Myeloid Growth Factors Research Articles

Low Incidence of Opportunistic Infections in CLL Patients Treated with Single Agent Flavopiridol.

Background: Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). Standard therapies such as purine nucleoside analogs and alemtuzumab have been associated with a high incidence of opportunistic infections, particularly in heavily pretreated patients. To date no studies have evaluated the incidence of infections in patients receiving flavopiridol.Study design: Patients with CLL who had relapsed following fludarabine-based therapy were eligible for participation. Treatment consisted of single agent flavopiridol administered as a 30 minute bolus followed by a 4 hour infusion weekly for 4 weeks every six weeks for up to 6 cycles. There were no exclusions for neutropenia if it was attributable to disease. All patients received prophylactic antimicrobials for prevention of HSV/VZV reactivation and P. jerovici infection unless contraindicated. Myeloid growth factors support was not utilized. Patient outcomes were retrospectively analyzed for infectious toxicities.Results: From April 2004 to August 2006 121 patients received single agent flavopiridol as part of two clinical trials. Of these, 34 patients experienced either a febrile episode or an infectious complication, or both. Twenty-four patients were male, 10 were female. There were 43 total infectious episodes in 34 patients. Of the patients experiencing an infections complication, the median number of prior therapies was 4 (range 1–11). 17 had received a purine nucleoside analog within the previous 12 months and 9 had received alemtuzumab within the previous 12 months. Of total patients treated, 5 (4%) developed pneumonia, 1 (0.8%) developed bacterial sepsis, 10 (8.3%) developed sinusitis or bronchitis, and 3 developed suspected viral respiratory infections. There were 5 (4%) skin/soft tissue infections, 7 (5.8%) catheter-related infections, and 2 (1.7%) urinary tract infections. One patient developed esophagitis and was treated empirically, as an endoscopy was contraindicated due to thrombocytopenia. Two patients were found to have aspergillus species in sputum cultures, and one of these patients had a concurrent pulmonary infiltrate. One patient experienced exacerbation of his genital HSV. No patients experienced CMV reactivation, PCP, EBV, Candida, or Legionella infections. 9 patients (7.4%) had fever of unknown origin, 5 of these in the context of cytokine release syndrome during therapy. Twenty-two episodes were associated with grade 3 or 4 neutropenia. Two patients died during infectious episodes.Conclusion: Flavopiridol is associated with an acceptable incidence of opportunistic infections when administered as a single agent, even in heavily pretreated patients. Most infections were bacterial in origin and may reflect altered immunity in patients with CLL, as well as therapy-associated myelosuppression. These results compare favorably to previous studies of infections in fludarabine-refractory patients.

Pre-Transplant Rituximab Therapy Is Associated with Improved Progression-Free and Overall Survival in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma (DLBCL).

Outcomes following first-line therapy for patients (pts) with DLBCL have improved significantly with the availability of the chimeric anti-CD20 monoclonal antibody rituximab (R). Despite this progress, many pts develop refractory or recurrent DLBCL and are considered candidates for autologous hematopoietic stem cell transplantation (AuHCT). For such pts, it is possible that R given pre-transplant and/or during conditioning therapy affects the natural history of DLBCL, such that traditional methods of risk assessment and patient selection for AuHCT may need revision. We therefore studied the outcomes of 1,006 pts who underwent peripheral blood AuHCT for DLBCL between 1996 and 2003 reported to the CIBMTR, analyzed according to whether R was (n=188, “+R” group) or was not (n=818, “-R” group) administered prior to AuHCT. Using the chi-square statistic for categorical and the Kruskal-Wallis for continuous variables, there were no significant differences between the +R and -R groups with regard to gender, pre-transplant performance status, disease status at transplant, pre-transplant chemosensitivity, second-line aa-IPI score distribution, Ann Arbor stage at transplant, interval from diagnosis to transplant, bulky disease, bone marrow involvement, post-transplant radiation therapy, or post-transplant myeloid growth factor therapy. The +R group had a higher proportion of pts age 61 or older (40% vs. 23%, p<0.001). AuHCT occurred between 1999–2003 in 96% of pts in the +R group, and between 1996–2001 in 93% of the -R pts (p<0.001). For the +R pts, 94% received R only with pretransplant chemotherapy, 3% only with conditioning therapy, and 3% with both pretransplant chemotherapy and conditioning therapy. Conditioning regimens were similar in the +R and -R groups, with the majority receiving the BEAM regimen. In univariate analysis, platelet and neutrophil engraftment were not affected by use of R. Treatment-related mortality (TRM) at 1, 3, or 5 years did not differ significantly between the +R and -R groups. Progression-free survival (PFS) at 1 and 3 years was superior in the +R group (62% vs. 49% at 1 year, p=0.002; 49% vs. 38% at 3 years, p=0.010). Overall survival (OS) was superior in the +R group (68% vs. 60% at 1 year, p=0.032; 57% vs. 45% at 3 years, p=0.003). In multivariate analysis, later year of transplant (2000–2003) and age <55 were associated with lower TRM, but pre-transplant R was not. Conversely, pre-transplant R, age <55, and fewer than 3 lines of chemotherapy were associated with improved PFS, while year of transplant was not. Finally, pre-transplant R, age <55, fewer than 3 lines of chemotherapy, and year of transplant 2000–2003, were all associated with improved OS. We conclude that pre-transplant rituximab is associated with improved PFS and OS following AuHCT for DLBCL, with no evidence of impaired engraftment or increased TRM.

