Testing G-CSF responsiveness predicts the individual susceptibility to infection and consecutive treatment in recipients of high-dose chemotherapy

The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 μg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/μL), medium (quartile 2; leukocytes > 10 100-18 300/μL), and high (quartiles 3/4; leukocytes > 18 300-44 800/μL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058.     

Responsiveness of neoadjuvant chemotherapy before surgery predicts favorable prognosis for cervical cancer patients: a meta-analysis

Background

Neoadjuvant chemotherapy (NAC) before surgery has already shown the therapy effectiveness in patients with cervical cancer. The present meta-analysis was conducted to determine whether the response to NAC predicts for prognosis.

Methods

Systematic computerized searches of the PubMed and Web of Knowledge were performed. Prognosis outcomes included progression-free survival (PFS), and overall survival (OS). The pooled odd ratio (OR) was estimated by using fixed-effect model or random-effect model according to heterogeneity between studies.

Results

Eighteen studies with 1,785 patients were included. Cisplatin-based NAC treatments were most commonly used. The clinical response rate ranged from 48.4 to 93.0 %, and the pathological response rate ranged from 27.6 to 30.6 %. The pooled ORs estimating the association of PFS with NAC response were 5.707 (95 % CI 3.564–9.137), 6.798 (95 % CI 4.716–9.799), 6.327 (95 % CI 4.398–9.102), and 5.214 (95 % CI 3.748–7.253) at 1-, 2-, 3-, and 5-year follow-up, respectively, and the pooled ORs estimating the association of OS with NAC response were 6.179 (95 % CI 3.390–11.264), 9.155 (95 % CI 5.759–14.555), 8.431 (95 % CI 5.667–12.543), and 5.785 (95 % CI 4.124–8.115) at 1-, 2-, 3-, and 5-year follow-up, respectively. No obvious statistical heterogeneity was detected. Funnel plots and Egger’s tests did not reveal publication bias. Sensitivity analysis showed the results of meta-analysis were robust.

Conclusion

This meta-analysis confirms that response to NAC is an indicator for PFS and OS, and suggests that patients-achieving response of NAC before surgery predicts favorable prognosis for cervical cancer patients.     

Gynaecomastia with hypergonadotrophic hypogonadism and Leydig cell insufficiency in recipients of high-dose chemotherapy or chemo-radiotherapy.

Late side-effects of stem cell transplantation include hypogonadism with infertility and sexual dysfunction, but gynaecomastia is less well recognised. We report five cases of gynaecomastia with features of hypergonadotrophic hypogonadism (primary testicular failure), who received either a TBI/cyclophosphamide conditioned allograft (n = 3) or a BEAM autograft (n = 2). Patients receiving an allograft had gynaecomastia, Leydig cell insufficiency (LCI) diminished libido and erectile dysfunction. Surgery was required in one case, while in two cases the gynaecomastia resolved spontaneously after 6 months. Two patients also had gynaecomastia and sexual dysfunction, severe hypogonadism, very low testosterone levels and marked hyperprolactinaemia following autoBMT. Both responded well to testosterone replacement therapy (TRT). As a group, all patients had primary testicular failure and all except one, had LCI (compensated or frank). However, there was no correlation between the severity of gynaecomastia and the degree of endocrine dysfunction. This preliminary study is the first to suggest that gynaecomastia, due to primary hypogonadism and LCI, may be a significant complication of myeloablative conditioning therapy. Therefore gynaecomastia in BMT recipients must always be treated as a pathological entity as it may be the external manifestation of a complex endocrine pathology. It is a potentially treatable condition. Although spontaneously reversible, some patients may require TRT or even surgery. We recommend comprehensive endocrine testing in conjunction with a reproductive endocrinologist and prompt intervention to alleviate embarrassment and anxiety in afflicted BMT recipients.     

