Administration Of Hematopoietic Growth Factors Research Articles

Persistent Elevation of Plasma Thrombopoietin Levels in Severe Aplastic Anemia, Even with Hematologic Recovery

In bone marrow failure, levels of circulating hematopoietic growth factors (HGFs) are extremely elevated, in compensation for low blood counts. In general, administration of recombinant HGFs is not effective in aplastic anemia (AA) and related syndromes. We have established the utility of eltrombopag, a thrombopoietin (Tpo) mimetic, in severe AA (SAA) refractory to immunosuppression (IST) (Olnes, N Engl J Med, 2012; Desmond, Blood, 2014). Eltrombopag in combination with standard IST also appears to increase the rate and speed of recovery in treatment-naive SAA (Townsley, EHA. 2015). These clinical results are surprising, as plasma Tpo is markedly increased in SAA (Feng, Haematologica, 2011). In investigating possible mechanisms of action of eltrombopag, we studied HGF dynamics over time in SAA patients undergoing various treatment regimens and manifesting a range of hematologic responses. In a cohort of 37 treatment-naive SAA patients who were treated with either standard IST (horse antithymocyte globulin/cyclosporine A:ATG/CsA, n = 10) alone or with the addition of eltrombopag (n = 27), among whom 8 were non-responders and 29 responders at 6 months, we measured plasma Tpo, granulocyte-colony stimulating factor (G-CSF) and erythropoietin (Epo) using magnetic multiplex assays. Concentrations of these HGFs were greatly elevated before treatment. In a majority of patients, G-CSF declined rapidly to the normal range by 6 months, with no difference between responders and non-responders, and no correlation between G-CSF and absolute neutrophil counts. Epo concentrations decreased to the normal range at 6, 12, and 24 months post treatment in responders, to a significantly greater degree than in non-responders (p = 0.001, 0.0012, 0.038, respectively). There was a negative correlation between Epo and hemoglobin (r2 = 0.3126, p<0.0001). Tpo levels did decrease by 6 months and later, but remained much higher than the normal range, however Tpo levels in responders were significantly lower than in non-responders at 6, 12, and 24 months, respectively (p = 0.0009, 0.0477, 0.0036), with Tpo in non-responders remaining at high baseline levels (Figure 1A). These data suggest that a decrease in Tpo and/or Epo levels following initial IST therapy is an indicator of hematologic response. Linear regression analysis reveals a negative correlation between Tpo levels and platelet counts (r2 = 0.3243, P < 0.0001), consistent with previous reports. In a cohort of 7 SAA patients refractory to IST but who achieved a clinical response to eltrombopag, Epo and G-CSF levels in plasma decreased to the normal range at 3-4 months post initiation of eltrombopag treatment, but Tpo levels remained significantly elevated over the normal range for up to 5 years of follow-up, despite sustained clinical response (Figure 1B). Regression analysis revealed a negative correlation between Tpo and platelet counts (r2 = 0.3696, p < 0.0001). We asked if persistently elevated levels of Tpo even in responders are due to incomplete recovery of platelets or megakaryocytes, and thus followed up Tpo levels up to 7 years post horse ATG/CsA treatment in a cohort of 9 patients who obtained stable complete remission with platelet counts greater than 100 K/uL. Tpo levels in these patients had declined by 3 and 6 months post treatment, gradually decreased, then stabilized at levels still higher than healthy controls (Figure 1C) despite platelet counts of 102-314 K/uL (median, 174 K/uL) by 6 months and later post treatment, and recovery of bone marrow megakaryocyte frequency to normal or only mildly decreased. Tpo levels in these patients negatively correlated with platelet counts (r2 = 0.3904, p < 0.0001. Figure 1D). In conclusion, Epo and G-CSF levels fall promptly in patients with SAA who recover blood counts. In contrast, circulating Tpo levels remain markedly elevated for long periods even after complete response to treatment. Likely, Tpo is high due to low megakaryocyte mass. The consequences of sustained high Tpo levels on primitive progenitors and stem cells in these circumstances are unclear, and may play a role in stem cell exhaustion and clonal evolution. [Display omitted] DisclosuresTownsley:Novartis: Research Funding; GSK: Research Funding. Winkler:Novartis: Research Funding; GSK: Research Funding. Dumitriu:Novartis: Research Funding; GSK: Research Funding. Young:Novartis: Research Funding; GSK: Research Funding.