Novel therapeutic options in the inflammatory bowel disease world

Advances in the understanding of the pathogenesis of inflammatory bowel disease have encouraged the development of many new therapies targeted at specific and non-specific mediators of the inflammatory bowel disease inflammatory pathway. The role of these therapies, including novel anti-tumour necrosis factor-α agents, anti-adhesion molecules, recombinant cytokines, myeloid growth factors, helminths, and probiotics, in the management of paediatric onset inflammatory bowel disease is promising and warrants further investigation.

Developmental Defects in Neutrophils from Preterm Infants

Neutrophil development starts in the early second trimester in the human fetus and continues through the rest of the gestation. Preterm birth can interrupt the maturation of fetal neutrophils and place the preterm neonate at risk of life-threatening infections. Various developmental defects have been identified in preterm neutrophils, such as in the ability of circulating neutrophils to cross the endothelial barrier and abnormalities in chemotaxis, respiratory burst, and degranulation. The availability of recombinant human myeloid growth factors has renewed interest in understanding the mechanisms and natural history of such defects. In this article, we review various aspects of the developmental immaturity of preterm neutrophils.

Granulocyte colony-stimulating factors: finding the right indication

Neutropenic complications including febrile neutropenia represent major dose-limiting toxicities of cancer chemotherapy. Recommendations for the use of recombinant myeloid growth factors to reduce the risk of neutropenic complications and sustain dose intensity continue to evolve. Several randomized controlled trials and meta-analyses have confirmed that the myeloid growth factors reduce the risk of neutropenic complications and may facilitate delivered dose intensity in patients receiving cancer chemotherapy. Older age and certain comorbidities significantly increase the risk of febrile neutropenia and its consequences. Three new clinical practice guidelines for the use of the myeloid growth factors have been published by major professional oncology organizations including the American Society of Clinical Oncology, the European Organization for Research and Treatment of Cancer and the National Comprehensive Cancer Network. The recommendations and evidence basis for these guidelines are presented here. All three new or updated guidelines recommend prophylactic use of the myeloid growth factors in cancer patients receiving chemotherapy at 20% or greater risk of febrile neutropenia and in those with important variables that increase individual risk of neutropenic complications. Consistent clinical practice guidelines based on multiple randomized control trials and meta-analyses should further guide the appropriate and cost-effective use of these agents.

A validated risk model for early neutropenic events in older cancer patients receiving systemic chemotherapy

