Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

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.

Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib.

Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections-PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments-identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.

Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study.

We performed an observational study on the efficacy of ben-damustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion.

CD200 included in a 4-marker modified Matutes score provides optimal sensitivity and specificity for the diagnosis of chronic lymphocytic leukaemia.

CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin superfamily, has been shown to have a differential expression in B-cell neoplasms. Here, we retrospectively assessed the diagnostic relevance of CD200 on 427 patients with B-cell chronic neoplasms in leukemic phase (median age, 69 y; range, 35-97 y). The final diagnosis based on the investigator's assessment was chronic lymphocytic leukaemia (CLL) in 75% of cases and non-CLL in 25% of cases. Sensitivity and specificity for the diagnosis of CLL (vs non-CLL) were calculated for the following markers: CD200, CD5, CD22, CD23, CD79b, FMC7, and SmIg. CD23 was the only marker without a statistically significant difference between the investigator assessment and the flowcytometric analysis. The other markers were unable-when individually evaluated-to discriminate between CLL and non-CLL, requiring the integration into a scoring system. The modified score no. 1 (addition of CD200) showed superimposable sensitivity and specificity compared with the Matutes score. The substitution of CD79b (modified score no. 2), surface membrane immunoglobulins (SmIg) (modified score no. 3), and CD79b and FMC7 (modified score no. 4) with CD200 showed that only the modified score no. 4 had both higher sensitivity and higher specificity compared with standard Matutes score. In conclusion, this work defines a simplified score, compared with the classical Matutes score, for the differential diagnosis of chronic B-cell leukaemia-which only requires 4 markers instead of 5 (CD5, CD23, CD200, and SmIg).

Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials.

Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine-rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first-line treatment during the 2008-2014 period. The primary objective of this study was to evaluate the efficacy and safety of BR administered as front-line therapy, outside of controlled clinical trials. Median age was 70 years (range, 43-86 years); 62.4% were males and 35.8% had Binet stage C. Forty-two patients (15.2%) were unfit (cumulative illness rating scale [CIRS] score ≥7), and 140 (50.2%) had creatinine clearance ≤70 ml/min. Fluorescent in situ hybridisation analysis, available for 192 cases, showed that 21 (10.9%) had del11q and 18 (9.4%) del17p. The overall response rate (ORR) was 86.4%, with a complete remission rate of 28%. Patients with del17p had an ORR of 66.7%. After median follow-up of 24 months, the 2-year progression-free survival (PFS) was 69.9%; CIRS ≥7, immunoglobulin heavy-chain variable-region (IGHV) unmutated status, del17p and BR dose intensity <80% were independently associated with shorter PFS. Grade III or IV neutropenia, thrombocytopenia, and anaemia were observed in 25.9%, 15.4%, and 15.1% of patients, respectively. Twenty-four patients (8.6%) had severe infections. BR is also an effective and safe regimen for untreated CLL patients, outside of controlled clinical trials.

Bendamustine in combination with rituximab for elderly patients with previously untreated B-cell chronic lymphocytic leukemia: A retrospective analysis of real-life practice in Italian hematology departments.

The front-line therapy for CLL young and fit patients is chemo-immunotherapy with fludarabine-cyclophosphamide-rituximab (FCR). FCR regimen results in a significant myelosuppression and high rates of early and late infections especially in elderly patients. German CLL study group compared FCR vs. bendamustine-rituximab (BR) in fit untreated patients. The response rates with BR or FCR were comparable, BR could be an alternative 1st-line treatment for elderly patients. Here we report retrospective data of 70 elderly (≥65 years) CLL patients from 12 Italian centers treated with BR as front-line therapy. The primary end points were overall response rate (complete remission/partial remission) and safety. Forty-seven males and 23 females, with a median age of 72 years, were included in the study. Eight patients were unfit for CIRS. The OR rate was 88.6% (31.4% CR and 57.2% PR). Progression free survival, treatment free survival and overall survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only del17 was independent unfavorable parameter on the response rate and PFS. Our results indicate that BR front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a bendamustine dose reduction until 70 mg/m2.