Optimizing stem cell collection through CXCR4 antagonists

Currently, nearly all the autologous stem cell transplantation and majority of allogeneic stem cell transplantation are performed using circulating peripheral blood stem cells. At steady conditions, less than 0.05 percent of the peripheral white cells are believed to be CD34+, a surrogate marker for stem cells. The content of hematopoietic CD34+ cells in the blood can be increased dramatically following recovery from myelosuppressive chemotherapy and/or the administration of hematopoietic growth factors (GM-CS or G-CSF), and an engrafting dose of stem cells can be collected by large volume apheresis following hematopoietic cytokine treatment. However these strategies fail to result in an adequate number of hematopoietic cells in 5-30 percent of the cases, limiting the ability of patients to receive high dose chemotherapy and stem cell transplantation in the treatment of their cancer. Plerixafor, a CXCR4 antagonist has been found to be a potent stem cell mobilizer and it's superiority used in combination with G-CSF over G-CSF alone has been seen in non-Hodgkin's lymphoma and multiple myeloma in double blind randomized phase III clinical trials, leading to FDA (Food and Drug Administration) approval. This review article describes the development of plerixafor to mobilize stem cells and optimal strategies for stem cell collection from peripheral blood.

Clinicohistologic Assessment of Bone Marrow Engraftment In Patients with Hematologic Malignancies Received Double Umbilical Cord Blood Transplantation – A Single Institutional Observation

Abstract 4578 Background:Double umbilical cord blood transplantation (dUCBT) has been gradually accepted as an alternative for the treatment of patients with hematologic malignancy requiring allogeneic hematopoietic stem cell transplant but who lack suitable adult donors. The therapeutic strategy has achieved success with either reduced intensity conditioning (RIC) or myeloablative regimens (MAC). According to large series, the 3-year event free survival (EFS) and median overall survival (OS) for RIC-dUCBT approaches 39% and 45%, respectively. Nevertheless, early mortality and development of graft-versus host disease (GVHD) exist. In addition, since UCB contains 10-fold fewer hematopoietic stem cells (HSCs) than adult donor HSC sources, engraftment takes longer even with protracted or double dosage hematopoietic growth factor administration. The relationship between bone marrow (BM) status and delayed engraftment and survival in UCBT patients is not well illustrated. This study aims to retrospectively evaluate our institutional UCBT cases and correlate the bone marrow findings with the clinical outcome. Design:Clinical and pathologic data from patients with hematopoietic malignancies receiving dUCBT between 11/2009 and 05/2011 were reviewed. Sequential BM biopsies from each patient pre- and post- dUCBT were reviewed by two hematopathologists. BM cellularity and peripheral blood counts about day 21, 30, and 90 were correlated with CBCs, chimerism and the clinical outcomes as well as survival. Results:Thirty-one patients with hematologic malignancies (AML = 13, ALL = 6, CLL = 3, FL = 2, DLBCL = 2, HL = 1, MCL = 1, PTCL =1, Myeloma =1, and MDS = 1) received conditioning with chemotherapy and total body irradiation (MAC = 12; RIC = 19) followed by dUCBT. The median age was 45.7 years (range, 18–68 years) with a male to female ratio of 1.1:1. All patients received GvHD prophylaxis with cyclosporine and MMF and G-CSF from day +1 until engraftment. The median time to neutrophil engraftment was 22 days (range, 15 – 59) following MAC and 22 days (range 6 – 43) following RIC. Bone marrow cellularity, the corresponding WBC, and chimerism data are shown (Table 1). On the day 21 BM assessment, 80% (8/10) of patients receiving MAC achieved a marrow cellularity at or above the median and 87.5% (7/8) were alive at last follow-up. Following RIC, 59% (10/17) of patients achieved at least the median cellularity (10%) and 70% (7/10) survived. For patients below the median cellularity at day 21, survival was only 50% (1/2) and 43% (3/7) following MAC and RIC, respectively. With a median follow-up for survivors of 264 days (range 72 – 613) (MAC 286 days; RIC 239 days), the estimated overall survival at 1 year was 47% (28 – 68%). Thirteen patients died due to infection (n = 6), relapse (n = 3), GvHD (n = 2), or hemorrhage (n = 2).Table 1Post UCBT bone marrow status in correlation with clinical and laboratory parametersVariableMyeloablative Conditioning (n = 10)Reduced Intensity Conditioning (n = 17)Myeloablative Conditioning (n=7) (nReduced Intensity Conditioning (n=11) (nDay 21Number alive at last follow-up with value ≥ medianDay 21Number alive at last follow-up with value ≥ medianDay 28Number alive at last follow-up with value ≥ medianDay 28Number alive at last follow-up with value ≥ medianBM % cellularity Median (range)5% (4-20)8/1010% (4-35)10/1128% (25-45)4/720% (5-50)5/11% Blast count (%) Median (range)4% (0.5-10.5)5/71.85% (0-17)4/81.5% (0-8)1/31% (0-1.5)4/6WBC ( x 109/L) Median (range)0.85 (0.04-2.5)6/60.4 (0-1.4)5/105 (0-7.6)4/62 (1-4)2/5≥90% donor Number (%)7/10 (70%)5/85/17 (29.4%)4/94/6 (66.7%)3/66/11 (54.5%)3/5 Conclusion:Our results demonstrate that the bone marrow cellularity early post-transplant may serve as a predictor of survival following transplant. Since 6 of 13 patients (46%) died due to infection, this may indicate further impaired immune recovery regardless of total WBC. Larger case series are needed to elucidate a correlation between the bone marrow environment and the long term survival following dUBCT. Disclosures:No relevant conflicts of interest to declare.

