Received Growth Factor Research Articles

Granulocyte Colony-Stimulating Factor: Key (F)actor or Innocent Bystander in the Development of Secondary Myeloid Malignancy?

Granulocyte colony-stimulating factor (G-CSF), the major cytokine involved in the control of neutrophil production, is used in the clinic for treatment of congenital and acquired neutropenias and to reduce febrile neutropenia before or during courses of intensive cytoreductive therapy. In addition, healthy stem cell donors are treated with G-CSF for mobilization of hematopoietic stem cells in the peripheral blood. Recent studies have uncovered novel roles for G-CSF in myocardial regeneration following cardiac infarction ( 1 – 3 ) and in ameliorating programmed cell death in neuronal cells caused by acute ischemic stroke, thereby reducing the volume of the brain infarct ( 4 ). Thus, it may be anticipated that the therapeutic application of G-CSF will increase considerably in the near future, making careful and timely risk assessment of vital importance. In this issue of the Journal, Hershman et al. ( 5 ) report a two fold increased risk of secondary myelodysplasia (MDS) or acute myeloid leukemia (AML) in breast cancer patients who received G-CSF (or granulocyte-macrophage CSF) during adjuvant chemotherapy, compared with patients who did not receive growth factor treatment. This and other recent studies raise questions concerning the underlying molecular and cellular mechanisms whereby myeloid growth factors would initiate or accelerate the development of MDS/AML and how to deal with the potential

A Phase II Study of Sequential Neoadjuvant Gemcitabine and Paclitaxel, Radiation Therapy With Cisplatin and 5-Fluorouracil and Surgery in Locally Advanced Esophageal Carcinoma

To evaluate the feasibility and efficacy of sequential neoadjuvant chemotherapy, chemoradiation, and surgery in patients with locally advanced esophageal cancer. There were 29 patients who received paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2 2 weeks apart. Two weeks later, patients received cisplatin 75 mg/m2 and 5-fluorouracil (5-FU) 1000 mg/m2/d continuous infusion for 4 days with concurrent radiotherapy in 15 fractions to a total dose of 4000 cGy. After 6 weeks, cisplatin and 5-FU were repeated at the above doses. After 4 to 6 weeks, patients were restaged and underwent surgical resection. All 29 patients completed the prescribed gemcitabine, paclitaxel, and radiation therapy. Febrile neutropenia occurred in 1 patient and 4 patients received growth factor support. After neoadjuvant treatment, 1 patient refused surgery, 23 underwent R0 resection (82%), while 5 developed progressive disease. Four patients developed anastomotic leaks (17%). Four patients had complete pathologic responses (14%) and 4 (14%) had only residual microscopic disease. Nine patients remain alive at a median follow-up of 48 months. Three-year survival for the entire cohort was 36%. This regimen was associated with a high rate of compliance and induction therapy had an acceptable toxicity profile. The R0 resection rate and 3-year survival data are similar to recently reported studies. While active, gemcitabine and paclitaxel induction therapy was associated with an increased rate of postoperative complications, but no increase in survival. Patterns of failure continue to demonstrate the need for regimens incorporating greater emphasis on systemic therapy for locally advanced esophageal cancer.

CLINICOPATHOLOGICAL FEATURES OF NIGERIANS WITH MYELODYSPLASTIC SYNDROMES

Aim: Myelodysplastic syndromes are a group of haematologic disorders characterized by varying degrees of cytopenias and a propensity to leukaemic transformation. The aim of this study is to determine the prevalence, clinical and laboratory characteristics and the outcome of management in Nigerians with this disorder. Methods: Ten patients who have full clinical and laboratory information were retrospectively studied. Data extracted included demographic parameters, clinical features at presentation, haematological parameters, including bone marrow cytology (and cytogenetic findings, where available), management instituted and outcome of such therapy. Results: Ten patients with de novo MDS were managed and followed-up for a median period of 3 months. The majority (90.0%) were aged 50 years or above with a median age of 65 years. All presented with symptoms of cytopenias such as anaemia (100%), neutropenia (50.0%), and thrombocytopenia (10.0%). Patients had mainly supportive management such as blood product supports. One patient, however, in addition received growth factor and cytotoxic chemotherapy, while one received cytotoxic drugs alone. These were however not adequate due to financial constraints. Eight deaths were recorded (88.9%), either cytopenia related (five) or renal failure (three). Cause of death in one was not known as he died at home. The mean survival was 50.5 ± 96.1 weeks (range=2.1–308.4 weeks) Conclusion: It could be concluded that though clinical and laboratory features of Nigerians with MDS are similar to what is obtained from other parts of the world, non-availability of both specific and supportive drugs, and poor socio-economic status of most patients contributed significantly to the poor outcome recorded in this report.

