Assessing patients' risk of febrile neutropenia: is there a correlation between physician-assessed risk and model-predicted risk?

This study evaluated the correlation between the risk of febrile neutropenia (FN) estimated by physicians and the risk of severe neutropenia or FN predicted by a validated multivariate model in patients with nonmyeloid malignancies receiving chemotherapy. Before patient enrollment, physician and site characteristics were recorded, and physicians self-reported the FN risk at which they would typically consider granulocyte colony-stimulating factor (G-CSF) primary prophylaxis (FN risk intervention threshold). For each patient, physicians electronically recorded their estimated FN risk, orders for G-CSF primary prophylaxis (yes/no), and patient characteristics for model predictions. Correlations between physician-assessed FN risk and model-predicted risk (primary endpoints) and between physician-assessed FN risk and G-CSF orders were calculated. Overall, 124 community-based oncologists registered; 944 patients initiating chemotherapy with intermediate FN risk enrolled. Median physician-assessed FN risk over all chemotherapy cycles was 20.0%, and median model-predicted risk was 17.9%; the correlation was 0.249 (95% CI, 0.179-0.316). The correlation between physician-assessed FN risk and subsequent orders for G-CSF primary prophylaxis (n = 634) was 0.313 (95% CI, 0.135-0.472). Among patients with a physician-assessed FN risk ≥ 20%, 14% did not receive G-CSF orders. G-CSF was not ordered for 16% of patients at or above their physician's self-reported FN risk intervention threshold (median, 20.0%) and was ordered for 21% below the threshold. Physician-assessed FN risk and model-predicted risk correlated weakly; however, there was moderate correlation between physician-assessed FN risk and orders for G-CSF primary prophylaxis. Further research and education on FN risk factors and appropriate G-CSF use are needed.

Retrospective analysis of relative dose intensity in patients with non-Hodgkin lymphoma receiving CHOP-based chemotherapy and pegfilgrastim.

OBJECTIVES: To evaluate primary prophylaxis with pegfilgrastim, a recombinant human granulocyte colony-stimulating factor, on maintaining relative dose intensity (RDI) in patients with non-Hodgkin lymphoma (NHL) receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-rituximab (CHOP-R). METHODS: This retrospective analysis pooled data from pegfilgrastim NHL clinical trials. Patients received up to 6 cycles of CHOP/CHOP-R every 2 (Q2W) or 3 (Q3W) weeks. RDI and the patient incidence of dose delay, reduction, discontinuation, and adverse events leading to dose alteration/discontinuation were summarized overall and by age group (below 65, 65 to 75, and above 75 y) and treatment schedule. RDI during treatment exposure and RDI adjusted by the planned 6 cycles of treatment were calculated. The adjusted RDI was also evaluated with multiple regression analysis. RESULTS: Mean RDI during treatment exposure was 93% and 94% in overall patients in the Q2W and Q3W regimens, respectively. Mean adjusted RDI was 88% and 80%, respectively. The incidence of patients with RDI>85% was lower in older patients (65 y and above). In older patients, the incidence of dose reduction and discontinuation were higher regardless of treatment schedule, whereas dose delay was higher in the Q2W regimen. Multiple regression analysis identified age and cancer stage as potential factors associated with RDI. Adverse events leading to dose alteration/discontinuation were spread across hematological and nonhematological toxicities; older patients had a higher incidence of these adverse events. CONCLUSIONS: Pegfilgrastim primary prophylaxis maintained RDI in NHL patients receiving CHOP/CHOP-R during treatment. Adjusted RDI was lower in elderly patients because of early termination of chemotherapy.

Biosimilars 101: considerations for U.S. oncologists in clinical practice.

Biosimilars of biologics used for cancer treatment and supportive care are expected to enter the U.S. market soon. Biosimilars will be highly similar to their reference products, but unlike generic drugs, not identical. Differences between a biosimilar and its reference product may arise because of the complexity of biologics, and differences in the cell lines and processes used during manufacturing. Biosimilars will be approved in the United States through a regulatory pathway based on comparative analytical and clinical studies for their characterization and demonstration of no clinically meaningful differences from their reference products. Unlike generics, initial approval may not include interchangeability, as additional evidence may be required before a biosimilar could be approved as interchangeable with its reference product; interchangeable designation could allow pharmacy-level substitution without prescriber intervention. In some cases, the U.S. Food and Drug Administration (FDA) may extrapolate an indication that has not been formally investigated for the biosimilar but that is approved for the reference product. Robust safety monitoring of all biologics is important to track and accurately attribute adverse events, particularly because their inherent complexity and manufacturing differences make them susceptible to structural changes that can affect safety (e.g., immunogenicity). Accuracy of postapproval safety reports will partly depend on the biosimilar naming approach. Potential cost savings should be evaluated in the context of differences in manufacturers' patient-assistance programs, copayments, and institutional costs. A manufacturer's ability to ensure reliable supply of high-quality biosimilars should also be considered. Broad understanding of these issues is critical for oncologists preparing for their use in clinical practice.