Evaluation of direct medical costs of hospitalization for febrile neutropenia

Treatment of febrile neutropenia (FN) is costly, because it typically involves hospitalization. As cancer rates continue to increase, the number of patients suffering from FN will also increase, making it important to quantify the costs of treating this condition accurately and comprehensively. A consecutive sample of patients admitted to an inpatient hematology/oncology ward at a tertiary care hospital for the treatment of chemotherapy-induced FN was enrolled in this study. Patients were followed prospectively during hospitalization, and information on medical resource utilization including length of stay, medications, and laboratory and diagnostic tests was collected. Costs, extracted from hospital and provincial databases, were used to calculate the overall cost per FN episode, from the hospital perspective. Fifty-one episodes of FN that occurred in 46 patients were included in the study. Approximately 52% of these episodes occurred in women, and 65% of these episodes occurred in patients with hematologic malignancies. The mean +/- standard deviation age of patients was 60.3 +/- 13.4 years. The mean length of stay per episode was 6.8 +/- 4.9 days. The mean overall cost per episode was 6324 +/- 4783 in 2007 Canadian dollars. Hospitalization for the treatment of FN is expensive. The results of this study could be used in future economic evaluations of preventive measures and treatments for FN, including primary prophylactic administration of hematopoietic growth factors and outpatient treatment of this condition.

Poor Hematopoietic Stem Cell Mobilizers in Multiple Myeloma:A Single Institution Experience.

Abstract 4237High-dose chemotherapy rescued by autologous peripheral blood stem cell transplantation is considered standard of care for patients with multiple myeloma. Hematopoietic stem cell mobilization is accomplished by administration of hematopoietic growth factors combined or not with myelosuppressive chemotherapy. In a single institution, in a group of twenty eight myeloma patients deemed eligible for autologous transplant, stem cell mobilization was attempted using only filgrastim: Twenty six individuals were given 31 autografts employing one to four (median three) apheresis sessions, to obtain a target stem cell dose of 1 × 106 CD34 viable cells / Kg of the recipient. The median number of grafted cells was 7.56 × 106 CD34 viable cells / Kg of the recipient; the range being 0.92 to 14.8. By defining as poor mobilizers individuals in which a cell collection of less than 1 × 106 CD34 viable cells / Kg was obtained, a subset of eight poor mobilizers was identified; in two patients the autograft was aborted because of an extremely poor CD34 cell yield (less than 0.2 × 106 CD34 viable cells / Kg of the recipient) after four apheresis sessions. The long-term overall survival of the patients grafted with more than 1 × 106 CD34 viable cells / Kg was better (80% at 80 months) than those grafted with less than 1 × 106 CD34 viable cells / Kg (67% at 76 months). Methods to improve stem cell mobilization are needed and may result in obtaining better results when autografting multiple myeloma patients. Disclosures:No relevant conflicts of interest to declare.

From Bench to Bedside: Hematopoietic Growth Factors (HGFs)- a Cause of Serious and Unanticipated Class Toxicities.