The Importance of the Patient-Physician Relationship in Myelodysplastic Syndromes.

Most physicians presume their relationship with the patient is a crucial component when managing chronic illness, such as myelodysplastic syndromes (MDS). This assumption was validated in a convenience sample of 70 adults with MDS who participated in five focus groups throughout the United States. The primary purpose of this qualitative study was to explore the impact of MDS on patients' quality of life (QOL). The groups were facilitated by an advanced practice nurse with clinical expertise in MDS and qualitative research experience. Given the exploratory nature of the study design, discussions proceeded in differing directions; however, core questions were asked at each session (based on Ferrell's work exploring QOL in patients with cancer (Oncology Nursing Forum, 1996). Sessions were audio-taped and professionally transcribed. Transcripts were coded and emerging themes identified using thematic analysis methods aided by the qualitative analysis program N5 (QSR International). The sample was 93% Caucasian, 51% male, with a mean age of 69 ± 9 years; 26% lived alone. Known MDS subtype was: 19 RA, 19 RARS, 11 RAEB, 3 5q-, 2 other (16 unknown); median time since diagnosis was 26 months (3 - 276). 73% received growth factors, 61% transfusions, 19% azacitidine, 16% thalidomide, 14% iron chelation; 29% all other; many patients received multiple (often concurrent) therapies. A significant finding from the focus groups revealed a detailed depiction of the patient-physician relationship from the patient's perspective (discussed by 46 of the 62 patients who actively participated). Patients acknowledged many barriers that interfered with the relationship. These barriers were system related (e.g., extreme time constraints for physicians, priority to others who were more ill) or treatment related (e.g., lack of cure, limited treatment options). In addition, patients identified physician attributes that adversely impacted the relationship, including seeming indifference to the patient's concerns, displays of arrogance, limited knowledge about MDS and its treatment, and especially, lack of confidence in managing the illness. In contrast, positive physician attributes that enhanced the relationship included: providing comprehensible explanations, willingness to seek assistance or opinions from MDS experts when the physician was unsure of the best treatment approach, and displays of compassion and concern. Patients identified displaying respect and interest in them as individuals as essential elements in establishing and maintaining a therapeutic relationship. Patients reacted to a difficult patient-physician relationship in various ways. Those patients who ascribed to the view that a physician had a revered position and was not to be challenged tended to suffer in silence, and remained anxious or depressed. Other patients described a more proactive position, where they continually sought new information about the disease and managing side effects and even felt responsible to explore other treatment options. However, this approach required much work and energy, and did not consistently alleviate the patient's anxiety. MDS is a complex disease, where advances in understanding its pathology and identifying new treatments are beginning to have an impact in routine clinical practice. Data from this study suggest that physicians need to be aware of the barriers present in the patient-physician relationship and strive to ameliorate them. In so doing, patient's anxiety, depression, and hyper-vigilance may be diminished, and quality of life enhanced.

Age Significantly Influences Presentation and Patterns of Care in Patients with Newly Diagnosed Diffuse Large Cell Lymphoma (DLCL): Collective Data from 5 Centers Participating in the National Comprehensive Center Network (NCCN) NHL Outcomes Project.