9036 Background: A prospective, nationwide study was undertaken to develop and validate a risk model for early neutropenic events (NE) in older cancer patients undergoing chemotherapy. Methods: 1,386 patients =65 years of age with lung, breast, colorectal, ovarian cancer or lymphoma were prospectively registered at 117 randomly selected sites. Data on up to 4 cycles were collected upon initiation of chemotherapy. A logistic regression model for cycle 1 NE consisting of febrile neutropenia (FN; fever/infection and absolute neutrophil count nadir &lt;1x109/L) or severe neutropenia (SN; neutrophils &lt;.5x109/L) was derived on 1,378 patients with available data. Validation was performed using a split sample random selection process. Results: No significant differences in distribution of NE or predictive factors were observed between derivation dataset (n=922) and validation dataset (n=464). Major independent baseline clinical risk factors for cycle 1 NE in the derivation model (DM) included: anthracycline based regimens (p&lt;.001), non-chemotherapy immune-modulatory agents (p=.003), elevated bilirubin (p=.016), reduced glomerular filtration rate (p&lt;.001), cancer type (p=.02), planned relative dose intensity =85% (p=.027), and regimens containing cyclophosphamide (p&lt;.001), etoposide (p=.002) or ifosfamide (p=.032). Reduced risk of cycle 1 NE was associated with myeloid growth factor (MGF) prophylaxis (p&lt;.001). DM R2 was 0.478 and c-statistic 0.88 [95% CI 0.86–0.91; p&lt;.001]. At median predicted risk of cycle 1 NE of 7%, model test performance (MTP) showed: sensitivity 90%; specificity 59%; and predictive value positive and negative of 32% and 97%, respectively. Cycle 1–4 FN risk in the DM was 16.6% and 3.3% among high and low risk patients, respectively. The validation model (VM) R2 was 0.508 and c-statistic 0.89 [95% CI: 0.86–0.93; p&lt;.001]. MTP in the VM demonstrated: sensitivity 90%; specificity 65%; predictive value positive and negative of 36% and 97%, respectively. Cycle 1–4 FN risk in the VM was 16.8% and 1.6% in high and low risk patients, respectively. Conclusions: This validated risk model demonstrated good discrimination between older cancer patients at decreased risk for NE, and those at increased risk who may benefit from targeted prophylaxis with MGF. No significant financial relationships to disclose.

Neutropenic complications in ovarian cancer patients receiving chemotherapy: Results of a prospective observational study

19610 Background: A nationwide, prospective cohort study of patients receiving cancer chemotherapy was undertaken to better define treatment-associated toxicities and delivered dose intensity. Methods: Following informed consent, 3,670 patients initiating a new chemotherapy regimen with lymphoma (n=547) or carcinomas of the colon (n=521), breast (n=1,473), lung (n=907) or ovary (n=312) were prospectively registered at 117 randomly selected US oncology practices between March 2002 and December 2005. Pretreatment characteristics including clinical and sociodemographic factors and practice setting associated with reductions in chemotherapy dose intensity over 4 cycles were evaluated. Results: Chemotherapy regimen standards and intended dose and schedule were defined in 97% and 93% of patients, respectively. Average initial (planned) relative dose intensity (RDI) was 90% while the mean RDI actually delivered over 4 cycles was 83%. Reductions in RDI =15% of standard were planned in 23% of patients and actually occurred over 4 cycles in 38%. Body surface area (BSA) calculated by the method of Mosteller exceeded the BSA utilized by the oncology practices in two-thirds of patients most often due to capping at 2 m2. Obese patients with a body mass index (BMI) =30 were more likely to receive planned RDI reductions =15% (30%) than patients with BMI &lt;30 (21%) (P&lt;.0001). Other factors associated with planned reductions in RDI in multivariate analysis included: older age, male gender, lower education, absence of myeloid growth factor prophylaxis and cancers of the lung or ovary as well as the practice setting, size and geographic location. Factors associated with unplanned (subsequent) reductions in RDI included: older age, male gender, poorer Charlson comorbidity index, prior chemotherapy, lung cancer, low baseline hematocrit, white blood or platelet count, poor renal or hepatic function and low serum albumin as well as smaller practice and rural setting. Conclusions: A substantial proportion of patients receiving cancer chemotherapy experience both planned and unplanned reductions in RDI. Further understanding of factors associated with such reductions may provide opportunities for improving the quality of cancer care and clinical outcomes. [Table: see text]

Factors associated with reductions in chemotherapy dose intensity: Impact of clinical, sociodemographic and practice setting