Abstract 4555 IntroductionHGFs have vastly improved the management of anemia, neutropenia, and thrombocytopenia, but are associated with unexpected toxicities. MethodsToxicities associated with granulocyte, erythroid, and thrombopoietic growth factors were reviewed. Data sources included systematic reviews, clinical trials, guidelines, and materials disseminated by the Food and Drug Administration (FDA), the European Medicines Agency (EMEA), and Canada Health and their advisory committees; product labels and safety notifications disseminated by manufacturers; and utilization data. Data abstracted were thromboembolic complications, immune-mediated cytopenias, bone marrow toxicities, systematic and synergistic toxicities, and regulatory responses.Results Granulopoiesis agentsPulmonary infiltrates were associated with administration of HGFs with bleomycin or chest radiation. Increased myelodysplasia (MDS) or acute myeloid leukemia (AML) risks among chemotherapy (chemo)-treated breast cancer patients were reported. ESAsIncreased mortality and tumor progression were seen when cancer patients received ESAs versus placebo; increased mortality and cardiovascular events were reported when chronic kidney disease (CKD) patients received ESAs targeted to complete anemia correction. Between 1998 and 2003, 191 CKD patients developed neutralizing antibodies and pure red cell aplasia (PRCA) following recombinant erythropoietin administration. Thrombopoietins (TPO)TPO receptor agonist administration is associated with bone marrow reticulin and collagen deposition. 3% of healthy volunteers who received repeated rHuMGDF developed neutralizing autoantibodies and severe thrombocytopenia. ConclusionsWhile ESAs, granulopoietic factors, and thrombopoietins have important clinical benefits, they also retain the potential to exhibit serious and unanticipated toxicities.ESAsGranulopoiesis agentsThrombopoietinsMortality risksIncreased risks among CKD patients targeted to complete anemia correction and ESA treated cancer patients**Increased countsPossibly related to mortality in cancer and CKD patientsSplenic rupture in peripheral stem cell donorsSeen with 2nd generation agents, no toxicityThrombosis1.6x increased risks among cancer patients, 1.3x increased risks among CKD patients randomized to complete anemia correctionRarely reported. Case reports of heart attack or stroke among healthy peripheral blood stem cell donors who received GCSF*Tumor cell stimulationDownstream and stimulatory effects identified with erythropoietin receptor activationIncreased risks of MDS/AML among breast cancer, chemo and chronic neutropenia patients who received GCSF* (TPO receptor not seen in tumors)Autoantibody formationPRCA with ESAs*Seen among 3% of 324 healthy volunteers who received rHuMGDFStem cell depletion*Severe cytopenias with granulopoiesis agents and 5-fluorouracil or radiation therapy*Bone marrow reticulin/ fibrosis**Seen with 2nd generation TPOsIncreased bone marrow collagen**Rarely seen with 2nd generation TPOsWorsening of cytopenia following treatment cessation**Seen with romiplostim and eltrombopagSystemic toxicities*Bone pain with GCSF and peg GCSF; pleural and cardiac effusions with GMCSFïz½Hepatic toxicity following eltrombopagSynergistic toxicitiesESAs and lenalidomide increase the risk of thrombosis ESAs are suspected to aid NSF pathogenesisGSCF combined with topoisomerase II inhibitors shown to increase myeloid leukemias Incidences of pulmonary toxicity when bleomycin is combined with GCSF*Toxicity among healthy individualsDeaths reported with ESA use among high performance athletes2 healthy donors developed AML after GCSF and peripheral blood donation 15 healthy peripheral blood stem cell donors had splenic ruptures with GCSF, GMCSF, or peg GCSF3% of 324 healthy volunteers developed neutralizing antibodies and severe thrombocytopenia following repeated rHuMGDF administration. 3 of the 324 volunteers developed lymphoid malignanciesToxicity with off-label administrationESA manufacturers report safety concerns with off-label ESA useHigh rates of neutropenia and thrombocytopenia when GCSF or GMCSF are administered in certain off-label settingsHigh rates of accelerated MDS or AML when TPOR activators administered off-label to MDS patients*=Not reported Disclosures:No relevant conflicts of interest to declare.

The potential of hematopoietic growth factors for treatment of Alzheimer's disease: a mini-review

There are no effective interventions that significantly forestall or reverse neurodegeneration and cognitive decline in Alzheimer's disease. In the past decade, the generation of new neurons has been recognized to continue throughout adult life in the brain's neurogenic zones. A major challenge has been to find ways to harness the potential of the brain's own neural stem cells to repair or replace injured and dying neurons. The administration of hematopoietic growth factors or cytokines has been shown to promote brain repair by a number of mechanisms, including increased neurogenesis, anti-apoptosis and increased mobilization of bone marrow-derived microglia into brain. In this light, cytokine treatments may provide a new therapeutic approach for many brain disorders, including neurodegenerative diseases like Alzheimer's disease. In addition, neuronal hematopoietic growth factor receptors provide novel targets for the discovery of peptide-mimetic drugs that can forestall or reverse the pathological progression of Alzheimer's disease.