Background: Older patients with DLCL are underrepresented in clinical trials, and little is known about the impact of age on therapeutic decisions outside the clinical trial setting. Treatment for older individuals can be influenced by comorbidities, possibly limiting the use of proven aggressive therapies. We investigated the effects of age on patterns of presentation and treatment for patients with DLCL.Methods: Data from the 5 centers participating in the NCCN NHL Outcomes Project were used for analysis. Patients with newly diagnosed DLCL, receiving some or all of their care at the NCCN institutions, with first presention between 7/01/2000 to 6/30/2004 were included. Independent variables evaluated were stage, International Prognostic Index (IPI), Charlson comorbidity score, NCCN center, and age (≤ 60 and >60). Components of IPI were evaluated as separate independent variables. Fisher's exact tests compared baseline characteristics between age groups. Univariate and multivariate logistic regression models were developed to identify factors associated with the receipt of anthracycline-based first-line therapy.Results: Of 417 patients presenting with newly diagnosed DLCL, 376 were eligible for analysis. Older patients (>60 years) accounted for 38% (142/376) of our cohort. The median age was 55.6 years; among older patients, over half were over 70. Older patients were significantly more likely to have HI/H IPI scores (52% vs. 27%, p=0.0001) and more than 2 major comorbidities (29% vs. 8%, p=0.0001). Overall, 18% (66/376) participated in first-line clinical trials, with no difference in participation by age (p=0.49). Among the 310 patients treated off protocol, 93% (289) received an anthracycline-containing first-line regimen. Older patients were less likely to receive anthracyclines [87% (105/120) vs. 97% (184/190)]. Among patients receiving anthracyclines, older patients were more likely to receive growth factor support [78% (82/105) vs.54% (100/184)]. In multivariable logistic regression adjusting for stage, comorbidity, and center, age was the only factor statistically significantly associated with treatment choice, with patients over 60 less likely to receive an anthracycline-based first-line regimen (OR=0.29; 95% CI=0.11 to 0.80 p=0.02).Conclusions: In a large cohort of patients with newly diagnosed DLCL, we found that older patients (>60 years) with DLCL had both higher risk disease, and more comorbidity at diagnosis. In our centers, there was no difference in clinical trail participation between older and younger patients; however, older patients were less likely to receive anthracyclines.

The Impact of Myelodysplastic Syndromes on Patients' Lives.

While recent research has greatly enhanced understanding of the pathology of the disease, and new treatment modalities have been developed, little is known about myelodysplastic syndromes (MDS) from the patient's perspective. The purpose of this qualitative study was to explore the impact of MDS on patients' quality of life (QOL). Five focus groups were convened at different geographic locations throughout the United States; 70 MDS patients attended and 62 actively participated in the discussions (89%). The framework for the study was based on Ferrell's work exploring the impact of cancer on QOL (Oncology Nursing Forum, 1996). Exploratory in nature, the discussions often proceeded in differing directions, but the core open-ended questions were asked at each session. Sessions were tape recorded and professionally transcribed. Transcripts were coded and emerging themes identified using thematic analysis methods aided by the qualitative analysis program N5 (QSR International). The patient sample was 93% Caucasian, 51% male, with a mean age of 69 ± 9 years; 26% lived alone. Known MDS subtype was: 19 RA, 19 RARS, 11 RAEB, 3 5q-, 2 other (16 unknown); median time since diagnosis was 26 months (3 – 276 months). MDS treatment varied considerably: 73% of patients received growth factors, 61% transfusions, 19% azacitidine, 16% thalidomide, 14% iron chelation; 29% all other; many patients received multiple (often concurrent) therapies. Findings from the focus groups revealed a multifaceted description of how MDS can affect one's QOL. QOL was typically defined by these patients as maintaining functional ability and independence, sustaining positive relationships, and maintaining control over one's life. In contrast, MDS was found to cause a substantial and sustained decrease in one's ability to function in a variety of areas, in part due to fatigue (reported by 81% of the patients). QOL was adversely affected by the work expended on managing the disease: frequent office visits, monitoring symptoms, administering therapy, and managing side effects. Family functioning was also disrupted, with family members resuming patients' roles, limiting activities, and providing direct care. Interestingly, the emotional impact from MDS was often viewed as more problematic than the physical impact; emotional reactions included shock, anger, depression, and anxiety. In contrast, spiritual well-being was often enhanced, with a renewed appreciation for life, relationships, and faith (29% of patients). Many patients (50%) voiced concern about their future and the inability to plan for it effectively. Frustration with their current status caused the majority of patients to continue to seek out additional information about MDS and potential treatment options, as well as to make attempts to take some control over a seemingly uncontrolled situation. Data from this study suggest that MDS has a substantial, often negative impact on patients' lives, and clinicians should be cognizant of this impact. Moreover, attention must be directed at providing more comprehensive support for the patient, including utilizing ancillary support services, throughout the illness trajectory. In so doing, the adverse impact of MDS on patients' QOL may be diminished.

