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Within the Campus ALL network we analyzed the incidence, characteristics, treatment and outcome of a central nervous system (CNS) relapse in 1035 consecutive adult acute lymphoblastic leukemia (ALL) patients treated frontline with pediatric-inspired protocols between 2009 and 2020. Seventy-one patients (6.8%) experienced a CNS recurrence, more frequently in T- (28/278; 10%) than in B-ALL (43/757; 5.7%) (p = 0.017). An early CNS relapse-12 months from diagnosis-was observed in 41 patients. In multivariate analysis, risk factors for early CNS relapse included T-cell phenotype (p = 0.001), hyperleucocytosis100 × 10

Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including DGKA, DGKD and DGKG, without a precise correlation with specific AML subtypes. In the TGCA database, high DGKA expression negatively correlates with survival, while high DGKG expression is associated with a more favorable prognosis. DGKA and DGKG also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high DGKH expression is correlated with shorter survival. To assess the suitability of DGKs as therapeutic targets, we treated HL-60 and HEL cells with DGK inhibitors and compared cell growth and survival with those of untransformed lymphocytes. We observed a specific sensitivity to R59022 and R59949, two poorly selective inhibitors, which promoted cytotoxicity and cell accumulation in the S phase in both cell lines. Conversely, the DGKA-specific inhibitors CU-3 and AMB639752 showed poor efficacy. These findings underscore the pivotal and isoform-specific involvement of DGKs in AML, offering a promising pathway for the identification of potential therapeutic targets. Notably, the DGKA and DGKH isoforms emerge as relevant players in AML pathogenesis, albeit DGKA inhibition alone seems insufficient to impair AML cell viability.

We compared the efficacy of azacitidine (AZA) and decitabine (DEC) in elderly patients with untreated AML, diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS) and disease free survival (DFS). The AZA and DEC groups included 139 and 186 patients, respectively. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 136 patient pairs. In the AZA and DEC cohort, median age was 75 years in both, (IQR, 71–78 and 71–77), median WBCc at treatment onset 2.5x109/L (IQR, 1.6–5.8 ) and 2.9x 109/L (IQR, 1.5–8.1), median bone marrow (BM) blast count 30% (IQR, 24–41%) and 49% (IQR, 30–67%), 59 (43%) and 63 (46%) patients had a secondary AML, respectively. Karyotype was evaluable in 115 and 120 patients: 80 (59%) and 87 (64%) had intermediate-risk, 35 (26%) and 33 (24%) an adverse risk karyotype, respectively. Median number of cycles delivered was 6 (IQR, 3.0–11.0) and 4 (IQR, 2.0–9.0), CR rate was 24% vs 29%, median OS and 2-year OS rates 11.3 (95% CI 9.5–13.8) vs 12.0 (95% CI 7.1–16.5) months and 20% vs 24%, respectively. No differences in CR and OS were found within the following subgroup: intermediate- and adverse-risk cytogenetic, frequency of WBCc at treatment ≥ 5x10^9L and

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107.

Introduction FLT3 receptor gene has been reported to be mutated in about 30% of AML, with two different kinds of mutations identified: in-frame duplications within the juxtamembrane region (FLT3-ITD) and point mutations in the tyrosine kinase domain (FLT3-TKD). In term of prognosis, the proper role of these mutations is still debated. Moreover, FLT3 mutations are often subjected to clonal evolution, thus how to properly monitor FLT3 mutated clones, evaluate minimal residual disease, manage FLT3 inhibitors (FLT3i) are only some of the open issues. FLAM is an observational study involving FLT3 positive AMLs to gain clinical and molecular data useful to ameliorate real-life physicians' management of this disease. Here we report the results of a preliminary analysis of the retrospective phase of the study. Methods The retrospective phase of FLAM multi-center observational study enrolled each AML patient treated in 33 participating Italian centers detected to carry a FLT3 mutation since 2012. Clinical and molecular data were collected in accordance with GCP and Helsinki declaration in electronic case report forms. Results At data cut-off , 1st of July 2020, 289 patients with FLT3 mutation at diagnosis were enrolled in the retrospective phase of FLAM study, being evaluable in this analysis, with a median age at diagnosis of 62 years (min-max: 18-94) and a M:F ratio of 141/148 (Patients' characteristics are summarized in table 1). 29 out 289 (10 %) patients had a low risk AML, 190/289 (65,7 %) had an intermediate risk AML and 27/289 (9,3 %) patients had a high risk AML, according to ELN 2017 risk stratification or ELN 2010 in case of allelic ratio unavailability (43 patients had no available ELN risk at baseline). A more frequent association between FLT3-ITD and normal karyotype and between FLT3-TKD mutation and other cytogenetic alterations not conferring a favorable/adverse risk has been observed (p = 0.045). Among the study population, 255/289 (88 %) patients carried a FLT3-ITD, 32/289 (11 %) a FLT3-TKD point mutation and 2/289 (1 %) patients both mutations. Capillary electrophoresis has been the technical method used to investigate FLT3-ITD in 163 of 226 (72 %) patients with information on the method used, while Sanger Sequencing in 47 out of 226 (21 %) patients and Next generation sequencing (NGS) in 16 out of 226 (7 %) patients. Overall, NGS has been adopted to investigate FLT3 gene status in 18 out of 259 patients (7 %). FLT3-ITD allelic ratio was available in 62 of 257 (24 %) ITD patients and was greater than or equal to 0.5 in 35/62 (56 %) patients. During patients' follow-up, 19/289 (7 %) patients affected by a FLT3 positive AML at diagnosis underwent a disease clonal evolution with a FLT3 negative AML progression or relapse. Regarding treatment options in FLT3-AML, in our cohort FLT3i were administered as first-line of therapy in only 36/289 (13 %) patients, always in a combination, of which in 26/36 (72.2 %) with intensive chemotherapy. As expected, intensive chemotherapy represented the induction regimen in the majority of the patients (211/289, 73 %). On the other hand, FLT3i were administered as rescue therapy in 62/171 (36 %) cases (47/62 single-agent and in 15/62 in combination) and as re-induction therapy in 22/80 (28 %) cases (10/22 single-agent and 12/22 in combination). Overall, a FLT3i has been administered as single-agent 81 times, of which Gilteritinib was the most frequently used (56/81, 69,1 %), followed by quizartinib (18/81, 22,2 %). Among the 52 documented combinations of a FLT3i with other drugs, particularly noteworthy is the administration of Sorafenib, in 20/52 (39 %) cases in this real-life study. Lastly, nine out of 289 (3 %) patients received a FLT3i as maintenance therapy after HSCT. Data regarding the correlation among the different regimens, with a special focus on FLT3i, other molecular features and response/survival are currently under analysis. Conclusions These data coming from a preliminary analysis portray the state of a large multi-center retrospective cohort of FLT3-positive AML patients treated in Italy between 2012 and 2020, including interesting insights regarding technical methods used to characterize the disease and the therapeutic scenario in which FLT3 inhibitors have been developed. Further safety and effectiveness data may reveal beneficial to ameliorate physicians' real-life clinical practice. Acknowledgements: work supported by Daiichi-Sankyo. Disclosures Martelli: Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Rigolin:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fracchiolla:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau. Bocchia:Incyte: Honoraria; CELGENE: Honoraria. Todisco:Jannsen, Abbvie, Jazz: Membership on an entity's Board of Directors or advisory committees. Papayannidis:Abbvie, Janssen, Novartis, Amgen, Pfizer: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. OffLabel Disclosure: Sorafenib is a registered drug for the treatment of hepatocellular carcinoma. Due to its multi-targeted tirosine kinase inhibitor effect it demonstrated efficacy in FLT3-AML when administered as an off-label prescription.