Rituximab, gemcitabine, vinorelbine, and methylprednisone (R-GVM), a hematopoietic cell (HC) mobilizing and salvage regimen for malignant lymphoma (ML)

17537 Background: The prognosis of pts with recurrent ML remains poor. High-dose therapy (HDT) with HC rescue can cure a proportion of such pts. HC mobilization can be adversely affected by number and duration of prior treatments, interval from diagnosis to HC collection, prior radiotherapy and marrow involvement. There remains a need for more effective and less toxic salvage regimens, capable of mobilizing HCs. Methods: The mobilizing potential of R-GVM salvage regimen with hematopoietic growth factor (HGF) support (G- and GM-CSF) was evaluated in 6 pts with relapsed (n=5) or primary refractory (n=1) ML. Pts received R-GVM salvage therapy [rituximab (375 mg/m2, day 1), gemcitabine (1 g/m2, day 1, 8), vinorelbine (30 mg/m2, day 1, 8) and methylprednisone (1 g/m2, day 1, 8)] with HGF administration and subsequent HC collection. The HGF support was started on day 9 and was continued through apheresis which started when the CD34+ cell count ≥ 20/μl (median day of R-GVM cycle: 15, range 14–19). Pts had daily apheresis with continued HGF support until at least 5 x 106 CD34+ cells/kg were collected. The hematologic and non-hematologic toxicity were tolerable in all pts; no pt required hospitalization. Results: 6 pts (age range 20–45 years) with Hodgkin (n =3) and non- Hodgkin lymphoma (n =3) were evaluated in this study. Pts had received 1–3 previous treatment regimens. The median number of R-GVM courses given before HC collection was 2.5 (range 1–5). Effective HC mobilization (≥5x106 CD34+ cells/kg) was obtained in all ps. A single apheresis resulted in satisfactory HC collection in 4 pts (range 8.2–17.7 x 106 CD34+ cells/kg); 2 pts required 3 aphereses to collect an adequate number of cells (6.7 and 7.4 x 106 CD34+ cells/kg). One pt was heavily pretreated and had failed two previous attempts of HC mobilization (one with HGF alone and one with cyclophosphamide and HGF); the other pt was HIV+ treated with HAART and had prior marrow involvement. As a salvage regimen, one pt had progressive disease, 1 had stable disease, 1 had a partial response, and 3 had a complete response before proceeding with HDT with HC rescue. Conclusions: R-GVM regimen is feasible, tolerable and effective in mobilizing HPC in patients with relapsed and refractory lymphoma. No significant financial relationships to disclose.

Immunomodulatory therapy in yeast infections

Invasive yeast infections are a significant cause of morbidity and mortality in patients with defective immune response, such as those with cancer-related immunosuppression, organ transplantation or other immunodeficiencies, and neonates. Hospitalization in the intensive care unit may increase the risk for such infections. Despite the advent of new antifungal agents, the problem is escalating as the number of susceptible hosts increase and virulent, more resistant fungal strains emerge. Over the past few years, advances in immunology and molecular biology have greatly contributed to a better understanding of the pathogenesis of yeast infections. There is evidence that reconstitution of the host immune function is a major contributor to the resolution of yeast infections. Strategies aiming to increase the phagocyte number (e.g., granulocyte transfusions), to stimulate immune response (e.g., administration of hematopoietic growth factors and other proinflammatory cytokines) and to stimulate antigen-specific immunity (e.g., antibody therapy or vaccination) benefit patients at risk of, or suffering from, yeast infections. Further preclinical and clinical studies, as well as improving our understanding of immune system functions and dysfunctions, remain a future challenge.

Hematopoietic Growth Factors Reduce Side Effects of Cancer Treatment: Results of Two Comprehensive Meta-Analyses.