Increase of monocytes predicts mobilization of peripheral stem and progenitor cells after chemotherapy followed by G-CSF administration

Abstract: Mobilization of primitive haematopoietic cells to the peripheral blood was studied in 25 patients with haematological malignancies. The optimal level of peripheral stem cells (PSC), defined by their surface expression of CD34, was significantly higher after mobilization with G-CSF, either following chemotherapy or alone (median: 123 × 10⁶/l and 143 × 10⁶/l of CD34+ cells respectively) than without administration of G-CSF subsequent to chemotherapy (median: 27 × 10⁶/l of CD34+ cells). An individual variation in when optimal mobilization of CD34+ cells and myeloid progenitors occurs after chemotherapy and G-CSF administration was noted (median: day 12, range 7–24 days), which makes it difficult to predict when PSC collections in a given patient should be performed. In this study, chemotherapy followed by G-CSF administration resulted in a short lasting (2–3 days) peak appearance of CD34+ cells that could predicted by a 2-fold increase in absolute numbers of monocytes, as compared to the previous day. After the peak level of CD34+ cells in the blood was reached, no further increase in monocytes was seen. The identification of an increase in monocytes, to be used as a predictive variable for when optimal mobilization of PSC will occur in a given patient, may be particularly useful in the individual timing of PSC collections from non-hospitalized patients.     

Immunomodulatory effects of moxifloxacin in comparison to ciprofloxacin and G-CSF in a murine model of cyclophosphamide-induced leukopenia.

We analyzed the effect of the two quinolones moxifloxacin and ciprofloxacin on the repopulation of hematopoietic organs and on the production of cytokines by various organs of cyclophosphamide (CP)-induced leukopenic mice. The effect was compared to that of G-CSF. Cyclophosphamide injection induced a severe leukopenia, with nadir at day 4 post-injection. All the quinolone and G-CSF-treated animals showed WBC>500/microL at the nadir, compared to 50% of saline-treated mice. Cyclophosphamide induced a marked decrease in the number of myeloid progenitors (CFU-C) in bone marrow (BM) and spleen. Quinolone or G-CSF treatment resulted in a 1.4-4.3-fold increase in CFU-C numbers in the BM; no enhancement was observed in the spleen. Treatment with CP resulted in enhanced colony-stimulating activity (CSA) in bone shaft and spleen and decreased activity in bladder and lung. Treatment of CP-injected mice with quinolones significantly enhanced CSA in the bone shaft, spleen, lung and bladder on different days. In normal mice the highest levels of GM-CSF and IL-6 were observed in lung-conditioned medium (compared to bone shaft, spleen and bladder). Injection of CP resulted in a 22.5- and 93-fold decrease in GM-CSF and IL-6 levels, respectively, in lung-conditioned medium, while treatment with quinolones resulted in 2-4-fold increase in GM-CSF with no effect on IL-6 production. G-CSF treatment had no enhancing effect on GM-CSF nor on IL-6 production. We conclude that moxifloxacin and ciprofloxacin administered to CP-injected mice revert some of the immune suppressive effects of cyclophosphamide.     

Contamination of autologous peripheral blood progenitor cell grafts predicts overall survival after high-dose chemotherapy in multiple myeloma

Background  Despite of the introduction of novel treatment modalities for multiple myeloma, high-dose chemotherapy with hematopoietic stem-cell rescue is still considered the standard of care for eligible patients <65 years of age. As we have previously reported, stem-cell grafts regularly contain quantities of plasma cells measurable by flow cytometry. However, the pathogenetic significance of this finding remains unknown. Methods  Multiple myeloma patients (n = 60) were mobilized with chemotherapy and filgrastim. Peripheral blood stem cell grafts were obtained by standard leukapheresis, and the number of CD38++/CD138+ cells/kg was determined by flow cytometry. Plasma cell contamination above a threshold of 4.5 × 10⁵ plasma cells/kg was considered “high”, whereas lower quantities of plasma cells or absent plasma cells in the graft were considered “low”. Results  Progression-free survival: the median statistical progression-free survival was 33.5 months (range 11–99 months) in the high-contamination group (n = 16) versus 47 months (range 8–148 months) in the low-contamination group (n = 44). This difference turned out not to be statistically significant (P = 0.15). However, the difference was highly significant regarding overall survival with 53 months (range 11–119 months) in the high-contamination group and with 114 months (range 8–158 months) in the low-contamination group (P = 0.012). Conclusions  Patients with >4.5 × 10⁵ plasma cells/kg contaminating the peripheral blood stem cell graft received after high-dose chemotherapy have a significantly reduced overall survival. Whether high contamination of grafts with plasma cells might reflect residual in vivo tumor mass prior to stem cell transplantation and a generally more aggressive behavior of malignant myeloma cells in these patients, or whether reinfused plasma cells contribute to an unfavorable course of disease remains to be determined.     