6550 Background: A nationwide, prospective cohort study of patients receiving cancer chemotherapy was undertaken to better define treatment-associated toxicities and delivered dose intensity. Methods: Following informed consent, 3,670 patients initiating a new chemotherapy regimen with lymphoma (n=547) or carcinomas of the colon (n=521), breast (n=1,473), lung (n=907) or ovary (n=312) were prospectively registered at 117 randomly selected US oncology practices between March 2002 and December 2005. Pretreatment characteristics including clinical and sociodemographic factors and practice setting associated with reductions in chemotherapy dose intensity over 4 cycles were evaluated. Results: Chemotherapy regimen standards and intended dose and schedule were defined in 97% and 93% of patients, respectively. Average initial (planned) relative dose intensity (RDI) was 90% while the mean RDI actually delivered over 4 cycles was 83%. Reductions in RDI =15% of standard were planned in 23% of patients and actually occurred over 4 cycles in 38%. Body surface area (BSA) calculated by the method of Mosteller exceeded the BSA utilized by the oncology practices in two-thirds of patients most often due to capping at 2 m2. Obese patients with a body mass index (BMI) =30 were more likely to receive planned RDI reductions =15% (30%) than patients with BMI &lt;30 (21%) (P&lt;.0001). Other factors associated with planned reductions in RDI in multivariate analysis included: older age, male gender, lower education, absence of myeloid growth factor prophylaxis and cancers of the lung or ovary as well as the practice setting, size and geographic location. Factors associated with unplanned (subsequent) reductions in RDI included: older age, male gender, poorer Charlson comorbidity index, prior chemotherapy, lung cancer, low baseline hematocrit, white blood or platelet count, poor renal or hepatic function and low serum albumin as well as smaller practice and rural setting. Conclusions: A substantial proportion of patients receiving cancer chemotherapy experience both planned and unplanned reductions in RDI. Further understanding of factors associated with such reductions may provide opportunities for improving the quality of cancer care and clinical outcomes. No significant financial relationships to disclose.

Growth factors G-CSF and GM-CSF differentially preserve chemotaxis of neutrophils aging in vitro

The ability of human neutrophils to migrate was studied during culture in vitro. Neutrophils were isolated from human blood and cultured at 37 degrees C. Apoptosis was determined by Annexin-V fluorescein isothiocyanate binding. Receptor expression was measured by fluorescence in situ hybridization analysis with monoclonal antibodies. Migration was assessed with Transwell Fluoroblock inserts and calcein-stained neutrophils. Extracellular signal-regulated kinase 1/2 (ERK-1/2) activation was determined with monoclonal antibody against phosphorylated ERK-1/2. Upon culture, untreated neutrophils downregulated the chemotaxin receptors FPR, CXC chemokine receptor 1, and CXC chemokine receptor 2 and lost the ability to migrate to formyl-methionyl-leucyl-phenylalanin, interleukin 8 (IL-8), and C5a. In contrast, expression of CXCR4 was induced; this receptor was able to signal (increase in intracellular free calcium ions [Ca(2+)](i), ERK-1/2 activation) but was nonfunctional (no chemotaxis to stromal cell-derived factor-1alpha). The myeloid growth factors granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) retarded the process of functional decay during cell culture. However, while preserving chemotaxis of neutrophils toward formyl-methionyl-leucyl-phenylalanin or C5a, GM-CSF-in contrast to G-CSF-did not preserve chemotaxis toward IL-8, with a corresponding downregulation of the IL-8 receptors. The decay in neutrophil chemotaxis occurred prior to detectable phosphatidylserine (PS)-exposure. In contrast, the induction of [Ca(2+)](i) rises and ERK-1/2 activation correlated with chemotaxin receptor expression unless the cells were truly apoptotic. Neutrophils aging in vitro lose their chemotactic capacity. Functional decay starts prior to PS exposure and can be partially prevented by G-CSF and GM-CSF, in a differential fashion. These growth factors act by increasing the number of viable neutrophils, by altering the levels of chemotaxin receptor expression, and-independently-by affecting signaling cascades.

Differentiation-promoting drugs up-regulate NKG2D ligand expression and enhance the susceptibility of acute myeloid leukemia cells to natural killer cell-mediated lysis

Natural killer (NK) cells are potent effectors of innate antitumor defense and are currently exploited for immune-based therapy of human leukemia. However, malignant blood cells in acute myeloid leukemia (AML) display low levels of ligands for the activating immunoreceptor NKG2D and can thus evade NK immunosurveillance. We examined the possibility of up-regulating NKG2D-specific UL16-binding protein (ULBP) ligands using anti-neoplastic compounds with myeloid differentiation potential. Combinations of 5-aza-2′-deoxycytidine, trichostatin A, vitamin D3, bryostatin-1, and all- trans-retinoic acid, used together with myeloid growth factors and interferon-γ, increased cell surface ULBP expression up to 10-fold in the AML cell line HL60 and in primary AML blasts. Up-regulation of ULBP ligands was associated with induction of myelomonocytic differentiation of AML cells. Higher ULBP expression increased NKG2D-dependent sensitivity of HL60 cells to NK-mediated killing. These findings identify NKG2D ligands as targets of leukemia differentiation therapy and suggest a clinical benefit in combining a pharmacological approach with NK cell-based immunotherapy in AML.