Background: Hematopoietic growth factors such as G-CSF/GM-CSF and erythropoietin (EPO) are used in clinical practice to reduce side effects of cancer treatment but also to improve tumour response and overall survival. We conducted two meta-analyses on the effects of hematopoietic growth factors in the treatment of malignant diseases a) to determine the effectiveness of G-CSF and GM-CSF to i) prevent infection, ii) improve tumor response and overall survival in lymphoma patients undergoing standard chemotherapy and b) to assess the effectiveness of EPO to i) prevent anemia, ii) improve tumor response and overall survival in cancer patients.Methods: The Cochrane Library, Medline, Embase and smaller databases were searched. Randomized controlled trials comparing G-CSF/GM-CSF or EPO versus placebo/no treatment were included in the reviews. Both study arms had to receive identical antineoplastic treatment and identical additional supportive care. We included full-text and abstract publications as well as unpublished data. Data were meta-analysed using fixed and random effects models.Results: Twenty one trials with 2,794 adults were included in the EPO meta-analysis. Use of EPO significantly reduced the relative risk of red blood cell transfusions (RR 0.67; 95% CI 0.62 to 0.73). For participants with baseline hemoglobin below 10 g/dL hematological response was observed more often in participants receiving EPO (RR 3.60; 95% CI 3.07 to 4.23). There was inconclusive evidence whether EPO improves tumour response (random effects: RR 1.21; 95% CI 0.92–1.59) and overall survival (unadjusted data: HR 0.84; 95% CI 0.69 to 1.02). 12 trials with 1,823 randomized patients were included in the G-CSF/GM-CSF meta-analysis. Compared with no prophylaxis, G-CSF/GM-CSF significantly reduced the relative risk for infections (RR 0.74; 95% CI 0.64–0.85). There was no evidence for G-CSF/GM-CSF to decrease infection related mortality (RR 1.37; 95% CI 0.66–2.32), to improve complete response (RR 1.02; 95% CI 0.94–1.11) or overall survival (HR 1.00; 95% CI 0.86–1.16).Conclusions: There is consistent evidence that the administration of EPO and G-CSF/GM-CSF reduces the side effects of antineoplastic therapy, such as risk for blood transfusions (EPO) and infections (G-CSF/GM-CSF). However, there is inconclusive evidence whether the administration of hematopoietic growth factors in these clinical settings also improve tumor response and overall survival.

Supportive treatment for anemic cancer patients.

Anemia in cancer patients is frequent but often underestimated. Anemia affects the health-related quality of life and impacts prognosis and outcome of therapy. Treatment options include the administration of hematopoietic growth factors and red blood cell transfusions. Blood transfusions result in rapid but often transient improvement of anemia. Administration of epoetin or darbepoetin alfa increases hemoglobin levels, decreases blood transfusions, and improves quality of life in patients with cancer. Presently, trials investigate whether treatment of anemic cancer patients with erythropoietin impacts on outcome of chemo- and/or radiotherapy and on overall survival. Oncologists must be aware of the clinical relevance of anemia and offer adequate treatment options to their patients. Supportive treatment of anemic cancer patients presenting anemia-related symptoms should be performed to reduce symptoms in cancer patients and optimize outcome to anticancer therapy.

Treatment of pancreatic cancer with a combination of irinotecan (CPT-11) and gemcitabine: a multicenter phase II study by the Greek Cooperative Group for Pancreatic Cancer

The efficacy and toxicity of gemcitabine (GEM) and irinotecan (CPT-11) is evaluated in previously untreated patients with inoperable or metastatic pancreatic cancer. From January 1999 to July 2001, 60 patients with pancreatic cancer (85% stage IV) were enrolled in a two-step extended phase II trial. Patients were treated with gemcitabine (1,000 mg/m2 on days 1 and 8) and CPT-11 (300 mg/m2 on day 8) in cycles of 3 weeks. No prophylactic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was initially planned. In an intention-to-treat analysis one (1.7%) complete and 14 (23.3%) partial responses were achieved [objective response rate (ORR) 24.7%; 95% confidence interval 14.04% to 35.96%]. Twenty-two (36.7%) and 23 (38.3%) patients had stable and progressive disease, respectively. The median duration of response was 5 months, the median time to tumor progression (TTP) was 7 months and the median overall survival 7 months. One-year survival was 22.5%. Pain improvement and asthenia during treatment were observed in 45% and 43% of patients, respectively; weight gain occurred in 19.5% of patients. Grade 3 anemia occurred in three (5%) patients who required transfusion of six packed red blood cell (RBC) units. Ten (16.7%) additional patients with grade 2 anemia were treated with recombinant erythropoietin. Grade 3 thrombocytopenia occurred in seven (11.7%) patients and grades 3 and 4 neutropenia in 27 (45%). Ten patients developed febrile neutropenia, two of whom died due to sepsis. Prophylactic use of rhG-CSF was eventually required in 93 (28.3%) of 329 administered cycles. Other toxicities were mild. The combination of gemcitabine and irinotecan is an active chemotherapy regimen against pancreatic cancer with a 25% ORR. Toxicity was acceptable for the great majority of patients but with a high percentage of hematopoietic growth factor administration.