Varicella zoster virus infection associated with high-dose chemotherapy and autologous stem-cell rescue

A retrospective evaluation of 215 consecutive recipients of high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) was conducted to ascertain the incidence, temporal course, and outcome of varicella zoster virus (VZV) infection. Herpes zoster was identified in 40 individuals at a median of 69 days following ASCR. Six of these cases occurred at a median of 33 days prior to ASCR but following the initiation of high doses of stem cell mobilization chemotherapy. Twenty-five percent of patients demonstrated cutaneous or systemic dissemination and 32.5% required medical intervention for post-herpetic neuralgia. All except two individuals received antiviral chemotherapy. One patient with active VZV infection died of multiorgan failure 39 days after ASCR. Multivariate analysis of risk factors disclosed the significance of prophylactic acyclovir use in Herpes simplex virus seropositive individuals in reducing the risk of VZV infection. Moreover, the use of busulfan, thiotepa and carboplatin as the conditioning chemotherapy regimen was associated with an increased risk of subsequent VZV infection. The incidence of VZV reactivation after HDC and ASCR is similar to that observed following bone marrow transplantation but has an earlier onset. This may be related to an earlier induction of immunosuppression by stem cell mobilization chemotherapy administered prior to ASCR. We demonstrated a marked reduction in the proliferative and synthetic capacities of peripheral blood mononuclear cells obtained prior to and following stem cell mobilizing chemotherapy. Moreover, greater than 80% of VZV infections occurred within 6 months following ASCR and late cases were seldom observed compared to allogeneic and autologous bone marrow transplantation. The role of antiviral chemoprophylaxis during the period of maximum immunocompromise needs to be studied further in the HDC-ASCR setting.     

Health-related quality of life assessed before and during chemotherapy predicts for survival in multiple myeloma

Measurement of health-related quality of life was integrated into a randomized trial (NMSG 4/90) comparing melphalan/prednisone to melphalan/prednisone + interferon α-2b in newly diagnosed multiple myeloma. One of the aims of the study was to assess the prognostic significance of quality-of-life scores, using the EORTC QLQ-C30 questionnaire. Univariate analysis showed a highly significant association with survival from the start of therapy for physical functioning as well as role and cognitive functioning, global quality of life, fatigue and pain. In multivariate analysis, physical functioning and W.H.O. performance status were independent prognostic factors ( P values=0.001 for both) when analysed in a Cox regression model with the somatic variables β-2 microglobulin, skeletal disease and age. The best prediction for survival from the start of therapy was obtained by combining the β-2 microglobulin and physical functioning scores in a variable consisting of three risk factor levels with an estimated median survival of 17, 29 and 49 months, respectively. At a 12 months landmark analysis, the relative risk for patients with physical functioning score 0–20 v 80–100 was 5.63 (99% CI 2.76–11.49), whereas the relative risk for patients without an objective response to chemotherapy compared to those with at least a minor response was 2.32 (99% CI 1.44–3.74). Quality-of-life assessment may be an independent and valuable addition to the known prognostic factors in multiple myeloma.     

Cavernosal arterial insufficiency and erectile dysfunction in recipients of high-dose chemotherapy and total body irradiation for multiple myeloma

Five patients with multiple myeloma who had an autologous bone marrow/stem cell transplant were studied to assess the cause of the erectile dysfunction by assessing markers of gonadal function and cavernosal vascular measurements by flow Doppler study.     