A phase II study of neoadjuvant chemotherapy with TAC in LABC in Pakistani patients

2119 Background: Neoadjuvant chemotherapy (NC) is the standard treatment for locally advanced breast cancer (LABC). The objective of this study is to determine the response rates and the rates of breast conservation therapy with NC containing taxotere, Adriamycin and cyclophosphamide (TAC) in patients with LABC. Methods: Phase II prospective study to determine the efficacy and tolerability of TAC in NC with LABC admitted at AKUH Pakistan. Study was started in 1/03 and is still ongoing. Women were eligible if they were; histological confirmed invasive infiltrating carcinoma, T3, T4, N2, N3, M0, as per AJCC. PS 0–1, with adequate renal, liver and hematological functions. Patients were treated with regimens containing T (75 mg/m2), A (50 mg/m2) and C (500 mg/m2) 3 to 6 cycles. Followed by surgery and pathological assessment. The post-surgical treatment cycles of TAC regimen and radiotherapy is given on the basis of staging. Tamoxifen was given if they were found hormonal receptor positive. Results: We have thus far accrued 30 patients with mean age 48 years; 53% were premenopausal; all pts were PS 0–1, 67% had T3, 33% had T4, while 20% had inflammatory breast cancer. Forty-seven percent had clinically positive axillary lymphadenopathy; 33% had grade III and 66% had grades I or II. All 30 pts had ductal invasive histology. Hormonal receptors were positive in 67%. The overall response rate in all 30 pts was 94% with complete pathological response (pCR) in 27% and partial response (PR) in 67%. Disease progression was seen in one patient. Grades III-IV toxicities were: alopecia 100%, asthenia 12%; neutropenic fever 20%; mucositis 33%, and nausea & vomiting 6%. Three pts received growth factors. All patients were operated, 60% had a radical mastectomy and 40% had BCT. Data on the DFS and OS will be presented in future. Conclusions: Neoadjuvant chemotherapy containing Taxotere, Adriamycin and Cyclophosphamide achieved significant pathological complete response and breast conservation therapy in patients with locally advanced breast cancer. No significant financial relationships to disclose.

Higher Mortality After Allogeneic Peripheral-Blood Transplantation Compared With Bone Marrow in Children and Adolescents: The Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry

Peripheral-blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Despite lack of data on PBSC transplantation in children, there has been a change in clinical practice, with increasing numbers of children receiving PBSC allografts. We compared the results of 143 PBSC and 630 BM transplants from human leukocyte antigen-identical sibling donors in children aged 8 to 20 years with acute leukemia. PBSC transplant recipients were older, and were more likely to have advanced leukemia, receive growth factors post-transplantation, and have undergone transplantation more recently. Risks of acute and chronic graft-versus-host disease (GVHD), treatment-related mortality, relapse, treatment failure (relapse or death), and overall mortality were compared using Cox proportional hazards regression to adjust for potentially confounding factors. Hematopoietic recovery was faster after PBSC transplantation. Risks of grade 2 to 4 acute GVHD were similar, but chronic GVHD risk was higher after PBSC transplantation (relative risk [RR], 1.85; 95% CI, 1.28 to 2.66; P = .001). In contrast to reports in adults, treatment-related mortality (RR, 1.89; 95% CI, 1.28 to 2.80; P = .001), treatment failure (RR, 1.31; 95% CI, 1.03 to 1.68; P = .03), and mortality (RR, 1.38; 95% CI, 1.07 to 1.79; P = .01) were higher after PBSC transplantation. Risks of relapse were similar. These data suggest poorer outcomes after PBSC compared with BM transplantation in children after adjusting for relevant risk factors. Given the trend toward increased use of PBSC allografts in children, prospective clinical trials are required to determine their appropriate role in this group of patients.