Introduction FLT3 receptor gene has been reported to be mutated in about 30% of AML, with two different kinds of mutations identified: in-frame duplications within the juxtamembrane region (FLT3-ITD) and point mutations in the tyrosine kinase domain (FLT3-TKD). In term of prognosis, the proper role of these mutations is still debated. Moreover, FLT3 mutations are often subjected to clonal evolution, thus how to properly monitor FLT3 mutated clones, evaluate minimal residual disease, manage FLT3 inhibitors (FLT3i) are only some of the open issues. FLAM is an observational study involving FLT3 positive AMLs to gain clinical and molecular data useful to ameliorate real-life physicians' management of this disease. Here we report the results of a preliminary analysis of the retrospective phase of the study. Methods The retrospective phase of FLAM multi-center observational study enrolled each AML patient treated in 33 participating Italian centers detected to carry a FLT3 mutation since 2012. Clinical and molecular data were collected in accordance with GCP and Helsinki declaration in electronic case report forms. Results At data cut-off , 1st of July 2020, 289 patients with FLT3 mutation at diagnosis were enrolled in the retrospective phase of FLAM study, being evaluable in this analysis, with a median age at diagnosis of 62 years (min-max: 18-94) and a M:F ratio of 141/148 (Patients' characteristics are summarized in table 1). 29 out 289 (10 %) patients had a low risk AML, 190/289 (65,7 %) had an intermediate risk AML and 27/289 (9,3 %) patients had a high risk AML, according to ELN 2017 risk stratification or ELN 2010 in case of allelic ratio unavailability (43 patients had no available ELN risk at baseline). A more frequent association between FLT3-ITD and normal karyotype and between FLT3-TKD mutation and other cytogenetic alterations not conferring a favorable/adverse risk has been observed (p = 0.045). Among the study population, 255/289 (88 %) patients carried a FLT3-ITD, 32/289 (11 %) a FLT3-TKD point mutation and 2/289 (1 %) patients both mutations. Capillary electrophoresis has been the technical method used to investigate FLT3-ITD in 163 of 226 (72 %) patients with information on the method used, while Sanger Sequencing in 47 out of 226 (21 %) patients and Next generation sequencing (NGS) in 16 out of 226 (7 %) patients. Overall, NGS has been adopted to investigate FLT3 gene status in 18 out of 259 patients (7 %). FLT3-ITD allelic ratio was available in 62 of 257 (24 %) ITD patients and was greater than or equal to 0.5 in 35/62 (56 %) patients. During patients' follow-up, 19/289 (7 %) patients affected by a FLT3 positive AML at diagnosis underwent a disease clonal evolution with a FLT3 negative AML progression or relapse. Regarding treatment options in FLT3-AML, in our cohort FLT3i were administered as first-line of therapy in only 36/289 (13 %) patients, always in a combination, of which in 26/36 (72.2 %) with intensive chemotherapy. As expected, intensive chemotherapy represented the induction regimen in the majority of the patients (211/289, 73 %). On the other hand, FLT3i were administered as rescue therapy in 62/171 (36 %) cases (47/62 single-agent and in 15/62 in combination) and as re-induction therapy in 22/80 (28 %) cases (10/22 single-agent and 12/22 in combination). Overall, a FLT3i has been administered as single-agent 81 times, of which Gilteritinib was the most frequently used (56/81, 69,1 %), followed by quizartinib (18/81, 22,2 %). Among the 52 documented combinations of a FLT3i with other drugs, particularly noteworthy is the administration of Sorafenib, in 20/52 (39 %) cases in this real-life study. Lastly, nine out of 289 (3 %) patients received a FLT3i as maintenance therapy after HSCT. Data regarding the correlation among the different regimens, with a special focus on FLT3i, other molecular features and response/survival are currently under analysis. Conclusions These data coming from a preliminary analysis portray the state of a large multi-center retrospective cohort of FLT3-positive AML patients treated in Italy between 2012 and 2020, including interesting insights regarding technical methods used to characterize the disease and the therapeutic scenario in which FLT3 inhibitors have been developed. Further safety and effectiveness data may reveal beneficial to ameliorate physicians' real-life clinical practice. Acknowledgements: work supported by Daiichi-Sankyo. Download : Download high-res image (459KB) Download : Download full-size image Disclosures Martelli: Amgen: Membership on an entity’s Board of Directors or advisory committees; AbbVie: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Rigolin: Abbvie: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fracchiolla: Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; ABBVIE: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau. Bocchia: Incyte: Honoraria; CELGENE: Honoraria. Todisco: Jannsen, Abbvie, Jazz: Membership on an entity’s Board of Directors or advisory committees. Papayannidis: Abbvie, Janssen, Novartis, Amgen, Pfizer: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. OffLabel Disclosure: Sorafenib is a registered drug for the treatment of hepatocellular carcinoma. Due to its multi-targeted tirosine kinase inhibitor effect it demonstrated efficacy in FLT3-AML when administered as an off-label prescription.

Philadelphia chromosome (Ph)-like (or BCR/ABL1-like) acute lymphoblastic leukemia (ALL) is a subtype of B-cell precursor acute lymphoblastic leukemia (B-ALL) with a transcriptional profile that res...

Background Outcomes in patients with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission ...

Background: Acute myeloid leukemia is a heterogeneous hematological disease, characterized by karyotypic and molecular alterations. Mutations in IDH2 have a role in diagnosis and as a minimal residue disease marker. Often the variant allele frequency during follow up is less than 20%, which represents the limit of detection of Sanger sequencing. Therefore, the development of sensitive methodologies to identify IDH2 mutations might help to monitor patients&rsquo, response to therapy. We compared three different methods to identify and monitor IDH2 mutations in patients&rsquo, specimens. Methods: Performances of PNA-PCR clamping, droplet digital PCR and Sanger for IDH2 status identification were evaluated and compared in 96 DNA patients&rsquo, specimens. Results: In contrast with Sanger sequencing, our results highlighted the concordance between PNA clamping and digital PCR. Furthermore, PNA-PCR clamping was able to detect more mutated DNA with respect to Sanger sequencing that showed several false negatives independently from the allelic frequency. Conclusions: We found that PNA-PCR clamping and digital PCR identified IDH2 mutations in DNA samples with comparable results in a percentage significantly higher compared to Sanger sequencing. PNA-PCR clamping can be used even in laboratories not equipped for sophisticated analyses, decreasing cost and time for IDH2 characterization.