Potential role of cysteinyl leukotrienes in trafficking and survival of hematopoietic progenitor cells.

In the clinical setting of a stem cell transplantation, progenitor and stem cells within the bone marrow (BM) can be mobilized into the donors’ peripheral blood by administration of hematopoietic growth factors. Since these cells retain the ability to repopulate the hematopoietic compartment of the bone marrow (a process referred to as ‘homing’), they can account for hematopoietic recovery within the patient [1]. Thus both mobilization to the peripheral blood and homing back to the bone marrow crucially depend on the extensive migratory capabilities of hematopoietic stem and progenitor cells (HPC).

Enteral administration of hematopoietic growth factors in the neonatal intensive care unit

Enteral administration of hematopoietic growth factors in the neonatal intensive care unit

Enteral administration of hematopoietic growth factors in the neonatal intensive care unit.

By 20 wk of gestation, the human fetal gastrointestinal (GI) tract morphologically resembles that of the term infant, but functional development is limited before 26 wk. By 30 wk of gestation, the fetus has the capacity for limited digestion and enteral absorption. GI growth and development continue postnatally. Trophic factors, including nutrients, peptides, hormones and growth factors, are recognized as having important influences on the morphology and histology of the developing GI tract. Other trophic factors are important in adaptation and repair following injury. Many such factors are provided in utero via amniotic fluid swallowing and later by human colostrum and milk. This review discusses cytokines with known GI trophic effects, either in vitro or in vivo, and focuses on those cytokines that have been used in the neonatal intensive care unit.

Hematopoietic Cell Renewal as the Limiting Factor in Low-Level Radiation Exposure: Diagnostic Implications and Therapeutic Options

In some radiation accidents, exposure doses are delivered over days or even months. In all cases the organ system most relevant to a patient's survival is the hematopoietic tissue. There appears to be a threshold of approximately 10 mSv per day above which hematopoietic effects become apparent and hematopoietic failure may occur. Experimental observations in dogs demonstrate that exposure to chronic gamma-irradiation may be tolerated for over a year if the daily dose does not exceed 7 mSv to 18 mSv. The pathophysiological mechanisms are being studied by hematological measures and biomathematical models. The results are in accordance with the assumption of excess cell loss and progressive diminution of the stem cell pool over time until a "turbulence region," with an increased probability of system failure, is approached. Diagnostic procedures require a thorough hematological assessment that includes the stem cell compartment. Therapeutic options include administration of hematopoietic growth factors and stem cell transplantation.

Effect of myelopoietic and pleiotropic cytokines on colony formation by blast cells of children with acute lymphoblastic leukemia.

The aim of this study was to see whether pleiotropic or myeloid hematopoietic growth factors, which do not stimulate normal lymphoid cells, can induce proliferation of blast cells of the acute lymphoid leukemia (ALL) of childhood. Bone marrow cells of 13 children with untreated ALL (nine common ALL, two myeloid antigen positive ALL and two early T-cell ALL) formed colonies of leukemic blast cells in primary methylcellulose cultures. Spontaneous growth was observed in three of 13 cases, whereas phytohemagglutinin-stimulated leukocyte conditioned medium (PHA-LCM), a conventional source of various natural human cytokines, induced colony formation in ten of 13 cases. A similar rate of responsiveness was seen with recombinant human granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF); a combination of these three cytokines induced colony formation in all cases studied. The effect of these growth factors on colony formation seemed to be dose-dependent in some cases. Of the stimuli studied, GM-CSF induced the smallest number of colonies, whereas the effects of G-CSF, SCF and PHA-LCM were similar in this respect. Combination of cytokines proved to be even more efficient in inducing clonal proliferation of leukemic lymphoblasts. In double combinations, G-CSF and GM-CSF as well as G-CSF and SCF were able to potentiate each other's effects. Triple combination of these cytokines mediated the most potent growth stimulus. Our results demonstrate that myeloid and pleiotropic cytokines are able to stimulate clonal proliferation of pediatric leukemic lymphoblasts. This may present a potential hazard to children with ALL while on adjuvant therapy with hematopoietic growth factors. In vitro colony assays performed prior to or in parallel with the administration of hematopoietic growth factors to ALL patients may help to forecast their possible effects on leukemic cells in vivo.