Tempo of neutrophil recovery and the definition of myeloid engraftment after allogeneic hematopoietic stem cell transplantation (HSCT) in patients not receiving growth factors post-transplant

Time to myeloid recovery after HSCT is usually defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) of 0.5 × 109/L. HSCT registries and FACT require ANC ≥0.5 for 3 days as adequate evidence of engraftment. The first day with ANC ≥0.5 can be considered the day of engraftment in autograft recipients (Bone Marrow Transplant 2002;30:749–752). We have shown this in 78 allograft recipients too (Rihn et al. ASH 2002). However, the allograft study was limited by the fact that most patients had received G-CSF post-transplant, and the stem cell source was not uniform. We have now studied 49 patients allografted using blood stem cells who did not receive post-transplant G-CSF to see if the tempo of myeloid recovery was sustained. The conditioning regimen, 100 mg/m2 melphalan (+ 50 mg/kg cyclophosphamide if no prior autograft), induced severe neutropenia (ANC <0.1) in all patients. The CD34+ cell dose was 1.4–11.8 × 106/kg (median 5.0). The time to ANC ≥0.5 was 10–23 days (median 13). Potentially acceptable evidence of engraftment, ANC on the 2 days following an initial value of ≥0.5, was available in 46 (94%). The remaining 3 patients had ANC ≥0.5 for the first and second days but died after that (n = 2) or did not have a differential count available (n = 1). ANC increased from day 1 to 2 in 41 of 46 patients, and declined in 5 (≥0.5 in 2, <0.5 in 3. 2 of the latter had ANC ≥0.5 the next day). ANC increased from day 2 to 3 in 44 of 46 patients, and declined in 2 (≥0.5 in both). ANC increased from day 1 to 3 in 45 of 46 patients; declining below 0.5 in 1 patient. Thus, in 43 of 46 patients, the first day with ANC 0.5 was also the first of 3 consecutive days with ANC 0.5. These data support our previous observations that in the majority of allografted patients, ANC does not decline significantly immediately after recovering to ≥0.5 whether or not myeloid growth factors are administered post-transplant. Therefore, it is not essential to obtain WBC counts on 3 consecutive days to define myeloid engraftment. The first day with ANC ≥0.5 should be considered the day of myeloid engraftment in allograft as well as autograft recipients. This simple change in definition and practice has significant potential impact on convenience (unnecessary clinic visits for patients; particularly out-patient mini-allografts), cost (blood counts, home health visits, ancillary charges), and compliance (acceptable definition of engraftment by HSCT registries and FACT). TableDay 1Day 2Day 3ANC (109/L)0.74 (0.53–2.10)1.43 (0.36–10.94)2.46 (0.44–30.74)Change from Day 1 (%)+67 (−36 to +574)+176 (−21 to +1793)Change from Day 2 (%)+50 (−17 to +1925)ANC <0.5 (n)03 (7%)1 (2%)

How long after neutrophil recovery should myeloid growth factors be continued in autologous hematopoietic stem cell transplant recipients?

Growth factors are routinely used after autotransplantation to accelerate hematopoietic recovery, and are continued until the absolute neutrophil count (ANC) is >/=0.5 x 10(9)/l on 3 consecutive days. Since ANC often increases to very high levels with this strategy, we discontinued growth factor on the first day ANC reached 0.5 x 10(9)/l in 45 patients (Study Group), and compared their subsequent ANC to 108 historic controls who received growth factor longer. While ANC on the day after reaching 0.5 x 10(9)/l was comparable between groups, ANC on the third day was significantly higher in the Control Group (2.3 vs 4.9 x 10(9)/l; P=0.0003). When compared to the first day, ANC in the Study Group was higher by a median of 140% on the third day and by 450% in the Control Group (P=0.0002). A significantly higher proportion of patients experienced a decline in ANC after the first day in the Study Group. However, only one patient in the Study Group became neutropenic transiently and ANC recovered spontaneously the next day. The incidence of fever and hospitalization were comparable. We conclude that growth factors can be discontinued after autotransplantation the day the ANC reaches 0.5 x 10(9)/l, without compromising neutrophil recovery.

A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group

AbstractThe optimal induction for older adults with acute myeloid leukemia (AML) is unknown. Several anthracyclines have been proposed, but the data remain equivocal. Additionally, few prospective trials of priming with hematopoietic growth factors to cycle leukemia cells prior to induction chemotherapy have been conducted. Three hundred and sixty-two older adults with previously untreated AML were randomized to either daunorubicin, idarubicin or mitoxantrone with a standard dose of cytarabine as induction therapy. In addition, 245 patients were also randomized to receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo beginning 2 days prior to induction chemotherapy and continuing until marrow aplasia. No difference was observed in the disease-free overall survival or in toxicity among patients receiving any of the 3 induction regimens or among those receiving growth factor or placebo for priming. However, the complete remission rate for the first 113 analyzable patients, who did not participate in the priming study and started induction therapy 3 to 5 days earlier than those who did, was significantly higher (50% versus 38%; P = .03). None of the anthracyclines is associated with improved outcome in older adults. Priming with hematopoietic growth factor did not improve response when compared with placebo. Furthermore, delaying induction therapy in older adults may lead to a lower complete remission rate.