Background. Ponatinib is a third-generation tyrosine kinase inhibitor indicated for adults with resistant or intolerant chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia, or those carrying the T315I mutation. Ponatinib has been commercially available since January 2015, yet there is a paucity of data on its use in the real-world setting. The goal of the Observational study of Iclusig ® (ponatinib) Treatment in patients with CML in Italy (OITI) was to evaluate treatment patterns and outcomes, including safety and efficacy, in patients with CML treated in Italy since the approval of ponatinib. Methods. This noninterventional study included patients aged ≥18 years with CP, AP, or BP CML who initiated ponatinib treatment in routine clinical practice across 26 Italian centers (academic and hospital settings). The study population comprised a prospective cohort, including patients who started treatment with ponatinib after site activation during the 12-month enrollment period; a retrospective cohort, including patients who started treatment with ponatinib but died or were lost to follow-up prior to site activation; and a retrospective/prospective cohort, including patients who started treatment with ponatinib prior to site activation and were still on treatment or in follow-up at the end of the study. Demographic, efficacy, and safety data were collected from patient medical charts at study entry and routine visits. The primary endpoint was the complete cytogenetic response (CCyR) rate in CP CML patients 6 months after starting ponatinib. In the absence of cytogenetic evaluation, molecular assessment was used, considering patients in MR2 or better to be in CCyR. Here, the primary analysis of all evaluable patients for the primary endpoint (median follow-up, 23.7 months [range, 1.3-70.8]) is presented. Results. A total of 119 patients (110 CP, 6 AP, and 3 BP CML) were analyzed. Fifty-nine (49.6%) received ponatinib in second-line (2L), 41 (34.4%) in 3L, and 19 (16.0%) in ≥4L. Prior cardiovascular disease/hypertension was recorded in 56 (47.1%) patients. Median age at ponatinib start was 60 years (range, 19-93). Of 68 evaluated patients, 24 (35.3%) had a confirmed ABL1 mutation, including 7 (10.3%) with the T315I mutation. Starting doses of ponatinib were 45 mg (37.0%), 30 mg (41.2%), or 15 mg (21.8%). Median treatment duration was 22.8 months (range, 1.4-73.6). At baseline, 56 patients with CP CML had less than CCyR and 53 were in CCyR. For 1 patient, assessment was not available. At 6 months, 80/107 evaluable patients with CP CML were in CCyR; 29/56 (51.8%) achieved and 50/50 (100%) maintained CCyR compared to baseline, respectively. For 1 patient, baseline data were unavailable. Additionally, 37 (34.6%) and 19 (17.8%) patients with CP CML achieved a major molecular response (MMR; MR3) and a deep molecular response (MR4-MR5), respectively (Table 1). Progression-free survival rates estimated for patients with CP CML at 12 and 24 months were 92.6% (95% CI, 87.8-97.7%) and 84.6% (95% CI, 77.2-92.6%), respectively. Corresponding overall survival rates were 95.4% (95% CI, 91.6-99.4%), and 88.4% (95% CI, 81.7-95.7%). Seventy-one (59.7%) patients had treatment-related adverse events (AEs), most commonly rash, hypertension (Grade 1-2), and thrombocytopenia (Grade 3). Treatment-related arterial occlusive events occurred in 2 (1.7%) patients. Dose modifications occurred in 77 patients: 37.1% were due to AEs, 13.5% were reductions after at least major cytogenetic response, 10.6% were increases due to lack of efficacy, 1.7% were medical decisions, and 37.1% were for other reasons. Thirty-three patients discontinued ponatinib due to AEs (33.3%), medical decisions (24.2%), and other reasons (42.4%), such as death, progression, and hematopoietic stem cell transplantation. Conclusions. This observational study demonstrates that ponatinib has a favorable efficacy and safety profile in patients with CML treated in standard clinical practice. By 6 months, 74.8% of evaluable patients were in CCyR and 52.3% achieved at least MMR. Further, the probability of survival at 2 years was >88%. No new safety signals emerged with ponatinib treatment compared to prior studies. The early use of ponatinib and careful dose selection appear key to the safety and efficacy outcomes observed in this real-world study. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Bonifacio: Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria. Castagnetti: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Inctye Bioscience Italy Srl: Current Employment. Iurlo: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

Introduction. The recent spread of the COVID-19 infection has represented an important challenge in the management of acute lymphoblastic leukemia (ALL) patients. Aims and methods. To investigate the incidence, features, source of contagion and outcome of patients with ALL who developed a COVID-19 infection, a survey was conducted among 34 hematology centers throughout Italy within the Campus ALL network. The period covered by the survey spanned from February 2020 to April 2021 and included 756 adult ALL patients actively followed during this time period. Results. Sixty-three of the 756 ALL patients (8.3%) developed a COVID-19 infection, with an equal distribution among the various regions. The majority of cases (90.5%) was recorded during the second wave of the pandemic, between September 2020 and April 2021. The source of the infection was nosocomial in 26 cases (41.3%), familial in 23 (36.5%), unknown in 13 (20.6%) and work-related in 1 (1.6%). The infected patients were prevalently male (n=43, 68.2%) with a similar distribution among age groups: 21 patients aged 18-35 years, 17 35-50, 15 50-65 and 10 older than 65. Seventeen patients (27%) had a diagnosis of T-ALL, 28 (44.4%) of Ph- B-ALL and 18 (28.6%) of Ph+ ALL. Thirty-six (57.1%) of the infected patients had no concomitant comorbidities, whereas 27 (42.9%) had one or more comorbidities. The infection was documented at the onset of the disease in 4 patients (6.3%), during induction in 10 (15.9%), consolidation in 13 (20.6%), chemotherapy maintenance in 11 (17.5%), after allogenic transplant in 15 (23.8%), during maintenance with tyrosine kinase inhibitors (TKI) treatment or off-treatment in 8 (12.7%) and at relapse in 2 (3.2%). Of the infected patients, 9 were asymptomatic, 10 had only isolated fever, 36 had respiratory symptoms and 8 presented other symptoms, including - but not limited to - ageusia and anosmia. As a consequence, management of the infection was variable: 29 (46%) patients did not require hospitalization, 28 (44.4%) were hospitalized in a COVID ward and 13 of them required respiratory assistance; finally, 6 (9.5%) patients were transferred to an ICU. Importantly, in 54 patients (85.7%) there were no sequelae, in 1 patient a pulmonary fibrosis was documented and in 1 patient the delay in treatment led to a relapse of the disease, while 7 (11.1%) succumbed to the infection. Finally, in 6 cases (9.5%) the infection was still ongoing at the time of the survey, and at the last update (July 2021) it had resolved in all. Since a key aspect in the management of ALL is the adherence to the timing of treatment, we also investigated if COVID-19+ patients stopped treatment during the infection. Out of the 42 evaluable patients (patients who had undergone an allogeneic transplant or were off-treatment were excluded from this analysis), ALL treatment was suspended in 28 (66.6%). Importantly, while in Ph+ ALL only very few patients stopped treatment (3/12), in Ph- B-ALL the majority did interrupt it (18/22, p Conclusions. The incidence of SARS-CoV-2 infection in adult ALL patients in Italy over a 15 month period has been similar to that observed in the general population and has been recorded mostly during the second wave of the pandemic. The contagion was mainly nosocomial, suggesting that outward care should be pursued as much as possible in ALL. The infection was manageable, with 46% of patients not requiring any medical intervention and an overall death rate of 11%. Strikingly, in line with previous reports 1, it appears that Ph+ ALL patients were more manageable, with less treatment interruptions. These findings underline the advantage of the TKI-based induction/consolidation strategy without systemic chemotherapy in Ph+ ALL used in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) protocols and further point to a possible protective role of TKIs in COVID-19-infected patients. Foà R et al, Br J Haematol. 2020;190(1):e3-e5 Disclosures Chiaretti: Incyte: Consultancy; novartis: Consultancy; pfizer: Consultancy; amgen: Consultancy. Bonifacio: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Marco: Jazz: Consultancy; Insight,: Consultancy; Janssen: Consultancy. Curti: Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Delia: Gilead: Consultancy; Amgen: Consultancy; abbvie: Consultancy; Jazz pharmaceuticals: Consultancy. Forghieri: Jannsen: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Honoraria. Lussana: Amgen: Honoraria; Astellas Pharma: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

