A European patient record study on diagnosis and treatment of chemotherapy-induced anaemia.

PURPOSE: Patients with cancer frequently experience chemotherapy-induced anaemia (CIA) and iron deficiency. Erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions are available therapies. This study evaluated routine practice in CIA management. METHODS: Medical oncologists and/or haematologists from nine European countries (n=375) were surveyed on their last five cancer patients treated for CIA (n=1,730). Information was collected on tests performed at diagnosis of anaemia, levels of haemoglobin (Hb), serum ferritin and transferrin saturation (TSAT), as well as applied anaemia therapies. RESULTS: Diagnostic tests and therapies for CIA varied across Europe. Anaemia and iron status were mainly assessed by Hb (94%) and ferritin (48%) measurements. TSAT was only tested in 14%. At anaemia diagnosis, 74% of patients had Hb ≤ 10 g/dL, including 15% with severe anaemia (Hb <8 g/dL). Low-iron levels (ferritin ≤ 100 ng/mL) were detected in 42% of evaluated patients. ESA was used in 63%of patients, blood transfusions in 52 % and iron supplementation in 31% (74% oral, 26% intravenous iron). Only 30% of ESA-treated patients received a combination of ESA and iron supplementation. Blood transfusions formed part of a regular anaemia treatment regimen in 76% of transfused patients. Management practices were similar in 2009 and 2011. CONCLUSION: Management of anaemia and iron status in patients treated for CIA varies substantially across Europe. Iron status is only assessed in half of the patients. In contrast to clinical evidence, iron treatment is under utilised and mainly based on oral iron supplementation. Implementation of guidelines needs to be increased to minimize the use of blood transfusions.

The use of intravenous iron in patients with cancer-related anaemia.

Intravenous iron has become the standard of care in patients with renal failure receiving treatment with erythropoiesis stimulating agents (ESAs) to treat true and functional iron deficiency and to prevent its development in haemodialysis patients. In cancer-related anaemia, several recently published, randomised studies suggested that intravenous iron improved haemoglobin response rates in ESA-treated patients compared to those treated with oral iron or placebo. The data supporting the efficacy of intravenous iron instead of oral iron in this setting are increasingly persuasive but larger randomised trials are needed before definitive recommendations are made.

Granulocyte and erythropoietic stimulating proteins after high-dose chemotherapy for myeloma.

High-dose chemotherapy is an established treatment for patients with myeloma. In randomized trials it has been shown to prolong disease-free survival by around 1 year compared to patients receiving chemotherapy alone. Physically and psychologically high-dose therapy takes its toll on the patient who may be in hospital for around 3 weeks and take some weeks or months to convalesce after discharge. Granulocyte colony stimulating factors and erythropoietic stimulating agents will speed neutrophil and red cell recovery, respectively, when used at an appropriate time after the high-dose chemotherapy. The clinical value of these laboratory findings is uncertain and the role of these agents after high-dose chemotherapy remains a subject for debate.

hTERT, the catalytic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemia.

Telomere shortening is associated with disease progression in chronic myeloid leukaemia (CML). To investigate the biology and regulation of telomerase in CML, we evaluated expression of the telomerase components, its regulators and several telomeric-associated proteins. Quantitative real-time-polymerase chain reaction (PCR) was used to compare gene expression in the CD34+/leukaemic blast cells of 22 CML patient samples to the CD34+ cell population of healthy individuals. hTERT, the catalytic component of telomerase, was downregulated in eight of 12 chronic phase (CP) patients (P = 0.0387). Furthermore, hTERT was significantly downregulated in two of three patients in accelerated phase (AP) and seven of seven patients in blast crisis (BC), P = 0.0017. Expression of hTR and telomeric-associated proteins TEP1, TRF1, TRF2, tankyrase and PinX1 was high in the majority of CP and AP patients. With the exceptions of TEP1 and hTR, expression of these factors was highest in CP and decreased during disease progression. Expression of c-Myc, a positive regulator of hTERT transcription, correlated with hTERT expression and decreased with disease progression, falling below control levels in BC. hTERT levels were increased in CP patients following successful treatment with imatinib, relative to untreated CP patients. We suggest that reduced hTERT expression directly causes the shortened telomeres observed in CML.

High proportions of regulatory T cells in PBSC grafts predict improved survival after allogeneic haematopoietic SCT.

