Safety and efficacy of switching from branded to generic imatinib in chronic phase chronic myeloid leukemia patients treated in Italy

The use of generic drugs after patent expiration of their originators is a relative novelty in the treatment of chronic cancer patients in Western countries. In this observational study we analyzed a cohort of 294 Italian chronic phase chronic myeloid leukemia patients treated frontline with branded imatinib (Glivec\uae) for at least 6 months and then uniformly switched to generic imatinib upon requirement of health authorities in early 2017. Median age at diagnosis was 57 years (range 19-87). Sokal risk was low/intermediate/high in 55%, 32% and 8% of cases, respectively. Median duration of branded imatinib treatment was 7.4 years (range 0.5-16.7). At a median follow-up of 7.5 months after switch to generic imatinib, 17% of patients reported new or worsening side effects, but grade 3-4 non-hematological adverse events were rare. Six patients switched back to branded imatinib, with improvement in the side effect profile, and 4 pts moved to bosutinib or nilotinib for resistance/intolerance. The majority of patients were in major (26%) or deep molecular response (66%) at the time of switch. Molecular responses remained stable, improved or worsened in 61%, 25% and 14% of patients, respectively. We conclude that switch to generic imatinib for patients who have been receiving branded imatinib appears to be effective and safe. Molecular responses may continue to improve over time. Some patients experienced new or worsened side effects but less than 5% of the whole cohort needed to switch back to branded imatinib or move to other treatments. Savings were around 3 million Euros

The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study.

Though most follicular lymphoma biomarkers rely on tumor features, the host genetic background may also be relevant for outcome. Here we aimed at verifying the contribution of candidate polymorphisms of FC\u3b3 receptor, DNA repair and detoxification genes to prognostic stratification of follicular lymphoma treated with immunochemotherapy. The study was based on 428 patients enrolled in the FOLL05 prospective trial that compared three standard-of-care regimens (rituximab-cyclophosphamide-vincristine-prednisone versus rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone versus rituximab-fludarabine-mitoxantrone) for the first line therapy of advanced follicular lymphoma. Polymorphisms were genotyped on peripheral blood DNA samples. The primary endpoint was time to treatment failure. Polymorphisms of FCGR2A and FCGR3A, which have been suggested to influence the activity of rituximab as a single agent, did not affect time to treatment failure in the pooled analysis of the three FOLL05 treatment arms that combined rituximab with chemotherapy (P=0.742, P=0.252, respectively). These results were consistent even when the analysis was conducted by intention to treat, indicating that different chemotherapy regimens and loads did not interact differentially with the FCGR2A and FCGR3A genotypes. The genotype of MLH1, which regulates the genotoxic effect of doxorubicin, significantly affected time to treatment failure in patients in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone arm (P=0.001; q<0.1), but not in arms in which patients did not receive doxorubicin (i.e., the rituximab-cyclophosphamide-vincristine-prednisone and rituximab-fludarabine-mitoxantrone arms). The impact of MLH1 on time to treatment failure was independent after adjusting for the Follicular Lymphoma International Prognostic Index and other potential confounding variables by multivariate analysis. These data indicate that MLH1 genotype is a predictor of failure to benefit from rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone treatment in advanced follicular lymphoma and confirm that FCGR2A and FCGR3A polymorphisms have no impact when follicular lymphoma is treated with rituximab plus chemotherapy (clinicaltrials.gov identifier: NCT00774826)

Relationship between cytogenetic anomalies and biomarkers in Binet stage A patients with Chronic Lymphocytic Leukemia at diagnosis : preliminary results of a prospective, multicenter O-CLL1 GISL study

Background Renal impairment is a common complication of multiple myeloma. Cystatin-C is considered an accurate marker of glomerular filtration rate in several renal disorders. Microarray analysis has revealed that cystatin-C is one of the most highly up-regulated genes in multiple myeloma. The aim of this study was to evaluate the serum levels of cystatin-C in myeloma patients, explore possible correlations with clinical data, including survival, and assess the effect of bortezomib on cystatin-C in relapsed multiple myeloma. Results We measured serum cystatin-C in 157 newly diagnosed, previously untreated myeloma patients, in 28 patients with relapsed disease pre- and post-bortezomib therapy and in 52 healthy controls, using a latex particle-enhanced nephelometric immunoassay. Results In newly diagnosed patients, cystatin-C was elevated and showed strong correlations with advanced ISS stage, extensive bone disease, high ffc-microglobulin, high serum creatinine, and low creatinine clearance. Multivariate analysis revealed that only cystatin-C and lactate dehydrogenase had an independent prognostic impact on patients' survival. The combination of cystatin-C and lactate dehydrogenase revealed three prognostic groups of patients: a high-risk group (both elevated cystatin-C and lactate dehydrogenase) with a median survival of 24 months, an intermediate-risk group (elevated cystatin-C or elevated lactate dehydrogenase) with a median survival of 48 months and a low-risk group (both low cystatin-C and lactate dehydrogenase) in which median survival has not yet been reached (p<0.001). Cystatin-C could also identify a subset of ISS-II patients with worse outcome. Relapsed patients had higher cystatin-C levels even compared to newly diagnosed patients. Treatment with bortezomib produced a significant reduction of cystatin- C, mainly in responders. Conclusions Serum cystatin-C is not only a sensitive marker of renal impairment but also reflects tumor burden and is of prognostic value in myeloma. Its reduction after treatment with bortezomib reflects bortezomib's anti-myeloma activity and possibly bortezomib's direct effect on renal function

Long-Term results of the FOLL05 trial comparing R-CVP Versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma

Purpose The FOLL05 trial compared R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-FM (rituximab plus fludarabine and mitoxantrone) regimens without rituximab maintenance as initial therapy for patients with advanced-stage follicular lymphoma (FL). A previous analysis with a median follow-up of 34 months showed a superior 3-year time to treatment failure, the primary study end point, with R-CHOP and R-FM versus R-CVP and showed R-CHOP to have a better risk-benefit ratio in terms of toxicity than R-FM. We report a post hoc analysis of this trial after a median follow-up of 7 years. Patients and Methods Of the 534 enrolled patients, 504 were evaluable. At the time of analysis, the median follow-up was 84 months (range, 1 to 119 months). Results The 8-year time to treatment failure and progression-free survival rates were 44% (95% CI, 39% to 49%) and 48% (95% CI, 43% to 53%), respectively. The hazard ratio for progression-free survival adjusted by FL International Prognostic Index 2 versus R-CVP was 0.73 for R-CHOP (95% CI, 0.54 to 0.98; P = .037) and 0.67 for R-FM (95% CI, 0.50 to 0.91; P = .009). The 8-year overall survival (OS) rate was 83% (95% CI, 79% to 87%), with no significant differences among study arms. Overall, we observed a higher risk of dying as a result of causes unrelated to lymphoma progression with R-FM versus R-CVP. Conclusion With an 83% 8-year OS rate, long-Term follow-up of the FOLL05 trial confirms the favorable outcome of patients with advanced-stage FL treated with immunochemotherapy. The three study arms had similar OS but different activity and toxicity profiles. Patients initially treated with R-CVP had a higher risk of lymphoma progression compared with those receiving R-CHOP, as well as a higher risk of requiring additional therapy

RELATIONSHIP BETWEEN CYTOGENETIC ANOMALIES AND BIOMARKERS IN BINET STAGE A PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AT DIAGNOSIS: PRELIMINARY RESULTS OF A PROSPECTIVE, MULTICENTER O-CLL1 GISL STUDY

Background. The clinical heterogeneity of chronic lymphocytic leukemia (CLL) requires parameters to stratify patients into prognostic subgroups to adapt treatment ranging from ‘watch and wait’ to allogeneic stem cell transplantation. Different parameters such as lymphocyte doubling time, b-2 microglobulin, CD38 and ZAP-70 expression, immunoglobulin variable heavy chain (IgVH) mutation status and genetic abnormalities have been integrated in clinical practice. By using fluorescence in situ hybridization (FISH), cytogenetic abnormalities can be found in approximately 80% of patients. Aims. In the present study, we performed FISH analysis to detect the major cytogenetic alterations in a series of patients in Binet stage A included in the prospective multicenter O-CLL1 GISL study started in April 2007. Methods. Molecular markers characterization and FISH analyses were previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. GCC, 2008). Results. Up to date, 275 patients have been enrolled in the trial and FISH data concerning trisomy 12 and 13q14, 17p13, 11q23 deletions were available in 192 patients. At least one abnormality was found in 131/192 (68.2%) patients. The most frequent abnormality was del(13)(q14) (100/192, 52%), followed by trisomy 12 (25/192, 13%) (in one case accompanied by 17p13 deletion), del(17)(p13) (6/192, 3%) and del(11)(q22.3) (10/192, 5%). 13q14 deletion was found as a sole abnormalities in 90 patients; in the remaining cases, it was combined with del(17)(p13) (3 pts), trisomy 12 (1 pts) and del(11q)(22.3) (6 pts). Among patients with 13q14 deletions, 71 were monoallelic, 7/100 biallelic, whereas 22 showed combined biallelic and monoallelic deletion patterns. We also analyzed the relationship between each single abnormality and CD38 and ZAP-70 expression, and IgVH mutational status. In particular, the CD38 percentages were 8.4±1.8 (mean value±SD), 19.5±2.8, 45.1±7.1, 30.3±8.4, 52.9±9.9 for del(13)(q14), normal, trisomy 12, del(11)(q22) and del(17)(p13) FISH alterations (p<0.0001), respectively. The percentages of IgVH mutations significantly (p<0.0001) correlated with cytogenetic alterations; namely, 5.3±0.4 for cases with del(13q14), 4.6±0.6 in normal, 1.8±0.6 in trisomy 12, 0.2±0.1 in del(11)(q22) and 1.6±1.7 in the 4 cases with del(17p13). Similarly, a significantly (p=0.0005) lower mean value of ZAP-70 expression was accounted in del(13q14) (29.7±2.3) as compared with normal cases (34.6±3.2), trisomy 12 (43.8±5.4), del(11)(q22) (55.9±9.7) and del(17)(p13) (54.8±11.8). Based on a scoring system in which 1 point was assigned to each unfavorable biomarker (i.e. CD38, ZAP-70 or IgVH mutational status) we stratified our series in three different groups from 0 to 3 according to the absence or presence of one, two or all three biomarkers. Similarly, cytogenetic abnormalities were clustered in 3 risk groups [i.e. low del(13)(q14) and normal; intermediate (trisomy 12); and high risk del(11)(q22) and del(17)(p13)] as suggested by others. Interestingly, 72/77 cases scoring 0 for the biomarkers, gathered in the low FISH group. Conversely, out of the 13 cases with high FISH risk, 10 cluster in scoring 2-3. Conclusions. Our preliminary results indicate that in Binet stage A CLL patients at diagnosis cytogenetic abnormalities with an expected negative clinical impact are relatively few (16/192, 8%) but significantly associated with prognostic biomarkers which negatively predict the clinical outcome in CLL