Intravenous immunoglobulins and haematopoietic growth factors in the prevention and treatment of neonatal sepsis: ground reality or glorified myths?

Neonatal sepsis is a significant cause of morbidity and mortality in the neonatal intensive care unit. The epidemiology of neonatal infections is complex; however, they are in large part secondary to developmentally immature host defence mechanisms. These immunodeficiencies, which are exaggerated in premature and sick neonates, include quantitative and qualitative deficits in phagocytes, complement components, cytokines and immunoglobulins. Therapies that modulate or augment host defences may attenuate the virulence of neonatal infections. In this paper, we have reviewed immunotherapies that modulate the immune system of the neonate, including intravenous immunoglobulins and myeloid haematopoietic growth factors. Future studies should focus on investigating other abnormalities of neonatal host defence and/or combined immunotherapy approaches in an attempt to circumvent the immaturity of host defence and potentially reduce both the incidence and severity of neonatal sepsis.

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

Summary and Comparison of Myeloid Growth Factor Guidelines in Patients Receiving Cancer Chemotherapy

Three different practice guidelines for the myeloid growth factors were recently published by major professional organizations. A comprehensive review and comparison of the guidelines using a priori structured content criteria and a previously validated quality appraisal tool are reported. The final recommendations from these guidelines are consistent for primary prophylaxis with the colony-stimulating factors (CSFs) when the risk of febrile neutropenia is in the range of 20% or greater. All 3 guidelines also recommend prophylactic use of myeloid growth factors in patients with important factors increasing individual risk of neutropenic complications. The recommendation that patients receiving regimens associated with lower risk should have CSF use guided by individual risk assessment is also consistent. Critical quality appraisal indicates that the scope, purpose, stakeholder involvement, and applicability of these guidelines differ little. The American Society of Clinical Oncology and European Organization for Research and Treatment of Cancer guidelines place more emphasis on comprehensive literature reviews, and the National Comprehensive Cancer Network guidelines are more current based on systematic annual updates. Presentation clarity also favors National Comprehensive Cancer Network guidelines, with recommendations generally presented as both text and algorithmic diagram.

Myeloid Growth Factor Therapy for Prophylaxis of Febrile Neutropenia in Non-Myeloid Malignancies: Appropriate Doses and Schedules

Myeloid growth factors (MGFs) are used for the prophylaxis of febrile neutropenia and maintenance of scheduled dose delivery in the treatment of patients undergoing cancer chemotherapy. To spare cost and for patient convenience, in adults MGFs are used at schedules, doses, and durations that differ from the approved prescribing information of the U.S. Food and Drug Administration. These variations include rounding doses to convenient sizes, fewer days of treatment, a shorter interval between cycles, and same-day administration with chemotherapy. Some of these variations are supported by clinical trial results and practice guidelines.

Growth Factors in Leukemia

The role of myeloid growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, in the management of acute myeloid and acute lymphoblastic leukemias has been evaluated extensively in multiple clinical trials. Growth factors have been given before, concurrently, or sequentially with chemotherapy with the goal of reducing the duration of neutropenia and consequently the incidence and severity of infections, and improving the rate of remissions and overall survival. They also have been studied as chemotherapy-sensitizing agents in an effort to recruit dormant myeloid stem cells into the sensitive phase of the cycle. Additionally, growth factors, shown to stimulate proliferation and differentiation of leukemia cells in vitro, were evaluated as monotherapy in patients with acute leukemia. Most studies show modest improvement in the duration of the neutropenia, which does not consistently correlate with the severity of infection, rate or duration of remissions, or disease-free and overall survival. Attempts to enhance the chemosensitivity of the leukemic cells and decrease drug resistance failed to improve the rate of remission and survival in several large series. However, more recent reports suggested an improved outcome in younger patients with acute myeloid leukemia with normal karyotype. Several anecdotal case reports have shown that growth factor monotherapy can induce a complete remission in patients with acute leukemia. Data from the published clinical trials do not seem to support emergence of drug-resistant leukemia, worsening toxicity, and bone marrow failure with growth factor administration.