Severe neutropenia and relative dose intensity among patients<65 and ≥65 years with non-Hodgkin's lymphoma receiving CHOP-based chemotherapy.

PURPOSE: The objective of this study was to describe the incidence of grade 3/4 neutropenia, patterns of chemotherapy treatment, and granulocyte colony-stimulating factor (G-CSF) use patterns among patients with non-Hodgkin's lymphoma (NHL)<65 and ≥65 years. METHODS: This retrospective, observational study included adult patients with NHL who received cyclophosphamide, doxorubicin, vincristine, and prednisone±rituximab (CHOP±R) from January 2006 to June 2010. RESULTS: A total of 1,579 patients were included, with 54.1%<65 years and 45.9%≥65 years. Most received CHOP-R on a Q3W schedule. Among patients<65 years, the incidence of grade 3/4 neutropenia was 52.3%, the mean relative dose intensity (RDI) was 80.4%, and the incidences of dose delays and reductions were 26.5 and 9.6%, respectively. Among patients≥65 years, the incidence of grade 3/4 neutropenia was 63.2%, the mean RDI was 73.9%, and the incidences of dose delays and reductions were 24.6 and 24.9%, respectively. Most patients (86.9%) received G-CSF. Among patients<65 years, 71.9, 17.4, and 10.7% first received G-CSF as primary prophylaxis, secondary prophylaxis, or treatment, respectively. Among patients≥65 years, 80.1, 11.6, and 8.3% first received G-CSF as primary prophylaxis, secondary prophylaxis, or treatment, respectively. CONCLUSIONS: Chemotherapy regimens and schedules were similar among age groups. Grade 3/4 neutropenia, reduced RDI, and dose delays were common in both age groups, though patients≥65 years had a higher incidence of dose reductions. In spite of these similarities, patients<65 years were less likely to receive primary prophylactic G-CSF. Thus, careful assessment of neutropenia risk factors is needed across age groups to determine appropriate G-CSF use and support planned chemotherapy.

Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review.

Neutropenia with fever (febrile neutropenia [FN]) is a serious consequence of myelosuppressive chemotherapy that usually results in hospitalization and the need for intravenous antibiotics. FN may result in dose reductions, delays, or even discontinuation of chemotherapy, which, in turn, may compromise patient outcomes. It is important to identify which patients are at high risk for developing FN so that patients can receive optimal chemotherapy while their risk for FN is appropriately managed. A systematic review of the literature was performed to gain a comprehensive and updated understanding of FN risk factors. Older age, poor performance status, advanced disease, certain comorbidities, low baseline blood cell counts, low body surface area/body mass index, treatment with myelosuppressive chemotherapies, and specific genetic polymorphisms correlated with the risk of developing FN. Albeit many studies have analyzed FN risk factors, there are several limitations, including the retrospective nature and small sample sizes of most studies.

Using RB1 mutations to assess minimal residual disease in metastatic retinoblastoma.

To assess complete remission before subjecting nongermline metastatic retinoblastoma patients to an autologous peripheral stem cell transplant, we tested for patient-specific retinoblastoma tumor suppressor gene (RB1) mutant alleles in cerebrospinal fluid (CSF) and bone marrow. In 1 child with CSF and 1 with bone marrow metastases, allele-specific polymerase chain reaction (AS-PCR) detected the biallelic RB1 mutations specific to their tumors. The tumor of Child A was homozygous for R251X, and in Child B, it was homozygous for R358X. In Child A, the R251X mutation was detected in mutant controls diluted to 1:12,800 but not in CSF samples, corroborating clinical remission after chemotherapy. In Child B's bone marrow, AS-PCR for R358X was strongly positive at the detection of relapse, and subsequent bone marrow samples corroborated clinical remission after chemotherapy. No mutant tumor RB1 alleles were detected in their harvested peripheral blood stem cells. Both children were deemed suitable candidates for supralethal-dosage consolidation chemotherapy followed by autologous peripheral stem cell rescue of the bone marrow aimed at curing their metastatic retinoblastoma. When Child A recurred, the mutant tumor RB1 allele was detected 3.5 months before conventional pathology detected retinoblastoma tumor cells in the CSF. Assaying tumor-specific RB1 mutations complements cytological and immunohistochemical assessment of retinoblastoma involvement of CSF and bone marrow. Tumor cells can be detected in numbers lower than possible by conventional methods. An early diagnosis of relapse may allow an early institution of new therapy. A prospective international multicenter trial of the rare patients with metastatic retinoblastoma would assess the role of molecular monitoring in surveillance for minimal residual disease and recurrence.