Regulatory T cells (Tregs) modulate immune responses and improve survival in murine transplant models. However, whether the Treg content of allogeneic cell grafts influences the outcome in human haematopoietic stem cell (HSC) transplantation is not well established. In a prospective study of 94 adult allogeneic PBSC transplants (60% unrelated; 85% reduced intensity conditioning), the median Treg (CD3(+)CD4(+)CD25(+)FOXP3(+)CD127(dim/-)) dose transplanted was 4.7 × 10(6)/kg, with Tregs accounting for a median of 2.96% of CD4(+) T cells. Patients transplanted with grafts containing a Treg/CD4(+) T-cell ratio above the median had a 3-year overall survival of 75%, compared with 49% in those receiving grafts with a Treg/CD4(+) T-cell ratio below the median (P=0.02), with a 3-year non-relapse mortality of 13% and 35%, respectively (P=0.02). In multivariate analysis, a high graft Treg/CD4(+) T-cell ratio was an independent predictor of lower non-relapse mortality (hazard ratio (HR), 0.30; P=0.02), improved overall survival (HR, 0.45; P=0.03) and improved sustained neutrophil (HR, 0.52; P=0.002), platelet (HR, 0.51; P<0.001) and lymphocyte (HR, 0.54; P=0.009) recovery. These data support the hypothesis that the proportion of Tregs in allogeneic HSC grafts influences clinical outcome and suggest that Treg therapies could improve allogeneic HSC transplantation.

Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial.

PURPOSE: This randomized, double-blind, placebo-controlled clinical trial assessed the effects of epoetin alfa on transfusion requirements, hematopoietic parameters, quality of life (QOL), and safety in anemic cancer patients receiving nonplatinum chemotherapy. The study also explored a possible relationship between increased hemoglobin and survival. PATIENTS AND METHODS: Three hundred seventy-five patients with solid or nonmyeloid hematologic malignancies and hemoglobin levels < or = 10.5 g/dL, or greater than 10.5 g/dL but < or = 12.0 g/dL after a hemoglobin decrease of > or = 1.5 g/dL per cycle since starting chemotherapy, were randomized 2:1 to epoetin alfa 150 to 300 IU/kg (n = 251) or placebo (n = 124) three times per week subcutaneously for 12 to 24 weeks. The primary end point was proportion of patients transfused; secondary end points were change in hemoglobin and QOL. The protocol was amended before unblinding to prospectively collect and assess survival data 12 months after the last patient completed the study. RESULTS: Epoetin alfa, compared with placebo, significantly decreased transfusion requirements (P =.0057) and increased hemoglobin (P <.001). Improvement of all primary cancer- and anemia-specific QOL domains, including energy level, ability to do daily activities, and fatigue, was significantly (P <.01) greater for epoetin alfa versus placebo patients. Although the study was not powered for survival as an end point, Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa (P =.13, log-rank test), and Cox regression analysis showed an estimated hazards ratio of 1.309 (P =.052) favoring epoetin alfa. Adverse events were comparable between groups. CONCLUSION: Epoetin alfa safely and effectively ameliorates anemia and significantly improves QOL in cancer patients receiving nonplatinum chemotherapy. Encouraging results regarding increased survival warrant another trial designed to confirm these findings.

Efficacy and safety of oral fludarabine phosphate in previously untreated patients with chronic lymphocytic leukemia.

PURPOSE: A prospective, multicenter, open-label, phase II clinical trial to assess oral fludarabine phosphate treatment in terms of safety, efficacy, and quality of life. Reference to a historical group of patients treated with the intravenous (IV) formulation allowed the two formulations to be compared. PATIENTS AND METHODS: Patients with previously untreated B-cell chronic lymphocytic leukemia received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. Efficacy was assessed using International Workshop on Chronic Lymphocytic Leukemia and National Cancer Institute criteria for response. Safety monitoring included WHO toxicity grading for adverse events. Quality of life was also assessed. RESULTS: Eighty-one patients received treatment. According to International Workshop on Chronic Lymphocytic Leukemia criteria, the overall response rate was 71.6% (complete remission, 37.0%; partial remission, 34.6%). The response rate using National Cancer Institute criteria was 80.2% (complete remission, 12.3%; partial remission, 67.9%). Median time to progression was 841 days (range, 28 to 1,146 days). The most frequently reported grade 3/4 toxicity was myelosuppression. WHO grade 3/4 hematological toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). Gastrointestinal toxicity was more common with the oral formulation than with IV fludarabine phosphate, but was generally mild to moderate and did not require treatment. Statistically significant improvements in mean emotional and insomnia quality-of-life scores were seen after treatment. CONCLUSION: This study demonstrates that oral fludarabine phosphate is clinically effective and generally well tolerated by patients with previously untreated B-cell chronic lymphocytic leukemia. Oral fludarabine phosphate has a similar clinical efficacy and safety profile to the IV formulation. Oral fludarabine phosphate does not adversely affect quality of life and may improve emotional and insomnia scores.

Impact of ABO blood group mismatch in alemtuzumab-based reduced-intensity conditioned haematopoietic SCT.

The impact of ABO incompatibility on clinical outcomes following haematopoietic SCT (HSCT) remains controversial. This retrospective study assessed the effect of ABO mismatch on transplant outcomes and transfusion requirements in 594 patients undergoing reduced-intensity conditioned (RIC) HSCT with alemtuzumab in three UK transplant centres. We found no significant effects of minor, major or bidirectional ABO mismatch on overall survival, relapse-free survival, nonrelapse mortality or relapse incidence. Although the rate of acute GVHD was unaffected by ABO mismatch, the incidence of extensive chronic GVHD was higher in patients with minor and major mismatch compared with those who were ABO matched (hazard ratio (HR) 1.74, P=0.032 for minor, HR 1.69 P=0.0036 for major mismatch). Red cell and platelet transfusion requirements in the first 100 days post transplant did not differ by ABO mismatch. In this large UK series, ABO mismatch in RIC HSCT has no clinically significant effect on survival outcomes but appears to modify susceptibility to extensive chronic GVHD.