Nurses' Guide to Understanding and Implementing the National Comprehensive Cancer Network Guidelines for Myeloid Growth Factors

To review and determine the applicability of the 2006 National Comprehensive Cancer Network (NCCN) clinical practice guidelines for the use of myeloid growth factors in adult patients treated with chemotherapy for solid tumors and nonmyeloid malignancies. Published guidelines, original research, review articles, and conference presentations. Chemotherapy-induced neutropenia is a common adverse effect of myelosuppressive chemotherapy that may lead to life-threatening infections, prolonged hospitalization, increased IV antibiotic use, and dose reductions or delays that affect patients' quality of life and clinical outcomes. Before treatment begins, nurses should determine which patients are at greater risk for chemotherapy-induced neutropenia and implement an appropriate plan of care. Nurses are in an ideal position to implement a risk assessment tool and play an integral role in directing the quality of patient care. Implementing the NCCN guidelines is one way to facilitate standardization of care.

Myeloablative Allogeneic Bone Marrow Transplantation (AlloBMT) with T Cell Depletion (TCD) and Post-Transplant GM-CSF for Patients with High Risk MDS.

Myelodysplastic syndromes (MDS) are a complex and heterogeneous group of hematopoietic stem cell malignancies that are generally incurable outside allo BMT. The toxicities of allo BMT, specifically graft-vs-host disease (GVHD) and end organ toxicity, have limited its use in this traditionally older group of patients (pts) who often have medical co-morbidities. Efforts to apply allo BMT to more pts have focused on reducing the toxicities. Graft manipulation, including TCD, and reduced-intensity conditioning (RIC) regimens have been shown to decrease the upfront mortality of allo BMT; yet improvements in overall survival have been limited due to associated increased post-BMT relapse rates and increased graft failure. Myeloid growth factors have been used commonly, though not systematically, following allo BMT to speed engraftment. Our data, and that of others, suggest that myeloid growth factors may also have anti-tumor properties in MDS by impacting differentiation pathways and/or through their immunomodulatory effects. We developed a clinical trial to determine if the addition of GM-CSF could safely decrease the relapse rate following a TCD allo BMT in pts with high risk MDS. Pts with MDS ≤ 65 undergoing evaluation for a matched sibling allo BMT at the Sidney Kimmel Cancer Center at Johns Hopkins were considered eligible. Pts received a TCD allograft (elutriation and CD34 isolation) following a myeloablative busulfan/cytoxan preparative regimen; GM-CSF @ 250 mcg/m2/day from Day +5 until ANC >2000/m3 × 3 days and then 125mcg/m2/day subcutaneously thru Day +60. A total of 43 pts were treated on the protocol with a median age of 56 (range 30 to 65) yrs. Forty pts had poor risk MDS (cytogenetics and IPSS) and 3 pts had AML upon retrospective pathology review. The addition of GM-CSF was well tolerated post-allo BMT with only 1 pt unable to complete the full dose, planned therapy. The overall survival @ 1 and 3 years was 54% and 50% respectively while the event free survival @ 1 and 3 years was 47% and 33% respectively with median follow-up in the surviving group of 37.5 months. Treatment related toxicity was low with a 9% cumulative incidence of grade III/IV aGVHD and a transplant-related mortality (TRM) of 21% (9/43) with 4 deaths related to GVHD, 4 related to engraftment, and 1 secondary to venoocclusive disease. Cumulative incidence of relapse at data analysis was 40% (17/43) with one patient achieving remission after donor lymphocyte infusion. Engraftment failure was seen in only 9% (4/43) of pts. Taken together, ablative preparative regimens followed by TCD allo BMT can safely be used in older MDS pts with the addition of GM-CSF resulting in acceptable engraftment without increased toxicity. Myeloablative conditioning with TCD and prolonged post-transplant GM-CSF produced favorable results in this group of older, high-risk MDS patients. The role of high dose conditioning for alloBMT for MDS is unclear, but the TRM was similar to the low mortality reported with RIC regimens, and the graft failure and relapse rates may be superior.

Quality of Life in Myelodysplastic Syndromes (MDS): Results from U.S. & European Patient Forums.