Salmon fibrin supports an increased number of sprouts and decreased degradation while maintaining sprout length relative to human fibrin in an in vitro angiogenesis model

Salmon-derived fibrin has been proposed as a preferred alternative to human or bovine fibrin because of its reduced potential for disease transmission. Here we evaluate salmon fibrin as an alternative ECM support for therapeutic angiogenesis applications, such as vascularizing engineered tissues. Human umbilical vein endothelial cells (HUVEC) seeded on gelatin beads and suspended in either salmon or human fibrin sprouted and formed capillary-like structures. Sprout length was generally increased with the addition of bFGF and VEGF and further increased with the addition of phorbol myristate acetate (PMA). The number of sprouts per bead was increased 61-188% in salmon fibrin relative to human fibrin (α < 0.0005) in cultures receiving growth factors and PMA, while average sprout lengths were similar for HUVEC within human or salmon fibrin. Additionally, under these conditions in the absence of a protease inhibitor, HUVEC appeared to degrade human, but not salmon, fibrin. These results support the idea that salmon fibrin may be an attractive alternative ECM able to support microvascular network formation.

The effect of hematopoietic growth factors on the risk of graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis.

The effect of hematopoietic growth factors on neutrophil recovery after allogeneic transplantation is well-recognized. Recent laboratory studies demonstrated that these cytokines may also modify T-cell and dendritic cell function, but whether the effect is strong enough to alter the risk of GVHD is unclear. We performed a meta-analysis to determine the effect of G-CSF or GM-CSF on the risk of nonhematopoietic outcomes after allogeneic transplantation. A search of the literature from 1986 to present yielded 18 publications in which data were provided for cohorts receiving growth factor vs either placebo or no therapy. These included nine prospective randomized studies, eight retrospective cohort studies, and one case-control study comprising a total of 1198 patients. The publication types were heterogeneous with regard to demographic and treatment characteristics, although within publications, comparative groups were generally balanced. The pooled risk ratio estimates with use of growth factor was 1.08 (95% CI 0.87-1.33, P=0.48) for grades 2-4 acute GVHD, 1.22 (95% CI 0.80-1.86, P=0.99) for grades 3-4 acute GVHD, and 1.02 (95% CI 0.82-1.26, P=0.87) for chronic GVHD. This analysis did not detect a significant change in the risk of acute or chronic GVHD after allogeneic hematopoietic stem cell transplantation when hematopoietic growth factors were used to shorten the initial period of neutropenia.

Granulocyte colony-stimulating factor administration upregulates telomerase activity in CD34+ haematopoietic cells and may prevent telomere attrition after chemotherapy.

Hematopoietic reconstitution could be associated with premature ageing of the transplanted cells and a high frequency of myelodysplastic syndrome and secondary leukaemia. Telomere length decreases with cell divisions and age, and at a crucial length it is associated with chromosomal instability and cell senescence. Telomerase is a reverse transcriptase enzyme that adds nucleotides to chromosomal ends. Most somatic cells lack telomerase activity yet haematopoietic stem cells retain low levels of telomerase. Some studies have found that chemotherapy and stem cell transplantation lead to the accelerated shortening of telomere length. As granulocyte colony-stimulating factor (G-CSF) is routinely used in the mobilization of stem cells for transplantation, we evaluated its effects on telomerase activity and regulation, and on telomere dynamics, in normal donors and selected lymphoma patients. Administration of G-CSF increased telomerase activity in CD34+ haematopoietic cells compared with controls. In marrow-derived CD34+ cells, telomerase activity increased sevenfold, compared with a 14-fold increase in peripheral-blood-mobilized CD34+ cells. A parallel increase in the expression of human telomerase enzyme reverse transcriptase RNA and protein kinase C alpha occurred. In addition, G-CSF administration to five lymphoma patients after consecutive courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, resulted in telomere length preservation or elongation, as opposed to marked attrition in patients who did not receive growth factors. We conclude that the in vivo administration of G-CSF prevents or attenuates telomere attrition associated with chemotherapy administration. This attenuation may contribute to the preservation of telomere integrity inG-CSF-primed transplanted stem cells.

