Setting Of High-dose Chemotherapy Research Articles

S2945 Check Point SOS! A Case of Cemiplimab-Associated Sinusoidal Obstruction Syndrome

Introduction: Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS), is a clinical syndrome characterized by hepatomegaly, right-upper quadrant pain, and ascites that occurs most commonly in the setting of high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT). The diagnosis can be confirmed on biopsy. Cemiplimab is an immune checkpoint inhibitor recently approved for the treatment of cutaneous squamous cell carcinoma. There are currently no known reports of immune checkpoint inhibitor-related VOD/SOS. Case Description/Methods: A 58-year-old female with a history of locally advanced basal cell carcinoma of the left eye treated with six months of Cemipilimab presented with ascites. On admission, labs were notable for a total bilirubin of 1.2, mildly elevated liver function tests, alkaline phosphatase 884, and international normalized ratio 2.1. A diagnostic tap revealed a high SAAG ascites that was negative for infection. A comprehensive serological workup for viral, metabolic and autoimmune causes was unrevealing. A transjugular liver biopsy demonstrated a hepatic venous pressure gradient of 18mmHg, nodular regenerative hyperplasia (NRH), and portal venopathy. The patient was discharged on steroids but returned one month later for recurrent ascites and worsening bilirubin to 12.6 (direct 7.3); COVID PCR was negative. A full rheumatologic and vasculitis workup was unremarkable. Repeat biopsy (Figure 1) demonstrated moderate NRH changes, prominent central vein sclerosis with fibrous obliteration, signs of SOS/VOD and central venulitis with fibrotic changes with sinusoidal portal hypertension. Discussion: VOD occurs most often with hematopoietic stem cell transplantation, and chemotherapeutic agents. Here we present the first case of checkpoint inhibitor-induced VOD/SOS. Despite discontinuation of the offending agent and a trial of steroids, the patient’s clinical course continued to deteriorate. She eventually developed refractory ascites and portosystemic encephalopathy. She was deemed not a candidate for liver transplant given her underlying malignancy. She was transitioned to home hospice before further treatment, such as Defibrotide could have been pursued. VOD associated with immune checkpoint inhibition should be considered in the differential of patients who develop new onset liver dysfunction and ascites while receiving these medications.Figure 1.: Sinusoidal dilatation and congestion alongside central vein sclerosis. These are common findings of sinusoidal obstruction syndrome on liver biopsy.

Systematic review of growth factors and cytokines for the management of oral mucositis in cancer patients and clinical practice guidelines.

To update the clinical practice guidelines for the use of growth factors and cytokines for the prevention and/or treatment of oral mucositis (OM). A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, the following guidelines were determined: recommendation, suggestion, and no guideline possible. A total of 15 new papers were identified within the scope of this section and were merged with 51 papers that were reviewed in the previous guidelines update. Of these, 14, 5, 13, 2, and 1 were randomized controlled trials about KGF-1, G-CSF, GM-CSF, EGF, and erythropoietin, respectively. For the remaining agents there were no new RCTs. The previous recommendation for intravenous KGF-1 in patients undergoing autologous hematopoietic stem cell transplantation (HSCT) conditioned with high-dose chemotherapy and TBI-based regimens is confirmed. The previous suggestion against the use of topical GM-CSF for the prevention of OM in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation remains unchanged. Of the growth factors and cytokines studied for the management of OM, the evidence supports a recommendation in favor of KGF-1 and a suggestion against GM-CSF in certain clinical settings.

Long-Term Outcome of Inflammatory Breast Cancer Compared to Non-Inflammatory Breast Cancer in the Setting of High-Dose Chemotherapy with Autologous Hematopoietic Cell Transplantation.