The impact of hemoglobin levels on treatment outcomes in patients with cancer.

Clinical trials and surveys have shown that a majority of patients with cancer have low hemoglobin levels as a result of the disease and/or treatment. Clinical trials also have shown that the impact of anemia may be more insidious and far-reaching than generally appreciated. Specifically, studies have shown that low hemoglobin levels have significant impact on treatment outcomes, including survival. The mechanisms by which treatment efficacy and survival are compromised have not been fully elucidated but may include cellular compromise (eg, impaired tumor oxygenation), or more general patient compromise (eg, decreased quality of life and treatment delivery). Recent studies have suggested that increasing hemoglobin levels with recombinant human erythropoietin (r-HuEPO, epoetin alfa) have resulted in better outcomes following radiotherapy, chemotherapy, and the combined-treatment modality.

Encephalopathy complicating high-dose melphalan.

High-dose melphalan (HDM) with peripheral blood stem cell transplant (PBSCT) is a common treatment for patients with multiple myeloma (MM) and more recently also with AL amyloidosis (ALA). We report two female patients with severe renal failure who underwent treatment with HDM for MM (patient 1) and ALA (patient 2). Both patients developed severe encephalopathy with generalised tonic-clonic seizures and a Glasgow Coma Scale (GCS) of 3/15. Causes for coma such as infections, metabolic disturbances, cerebral ischaemia or haemorrhage were excluded. Patient 1 died on day 25 post transplant while comatose. Patient 2 recovered from her comatose state 18 days after transplantation. To our knowledge this is the first report on a possible role of high-dose melphalan in the development of encephalopathy.

Prenatal determination of fetal rhesus D status by DNA amplification of peripheral blood of rhesus-negative mothers.

We have developed a sensitive PCR-based assay for the RhD gene and used it to detect circulating fetal cells from RhD-positive fetuses from peripheral blood of RhD-negative mothers. With further improvement in diagnostic accuracy, this assay may have implications in the management of RhD-sensitized pregnancies in women whose partners are heterozygous for the RhD gene. Further studies are required to determine the relationship between maternal anti-D levels and circulating fetal cell numbers.

Intraarticular and intraperitoneal administration of etoposide in haematological malignancy.

Etoposide is frequently used in the treatment of a wide variety of malignant disorders. Administration is usually by intravenous infusion, but etoposide can also be given by mouth, by intraarterial infusion and by direct instillation into the pleural cavity. Two patients are described who were treated with injections of etoposide into the peritoneal cavity and knee joint, respectively.

Evidence for a GVL effect following reduced-intensity allo-SCT in ALL: a British Society of Blood and Marrow Transplantation study.

Myeloablative allo-SCT decreases relapse incidence (RI) in ALL. Reduced intensity conditioning (RIC) may extend allo-SCT to older and less fit patients. Sixty-nine ALL patients reported to the BSBMT underwent fludarabine-based RIC allo-SCT, 38 from unrelated donors (UD). Forty-four patients received alemtuzumab. ALL was in CR in 64 patients (93%). This was a second or third SCT in 23 patients. Two-year OS and PFS were 36% and 32%, respectively. In multivariate analysis male recipients demonstrated better OS and PFS (hazard ratio (HR) = 0.42, P = 0.008 and HR = 0.45, P = 0.012, respectively). Two-year TRM was 29%: higher with younger age (HR = 0.97/year, P = 0.041), female recipient (HR = 2.55, P = 0.049) and increasing grade of acute GVHD (HR = 1.87, P = 0.001). Two-year RI was 38% and was lower in patients with acute and chronic GVHD (HR = 0.62 per increasing grade, P = 0.035 and HR = 0.52, P = 0.025, respectively). Long-term ALL-free survival is achievable following fludarabine-based RIC allo-SCT. The association between GVHD and decreased RI suggests the presence of a GVL effect.

The investigation and treatment of secondary anaemia.

Secondary anaemia or the anaemia of chronic disease (ACD) is the commonest form of anaemia in hospitalised patients and the second most prevalent anaemia worldwide after iron deficiency. It is characterised by defective iron incorporation in erythropoiesis, an impaired response to erythropoietin, a decrease in erythropoietin production and cytokine induced shortening of red cell survival. For many patients with ACD the cause is apparent but for many others the underlying disease needs to be determined and such patients are often referred to haematologists for investigation. The search for the cause can be a fascinating exercise in good history taking, examination skills and performing and interpreting appropriate investigations. This review covers the pathogenesis and causes of ACD and then discusses the clinical and laboratory investigation of a patient with suspected ACD. Finally, the management of a patient with ACD is discussed including erythropoiesis stimulating agents (ESAs), intravenous iron and future therapies.