Phase III Trial Comparing Granulocyte Colony-Stimulating Factor to Leridistim in the Prevention of Neutropenic Complications in Breast Cancer Patients Treated with Docetaxel/Doxorubicin/Cyclophosphamide: Results of the BCIRG 004 Trial

This randomized, double-blind, phase III trial compared granulocyte colony-stimulating factor (G-CSF; filgrastim) and leridistim (formerly myelopoietin), a chimeric dual agonist that binds both G-CSF and interleukin- 3 receptors, for the prevention of neutropenic complications in patients with breast cancer receiving TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy. Patients with metastatic (44%) or localized breast cancer (56%) were randomized to G-CSF 5 νg/kg subcutaneously (s.c.) daily (n = 135), leridistim 5 νg/kg s.c. daily (n = 139), or leridistim 10 νg/kg s.c. every other day alternating with placebo (n = 139). Following administration of TAC (docetaxel 75 mg/m 2, doxorubicin 50 mg/m 2, cyclophosphamide 500 mg/m 2) on day 1, patients received growth factor beginning on day 2 until the postnadir absolute neutrophil count exceeded 1500 cells/ νL. Chemotherapy cycles were repeated every 21 days. The incidence of febrile neutropenia was 7% in the G-CSF arm, 19% in the daily leridistim arm ( P = 0.003 for comparison with GCSF) and 22% in the alternate-day leridistim arm ( P < 0.001 for comparison with G-CSF). There was no significant difference between treatment arms in the cumulative percentage of patients experiencing grade 4 neutropenia at some point during therapy (85%–88%). However, grade 4 neutropenia occurred in 53% of cycles in the G-CSF cohort, 61% of cycles in the daily leridistim group ( P = 0.063 for comparison with G-CSF), and 63% of cycles in the alternate-day leridistim group ( P = 0.015 for comparison with G-CSF). We conclude that G-CSF is superior to leridistim in the prevention of febrile neutropenia in patients with advanced breast cancer receiving TAC chemotherapy. The up-front prophylactic use of G-CSF is a reasonable supportive therapy for patients treated with docetaxel/anthracycline—based combination chemotherapy.

Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkin's lymphoma.

Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceutical, San Diego, CA) is an effective therapy for patients with relapsed B-cell non-Hodgkin's lymphoma. The predominant toxicity of 90Y ibritumomab tiuxetan has been myelosuppression, and concern has been expressed about the tolerability of further treatment after this therapy. The goal of this analysis was to evaluate the therapy given to patients who relapsed after 90Y ibritumomab tiuxetan. A retrospective analysis was performed on 58 patients treated at a single institution on five separate protocols that used 90Y ibritumomab tiuxetan 0.4 mCi/kg. All patients had experienced disease progression after 90Y ibritumomab tiuxetan treatment and received subsequent therapy. The toxicity seen in this cohort of patients with subsequent treatment regimens was analyzed and compared with that of control groups who did not receive 90Y ibritumomab tiuxetan. The median number of subsequent therapies was two (range, one to seven). Sixteen (28%) of the 58 patients received growth factor support with subsequent chemotherapy, and two patients were treated with reduced doses because of persistent pancytopenia. Eight patients subsequently had an autologous stem-cell transplantation with stem cells collected after 90Y ibritumomab tiuxetan therapy. Excluding patients hospitalized at the time of transplantation, 13 patients were hospitalized for neutropenic fever, thrombocytopenia, or both. When compared to patients who did not receive 90Y ibritumomab tiuxetan, there was no significant difference in toxicity. We conclude that chemotherapy or autologous stem-cell transplantation after prior therapy with 90Y ibritumomab tiuxetan is feasible and reasonably well tolerated. The toxicity with subsequent therapy seems similar to that in patients not treated with 90Y ibritumomab tiuxetan.