Introduction: Inflammatory breast cancer (IBC) is a rare aggressive form of breast cancer. It is well known that the long-term survival and progression-free survival of IBC are worse than that of non-IBC. We report the long term outcomes of patients with IBC and non-IBC who had undergone high-dose chemotherapy (HDC) with autologous hematopoietic cell transplantation (AHCT).Methods: All 3387 patients with IBC or non-IBC who underwent HDC with AHCT between1990-2002 and registered with CIBMTR were included in this analysis. Transplant-related mortality (TRM), disease relapse/progression, progression-free survival (PFS) and overall survival (OS) were compared between the two cohorts. Multivariate Cox regression model was used to determine the independent impact of stage on outcomes.Results: 527 patients with IBC and 2,860 patients with non-IBC were included; the median age at transplantation (47 vs 46 years old) and median follow-up period in the 2 groups (167 vs 168 months) were similar. The most common conditioning regimen was cyclophosphamide and carboplatin based in both groups (54% in IBC and 50% in non-IBC). AHCT was well tolerated in both groups. TRM was similar in both groups (one year TRM was 2% for IBC and 3% for non-IBC, p=0.16). The most common cause of death was disease progression or relapse (81% in IBC and 75% in non-IBC). The median survival for both IBC and non-IBC was the same at 40 months. The PFS at 10 years was 27% (95% CI: 23-31%) for IBC and 24% (95% CI: 22-26%) for non-IBC (p=0.21), and the OS at 10 years was 31% (95% CI: 27-35%) for IBC and 28% (95% CI: 26-30%) for non-IBC (p=0.16). In univariate analysis, patients with stage III IBC and no active diseases at transplantation had lower PFS and OS than that in non-IBC. In multivariate analysis, controlling for age, disease status at AHCT, hormonal receptor status, time from diagnosis to AHCT, and performance status at AHCT, patients with stage III IBC had higher mortality (HR 1.16, 95% CI: 1-1.34, p= 0.0459), worse PFS (HR: 1.17, 95% CI: 1.01-1.36, p= 0.0339) and higher risk of disease relapse/progression (HR: 1.24, 95% CI: 1.06-1.45, p= 0.0082) as compared to stage III non-IBC. Amongst all patients a higher stage disease was associated with worse PFS, OS and disease relapse/progression.Conclusions: Long-term outcomes of stage III IBC patients who underwent AHCT were poorer than that in non-IBC patients confirming that the poor prognosis of IBC even in the setting of HDC with AHCT.

Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences

We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.

Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients

The aim of this project was to review the literature and define clinical practice guidelines for the use of cytokines and growth factor agents for the prevention or treatment of oral mucositis induced by cancer chemotherapy or radiotherapy. A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, No guideline possible. Sixty-four clinical studies across 11 interventions were evaluated. A recommendation was made for the use of recombinant human KGF-1 (palifermin) at a dose of 60 μg/kg per day for 3 days prior to conditioning treatment and for 3 days post-transplant for prevention of oral mucositis in patients receiving high-dose chemotherapy and total body irradiation followed by autologous stem cell transplantation for hematological malignancies. A suggestion was made against using granulocyte macrophage colony-stimulating factor mouthwash for the prevention of oral mucositis in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation. No guideline was possible for any other cytokine or growth factor agents due to inconclusive evidence. Of the cytokine and growth factor agents studied for oral mucositis, the evidence only supports use of palifermin in the specific population listed above. Additional well-designed research is needed on other cytokine and growth factor interventions and in other cancer treatment settings.

Effect of leukapheresis on efficient CTC enrichment for comprehensive molecular characterization and clinical diagnostics.

e21020 Background: Circulating tumor cells (CTCs) are promising biomarkers for diagnosis and systemic therapy. However, their infrequent detection rates limit currently their clinical use. Here we tested whether leukapheresis could be a suitable method to increase CTC yields and detection rates by increasing dramatically the analyzed blood volume. Methods: We screened 3x106 PBMNCs of 48 historical leukapheresis products harvested from 24 breast cancer patients in the setting of high-dose chemotherapy and from a non-cancer control group (n=10), respectively, with a standard immuno-assay using an anti-cytokeratin antibody (A45/BB3) to detect CTCs. Detected CTCs were isolated, their genomic DNA amplified, and the whole genome screened for chromosomal aberrations using comparative genomic hybridization (CGH) (n=48). To validate the CTC detection frequencies in leukapheresis products, we initiated a prospective pilot-study and performed leukapheresis in 13 cancer patients (breast and pancreatic cancer). 1 mL of the leukapheresis product (total volume: up to 150 ml) was analyzed using the CellSearch® system as well as 7.5 ml peripheral blood taken from the same patients. Results: 44/48 (91.7%) of leukapheresis samples contained CTCs with a median count of 3.0 in 3x106 PBMNC (range: 1-35 CTCs). None of the 10 analyzed healthy controls displayed CTCs. We successfully performed single cell CGH of 48 CTCs from 19 patients revealing aberrant CGH profiles in 56% with gains and losses typical for breast cancer. Interestingly, CTCs with high aberration numbers were associated with early metastatic relapse. The validation study using CellSearch® in 13 cancer patients demonstrated in leukapheresis products significantly higher CTC detection frequencies (13/13 vs. 5/13) and CTC numbers (median: 13, range: 1-51 vs. median 0, range: 0-7; p&lt;0.001) compared to the matched peripheral blood samples. Conclusions: Our results indicated that leukapheresis provides CTC detection rates and yields at unprecedented scale. Thus we believe, that leukapheresis will help to exploit the full clinical potential of CTCs as biomarkers for diagnosis and systemic therapy.