Both early and committed haemopoietic progenitors are more frequent in peripheral blood than in bone marrow during mobilization induced by high-dose chemotherapy + G-CSF

Summary. Haemopoietic growth factor administration following high-dose chemotherapy markedly amplifies progenitor cell pool in the peripheral blood (PB). Collection and reinfusion of these cells enable rapid haemopoietic recon-stitution following autograft. Less is known on engraftment potentiality of bone marrow (BM) cells taken under analogous conditions. To investigate this tissue, PB and BM were evaluated simultaneously during maximal mobilization in a series of 14 patients undergoing the HDS chemotherapy programme. A significantly higher growth of committed progenitors was found from PB rather than from BM (663 ± 123 v 267±40CFU-GM/10⁵ MNC, respectively). Also, significantly more CFU-GM could be collected by a median of three leukaphereses, compared to those harvested from BM (158 ± 31 v 16 ± 4 ± 10⁴ CFU-GM/kg, respectively). Most mobilized CFU-GM were phenotypically immature (CD15⁻); in addition, circulating cells included primitive progenitors, as assessed by LTC-IC assay, or by evaluation of non-proliferating pre-CFU-GM, selected by an anti-CD71 immunotoxin. The amount of pre-CFU-GM determined by both techniques was consistently higher in PB than in BM. Moreover, a direct correlation could be established between circulating CFU-GM and primitive precursors. Thus, during optimally induced mobilization, PB contains many more haemopoietic progenitors, of both committed and primitive stages, than does BM. Under such conditions, PB is probably the best source of material for graft purposes.     

Mobilizing peripheral blood stem cells with high-dose G-CSF alone is as effective as with Dexa-BEAM plus G-CSF in lymphoma patients

We compared retrospectively the efficacy of granulocyte colony stimulating factor (G-CSF) alone with chemotherapy plus G-CSF in mobilizing CD34-positive cells in patients with malignant lymphoma. 35 patients underwent peripheral blood stem cell (PBSC) collection following mobilization either with 24 μg/kg G-CSF for 4 consecutive days (n = 18) or Dexa-BEAM chemotherapy plus 5 μg/kg G-CSF (n = 17). High-dose G-CSF was well tolerated with only slight bone pain and/or myalgia. The Dexa-BEAM therapy required hospitalization with a median duration of 21 d. The median number of apheresis procedures in both groups was two (range two to four), resulting in a median of 5.3 and 5.1 × 10⁶ CD34⁺ cells/kg. No patients in the G-CSF group, but one in the Dexa-BEAM group, failed to reach the target of collecting >2.0 × 10⁶ CD34⁺ cells/kg. The number of CFU-GM (10.4 v 6.0 × 10⁵/kg) and of BFU-E (10.6 v 4.5 × 10⁵/kg; P = 0.04) was higher in the G-CSF group than in the Dexa-BEAM group. A subset analysis of CD34⁺ cells was performed in 16 patients showing a higher mean of Thy-1 (CD90w) coexpression in the G-CSF than in the Dexa-BEAM group (4.8 v 1.8%, P = 0.12). Additionally the percentage of CD34⁺/CD38^? cells was higher in the G-CSF group (10.6% v 8.8%). However, these differences were not stastistically significant. The median time to leucocyte and platelet engraftment after high-dose chemotherapy was slightly shorter in the G-CSF than in the Dexa-BEAM group (9 v 10 and 12 v 13.5 d, respectively). These results demonstrate that high-dose G-CSF is as effective as Dexa-BEAM plus G-CSF in mobilizing peripheral blood stem cells and produces prompt engraftment. The major advantages of G-CSF mobilization were the safe outpatient self-application and the fixed-day apheresis.     