Total parenteral nutrition delays platelet engraftment in patients who undergo autologous hematopoietic stem cell transplantation

OBJECTIVES: One of the major challenges in the post-transplant period is nutrition. In this prospective, non-randomized study, total parenteral nutrition (TPN) was given to 31 patients and partial parenteral nutrition (PPN) was given to 30 patients undergoing autologous hematopoietic stem cell transplantation for solid tumors or hematologic malignancies to compare the effects of these parenteral nutrition modalities on post-transplant hematological engraftment, blood chemistry, and supportive therapy requirements. METHODS: All patients in the TPN group and 17 patients in the PPN group received growth factor in the post-transplant period. Both groups did not differ with respect to sex, age, and reinfused CD34 + cell numbers. RESULTS: After transplantation body mass index and body weight decreased significantly in both groups ( P < 0.001). Whereas serum albumin concentrations did not decrease significantly in the TPN group, it fell markedly in the PPN group at the end of parenteral nutrition ( P = 0.019). After parenteral nutrition, blood chemistry was also remarkable for serum urea and glucose levels, which were elevated significantly in the TPN group ( P < 0.001 and P = 0.03, respectively). Patients receiving TPN had a higher incidence of positive microbial cultures and clinical infection than did patients receiving PPN (64.5% versus 40%, P = 0.05). The most striking result was a delay in platelet engraftment for the TPN group compared with the PPN group (15.54 and 12.93 d, respectively; P = 0.014). This difference was also noted in patients using growth factor in the PPN group ( P = 0.017). Parallel to these results, platelet transfusion requirement increased in the TPN group compared with the PPN group (1.93 versus 1.16 U, P = 0.004). Both groups were unremarkable for leukocyte recovery and red blood cell transfusion requirement. CONCLUSIONS: Consequently, TPN has some pitfalls of hyperglycemia, infection tendency, delayed platelet engraftment, and increased platelet transfusion requirement. Therefore, it should not be used as a standard nutrition support for patients undergoing autotransplantation.

Efficacy and Costs of Granulocyte Colony-Stimulating Factor in Allogeneic T-Cell Depleted Bone Marrow Transplantation

Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P < .0001) and time from marrow infusion to discharge (23 days v 17 days,P < .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs.© 1998 by The American Society of Hematology.

Efficacy and Costs of Granulocyte Colony-Stimulating Factor in Allogeneic T-Cell Depleted Bone Marrow Transplantation

Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P &lt; .0001) and time from marrow infusion to discharge (23 days v 17 days,P &lt; .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs. © 1998 by The American Society of Hematology.

High-dose thiotepa and etoposide-based regimens with autologous hematopoietic support for high-risk or recurrent CNS tumors in children and adults.

The prognosis in patients with primary brain tumors treated with surgery, radiotherapy and conventional chemotherapy remains poor. To improve outcome, combination high-dose chemotherapy (HDC) has been explored in children, but rarely in adults. This study was performed to determine the tolerability of three-drug combination high-dose thiotepa (T) and etoposide (E)-based regimens in pediatric and adult patients with high-risk or recurrent primary brain tumors. Thirty-one patients (13 children and 18 adults) with brain tumors were treated with high-dose chemotherapy: 19 with BCNU (B) and TE (BTE regimen), and 12 with carboplatin (C) and TE (CTE regimen). Patients received growth factors and hematopoietic support with marrow (n = 15), peripheral blood progenitor cells (PBPC) (n = 11) or both (n = 5). The 100 day toxic mortality rate was 3% (1/31). Grade III/IV toxicities included mucositis (58%), hepatitis (39%) and diarrhea (42%). Five patients had seizures and two had transient encephalopathy (23%). All patients had neutropenic fever and all pediatric patients required hyperalimentation. Median time to engraftment with absolute neutrophil count (ANC) >0.5 x 10(9)/l was 11 days (range 8-37 days). Time to ANC engraftment was significantly longer (P = 0.0001) in patients receiving marrow (median 14 days, range 10-37) than for PBPC (median 9.5 days, range 8-10). Platelet engraftment >50 x 10(9)/l was 24 days (range 14-53 days) in children. In adults, platelet engraftment >20 x 10(9)/l was 12 days (range 9-65 days). In 11 patients supported with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho = -0.87, P = 0.009) and platelet engraftment (rho = -0.85, P = 0.005), with CD34+ dose predicting time to engraftment following HDC. Overall, 30% of evaluable patients (7/24) had a complete response (CR) (n = 3) or partial response (PR) (n = 4). Median time to tumor progression (TTP) was 7 months, with an overall median survival of 12 months. These TE-based BCNU or carboplatin three-drug combination HDC regimens are safe and tolerable with promising response rates in both children and older adults.