Obstacles to managing chemotherapy-induced nausea and vomiting in high-dose chemotherapy with stem cell transplant

Dear Editor, We have read with great interest the paper by Einhorn et al. [1], entitled “Antiemetic therapy for multiple-day chemotherapy and additional topics consisting of rescue antiemetics and high-dose chemotherapy with stem cell transplant: review and consensus statement,” in particular the “High-dose chemotherapy” section, in which the authors rightly point out the difficulty in defining evidence based guidelines in the setting of high-dose chemotherapy and hemopoietic stem cell transplant (HSCT); in this regard however, we think we can provide a contribution, examining, with some valuable clarification, aspects which we feel may be responsible for the current difficulties of chemotherapy-induced nausea and vomiting (CINV) management in this setting. Variations in ages, gender and diagnosis are certainly barriers to adequate epidemiological analysis and evaluation of therapeutic and prophylactic measures effectiveness, as stated by authors. Conversely, conditioning regimens for the different diseases vary less, when compared to first-line treatments, often being the same for groups of diseases, both in autologous (e.g., BEAM in lymphoma), and perhaps evenmore in allogeneic transplant, where treatment — having mostly myeloablative and immunosuppressive function — is often identical for different disease groups. On the other hand, the predominantly inpatient management of HSCT also facilitates monitoring and assessment of CINV in these patients. Multiple days and often multiple daily doses regimen, commonly used as condition for HSCT, not doubtfully represents the biggest barrier both to categorization of emetogenic risk (lack of evaluation methodologies for emesis from multiple drugs administration) and possibility to deduce a CINV prophylactic guidelines for such a regimens. However, not all condition regimens include multiple days’ administrations. Indeed, one of the most commonly used regimens, MEL200, provides for a single-day administration of high dose melphalan alone, therefore representing as an ideal test-bed for the study of high-dose therapy effects, whose CINV prophylaxis, should be, in our opinion, the encoded three drugs schedule for HEC regimens (aprepitant, dexamethasone and 5-HT3 receptor antagonist) [2]. Stem cell infusion is one of the least studied and reported confounding factors. Actually, nausea and vomiting are reported among the side effects of the cryopreservation mean dimethyl sulfoxide (DMSO), and cytokine release from infused non-viable cells may also potentially induce similar effects [3]. Supportive A. Tendas (*) :A. Bruno : L. Cupelli : P. Niscola : T. Dentamaro : P. de Fabritiis Hematology, S. Eugenio Hospital, Piazzale dell’Umanesimo 10, Rome 00144, Italy e-mail: tendas.andrea@aslrmc.it

Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy

Hematopoietic recovery after high-dose chemotherapy (HDC) in the treatment of hematological diseases may be slow and/or incomplete. This is generally attributed to progressive hematopoietic stem cell failure, although defective hematopoiesis may be in part due to poor stromal function. Chemotherapy is known to damage mature bone marrow stromal cells in vitro, but the extent to which marrow mesenchymal stem cells (MSCs) are damaged by HDC in vivo is largely unknown. To address this question, the phenotype and functional properties of marrow MSCs derived from untreated and chemotherapeutically treated patients with hematological malignancy were compared. This study demonstrates a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens, thus implicating potential disadvantages in the use of autologous MSCs in chemotherapeutically pretreated patients for future therapeutic strategies. The clinical importance of these HDC-induced defects we have observed could be determined through prospective randomized trials of the effects of MSC cotransplantation on hematopoietic recovery in the setting of HDC with and without hematopoietic stem cell rescue.

High-dose chemotherapy and stem cell support in the management of metastatic germ cell cancer: A quantitative review