The MDS Foundation, Inc., an international non-profit organization established by physicians and researchers to foster information exchange, conducted a series of patient forums in 16 U.S. and European cities to assess patients' knowledge about their disease and key issues affecting quality of life (QoL). MDS patients and spouses, friends, or caregivers were recruited to participate in forums in 2005–2006 through the MDS Foundation Center of Excellence in participating cities: Chicago, New York, Palo Alto, Philadelphia, Pittsburgh, Scottsdale, Tampa, Bournemouth (U.K.), Leeds (U.K.), Edinburgh, London, Marseille, Paris, Stockholm, Vienna. Clinical nurse specialists with expertise in QoL issues in MDS patients conducted the interactive 1-day forums. A single written questionnaire was developed, vetted, and translated by participating Centers. Completion of the anonymous questionnaire, distributed and collected onsite at the forums, was voluntary. Responses to questionnaires were analyzed using descriptive statistics only. A total of 287 MDS patients and caregivers, spouses, or friends participated in the forums (186 patients; 101 caregivers, spouses, or friends). In both Europe and the U.S., the patient sample was approximately equal with respect to gender (slightly higher percentage of males), and the majority of patients were <75 years of age. Patients' knowledge about their disease appears to be variable between and within countries: 20 to 40% of patients reported that they did not know their MDS subtype and 82–100% did not know their International Prognostic Scoring System (IPSS) risk category. However, 95–96% of patients reported knowing that they had a bone marrow biopsy to diagnose their disease. Interestingly, the percentage of patients who reported having bone marrow biopsy at any time after their diagnosis was substantially lower for the Leeds, Bournemouth, Philadelphia (2 forums), and Pittsburgh forums (57%) than that for all other forums (83%). Several questionnaire responses revealed that disease symptoms and clinical management impact patients' QoL. Infections requiring hospitalizations was reported to be 32% at European forums (range: 20–50%) and 28% at U.S. forums (range: 21–33%). The majority of patients reported needing or being treated with transfusions (64%, U.S.; 81%, Europe) or myeloid growth factors (80%, U.S.; 44%, Europe). A low, but not insignificant, percentage of patients reported having iron chelation therapy (15%, U.S.; 17%, Europe). The survey responses indicate that MDS patients in the U.S. and Europe hold similar views about the impact the disease has on their QoL. Patient QoL was similar between sites and reflected feelings of life disruption due to MDS and time required for disease management. Fatigue was most frequently cited disease symptom affecting QoL by interfering with patients' ability to perform daily living activities, work, and participation in social and family life. Several factors appear to contribute to patients' feelings of “loss of life control,” including physician visits, diagnostic testing, transfusions, treatment, travel time, and symptom or adverse event management. Physicians and other healthcare professionals should be aware of the factors that impact patients' QoL and attempt to provide patients with information, treatment options, and availability of support services to lessen disease burden and minimize impact on QoL.

Palifermin Treatment in Patients Receiving High Dose Melphalan or BEAM Prior to Autologous Peripheral Blood Stem-Cell Transplantation.