Appropriate use of bendamustine in first-line therapy of chronic lymphocytic leukemia. Recommendations from SIE, SIES, GITMO Group.

By using the GRADE system we produced the following recommendations for the use of bendamustine in the first-line treatment of CLL: (1) bendamustine with rituximab is recommended in elderly fit patients potentially eligible to FCR; (2) Bendamustine alone is recommended in patients who are candidate to chlorambucil alone; (3) Rituximab-bendamustine is recommended in patients not eligible to FCR, but suitable to receive rituximab. Consensus-based recommendations addressed evidence-orphan issues concerning the use of bendamustine in genetically-defined high-risk patients and the appropriate dose of bendamustine as single agent or in association with rituximab.

Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients.

In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m(2) /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m(2) ; cycles 4-8, 500 mg/m(2) ). Responders were randomized to 12 8-week doses of R (375 mg/m(2) ) or observation. As per intention-to-treat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; ≥75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients.

Effects on bone metabolism of new therapeutic strategies with standard chemotherapy and biologic drugs.

Recent biological advances have provided the framework for novel therapeutic strategies in oncology. Many new treatments are now based on standard cytotoxic drugs plus biologic agents. In Multiple Myeloma, a plasma cell neoplasm characterized by a severe bone disease, biologic drugs such as proteasome inhibitors and immunomodulatory agents, above their antineoplastic efficacy have a beneficial effects on bone disease. Bortezomib, a clinically available proteasome inhibitor active against myeloma, induces the differentiation of mesenchymal stem/progenitor cells into osteoblasts, resulting in new bone formation. Immunomodulatory drugs (e.g., thalidomide and lenalidomide), which are active against myeloma, also block the activity of bone-resorbing osteoclasts. These data reflect the utility of targeting endogenous mesenchymal stem/progenitor cells for the purpose of tissue repair and suggest that combining different classes of agents that are antineoplastic and also inhibit bone destruction and increase bone formation should be very beneficial for myeloma patients suffering from severe bone disease.

Multiple myeloma.

Multiple myeloma accounts for 10% of all hematologic cancers. Median age at diagnosis is 69 years for men and 72 years for women. The incidence of MM has remained relatively stable, but the associated mortality has declined since the early 1990s. The knowledge acquired about the bone marrow microenvironment in MM and the availability of new drugs has significantly improved patients survival in the past 10 years. Immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib, carfilzomib) can induce apoptosis of myeloma plasma cells and suppress cytokine release and metabolic ways which sustain the disease. These novel agents demonstrate substantial activity either alone or as part of a range of combination regimens. MM therapy is now based on 1 or 2 new drugs plus standard chemotherapy. Induction is patient tailored and first of all it depends on eligibility for stem-cell transplantation and key presenting features of the patients and the disease. Noteworthy, novel agent-based combination therapies may overcome most of poor prognostic factors. Up to 80% of newly diagnosed MM patients present with osteopenia, osteolysis and fractures. Thalidomide, lenalidomide and bortezomib have a beneficial effect on myeloma-related bone disease. Thalidomide reduces bone resorption, lenalidomide and bortezomib inhibit osteoclast growth and survival, and specifically target key factors in osteoclastogenesis, preventing development of osteolytic lesions. Noteworthy, new therapies offer higher complete response rates than previously reported with standard regimens.

An Italian retrospective study on the routine clinical use of low-dose alemtuzumab in relapsed/refractory chronic lymphocytic leukaemia patients.