e16094 Background: To analyze the independent associates of outcome in metastatic germ cell cancer (MGCC) patients treated with high dose chemotherapy (HDC) and stem cell rescue. Methods: Thirty-two published patient cohorts with MGCC (encompassing 2176 patients; 510 patients treated upfront and 1666 at relapse) were identified from PUBMED and Cochrane Registry of Clinical Trials. Weighed Regression Analyses of these trials were conducted to define prognosticators. Results: Correlate of overall survival (OAS) and survival with no evidence of disease (NED) in upfront HDC trials was number of chemotherapeutics in HDC (OAS with 2 agents: 60% vs. 3 or more agents: 72%, p = 0.047, survival with NED with 2 agents: 47% vs. 3 or more agents: 64%, p = 0.009). In trials of HDC at relapse, independent associates of OAS with multivariate analysis were line of chemotherapy index, an indicator of line of chemotherapy utilization (p = 0.004), and median age (≤30: 42%, &gt;30: 49%, p = 0.023), whereas independent correlates of better survival with NED were again number of chemotherapeutics in HDC (2 agents: 54% vs. 3 or more agents: 33%, p = 0.001), and seminoma fraction (seminoma fraction ≤9%: 28% vs. seminoma fraction &gt;9%: 49%, p &lt; 0.001 ). Toxic mortality of HDC regimens employed in these trials ranged between 0% and 17%. Conclusions: HDC can cure patients with MGCC both as initial or salvage therapies. However, this study shows that type and setting of HDC, as well as patient age, and seminoma fraction all appear to be linked with benefit from HDC in MGCC. Future trials should continue to address the usage of tandem HDC cycles with multiagent protocols in high risk patients with MGCC. No significant financial relationships to disclose.

Comparison of lenograstim and filgrastim: effects on blood cell recovery after high-dose chemotherapy and autologous peripheral blood stem cell transplantation

The aim of the study was to evaluate whether glycosylated granulocyte colony-stimulating factor (G-CSF) (lenograstim) offers a benefit over non-glycosylated G-CSF (filgrastim) in clinically relevant end points after high-dose chemotherapy (HDC) and autologous peripheral blood stem cell transplantation (PBSCT). We retrospectively analyzed the outcome of 261 patients treated with either lenograstim (n=68) or filgrastim (n=193). Time to blood cell recovery, toxicities, and infectious complications were analyzed in a total of 469 G-CSF treatment cycles. Mean time to leukocyte recovery was 10.7 days (SD+/-0.9) (lenograstim) and 10.8 days (SD+/-0.6) (filgrastim), respectively. Likewise, time to thrombocyte engraftment, febrile days, duration of therapeutic antibiotic treatment, severity of non-hematological toxicities, duration of in-hospital stay, and duration of G-CSF treatment were similar in both groups. Owing to the physicochemical and pharmacokinetic properties of lenograstim, the required dose until leukocyte recovery was significantly smaller as compared to filgrastim (38.5 vs 54.0 microg/kg of body weight). Collectively, our data indicate that both G-CSF preparations are equally effective in hastening leukocyte recovery in the setting of high-dose chemotherapy followed by autologous PBSCT.

Impact of obesity in the setting of high-dose chemotherapy.

Obesity is a common and increasing problem affecting the developed world. Chemotherapy pharmacokinetics in the context of obesity demonstrate prolonged elimination time for several agents, but there is no consensus regarding optimal dosing schemes. Retrospective studies suggest differences in toxicity for obese adult patients but these data may be greatly impacted by chemotherapy dose adjustments. Outcome data from several studies have suggested that obese adult patients suffer poorer disease-free survival and overall survival, although this is not a uniform conclusion in all studies. Prospective studies of chemotherapy pharmacokinetics are needed to address the issue of optimal chemotherapy dosing in the obese population.

The potential of amifostine in high-dose chemotherapy and autologous hematopoietic stem cell transplantation.

Amifostine treatment may allow chemotherapy dose increases beyond those permitted by autologous hematopoietic stem cell transplantation. In a recent study in patients with solid tumors receiving a high-dose regimen of etoposide, ifosfamide, and carboplatin plus autologous stem cell transplantation, amifostine pretreatment was associated with significant reductions in time to neutrophil and thrombocyte engraftment, fewer days of neutropenic fever, less need for salvage antibiotic therapy. Also, there were significant reductions in grade 3 or 4 stomatitis/diarrhea, and delayed nausea/vomiting. A phase I/II study in patients with refractory/high-risk malignancies indicated that a 140% increase of high-dose melphalan (up to 280 mg/m2) can be safely used with amifostine and autologous stem cell transplantation with manageable mucosal toxicity and a reduced incidence of regimen-related toxicity. Preliminary findings in another phase II study indicate that melphalan 280 mg/m2 can also be safely used with amifostine/stem cell transplantation in the treatment of patients with myeloma. Additional studies are ongoing or planned to examine the potential hematoprotective and hematostimulating effects of amifostine in the setting of high-dose chemotherapy and autologous stem cell transplantation.

