Clinical implications, safety, efficacy of Recombinant Human Granulocyte Colony-Stimulating Factors and Pegylated Equivalent

A wide use of recombinant human granulocyte colony-stimulating factors (G-CSFs) and their pegylated equivalent is a significant step forward in the treatment of both solid tumors and hematological malignancies. Evidence-based use of these molecules resulted in more intensive treatments, safely extended to frail and elderly patients, and development of response- and comorbidity-tailored approaches. The available G-CSFs are filgrastim, and the long-acting PegFilgrastim, which are produced in E. Coli cells, and are chemically different from native human G-CSF, and lenograstim, a molecule produced in mammalian cells, with a chemical structure identical to native human G-CSF. These chemical differences produce a diverse interaction with receptors and stimulated neutrophils. For instance, lenograstim binds to receptors in the same way of endogenous ligand, and neutrophils obtained from stimulation with this G-CSF have a physiological activity profile similar to neutrophils normally generated in humans. Conversely, the different interaction between filgrastim and G-CSF receptor is more frequently associated with morphological abnormalities, reduced motility and chemotaxis and a reduced response to bacterial stimuli in induced neutrophils. On this background, we reviewed available evidence in order to analyze the impact of these chemical and pharmacodynamic differences among G-CSF molecules on safety, particularly in healthy peripheral-blood stem-cells donors, functional qualities of inducted neutrophils, and mobilization of hematopoietic stem cells.&nbsp

Bendamustine in combination with gemcitabine and vinorelbine is an effective regimen as induction chemotherapy before autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma: Final results of a multicenter phase II study

Purpose: This multicenter, open-label, phase II study evaluated the combination of bendamustine, gemcitabine, and vinorelbine (BeGEV) as induction therapy before autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory Hodgkin lymphoma (HL). Patients and Methods: Patients with HL who were refractory to or had relapsed after one previous chemotherapy line were eligible. The primary end point was complete response (CR) rate after four cycles of therapy. Secondary end points were: overall response rate, stem-cell mobilization activity, and toxicity. Progression-free and overall survival were also evaluated. Results: In total, 59 patients were enrolled. After four cycles of therapy, 43 patients (73%) achieved CR, and six (10%) achieved partial response, for an overall response rate of 83%. The most common grade 3 to 4 nonhematologic toxicities included febrile neutropenia (n = 7) and infection (n = 4). Regarding hematologic toxicities, grade 3 to 4 thrombocytopenia and neutropenia were each experienced by eight patients (13.5%). CD34+ cells were successfully harvested in 55 of 57 evaluable patients, and 43 of 49 responding patients underwent ASCT. With a median follow-up of 29 months, the 2-year progression-free and overall survival rates for the total population were 62.2% and 77.6%, respectively. The same figures for patients undergoing autograft were 80.8% and 89.3%, respectively. Conclusion: This phase II study demonstrates that BeGEV is an effective salvage regimen able to induce CR in a high proportion of patients with relapsed or refractory HL before ASCT. These data provide a strong rationale for further development of the BeGEV regimen

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the FIL MCL0208 trial

In the FIL MCL0208 phase III trial, lenalidomide maintenance (LEN) after transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell surface receptors might predict drug efficacy. Genotypes were obtained by real-time polymerase chain reaction (RT-PCR) in peripheral blood (PB) germ line DNA. Polymorphisms of either ABCB1 or VEGF were found in 69% and 79% of 278 patients and predicted favorable PFS vs homozygous wild type (WT) in the LEN arm: 3-year PFS 85% vs 70% (p < 0.05) and 85% vs 60% (p < 0.01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (OS, 76%): in fact, in these patients LEN did not improve PFS vs OBS (3-year PFS 44% vs 60%, p = 0.62). Moreover, CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, while ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL. This trial is registered at eudract.ema.europa.eu as 2009-012807-25

Italian real life experience with ibrutinib: Results of a large observational study on 77 relapsed/refractory mantle cell lymphoma

Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventyseven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world