Factors that predict chemotherapy-induced myelosuppression in lymphoma patients: role of the tumor necrosis factor ligand-receptor system.

To analyze factors that predict the occurrence of chemotherapy-induced myelosuppression and, in particular, the role of the tumor necrosis factor (TNF) ligand-receptor system in lymphoma patients at the beginning of their treatment. We investigated the predictive factors for myelosuppression after the first course of chemotherapy in a cohort of 101 consecutive, previously untreated lymphoma patients receiving regimens that include doxorubicin and cyclophosphamide. Plasma samples were tested at baseline by enzyme-linked immunosorbent assay for TNF and its soluble receptors. Univariate and multivariate analyses were performed with a forward regression procedure that included all of the parameters that were found to be significant in the univariate analysis. The dose of chemotherapy and the prophylactic treatment with granulocyte colony-stimulating factor were deliberately included in this model. Sixty-seven patients experienced World Health Organization (WHO) grade 4 neutropenia, and 37 patients experienced febrile neutropenia, which was responsible for WHO grade 2 through 4 infections in 23 patients. In multiparametric regression analysis, the occurrence of grade 4 neutropenia was associated with high doses of cyclophosphamide (odds ratio ¿OR, 19.8; P =.008) and high levels of soluble p75-R-TNF (OR, 8.52; P =.001). The duration of grade 4 neutropenia for more than 5 days was associated with the lack of hematopoietic growth factor administration (OR, 6.76; P =.004) and high levels of soluble p75-R-TNF (OR, 5.84; P =.0023). The occurrence of febrile neutropenia was associated with high doses of cyclophosphamide (OR, 4.7; P =.007), altered performance status (OR, 18.8; P <.0001) and high levels of soluble p75-R-TNF (OR, 3.49; P =.029). This study indicates that in addition to the dose of chemotherapy and the administration of hematopoietic growth factors, poor performance status and high p75-R-TNF levels can predict the occurrence of chemotherapy-induced myelosuppression in lymphoma patients. This model may help in selecting patients for prophylactic growth factor administration.

Effects of peritransplant administration of hematopoietic growth factors on the development of chronic allograft rejection

Effects of peritransplant administration of hematopoietic growth factors on the development of chronic allograft rejection

EFFECTS OF PERITRANSPLANT ADMINISTRATION OF HEMATOPOIETIC GROWTH FACTORS ON THE DEVELOPMENT OF CHRONIC REJECTION

13 Purpose: Chronic allograft rejection remains as the major obstacle to successful organ transplantation. We have previously shown that persistent existence of donor hematolymphoid cells after transplantation participated in the resistance to chronic rejection, and hypothesize that augmentation of donor chimerism after transplantation is able to prevent chronic rejection. In this study, we examined effects of perioperative administration of hematopoietic growth factors on the development of chronic rejection using simultaneous heart and bone marrow transplantation model. Results were analyzed with the correlation to levels of chimerism. Methods: Female Brown Norway (BN, RT1n) rats received heterotopic heart allografts (Htx) and simultaneous bone marrow (BM, 2.5 × 108) infusion from male Lewis (LEW, RT11) donors. All recipients received tacrolimus (1.5 mg/kg/day) on days 0 to 13, 20, and 27. Hematopoietic growth factors of variable lineage specificity (table) were injected to recipients on days 0 to 6. All recipients were sacrificed on day 100 and tissues were analyzed for levels of chimerism by PCR and Southern blot hybridization using rat sex determining region-Y (Sry) specific oligonucleotide primers and 32P-labeled probe. Severity of chronic rejection in heart allografts was analyzed by histopathology and scored. Results: At day 100, male DNAs were more easily detected in recipient non-lymphoid organs (skin, native heart) than lymphoid organ (spleen, cervical lymph nodes) or blood. Donor BM infusion significantly augmented chimerism, and Flt-3 ligand and IL-6 were able to further significantly enhance chimerism levels. Histopathological analysis demonstrated the significant amelioration of overall inflammation and obliterative arteriopathy (OA) in recipients treated with BM infusion and GCSF or IL-6 treatment. In addition, a significant regression was found between the levels of overall inflammation and chimerism. Table P values vs Htx: a<0.05, b<0.01, c<0.001, d<0.0001, vs Htx+BM: c<0.05TableConclusions: This study demonstrates that simultaneous infusion of donor BM and the appropriate use of hematopoietic growth factors are effective in enhancing chimerism and improving histopathological abnormalities associated with chronic allograft rejection.