The potential of amifostine in high-dose chemotherapy and autologous hematopoietic stem cell transplantation

Amifostine treatment may allow chemotherapy dose increases beyond those permitted by autologous hematopoietic stem cell transplantation. In a recent study in patients with solid tumors receiving a high-dose regimen of etoposide, ifosfamide, and carboplatin plus autologous stem cell transplantation, amifostine pretreatment was associated with significant reductions in time to neutrophil and thrombocyte engraftment, fewer days of neutropenic fever, less need for salvage antibiotic therapy. Also, there were significant reductions in grade 3 or 4 stomatitis/diarrhea, and delayed nausea/vomiting. A phase I/II study in patients with refractory/high-risk malignancies indicated that a 140% increase of high-dose melphalan (up to 280 mg/m 2) can be safely used with amifostine and autologous stem cell transplantation with manageable mucosal toxicity and a reduced incidence of regimen-related toxicity. Preliminary findings in another phase II study indicate that melphalan 280 mg/m 2 can also be safely used with amifostine/stem cell transplantation in the treatment of patients with myeloma. Additional studies are ongoing or planned to examine the potential hematoprotective and hematostimulating effects of amifostine in the setting of high-dose chemotherapy and autologous stem cell transplantation. Semin Oncol 29 (suppl 19):53-56. Copyright 2002, Elsevier Science (USA). All rights reserved.

Absence of IL-6 receptor expression in fresh childhood Burkitt's lymphoma cells and induction of IL-6 receptors by Epstein-Barr virus in vitro.

Interleukin-6 (IL-6) is a cytokine which is necessary for the differentiation of activated B cells and growth of early haemopoietic progenitors. It is used for ex-vivo expansion of myeloid progenitors in the setting of high-dose chemotherapy with autologous bone marrow transplantation (BMT). Expression of the IL-6 receptor (IL-6R) was examined in six fresh Burkitt's lymphoma (BL) cell preparations and 12 BL cell lines by reverse transcriptase polymerase chain reaction (RT-PCR) and flow cytometry (FCM). Inducibility of IL-6R mRNA expression by Epstein-Barr virus (EBV) was studied by comparing two uninfected cell lines with the same cell lines infected by EBV The phenotype of the BL cells lines was analysed by FCM and by proliferation assays in the presence of anti-IgM antibodies. None of the fresh BL cells expressed the IL-6 receptor. The BL cell lines expressed varying degrees of IL-6R mRNA and protein. In vitro infection of EBV-negative BL cell lines resulted in up-regulation of IL-6R mRNA. There was no proliferative response of the BL cell lines to IL-6, including the cells that expressed the receptor. Compared to uninfected BL cell lines, EBV-infected cell lines and lymphoblastoid cell lines (LCLs) showed a weaker or no response to anti-IgM antibodies, indicating a more mature phenotype of these cells. We conclude that the IL-6 receptor is not expressed in fresh childhood BLs, but only in BL cell lines. EBV infection in vitro leads to an up-regulation of IL-6R mRNA but not to increased proliferation. This makes growth stimulation of contaminating BL cells in the setting of autologous BMT unlikely.

Characterization of the cytochrome P450 involved in side-chain oxidation of cyclophosphamide in humans.

Cyclophosphamide (CP) is an antineoplastic prodrug which requires bioactivation (4-hydroxylation) by the cytochrome P450 (CYP) enzymes in human liver. In parallel, P450-mediated side-chain oxidation (N-dealkylation) leads to the formation of the non-alkylating dechloroethylcyclophosphamide (DCI-CP) and chloroacetaldehyde, the latter being a potential neurotoxic agent. The enzyme responsible for side-chain oxidation has not been identified yet. We therefore used an in vitro approach to characterize the enzyme involved in N-dealkylation of CP. CP was incubated with the microsomal fraction of human liver in the presence of specific inhibitors for some P450 enzymes and in the presence of stable expressed P450 enzymes. Dechloroethylcyclophosphamide was analysed using gas chromatography and nitrogen-phosphorus detection. Formation of DCl-CP increased linearly with substrate concentration over the entire concentration range (20 mumol.l-1 to 36 mmol.l-1). Saturation of the enzyme was not observed. Incubation with stable expressed P450 enzymes and inhibition experiments indicated that CYP3A4 was the major enzyme involved in side-chain oxidation of CP. Our in vitro data indicate that side-chain oxidation of CP occurs in dose-dependent fashion in men with no saturation of this pathway even following dose escalation. Thus enhanced neurotoxicity following CP administration may result in the setting of high-dose chemotherapy. Moreover, we conclude that CP has the potential to interact with other CYP 3A4 substrates.