the degree of hemoglobin change. Patients with a > 2 gm/dl rise in hemoglobin had the most improvement.

Another novel QOL instrument designed to discriminate symptoms associated with chemotherapy-induced anemia was presented by Fortner, et al.¹⁰ The cancer care monitor anemia (CCM-A) scale consists of nine items scored on a 0-10 Likert scale with good internal consistency, inter-item correlation and criterion validity. The CCM-A scores were significantly different for grade 1 vs. grade 0 anemia and for grade 2 vs. grade 0 and 1 anemia (table 3).

Table 3. CCM-A Score by Grade of Anemia with Hb

An attempt to develop a screening tool for functional capacity in chemotherapy-induced anemia patients was presented by Vadhan-raj, et al.¹¹ The modified Harvard Step Test was designed to measure aerobic capacity. Unfortunately, in a large patient trial assessing Aranesp® in CIA, only one-third of patients were able to complete the test and it was judged not useful in this patient population. However, the study did yield results on fatigue and energy level as the FACT-F and the Energy Numerical Rating Grade (ENRG) scales were administered at baseline and at weeks 9 and 17. Increases in both scales were demonstrable at week 9 with further improvement at week 17. Again, a correlation with hemoglobin use was clearly evident, as shown in table 4.

Table 4. Change in Hb at End of Treatment

A change of greater than three points is considered clinically significant in the FACT-F scale. Response to Aranesp® correlated with the reduction of fatigue, improvement in energy and improved quality of life.

These reports suggest that the development of validated symptom burden scales are of use in correlating QOL change associated with different levels of anemia. They are likely to be useful in both research trials and as clinical practice management tools as part of the comprehensive approach to the treatment of CIA with ESPs.

The global benefit of ESP in the treatment of patients with malignant disease was the subject of a presentation by the Cochran group.¹² Their meta-analysis demonstrated significant benefit to erythropoietin in reducing risk of PRBC transfusions and yielding a hematologic response. While there is no evidence that EPO improves tumor response, there is an intriguing trend towards improved overall survival, HR 0.80, (95% CI 0.65-1.00) with the use of erythropoietin. More studies planned or in progress should help answer the question of a survival benefit for patients with cancer receiving ESPs.

Anemia and the Elderly

In the general population, anemia portends a worse outcome. Elderly individuals with anemia, representing 12.5% of a National Institute of Aging database, are more likely to die, spend time in the hospital, and be hospitalized more often than their non-anemic counterparts.¹³ Those with mild anemia had more health-related problems than individuals with normal hemoglobin levels. Similarly, an investigation into the relationship between anemia and frailty in older adults showed a direct correlation with frailty risk being highest for the lowest hemoglobin concentration.¹⁴ Even mildly low hemoglobin levels correlated, with hemoglobin <12 gm/dl showing an odds ratio of 2.13 (95% CI 1.1-4.3) for frailty, allowing adjustment for demographics and disease burden variables.

Another study addressed the association of anemia in the elderly with healthcare costs and resource utilization.¹⁵ Anemic patients, defined as hemoglobin <13 gm/dl in men and <12 gm/dl in women comprise 33% of a population of > 75 years of age in a large vertically integrated healthcare system. Anemic patients have significantly more total healthcare expenditures / year, more healthcare encounters, hospital admissions and longer hospital stays compared to nonanemic subjects.

Taken together, these results demonstrate that anemia is a relatively common problem in the elderly and has profound negative impact on health. Even mild anemias are associated with a worse outcome including higher risk of frailty, hospitalization, healthcare utilization and mortality. This is an area that should be intensively evaluated, including a careful look at nutritional and pharmacologic interventions that could treat anemia in this large and growing segment of the population.

New Agents

ASH 2003 saw the first results of novel agents in the treatment of anemia. CERA (Continuous Erythropoiesis Receptor Activator) has a prolonged serum half-life and is more potent than epoetin alfa in preclinical trials. Phase I trials in healthy volunteers examined four different doses from 0.4 - 3.2 mcg/kg by IV injection at 3 week intervals or subcutaneous injections at 2 week intervals.¹⁶ By either route, cumulative responses were seen for hematocrit, hemoglobin, and RBC. A phase I/II dose escalation study of CERA in patients with multiple myeloma receiving chemotherapy was also presented. Several different doses, ranging from 1.0 mcg/kg to 8.0 mcg/kg administered subq q3 weeks were explored.¹⁷ A dose response was seen through 3.5 mcg/kg after which the hemoglobin response plateaued. The mean hemoglobin response for doses of 3.5 - 8 mcg/kg was an increase in hemoglobin of 1.6-2.3 gm/dl with 50-60% of patients achieving a hemoglobin response. Adverse events included hypertension in four patients out of 63 and one episode of pyrexia. Further studies of CERA and other patient groups in phase II and III settings are awaited.

The study of a novel oral immunomodulatory factor, CC5013, in treating anemia and patients with MDS was presented by List, et al.¹⁸ This thalidomide analog has less neurologic toxicity than the parent compound and is a potent suppressor of an inflammatory cytokine generation. A safety and efficacy trial in 45 transfusion-dependent or symptomatic anemic MDS patients was performed. In 33 evaluable patients, 21 (64%) achieved an erythroid response including transfusion independence or >2 gm/dl hemoglobin rise in 19. Moreover, major cytogenetic remissions were recorded in 11/17 (65%) evaluable patients with 10 achieving normal karyotype. Myelosuppression was the most common adverse event and was dose dependent. Multicenter phase II studies are underway and should help to define the benefit of this new class of agents.

Conclusions

Anemia is a common complication of cancer, its treatment with chemotherapy, and in other populations such as the elderly. We now have the tools in hand to treat virtually all causes of non-nutritional, non-inherited anemia with ESPs. ASH 2003 helped clarify the benefits of treatment in these populations, including improvement in hemoglobin, reduction in transfusions, and improvement in fatigue and other quality of life measures.

There is considerable interest in exploring anemia treatment outside the chemotherapy induced anemia indication, and some provocative results which suggest eliminating anemia may be associated with tangible benefits in well being.

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