Early intervention with antithrombin III therapy to prevent progression of hepatic venoocclusive disease.

Venoocclusive disease (VOD) is the most frequent cause of early nonrelapse mortality among patients receiving high-dose chemoradiotherapy and hematopoietic stem cell transplantation. Endothelial injury of sinusoids and hepatic veins following chemotherapy is considered the initial event in the development of VOD. Activation of the coagulation cascade and inflammatory processes following endothelial injury results in a hypercoagulable state and a localized consumption of the natural anticoagulants, antithrombin III, protein C and protein S. The resultant coagulopathy can lead to multiorgan dysfunction and death. The objective was to retrospectively study the largest series of patients that has received antithrombin III for the treatment of VOD following hematopoietic stem cell transplantation. A total of 48 patients were diagnosed with VOD post hematopoietic stem cell transplantation (median age, 39 years; range, 1-69 years); 38 of the 48 received a nonradiation-based conditioning regimen and 21 of 48 received a transplant from an unrelated donor. Treatment was primarily directed at early intervention rather than prophylactic therapy to correct the antithrombin III deficiency associated with VOD. We attempted to achieve antithrombin III levels greater than 120%. There was no significant treatment-related morbidity. The overall 100-day mortality for the treatment cohort was 17%, with 10% for the mild/moderate group and 39% for the severe group, respectively. In conclusion, the encouraging results of this study suggest that this antithrombin III treatment should be further considered in patients with severe VOD.

Reduced intensity transplantation for metastatic renal cell cancer with 2-year follow-up.

Metastatic renal cell carcinoma (RCC) is a disease that is resistant to conventional systemic therapy. Nonmyeloablative allogeneic stem cell transplant has activity in patients with metastatic RCC. This approach has been used in related donor transplantation but there are limited data on outcomes in the setting of unrelated donor (URD) transplantation. This phase II trial assessed the efficacy, safety, and responses in 16 patients, 10 related and 6 URD transplants after a reduced intensity conditioning regimen and stem cell transplant as a treatment for metastatic RCC. Sixteen patients received a conditioning consisting of either fludarabine, cyclophosphamide (n=11) or fludarabine, total body irradiation (n=5) followed by transplantation from an HLA-matched sibling donor or a unrelated HLA-donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients were monitored for engraftment by short tandem repeat for myeloid and lymphoid lineages and clinical response was assessed by serial imaging. All patients achieved donor chimerism, 7 patients developed acute, grades 2 to 3, graft-versus-host disease. Chronic graft-versus-host disease occurred in 6 patients and transplant-related mortality was 12%. Of the 10 related donors, 1 obtained a complete response, 3 had a partial response, and 3 had stable disease. In the 6 patients who underwent URD transplant, 1 obtained a complete response and 1 patient had stable disease. These results suggest that similar outcomes are possible where either related or URD were used as the stem cell source in reduced intensity stem cell transplant for metastatic RCC.

A case report of a patient with microcephaly, facial dysmorphism, mitomycin-c-sensitive lymphocytes, and susceptibility to lymphoma.

We report on a 17-year-old boy with a unique lymphocyte mitomycin-C (MMC)-sensitive chromosomal breakage syndrome. He had failure to thrive, and has microcephaly, slight facial dysmorphism, and constitutional short stature but no other phenotypic or hematological manifestations of Fanconi anemia (FA). He developed B-cell lymphoma of the neck, which was treated with standard doses of alkylating agents. Major side effects related to chemotherapy did not occur. Normal erythrocyte corpuscular volume, MMC-insensitive fibroblasts, and the occurrence of lymphoma rather than AML sets this patient apart from typical FA. The combination of constitutional dwarfism, microcephaly, MMC-sensitive lymphocytes, and susceptibility to lymphoma represents an unusual constellation of symptoms among genetic disorders.

Successful bone marrow transplantation for life threatening xanthogranuloma disseminatum in neurofibromatosis type-1.