Blinatumomab (Blina) and inotuzumab (InO) have improved the outcome of relapsed/refractory B-lymphoblastic leukemia (R/R B-ALL). However, many patients (pts) relapse after these treatments and little is known on their outcomes after recurrence and re-treatment with subsequent immunotherapy. We hereby describe the clinical characteristics and outcome of 71 pts with R/R B-ALL treated with both Blina and InO in any sequence - Blina/InO or InO/Blina - at different disease recurrences. At diagnosis, the median age was 34 years (15-64) and the male/female ratio was 1.6. Sixteen pts (22%) were Ph+ ALL, 3 (4%) were t(4;11)+ and 9 (13%) carried a complex karyotypes. ECOG PS was 0-1 in 66 pts (93%). At the time of the first immunotherapy, pts had received a median of 2 previous lines of treatment (1-8). All Ph- pts received intensive chemotherapy front-line; Ph+ pts received TKIs and steroids in 13 cases and intensive chemotherapy plus TKIs in 3 cases. Blina was the first salvage treatment (Blino/InO sequence) in 57 pts (80%) and InO (InO/Blina sequence) in 14 (20%). Twenty-seven pts (38%) had underwent a previous allogeneic hematopoietic stem cell transplantation (HSCT). At the start of Blina as first immunotherapy, the median bone marrow (BM) blast count was 40% (0-100%); at the start of InO as first immunotherapy, the median BM blast count was 64% (2-90%). An extramedullary involvement was present in 5 patients (9%) in the Blina/InO group and in 1 patients (7%) in the InO/Blina group. During immunotherapy, the median number of lumbar punctures was 2 (0-9). A median of 2 cycles were administered for both Blina (range 1-9) and Ino (range 1-4). In the Blina/InO group, after Blina a G3/4 toxicity occurred in 15 cases (26%): non-hematologic in 12 cases (21%), neurologic in 6 (8%). Infections occurred in 17 pts (30%). In the InO/Blina group, after InO a G3/4 toxicity occurred in 3 pts (21%), with extra-hematologic toxicity in 2 cases (14%, liver toxicity 1 case). Infections occurred in 4 cases (28%). In the Blina/InO group, after Blina 36 pts (63%) achieved a complete remission (CR), with a negative minimal residual disease (MRD) in 24 (42%) pts; after InO, a CR was re-achieved in 47 pts (82.4%), with 34 (59.6%) being MRD-. In the InO/Blina group, after InO a CR was reached in 13 cases (93%), with 6 pts (42.8%) being MRD-; after Blina, a CR was re-achieved in 6 pts (42.8%), with 3 (21.4%) being MRD-. This salvage immunotherapy strategy represented a bridge to alloHSCT for 26 pts (37%). From the first immunotherapy, in the Blina/InO group, the median overall survival (OS) was 19 months and after InO 6.3 months (OS in MRD- vs MRD+, p ns). Disease free survival (DFS) after Blina was 7.4 months (11.6 vs 2.7 months in MRD- vs MRD+ pts, p .03) and after InO it was 5.4 months (MRD- vs MRD+ pts, p ns). In the InO/Blina group, the median OS was 9.4 months and after Blina 4.6 months (7.5 vs 2.8 months in MRD- vs MRD+ pts, p .02). DFS after InO was 5.1 months (MRD- vs MRD+ pts, p ns) and after Blina it was 1.5 months (8.7 vs 2.5 gg in MRD- vs MRD+ pts, p .02). OS and DFS in MRD- pts after Blina was significantly better, both in the Blina/InO and the InO/Blina groups. With a median follow-up of 16.5 months from the start of immunotherapy and 33.8 months from initial diagnosis, 24 pts (34%) are alive and 16 (22%) are alive in CR. Four patients (6%) died in CR due to veno-occlusive disease during HSCT after InO treatment. Interestingly, OS and DFS from the first immunotherapy was better in pts with a previous alloHSCT (median survival 24.2 vs 13 months, p=.0135). AlloHSCT after second immunotherapy was associated with a better OS and DFS (OS 9.8 and DFS 7.2 months vs 7.8 and 4.4 months, p ns). Our real-life study in R/R B-cell ALL pts with multiple previous lines of treatment demonstrates the feasibility and efficacy of a sequential immunotherapy strategy in terms of MRD response, DFS and OS, and as a bridge to HSCT. SM and PC: equal contributors Disclosures Papayannidis: Janssen: Honoraria; Astellas: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Chiaretti: amgen: Consultancy; pfizer: Consultancy; novartis: Consultancy; Incyte: Consultancy. Forghieri: Jannsen: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Honoraria. Bonifacio: Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cerrano: Janssen: Honoraria; Insight: Honoraria; Jazz: Honoraria. Fracchiolla: Gilead: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background This non-interventional retrospective study, is intended to analyze toxicity and effectiveness of venetoclax of a large cohort of R/R and de novo AML patients treated in Italy since 2015 outside clinical trials with the ultimate goal of improving the knowledge related to venetoclax treatment in the real-life setting. Interim analysis on first 59 patients enrolled is presented here. Aims The aim of this study is to collect data on safety and efficacy of venetoclax in a large cohort of AML patients treated in Italy from 2015 to 2020 in a real-life setting (out of clinical trials). Methods This is a multicenter, retrospective, observational study. All patients with AML treated outside clinical trials with venetoclax as single agent or in combination with other drugs from 1 January 2015 to 1 April 2020 in 40 Italian Hematology Units will be considered for enrollment. Data are collected in accordance with GCP and Helsinky declaration. For this interim analysis data registered into eCRF at 30 June 2020 have been considered. Adverse events (AEs) are graded according to CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results The study started on August 2019 and will be completed on August 2021. Up to 30 June 2020 (first data cut off) 30 sites have been activated and 59 AML patients have been registered, 27 males (46%) and 32 females (54%), with a median age of 64 years (range 35 - 83). At the time of venetoclax initiation, 14/59 (24%) patients had a refractory disease, 31 (52.5%) had relapsed disease (14 first relapse and 17 a second or further relapse), eight patients (15%) were newly diagnosed and received venetoclax as first line therapy while in six patients disease status was missing at the time of data cut off. At diagnosis, 52 patients (88%) had bone marrow involvement, of which four (7%) had extramedullary involvement (skin or subcutaneous and deep muscular localization) and one had CNS involvement. 35/59 (59%) patients were classified as fit for intensive chemotherapy, 16 (27%) unfit and two (3%) frail according to SIE, SIES and GITMO group. For six patients fitness status was missing at the time of data cut off. 45/59 (76%) patients had received previous therapy for AML, eight patients were treatment naïve at the time of venetoclax initiation. while for six patients data regarding previous AML therapy were missing at the time of data cut off. In the R/R setting (n=45), the median number of previous therapy lines were 2 (range 1-7). Nine patients had relapse after stem cell transplantation (SCT) and one of them had received double transplant. For 42/45 R/R AML patients the data regarding treatment with venetoclax were available at the time of data cut off. Three out of 42(7%) patients received venetoclax as single agents, 32 (76%) in combination with HMAs (31 Azacitidine and 1 Decitabine), and six with high or intermediate dose ARA-C. In the cohort of R/R patients treated with combination of venetoclax and HMA, in 29/32 patients venetoclax was started as a ramp up phase. The median number of venetoclax cycles was 2 (range 1-13) and the median dose administered was 400 mg daily (range 100-600). Regarding toxicity, 72 adverse events (AEs) were recorded of which 49 were grade III-IV (39 hematologic toxicities, 4 pneumonia, 2 sepsis and 4 other) and 2 fatal (sepsis). For 25 out of 32 patients treated with venetoclax and HMAs combination, a response evaluation was available at the time of data cut off. 15 patients had an evaluable response within 2 months, 7 within 4-months and for 3 the date was missing. 14 (56%) patients obtained composite complete remission (CR=9; 5 =CRi), three patients had a partial response (PR), one stable disease (SD) while seven patients were refractory. Overall, six out of 32 (19%) patients underwent allogenic transplantation after venetoclax-HMAs combination. Median OS of R/R patients treated with venetoclax plus HMA was 182 days (95% C.I 85-421.). Conclusions These preliminary data show that venetoclax in combination with HMAs has an acceptable toxicity profile and is effective in this setting of R/R patients with unfavorable prognosis. Data from more than 100 patients treated in real life setting with venetoclax in Italy since 2015 is expected by the end of 2020, and further analysis on RR patients is ongoing. Data on newly diagnosed patients treated with venetoclax alone or in combination with HMA or chemotherapy will be analyzed. *G.M. and C.C. contributed equally as last author Disclosures Todisco: Jannsen, Abbvie, Jazz:Membership on an entity's Board of Directors or advisory committees.Fracchiolla:Amgen:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau;ABBVIE:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses;Gilead:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau;Pfizer:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau.Papayannidis:Abbvie, Janssen, Novartis, Amgen, Pfizer:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.Martelli:Pfizer:Membership on an entity's Board of Directors or advisory committees;Novartis:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees;AbbVie:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Di Renzo:BerGenBio ASA:Research Funding.Tarella:ADC Therapeutics:Membership on an entity's Board of Directors or advisory committees, Research Funding;ImmunoGen:Research Funding;TG-therapeutics:Research Funding.Rossi:Jazz:Membership on an entity's Board of Directors or advisory committees;Abbvie:Membership on an entity's Board of Directors or advisory committees;Astellas:Membership on an entity's Board of Directors or advisory committees;Novartis:Other: Advisory board;Amgen:Honoraria;Pfizer:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo:Consultancy, Honoraria;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees;Alexion:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria.