A Fondazione Italiana Linfomi cohort study of R-COMP vs R-CHOP in older patients with diffuse large B-cell lymphoma

: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the most commonly used regimen for the upfront treatment of diffuse large B-cell lymphoma (DLBCL). However, it is associated with cardiotoxicity, especially in older patients. Substituting doxorubicin with non-PEGylated liposomal doxorubicin (R-COMP) may reduce the risk of cardiac events, but its efficacy has never been demonstrated in prospective trials. We describe the characteristics and outcome of patients with DLBCL aged ≥65 years prospectively enrolled in the Elderly Project by the Fondazione Italiana Linfomi and treated with full doses of R-CHOP or R-COMP per local practice. Starting from 1163 patients, 383 (55%) were treated with R-CHOP and 308 (45%) with R-COMP. Patients treated with R-COMP were older (median age, 76 vs 71 years), less frequently fit at simplified geriatric assessment (61% vs 88%;&nbsp;P&nbsp;&lt; .001), and had a more frequent baseline cardiac disorders (grade &gt;1, 32% vs 8%;&nbsp;P&nbsp;&lt; .001). Three-year progression-free survival (PFS) was similar between R-CHOP and R-COMP (70% and 64%); 3-year overall survival was 77%, and 71% respectively. R-CHOP was associated with better PFS vs R-COMP only in the Elderly Prognostic Index (EPI) low-risk group. The two groups had similar rates of treatment interruptions due to toxicities or of cardiac events (P&nbsp;= 1.00). We suggest R-COMP is a potentially curative treatment for older patients with intermediate- or high-risk EPI, even in the presence of a baseline cardiopathy. R-CHOP is confirmed as the standard therapy for low risk patients

MYC Rearranged Aggressive B-Cell Lymphomas: A Report on 100 Patients of the Fondazione Italiana Linfomi (FIL)

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Comparison between skeletal muscle and adipose tissue measurements with high-dose CT and low-dose attenuation correction CT of 18F-FDG PET/CT in elderly Hodgkin lymphoma patients: a two-centre validation

OBJECTIVES: High-dose CT (HDCT) is considered the gold-standard imaging for the measurements of skeletal muscle area (SMA), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and intramuscular adipose tissue (IMAT) areas in the abdomen. These parameters may reflect sarcopenia, which can have a prognostic impact in several oncological diseases. The aim of this study was to compare the agreement of measurements of SMA, VAT, SAT and IMAT areas between HDCT and low-dose CT (LDCT) of 18-fludeoxyglucose positron emission tomography ((18)F-FDG PET)/CT in elderly patients affected by Hodgkin lymphoma (HL). METHODS: We retrospectively included 90 patients affected by HL who underwent baseline (18)F-FDG-PET/CT and HDCT within a mean interval of 7 days. HDCT and LDCT images were analysed by two blinded observers using segmentation software (Slice-O-Matic, Tomovision) to quantify the areas. HDCT and LDCT measurements were compared using Bland–Altman plots and Passing-Bablock regression analyses. Pearson correlation coefficient (r) was used to correlate measurements from the two imaging modalities. RESULTS: Comparison of HDCT and LDCT data demonstrated a strong correlation for measurement of VAT(r = 0.942, p < 0.0001), SAT (r = 0.894, p < 0.0001) and SMA (r = 0.934, p < 0.0001). Instead considering IMAT, correlation was good but less significant (r = 0.742). The mean difference between the two methods was found to be very small, with a difference of 1% for SAT,+6.1% for VAT,+2.5% for SMA and −1.9% for IMAT. CONCLUSION: LDCT of PET/CT is a safe, accurate and precise method for the measurements of skeletal muscle area, visceral and subcutaneous adipose tissue. Their measurements are reproducible and correlate closely with HDCT. ADVANCES IN KNOWLEDGE: LLDCT of PET/CT is a safe and accurate method for the measurements of SMA, VAT and SAT; their measurements are closely correlated with HDCT. LDCT can be considered an accurate alternative tool for measuring abdominal fat and muscles in the clinical practice