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Key points Age per se does not influence outcome in CLL patients on ibrutinib, whereas CIRS score is predictive of treatment management, PFS, and EFS.ECOG-PS and neutropenia resulted as the only baseline parameters affecting overall survival., Visual Abstract, Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS > 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients’ vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

Background. Pegfilgrastim is a polyethylene glycol (PEG)-conjugated form of G-CSF in which filgrastim is bound covalently to a 20kDa PEG molecule; this formulation increases serum half-life of G-CSF due to decreased renal elimination. Following the subcutaneous injection of a 6 mg single dose of pegfilgrastim, serum levels of G-CSF are maintained over a period of 2 weeks. In patients with lymphoma, pegfilgrastim is as effective as filgrastim in shortening the time of neutropenia after cytotoxic chemotherapy; however, the ability of pegfilgrastim to mobilize stem cells after chemotherapy is poorly understood and the optimal mobilization strategy remains controversial. Aims. We evaluate the efficacy of a single fixed 6 mg dose of pegfilgrastim after salvage therapy with cisplatin-containing chemotherapy regimens in mobilizing peripheral blood stem cells in aggressive lymphoma patients. Moreover the possibility of a sufficient collection of CD34+ PBSC (cell dose > 2,5 x106/Kg) in a single procedure was tested. Methods. Between July 2004 and July 2005 twenty two pretreated patients with aggressive lymphoma (8 Hodgkin’s lymphoma, 11 diffuse large B cell lymphoma, 3 anaplastic lymphoma) received salvage chemotherapy with cisplatin-based regimens: (R)-DHAP, dexametasone, cisplatin, cytarabine, or (R)-IPAD idarubicin, dexametasone, cisplatin, cytarabine, with or without Rituximab. A 6 mg single dose of pegfilgrastim was given from day +1 or +2 after chemotherapy completion. Duration of grade 4 neutropenia, adverse events, time to neutrophil and CD34+ cell recovery were recorded. Stem cell collection was started when the absolute number of CD34+ was not less than 20/μL. Leukapheresis was daily performed until the minimum target cell dose of 2.5 x 10 6 CD34+ cells /kg was reached. Results. Following the administration of either (R)-DHAP or (R)-IPAD regimens, 21/ 22 pts (95%) were able to harvest a median of 14,2 x 10 6/Kg CD34+ cell (range 2,4– 45,8), after a median of 9 days from stimulation (range 8–12). A single apheresis procedure was sufficient to obtain a median of 14,8 x 10 6/kg CD34+ cell (range 5,2–45,8) in 18/21 pts (86%) Grade 4 neutropenia was present in all pts with a median duration of 3 days (range 1–7). Pegfilgrastim determined mild bone pain as only adverse event. Seven patients underwent autologous bone marrow transplantation and all of them showed a rapid and sustained engraftment after high-dose chemotherapy. Conclusions. In aggressive lymphoma patients a single dose of pegfilgrastim following chemotherapy completion was safe and highly effective in enhancing the mobilization of CD34+ PBSC. Stem cell collection was performed in a single procedure in most of patients (86%) obtaining a stem cell harvest of a median of 14,8 x 106/Kg CD34+ cells. In 7 autologous bone marrow transplanted patients these results determined early engraftment and sustained hematological reconstitution.