Patients with B‐lineage acute lymphoblastic leukemia treated with pegasparaginase‐containing regimens can develop hepatotoxicity related to it. The systemic hyperbilirubinemia due to hepatotoxicity can lead to the development of CSF xanthochromia., Key Clinical Message Patients with B‐lineage acute lymphoblastic leukemia treated with pegasparaginase‐containing regimens can develop hepatotoxicity related to it. The systemic hyperbilirubinemia due to hepatotoxicity can lead to the development of CSF xanthochromia.

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.

Background: Since its introduction ponatinib has proved great efficacy among patients (pts) with chronic myeloid leukemia (CML), representing in some settings like the T315I mutation the only therapeutical choice due to its unique conformation. Its use both in the cohort of heavily pretreated CML and frontline has led to promising results in terms of overall survival (OS) and progression free survival (PFS), as demonstrated in the PACE study (Cortes JE, Blood 2018) and in the single center experience of the MD Anderson (Jain P, Lancet Haematol 2015). The cardiovascular toxicity associated with treatment has been addressed both in protocols and real-life experiences: it is clear that the benefits of ponatinib in terms of molecular response have to be balanced with the possibility of adverse events such as arterial and venous thromboembolism, dyslipidemia and hypertension which have to be managed and, whenever possible, prevented (Dorer JD, Leuk Res 2016; Caocci G, Int J Cardiol 2019). Before the final registration of the drug by AIFA, ponatinib has been available in Italy since October 2011 to March 2015 in compassionate regimen: the results collected here represent a real-life experience on ponatinib use in a cohort of Italian patients mostly heavily pre-treated. Methods: Italian chronic-phase (CP) CML pts treated with ponatinib in compassionate regimen since October 2011 were collected in the GIMEMA retrospective multicenter protocol CML1214 (clinicaltrials.gov NCT02448095). Primary objective of the study was the assessment of the tolerability and safety profile; secondary objectives were the assessment of the OS, PFS, best response, mutational status, rate of dose reductions. Data were collected following the rules of retrospective studies in Italy and all patients signed an informed consent. Results: 34 pts with CP-CML were enrolled. Accelerated phase or blastic phase were considered as exclusion criteria. There were 17 males and 17 females, with a median age of 62 (25-84) years at ponatinib initiation. Sokal score was high in 7 (23.33%), intermediate in 17 (56.67%), low in 6 (20%) and unknown in 4 pts. Regarding previous TKIs, 22 (64.7%) pts had three previous lines of therapy, 10 (29.41%) two lines, 2 (5.8%) only one TKI before ponatinib. Two patients experienced a previous stem cell transplant (SCT) and other 10 (29.4%) harbored a T315I mutation before ponatinib initiation. At baseline none of the 34 patients were in major molecular remission (MMR). The median follow-up on ponatinib was 46.6 months (range 15.2-74.5). Cumulative incidence of MMR was 14.7% at three months, 20.6% at six months, 29.4% at nine months, and 55.5% at 36 months. Rate of OS at 36 months was 80% (Figure 1); the presence of T315I did not affect survival. At last follow-up 17 pts were still on treatment with ponatinib; eight pts died, 3 after SCT, 1 for cardiovascular toxicity, 3 for disease progression; one for unknown reason. The treatment-related vascular adverse events (AEs) represented 20.6% of total AEs reported: 6 of them were cardiovascular, 2 cerebrovascular, 2 peripheral, 3 new-onset hypertension, 2 cardiac failures. Non cardiovascular AEs were mostly due to hematological intolerance, with 43 events of neutropenia/thrombocytopenia out of 73 total collateral effects, followed by 9 reported skin problems (which varied from simple rash or desquamation to one episode of ichthyosis). Conclusions: After a median follow up of 46.6 months, ponatinib provided substantial benefits in a cohort of pts in a timeframe where, after failing 2nd generation TKIs, no other chances were available except transplantation, and T315I positive patients were practically orphan of treatment before ponatinib. Aside from the large prospective PACE trial, results from GIMEMA CML1214 pair with other real-life experiences like the French PEARL (Heiblig M, Exp Hematol 2018) or the Spanish GELMC (Garcia-Gutierrez V, EHA 2016) reports, thus confirming the manageability and the effectiveness of this therapy in challenging clinical situations. Disclosures Fava: Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Pregno:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Meyers Squibb: Consultancy. Elena:Pfizer: Consultancy; Novartis: Consultancy. Iurlo:Pfizer: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria. Saglio:Celgene: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy.