Background. Oral mucositis (OM) is a common complication of high-dose (HD) chemotherapy conditioning regimens used with peripheral blood stem-cell transplantation (PBSCT). Severe grades of OM are associated with higher morbidity such as infections, need for total parenteral nutrition (TPN), opioid analgesics and prolonged hospitalization and has been historically underreported. Recent epidemiology reveals an incidence of severe OM of 50–60%. Moreover, OM is reported by patients as the worst and most debilitating complication of PBSCT. The keratinocyte growth factor, palifermin, stimulates the growth, differentiation, migration, and survival of epithelial cells. Palifermin is now approved in the US and the EU to decrease the incidence, duration, and severity of OM in patients (pts) with hematological malignancies requiring autologous PBSCT.Objective. This report describes the treatment of 60 pts who received palifermin through an early access program in Belgium. We evaluated the effect of palifermin on OM in pts with multiple myeloma or non-Hodgkin's lymphoma receiving HD melphalan (HD Mel) or BEAM conditioning regimen, respectively, prior to autologous PBSCT.Methods. The pts received palifermin (IV bolus: 60 μg/kg/day) for 3 days before and 3 days after HD Mel or BEAM. The common OM prevention strategy included basic oral hygiene, mouth washes and oral cryotherapy during HDM administration (n=9). For each patient, follow-up data were collected on mucositis grading, duration of hospitalization, neutropenic fever, treatment with G-CSF, IV antibiotics, opioids, and TPN. The grade of OM during treatment was assessed according to the WHO oral-toxicity scale (grade 0 to 4). Drug-related adverse events were also recorded.Results. Thirty pts received HD Mel and 30 pts received BEAM before PBSCT. All 60 pts received at least 3 palifermin bolus injections; the scheduled doses (6 bolus) were administered to 55 (91%) of 60 pts. Analysis of the follow-up data revealed that 10 (16%) pts experienced no OM. Furthermore, a low incidence (31%) of severe (grade 3 and 4) OM was observed with each conditioning regimen. The median duration of severe OM with the HD Mel regimen was 7 days (range 3–27) contrasting with a median OM duration of 3 days (range 2–12) with the BEAM regimen. Two pts in each regimen required prolonged hospitalization due to OM. With either regimen, neutropenic fever and use of IV antibiotics were common (70% of pts), while bacteremia was infrequent (20% of pts). Myeloid growth factors were administered post PBSCT to the majority of pts. Forty percent (40%) of HD Mel-treated pts and 26% of BEAM-treated pts required opioid analgesics. The percentages of pts receiving TPN were similar in the 2 conditioning regimens (66% of all pts). TPN was used in 16 (84%) pts with severe OM and in 24 (58%) pts with no or grade 1–2 OM. Adverse events clearly related to palifermin were reported in 25 (41%) of 60 pts. The most common adverse events included rash (18 events, 8 severe), disorders of tongue and oral mucosa (13 events, 2 severe), edema (10, no severe) and pruritus (7, no severe).Conclusions. These results indicate that palifermin use prior to HD Mel or BEAM and immediately following the transplantion may provide effective support in the prophylaxis of severe OM in pts undergoing autologous PBSCT, without major toxicity.

PU.1 and GATA-1, but Not SCL Elicit an Increase in General Transcription Associated with the Lineage Restriction of Multipotent Progenitors.

The lineage commitment of multipotent progenitor cells is coordinated by regulatory interactions between transcription factor programs associated with different lineage fates. Accordingly, mutations which interfere with these programs can block differentiation and contribute to leukemogenesis. A thorough understanding of lineage commitment processes should therefore identify targets and strategies for differentiation therapy. We have compared the effects of transient over-expression of the hematopoietic transcription factors PU.1, GATA-1 and SCL on the response of a multipotent hematopoietic progenitor cell line (FDCPmix) to conditions supporting either self-renewal, myeloid differentiation or erythroid differentiation.Methods: Pure populations of FDCPmix cells productively transfected with transcription factor cDNA/IRES/GFP expression vectors were isolated by FACS sorting and entered directly into liquid media containing either IL-3 (for self-renewal); GM-CSF + G-CSF (for myeloid differentiation) or erythropoietin + hemin (for erythroid differentiation). Semi-solid medium containing IL-3 was used to assess the maintenance of that sub-population of cells which can undergo self-renewal in isolation, and which are assumed to represent the earliest progenitors in an FDCPmix culture. Transcription factor function was confirmed by co-transfection with reporter genes driven by specific target promoters.Results: The yield of FDCPmix cells from self-renewal medium was markedly enhanced by the transient expression of SCL but reduced by either PU.1 or GATA-1. These differences in yield reflect alterations in survival and/or proliferation over the two day period of transgene expression immediately following transfection. As expected, the transient expression of PU.1 severely reduced the potential of multipotent progenitors to respond to erythroid growth factors, while GATA-1 similarly reduced the response to myeloid growth factors, consistent with an antagonistic relationship between myeloid and erythroid transcription factors during lineage restriction. However, while all three transcription factors demonstrated the appropriate activity on their respective target promoters, PU.1 and GATA-1 also increased general transcriptional activity. Transient expression of GATA-1 actually raised the activity of the cfms (PU.1 target) promoter, while PU.1 activated the serpin 2A (GATA-1 target) promoter. Of the transcription factors tested, only PU.1 consistently reduced the frequency of colony forming cells, suggesting that the earliest multipotent progenitors in an FDCPmix population can be recruited to commitment by PU.1 but not by GATA-1.Conclusion: These results are consistent with a multi-step process of lineage commitment in which general transcriptional activity in multipotent progenitors is maintained at a low level, base state. An increase in general transcriptional activity would then be required as an early event in commitment, activating the transcription factor networks subsequently responsible for coordinating lineage restriction.