A 2-yr and 9-month-old female patient with neurofibromatosis type-1 presented with hepatomegaly, anemia, thrombocytopenia, and croupy cough and diagnosed with xanthogranuloma disseminatum (XD). She failed chemotherapy consisting of steroids, 6-mercaptopurine and methotrexate. A partial response to HLH-94 therapy that included etoposide and cyclosporine A was initially observed. However, she continued to have significant organ dysfunction without further improvement at 6 months of therapy. She then received matched unrelated donor bone marrow transplantation (BMT) following carmustine, etoposide, cytarabine and melphelan conditioning with complete resolution of symptoms. BMT is an option in therapy-resistant, life threatening XD cases.

Severe neutropenia and thrombocytopenia following cardiac transplantation in a child.

Hematological complications have been occasionally described after cardiac transplantation. We are reporting a 5-yr-old child who developed sequential severe neutropenia and thrombocytopenia following cardiac transplantation while on tacrolimus-based immune suppression therapy. There was no improvement in blood counts following a change in immune suppression to cyclosporine A. The neutropenia was associated with a maturation arrest in the bone marrow. The occurrence of thrombocytopenia coincided with rising anti-herpes virus 6 IgG titers suggesting a possible contributory role. Neutropenia resolved following treatment with rituximab, and the thrombocytopenia responded to Dapsone therapy eventually. This case points out the potential multifactorial pathogenesis of cytopenias following cardiac transplantation with differing response to various immune suppressive therapies.

Assessment of optimal size and composition of the U.S. National Registry of hematopoietic stem cell donors.

BACKGROUND: The National Marrow Donor Program (NMDP) receives federal funding to operate a registry of over 4 million volunteer donors for patients in need of a hematopoietic stem cell transplant. Because minority patients are less likely to find a suitably matched donor than whites, special efforts have been aimed toward recruitment of minorities. Significant financial resources are required to recruit and tissue type additional volunteer donors. METHODS: Population genetics models have been constructed to project likelihoods of finding a human leukocyte antigen (HLA)-matched donor for patients of various racial/ethnic groups. These projections have been made under a variety of strategies for expansion of the NMDP Registry. Cost-effectiveness calculations incorporated donor unavailability and other barriers to transplantation. RESULTS: At current recruitment rates, the probability of an available HLA-A,B,DRB1 matched donor is projected to increase from 27% to 34%; 45% to 54%; 75% to 79%; and 48% to 55%, for blacks, Asians/Pacific Islanders, whites and Hispanics, respectively, by the year 2007. Substantial increases in minority recruitment would have only modest impacts on these projections. These projections are heavily affected by donor availability rates, which are less than 50% for minority volunteers. CONCLUSIONS: Continued recruitment of additional volunteers can improve the likelihood of finding an HLA-matched donor, but will still leave significant numbers of patients of all racial/ethnic groups without a match. Efforts to improve donor availability (especially among minorities) and to increase the number of patients with access to the NMDP Registry may prove to be more cost-effective means of increasing transplants.

Anti-thrombin III in the management of hematopoietic stem-cell transplantation-associated toxicity.

OBJECTIVE: To describe the evidence assessing the use of anti-thrombin III (AT-III) in the management of toxicity associated with hematopoietic stem-cell transplantation (HSCT)-conditioning regimens. DATA SOURCES: Clinical literature was accessed through conference proceedings, EMBASE, the Cochrane database, and MEDLINE (1966-December 2003). STUDY SELECTION AND DATA EXTRACTION: Case reports, small case series, case-control and cohort studies, and randomized controlled trials of AT-III in HSCT were evaluated. Publications examining AT-III use in the non-HSCT setting were also explored. Key search terms included AT-III, transplantation, and veno-occlusive disease (VOD). DATA SYNTHESIS: Severe VOD and ensuing multiple organ dysfunction is associated with high mortality in HSCT. A low AT-III level has been shown to correlate with the development of organ dysfunction. Phase II trials, case series, and one small, randomized, placebo-controlled study suggest a benefit when AT-III therapy is instituted early in the course of VOD/multiple organ dysfunction syndrome. In all of these reports, AT-III use was devoid of adverse events. CONCLUSIONS: Although further studies are needed to ascertain the optimal target level, method, and duration of administration, AT-III is still a viable alternative for the treatment of severe VOD and ensuing multiple organ dysfunction.

Infantile fibrosarcoma associated with urticaria pigmentosa.

The authors report the case of an infant with urticaria pigmentosa who developed infantile fibrosarcoma. The tumor was successfully resected but the skin lesions have persisted. This is the first report of a fibrosarcoma in association with urticaria pigmentosa. A brief review is presented of the available medical literature on associations of solid tumors with mastocytosis.