The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. Am. J. Hematol. 91:617-622, 2016. © 2016 Wiley Periodicals, Inc.

Background The unfavorable prognosis of Ph+ ALL has improved following the introduction of tyrosine kinase inhibitors (TKIs). While the GIMEMA trials are based on a chemo-free induction strategy, information is lacking on long-term follow-up of enrolled patients, and of patients treated outside of clinical trials. Aims and methods To evaluate the real-life experience on newly diagnosed adult Ph+ ALL patients treated with TKIs in Italy, we retrospectively collected data from 7 centers from 1/2000 to 12/2017 within the Campus ALL program. Results 158 patients (mean age: 51.8 years) were included; 69 were treated within GIMEMA trials. Induction therapy was: TKI+steroids (n=91), TKI+chemotherapy (n=39), and chemotherapy alone (n=28). A complete hematologic remission (CHR) was achieved in 99%, 100%, and 87% of patients, respectively. Minimal residual disease (MRD) at 3 months was available in 92 patients (52 outside of a clinical trial): 75% had MRD levels > 0.01 and 25% ≤0.01. Fifty-five patients received TKIs as consolidation and 77 chemotherapy. Seventy patients underwent an allogeneic and 5 an autologous transplant, 41 in first CHR. Of the allografted patients, 19/75 (25%) relapsed; 32 received TKIs post-transplant. Among the 77 non-transplanted cases, 35 (45%) relapsed; the majority (71%) continued TKI treatment: among those still alive, 3 stopped it. With a median follow-up of 61.8 months, overall survival (OS) and disease-free survival (DFS) at 5 years are 50% and 59% (median not reached). Prognostic factors for OS were transplantation (HR 0.44, p 65 yo; HR 2.14, p 40% of cases; nevertheless, the lack of its impact suggests that in MRD+ cases, salvage with novel treatments (i.e., newer generation TKIs and immunotherapy) can improve the outcome of Ph+ ALL. Conclusions We provide an overview of the long-term outcome of an unselected cohort of patients treated between 2000 and 2017, which documents the improved prognosis of Ph+ ALL also in the real-life setting. Further cases are being collected.

Chronic myelomonocytic leukemia (CMML) is a complex clonal hematological disorder classified among myelodysplastic (MDS)/myeloproliferative neoplasms. Prognosis is poor and there is a lack of effective treatments. The hypomethylating agent decitabine has shown activity against MDS and elderly acute myeloid leukemia, but there is little data focusing specifically on its efficacy in CMML. In this prospective, phase 2 Italian study, CMML patients received intravenous decitabine 20 mg/m2 per day on Days 1–5 of a 28-day treatment cycle. Response was evaluated after four and six cycles; patients responding at the end of six cycles could continue treatment with decitabine. Forty-three patients were enrolled; >50% were high-risk according to four CMML-specific scoring systems. In the intent-to-treat population (n=42), the overall response rate after six cycles was 47.6%, with seven complete responses (16.6%), eight marrow responses (19%), one partial response (2.4%) and four hematological improvements (9.5%). After a median follow-up of 51.5 months (range: 44.4–57.2), median overall survival was 17 months, with responders having a significantly longer survival than non-responders (P=0.02). Grade 3/4 anemia, neutropenia and thrombocytopenia occurred in 28.6%, 50% and 38% of patients, respectively. Decitabine appears to be an effective and well-tolerated treatment for patients with high-risk CMML.

The present observational study aimed to compare the efficacy of azacitidine (AZA) and intensive chemotherapy (IC) in elderly patients with untreated acute myeloid leukemia (AML), diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS), and disease-free survival (DFS). The AZA group included 89 patients; median age was 73 years (range 61–80) and median white blood cell count (WBCc) 2.5 × 109/L (range 0.27–83), 45% of the patients had BM blasts ≥ 30%, and 44 (49%) had a secondary AML (sAML). Karyotype was evaluable in 69 patients: 51 (74%) had intermediate-risk abnormalities and 18 (26%) an unfavorable risk karyotype. IC group consisted of 110 patients who received an induction course with mitoxantrone, cytarabine, and etoposide, followed by two consolidation cycles including idarubicin, cytarabine, and etoposide. Median age was 67 years (range 61–78) and median WBCc 8.0 × 109/L (range 0.69–258); 44 (40%) had a sAML. Karyotype was evaluable in 88 patients, 71 (81%) had intermediate risk, and 17 (19%) unfavorable risk karyotype. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 74 patient pairs. CR rate was significantly higher in IC vs AZA group (73 vs 25%, respectively) (p

Therapy with Tyrosine Kinase Inhibitors (TKIs) changed the fate of Philadelphia-positive Chronic Myeloid Leukemia (CML). At present, the therapeutic strategy aims to improve the management of the disease and the quality of life of the patients. In July 2015, we started a prospective multicentric randomized trial with the aim to validate the policy of the intermittent de-escalation treatment and to explore the impact of this strategy on the Quality of Life. To this purpose, CML patients older than 60 years in stable (≥2 years) MR3.0 or MR4.0 molecular response were randomized to receive a FIXED intermittent TKIs regimen (one month ON and one month OFF), as previously published (Russo D, Blood 2013; Russo D, BCJ 2015), versus a PROGRESSIVE intermittent TKIs regimen (one month ON and one month OFF for the 1st year; one month ON and two months OFF for the 2nd year; one month ON and three months OFF from the 3rd year) (OPTkIMA study, ClinicalTrials.gov: NCT02326311). Molecular monitoring was performed according to the 2015 ELN guidelines, every 3 months by RT-PCR on peripheral blood (Baccarani M,Blood 2013). In case of MR3.0 (MMR) loss, checked in two monthly consecutive RT-PCR analysis, patients were planned to exit the study and to resume TKIs daily. This first interim report have been focused on the patients who, by intention to treat, have completed the first year of the study for an historical comparison with the previous INTERIM trial (Russo D, Blood 2013; Russo D, BCJ 2015). During the first year, both the patients randomized in the FIXED and in the PROGRESSIVE arms were given the TKIs treatment one month ON and one month OFF. Up to June 2018, 177 patients have been enrolled by 26 Italian Hematological Centers (first patient randomized in July 2015) and 121/177 patients (68%) completed the first year of OPTkIMA study. The median age was 71 years (range 60-89) and 64% of the patients were belonging to the Sokal intermediate/high risk goup. 96/121 (79%), 14/121 (12%) and 11/121 (9%) patients were receiving imatinib (IMA), nilotinib (NILO) and dasatinib (DAS), at the time of enrollment. Overall, 59/121 (49%) and 62/121 (51%) patients have been randomized in the FIXED and PROGRESSIVE arm, respectively. 41/62 patients (66%) randomly assigned to the PROGRESSIVE arm have entered the second year of therapy. 34/121 patients (28%) went out of the study during the first year. The reasons for protocol discontinuation were: informed consent withdrawn (2 cases), second cancer (4 cases), loss of MR3.0 (28 cases). (Table 1). Among the 28 patients who lost the MMR, 17 and 11 were in MR4.0 and MR3.0, respectively, when they were enrolled into the study. Thus the probability of loosing the MR3.0 while on OPTkIMA was 21,7% at one year (Figure 1). All the 28 patients resumed TKIs continuously and all obtained at least the MR3.0 response, within 6 months and are currently included in the study follow up. The intermittent treatment was well tolerated, with 4 serious adverse events (1 appendicitis, 1 atrial fibrillation, 1 cardiac failure, 1 hip fracture) and 3 adverse events (1 diarrohea, 1 pruritus and 1 fever), none of which have been considered treatement-related. None of the patients experienced the TKI withdrawn syndrome. According to this first interim report, we found that a policy of intermittent TKIs administration in elderly patients is safe and well tolerated. Analysis of patient-reported QoL outcomes is ongoing and will further add information on the overall treatment effectivness of the new PROGRESSIVE intermittent TKI administration. After the 1st year, 28/121 patients (23%) lost MR3.0 and all of them re-gained the major molecular response within 6 months from resumption of continuous treatment. The probability of MR3.0 loss while on OPTkIMA at 1 year was 21,7% and this is quite comparable with the 20% MR3.0 loss observed in the previous INTERIM trial (Russo D, Blood 2013; Russo D, BCJ 2015). Disclosures Efficace: Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Research Funding; TEVA: Research Funding; AMGEN: Research Funding; Incyte: Consultancy; Amgen: Consultancy; TEVA: Consultancy; Orsenix: Consultancy. Abruzzese:Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Castagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Giai:Novartis: Consultancy; Pfizer: Consultancy.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by ineffective hematopoiesis, cytopenia, and risk of evolution into Acute Myeloid Leukemia (AML). It was shown t...