Leukaemoid monocytosis in M4 AML following chemotherapy and G-CSF

We describe a patient with M4 AML treated with standard chemotherapy followed by G-CSF who developed marked monocytosis on day 8 of G-CSF therapy. Fourteen days after discontinuation of G-CSF therapy his monocyte counts returned to normal levels and a marrow aspirate showed a reduction in blast cells. He received further chemotherapy without G-CSF and without any recurrence of the raised leucocyte count but failed to achieve full remission. Although this G-CSF-driven leucocytosis was alarming it did not appear to have adversely affected the patient's prognosis.     

Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support

We closely followed the pulmonary function of 150 consecutive high-risk breast cancer patients who underwent standard induction CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) chemotherapy, followed by randomization to either standard-dose CPB (cyclophosphamide, cisplatin, bischloroethylnitrosourea [BCNU]) chemotherapy (SDC) or to high-dose CPB chemotherapy (HDC) with autologous bone marrow transplantation (ABMT) and peripheral blood progenitor cell support (PBPCS). Previously, we have described a delayed pulmonary toxicity syndrome (DPTS) which characterizes the pulmonary dysfunction after HDC and ABMT in this patient population. However, little is known concerning the role induction chemotherapy plays in its development. We found that after three cycles of induction CAF, the mean diffusing capacity of the lungs for carbon monoxide (DL(CO)) significantly decreased by 12.6%. Additionally, in patients receiving HDC, the mean DL(CO) further decreased to a nadir of 55.2 +/- 14.1% which was significantly lower than those receiving SDC (nadir: 80.7 +/- 12.3%). DPTS occurred in 72% of patients receiving HDC as compared with only 4% of patients receiving SDC. All individuals diagnosed with DPTS were treated with prednisone and the 2-yr follow-up of pulmonary function revealed a gradual improvement in mean DL(CO) such that there were no differences between HDC and SDC groups at the end of the study. No mortality was attributable to pulmonary toxicity in either group. After induction chemotherapy, but before HDC, bronchoalveolar lavage (BAL) demonstrated significant elevations in interleukin-6 (IL-6), IL-8, neutrophils, and lymphocytes. We conclude that induction CAF produces asymptomatic pulmonary dysfunction and inflammation which may prime the lungs for further injury by HDC and predispose to the development of DPTS. Fortunately, in this specific ABMT patient population, the early and judicious use of prednisone appears to improve pulmonary function in patients who develop DPTS.     

Current aspects of high-dose chemotherapy in germ-cell tumors

The optimal treatment in patients with 'poor prognosis' germ-cell tumors (GCT) according to the 'International Germ Cell Cancer Collaborative Group' (IGCCCG)--classification and in patients with refractory or relapsed disease after cisplatin-based chemotherapy remains controversial. It is well known that the majority of these patients will suffer systemic relapses after primary or salvage treatment and most of them will ultimately die of their disease. Therefore, the optimizing of the standard treatment is clearly desirable. The question of using conventional-dose or high-dose chemotherapy (HDCT) in this high-risk patients is under discussion. However, HDCT as primary treatment in 'poor prognosis' patients and as first- or subsequent salvage therapy in patients with relapsed or refractory GCT remains to be a relevant curative option. Prognostic factors have recently been recognized to aid in this decision.     

Cavernosal arterial insufficiency is a major component of erectile dysfunction in some recipients of high-dose chemotherapy/chemo-radiotherapy for haematological malignancies