Low-dose alemtuzumab has shown a favourable toxicity profile coupled with good results in terms of efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). We conducted a multicentre retrospective study on the routine clinical use of low-dose alemtuzumab in this patient setting. One hundred and eight relapsed/refractory CLL patients from 11 Italian centres were included in the analysis. All patients had an Eastern Cooperative Oncology Group performance status ≤2 and the majority (84%) had adenopathies <5 cm. Low-dose alemtuzumab was defined as a total weekly dose ≤45 mg and a cumulative dose ≤600 mg given for up to 18 weeks. The overall response rate was 56% (22% complete remissions). After a median follow-up of 42.2 months, the median overall survival and progression-free survival were 39.0 and 19.4 months, respectively. In univariate analysis, response was inversely associated with lymph node (P = 0.01) and spleen (P = 0.02) size, fludarabine-refractoriness (P = 0.01) and del(11q) (P = 0.009). Advanced age and del(17p) were not associated with a worse outcome. Cumulative dose of alemtuzumab was not associated to response. Toxicities were usually mild and manageable; severe infections occurred in seven patients (7%) during therapy. This retrospective analysis confirms that low-dose alemtuzumab is a valid and currently used therapeutic option for the treatment of relapsed/refractory CLL.

The coexistence of chronic lymphocytic leukemia and myeloproliperative neoplasms: a retrospective multicentric GIMEMA experience.

Although the coexistence of chronic lymphocytic leukemia (CLL) and myeloproliferative neoplasms (MPN) has been sporadically reported in the literature, no systematic studies on this disease association are available. We retrospectively analyzed 46 patients affected by CLL/MPN referred by 15 Italian GIMEMA centers. The aim of this retrospective multicenter study was to define the following: clinico-biological characteristics, possible familiarity, clinical course of both diseases, and influence of MPN chemotherapy on the course of CLL. Among 46 patients, 30 patients were males, 16 patients were females; median age was 71 years. Only one case had familiar CLL. Myeloproliferative disorders consisted of essential thrombocytemia in 18 cases, polycythemia vera in 10 cases, chronic myeloid leukemia in 9 cases, primary myelofibrosis in 6 cases, and MPN/myelodysplastic syndrome in 3 cases. The lymphoproliferative disorder was diagnosed as monoclonal B-cell lymphocytosis in 8 patients and as Binet Stage A CLL in 38 patients. After a median follow-up of 49 months, 9 patients experienced progressive CLL and only 6 patients required treatment after a median of 57.5 months. The biological profile confirmed a subset of low-risk CLL. Twenty patients received chemotherapy for MPN without influence on the course of CLL: lymphocyte counts remained unchanged after 3, 6, and 12 months of treatment. This series is the largest so far reported in literature. The diagnosis of concomitant CLL/MPN is a rare event and lymphoproliferative disorders present a clinical indolent course with a low-risk biological profile. MPN therapy does not interfere with the prognosis of patients with CLL.

Safety and efficacy of bortezomib-based regimens for multiple myeloma patients with renal impairment: a retrospective study of Italian Myeloma Network GIMEMA.

Renal impairment (RI) is a severe complication throughout the course of multiple myeloma (MM). Bortezomib has been shown to be highly active in MM patients with RI. We designed this retrospective analysis to investigate the safety and efficacy of bortezomib-based therapy in 117 MM patients with RI, 14 cases required dialysis. A total of 603 cycles of bortezomib were administered (median number, five cycles/patient). Ten patients required early discontinuation of bortezomib because of WHO grade IV toxicity. The rate of bortezomib discontinuation in cases with severe, moderate and mild RI was 11%, 5% and 0%, respectively (P = NS). Overall, 91 episodes of WHO grade III/IV toxicity were observed. At least a partial response was documented in 83/113 evaluable patients (73%), including complete response (19%) and near complete response (8%). The overall response rate was similar across RI subgroups. Reversal of RI was documented in 41% of patients after a median of 2.3 months (range 0.4-7.9). In three of 14 patients on dialysis, renal replacement therapy was discontinued after 1, 1 and 4 months. The 2-yr estimate of response duration and overall survival was 70% and 51%, respectively. In conclusion, bortezomib-based regimens are safe and effective and should be considered as appropriate treatment options for MM patients with any degree of RI.