Background. The incorporation of tyrosine kinase inhibitors (TKIs) in treatment schemes of Ph+ ALL has remarkably improved survival. In adult patients with Ph+ ALL, ponatinib in combination with chemotherapy showed a 3-year event-free survival rate of 69%, a 3-year overall survival (OS) of 83%, and a higher rate of response when compared with dasatinib plus chemotherapy. However, in unfit or elderly ALL patients, TKIs combined with chemotherapy are associations with higher toxicity. Therefore, we examined the efficacy and safety of steroids plus ponatinib alone for the treatment of elderly or unfit patients with Ph+ ALL in a multi-center Phase II prospective clinical Italian trial, GIMEMA LAL1811 (EudraCT number 2012-002761-35). Methods. From March 2014 to December 2016, we enrolled 44 patients with untreated Ph+ ALL, ≥ 60 years or unfit (i.e. for intensive chemotherapy and stem cell transplantation). Two out of 44 patients were not elegible for the study. Patients received oral administration of 45 mg/day of ponatinib for 8 consecutive courses of 6 weeks (w). Steroids were administered from day -14 to day 29 during course 1. Intrathecal therapy with methotrexate, cytarabine and dexametasone was performed every 28 days for central nervous system (CNS) disease prophylaxis. In patients with CNS disease at diagnosis, intrathecal therapy was administered twice a week until complete remission. Dose reduction of ponatinib was allowed for adverse events. Patient samples were obtained at diagnosis and at every course, BCR-ABL mutational analisys and BCR-ABL/ABL ratio by quantitative real time PCR was performed. Complete molecular response (CMR) was defined as BCR-ABL/ABL ratio below 0.01 or undetectable, and with a sensitivity of at least 30,000 molecules of ABL. Results. Forty-two patients were eligible for the study. Median age was 68 years (range 27-85). Nine out of 42 patients were At week 24, 15/42 patients still received 45 mg of ponatinib daily, only 4/42 patients permanently withdrew study drug. During the study, 75 adverse events (AE) were reported; 36 of the 75 AEs were considered related to ponatinib. Twenty-six of the 75 AEs were considered serious (SAE); 13/26 SAEs were considered related to ponatinib. A death was suspected to be related to ponatinib. We performed BCR-ABL mutational analysis in 22 patients at diagnosis, and 15 patients at 24w. T315L (abundance 100%) was detected in a patient relapsed during ponatinib therapy. We could not identify the emergency of other mutations. Conclusions. Ponatinib and steroid show a high efficacy in newly diagnosed unfit/elderly Ph+ ALL patients. Toxicities were manageable and cardiovascular AEs were limited. In the small cohort of patients relapsed in the study, relapse mechanisms were unclear; only one patient had evidence of mutations that caused resistance to ponatinib. The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway could explain the therapeutic effectiveness. Acknowledgments. GIMEMA, ELN, AIL, AIRC, Regione-Università 2010-12, FP7 NGS-PTL, HARMONY, Fondazione del Monte BO e RA. Disclosures Soverini: Bristol-Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Bocchia: Novartis: Other: Travel grant; Celgene: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Cuneo: Abbvie: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Roche: Honoraria, Other: Advisory Board. Bonifacio: Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Falini: Roche: Research Funding. Galieni: Takeda: Other: Advisory Board; Abbvie: Other: Advisory Board. Foà: Sandoz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Baccarani: Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Interferon a (IFNa) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNa based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNa, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNa, and all 26 are alive and in CCyR. Forty-seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNa, respectively, and 39/47 (83%) are alive and in CCyR. At last follow-up, the BCR-ABL transcripts level was available in 96/101 living patients (95%) The BCR-ABL:ABL ratio was between 0.1 and 0.01% (MR 3.0 ) in 17%, and less than 0.01% (MR 4.0 ) in 81% of patients. No patient was completely molecular negative (MR 4.5 or MR 5.0 ). The OS at 10 and 20 years is 92 and 84%, respectively. This study confirms that CCyR achieved with IFNa and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR 4.0 . Complete molecular response (MR 4.5 or MR 5.0 ) seems to be unnecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNa. Am. J. Hematol. 89:119–124, 2014. V C 2013 Wiley Periodicals, Inc.