We studied 24 male patients aged 26-62 years (median 41) prospectively presenting over a 5 year period with clinical features of hypogonadism and erectile dysfunction (ED), who had been treated with autologous or allogeneic bone marrow/stem cell transplant for a variety of haematological malignancies and had received either high-dose chemotherapy or high-dose chemotherapy combined with total body irradiation (TBI). Ten healthy adult controls (aged 35-50 years) were also studied. Erectile dysfunction (ED) was assessed clinically and by colour flow Doppler studies of the cavernosal vessels. Testicular function was assessed by testicular volume including orchidometry, FSH, LH and testosterone measurements. Libido and ejaculatory function were also recorded. Patients had severe hypogonadism as evidenced by low mean testicular volume (7.0 +/- 2.4 ml vs 20 +/- 2.0 ml; P < 0.001), elevated gonadotrophins (FSH = 18.54 +/- 7.61 vs 5 IU/l (P < 0.001); LH = 8.02 +/- 2.89 vs 3. 9 IU/l (P < 0.001)) and low normal mean testosterone levels (16.4 nmol/l +/- 9.1 vs 22.4 nmol/l (P < 0.5)). Cavernosal arterial insufficiency was found in 11/14 of TBI-treated and in 3/10 HDC-treated patients, indicative of vasculogenic damage to corpora cavernosal vessels. Patients were given a therapeutic trial with testosterone replacement therapy (TRT). Those who had diminished libido had a marked improvement in their symptoms but the effect of TRT on ED was equivocal. In conclusion, this is the first report to show vasculogenic insufficiency in patients with haematological malignancies treated by BMT. Although hypogonadism can account for diminished libido, arteriogenic insufficiency is likely to be an important factor accounting for ED in these patients, especially those treated by TBI. We recommend a comprehensive assessment including endocrine profile and colour flow Doppler study in formulating the best management plan in recipients of high-dose therapy presenting after transplant with ED.     

Sustained G-CSF plasma levels following administration of pegfilgrastim fasten neutrophil reconstitution after high-dose chemotherapy and autologous blood stem cell transplantation in patients with multiple myeloma

OBJECTIVE: Pegfilgrastim has shown to decrease the duration of severe neutropenia after conventional chemotherapy, but its use after high-dose chemotherapy and autologous blood stem cell transplantation has not been established yet. Therefore we studied the efficacy and the pharmacokinetic profile of pegfilgrastim in patients with multiple myeloma undergoing high-dose chemotherapy. METHOD: In total, 21 patients received a single subcutaneous injection of 6 mg pegfilgrastim on day +1 after transplantation and pegfilgrastim plasma levels were measured daily by enzyme-linked immunosorbent assay. Clinical outcome was compared with pegfilgrastim levels of 282 plasma samples and data of a historical control group of patients without granulocyte colony-stimulating factor (G-CSF) support. RESULTS: Pegfilgrastim levels showed an inverse correlation (r = -0.68, p < 0.01) with neutrophil counts. Peak levels were reached at day +4 (94 ng/mL; range: 37-205) and were maintained until day +7 (85 ng/mL; range: 35-186). Comparison with the control group without G-CSF support showed that time to neutrophil reconstitution was significantly shorter in the pegfilgrastim group with 10 vs 15 days, respectively (p < 0.001). There was no correlation of pegfilgrastim levels and the duration of neutropenia, although patients with a fivefold increase in neutrophil counts the day after pegfilgrastim administration had a significantly shorter median duration of neutropenia in comparison to patients who were less susceptible to G-CSF stimulation (5 vs 7 days, p < 0.01). CONCLUSION: Neutrophil reconstitution after high-dose chemotherapy could be accelerated by the use of pegfilgrastim in patients with myeloma. Responsiveness of neutrophils to pegfilgrastim before neutropenia was correlated with faster neutrophil reconstitution, whereas G-CSF levels had no impact on neutrophil recovery.     

Peripheral blood stem cell mobilization using high-dose cyclophosphamide and G-CSF in pretreated patients with lymphoma

Summary. Peripheral blood stem cell (PBSC) mobilization for autologous transplantation is more difficult in treated patients and those with bone marrow involvement. In 17 pretreated lymphoma patients, cyclophosphamide (4 g/m²) and G-CSF mobilized a median circulating peak of 1959 CFU-GM/ml on day 12.5. PBSC harvesting commenced when WBC was 1×10⁹/l at day 10.5 collected a median of 21.2 × 10⁴/CFU-GM/kg. 13/17 (76%) patients exceeded the 10 × 10⁴ CFU-GM/kg threshold for engraftment. The CFU-GM yield was significantly higher in patients whose WBC recovered from 1–5 × 10⁹/1 in less than 3 days and correlated with the maximum WBC pre and post the cyclophospharnide induced nadir. This regime safely mobilized adequate PBSC in the majority of pretreated lymphoma patients.