Background. The management of adult patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL), including the elderly, has changed since the introduction of tyrosine kinase inhibitors (TKI). A significantly better survival is observed in patients who become minimal residual disease (MRD)-negative. Aims. To increase the rate of MRD-negative patients, we designed a front-line chemo-free induction-consolidation trial (D-ALBA, GIMEMA LAL2116) based on the combination of the second-generation TKI dasatinib with the bispecific monoclonal antibody blinatumomab. The primary endpoint of the study was the rate of patients who achieved a complete molecular remission (CMR) or a positive non-quantifiable (PNQ) disease after at least two cycles of blinatumomab. Secondary endpoints included disease-free survival (DFS), overall survival (OS), cumulative incidence of relapse (CIR) and safety. We also sought to evaluate the prognostic impact of additional genomic lesions - performed on diagnostic samples - and the potential changes in the immunologic compartment, in terms of T cells and T-regulatory cells (Tregs), evaluated by flow cytometry (CD3+/CD4+, CD3+/CD8+ and CD3+/CD4+/CD25+/FOXp3+, respectively). Methods. This multicenter phase II study enrolled Ph+ ALL patients aged 18 years or older, with no upper age limit. Prior to dasatinib, patients received a 7-day steroids pre-phase: steroids were continued for further 24 days and stopped at day 31. Dasatinib (140 mg/day) was administered as induction for 85 days. Thereafter, patients who obtained a complete hematologic response (CHR) received a post-induction consolidation treatment with blinatumomab at a flat dose of 28 μg/day. A minimum of 2 cycles was mandatory, while the administration of up to 3 additional cycles was allowed based on the response to blinatumomab and medical decision. Dasatinib was continued during treatment with blinatumomab. CNS prophylaxis was carried out during the whole treatment. Post-consolidation treatment was open. Results. Between May 2017 and January 2019, 63 patients have been enrolled. Median age was 54.5 years (range: 24.1-81.7), 54% were female, the median white blood cell count (WBC) was 42 x109/l (range: 0.63-63.5) and 65.1% carried the p190 fusion. Copy number aberration analysis showed that the most frequent lesion was, as expected, IKZF1 deletion (54%): 23.9% of patients were thus classified as IKZF1plus (i.e. IKZF1 and/or PAX5 and/or CDKN2A/B deletions). The median follow-up is 10 months (range: 0.9-21.5). So far, 61 patients have completed induction, 55 the 1st cycle of blinatumomab, 47 the 2nd cycle, 33 the 3rd, 26 the 4th and 17 the 5th. Two patients have gone off protocol for medical decision and toxicity, and 1 died during induction. At the end of the induction with dasatonib, 17/58 pts (29.3%) had a molecular response (6 CMR and 11 PNQ). At the primary endpoint (end of the 2nd cycle of blinatumomab), 27/47 (56.3%) had a molecular response (17 CMR and 10 PNQ). The rates of molecular responses further increased after subsequent cycles of blinatumomab: 65.7% after the 3rd cycle and 80% after the 4th cycle. ABL1 mutational analysis was carried out in 15 patients with evidence of a MRD increase: 8 cases were WT, while mutations were detected in 7 (6 T315I, and 1 E255K). All mutations but 1 occurred prior to the start of blinatumomab and all were "cleared" by blinatumomab. The analysis of the immunologic compartment carried out in 12 patients who completed all 5 cycles of blinatumomab showed a significant increase in the rate of CD8+ T cells (19.8% before the start of blinatumomab and 29% after the 5th cycle, p=0.04) and a significant reduction in the rate of Tregs (11% before blinatumomab and 3.7% after the 5th cycle, p=0.02). Overall, 5 relapses have been recorded (2 hematologic, 2 isolated CNS and 1 nodal). The 12-month OS and DFS are 94.2% and 87.8%. A significantly inferior DFS (61.4%, p=0.01) was observed in IKZF1plus cases: these patients were prone to develop deleterious mutations. So far, 12 patients have been allografted and no transplant-related mortality has been recorded. Conclusions. In the first chemo-free induction-consolidation protocol for adult Ph+ ALL patients of all ages based on a combination of a targeted and immunotherapeutic strategy, the rates of molecular responses and survival are highly promising; patients harboring IKZF1 plus represent, also in this setting, a clinical challenge. Disclosures Chiaretti: Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Bassan:Amgen Inc.: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Shire: Honoraria. Bonifacio:BMS: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Vignetti:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Educational Training. Rambaldi:Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.

Background and Rationale. Bosutinib (BOS), dasatinib (DAS) and nilotinib (NIL) are 2nd generation TKIs with similar second-line efficacy. The use of DAS and NIL may be burdened by pulmonary, infectious, cardiovascular and metabolic complications; these complications are more frequent and more clinically relevant in the elderly. BOS could represent an important therapeutic option in elderly patients intolerant to or failing a first-line TKI, but the dose of 500 mg OAD may be higher than necessary. Aims. All TKIs have been tested at a fixed initial dose, with dose adjustment in case of toxicity or treatment failure. On the contrary, the aim of our study was to evaluate in elderly CML patients if second-line BOS was effective and better tolerated at doses lower than 500 mg OAD, beginning with 200 mg OAD, then increasing the dose to 300 OAD or 400 mg OAD according to the molecular response, to find the minimum effective dose. Methods. A prospective phase 2 single-arm multicenter study has been designed by the GIMEMA CML Working Party (NCT02810990). Study design: all patients started with 200 mg OAD for 2 weeks ("run-in" period), then the dose was increased to 300 mg OAD; after 3 months, patients with BCR-ABLIS transcript ≤ 1% continued 300 mg OAD, while in patients with transcript > 1% the dose is furtherly increased to 400 mg OAD. In responsive patients, BOS dose was maintained, 300 mg or 400 mg OAD. Key inclusion criteria: > 60 yrs old, chronic phase CML, intolerance or failure of any first-line TKI (2013 ELN criteria), absence of T315I or V299L mutation. Sixty-three patients have been enrolled. The primary endpoint was the proportion of patients in MR3 at 1 year. Definitions: MR3, BCR-ABLIS < 0.1%; MR4, BCR-ABLIS < 0.01% with > 10.000 copies; MR4.5, BCR-ABLIS < 0.0032% with > 32.000 copies. Results. Median age: 73 yrs (range 60-90). Age distribution: 60-69 yrs, 18 pts (29%); 70-79 yrs, 31 pts (49%); > 80 yrs, 14 pts (22%). Sokal score at diagnosis: low 19%, intermediate 49%, high 32%. Reasons for switching to BOS: intolerance 63%, resistance 37%. First-line TKI: imatinib 83%, DAS 11%, NIL 6% (same TKI distribution in intolerant and resistant patients). Median follow-up: 9 mos (range 1-30). Overall, 10/63 patients had a dose-increase to 400 mg OAD, 49/63 to 300 mg OAD, while 4/63 continued on BOS 200 mg OAD without any dose increase. At baseline, 13 patients were already in MR3. The MR3 rates by 3 and 6 months were 43% and 56%, respectively. The cumulative rate of patients achieving or maintaining a MR3 by 12 months was 60% (65% in intolerant and 52% in resistant patients, p = 0.31). Interestingly, only 21% of patients > 80 yrs old achieved or maintained a MR3 (p < 0.001, compared to younger patients). Patients achieving MR4 or MR4.5 were 38% and 19%, respectively. Overall, 22%, 27% and 11% of patients had 1 log, 2 logs or > 3 logs reduction from baseline BCR-ABLIS transcript level. Selected adverse events: cardiac ischemia, 2 patients; pericardial effusion, 2 patients; no pleural effusions. Events leading to permanent treatment discontinuation: 2 unrelated deaths, 7 adverse events (3 hypertransaminasemia, 1 nephrotoxicity, 1 diarrhea, 1 skin rash, 1 myalgia/fatigue), 3 unsatisfactory responses (without progressions). Fifty-one out of 63 patients are still on BOS at the last contact: 6 on 400 mg OAD, 34 on 300 mg OAD, 11 on 200 mg OAD. Conclusions. A gradual dose increase, based on prospective molecular monitoring, allowed the great majority of enrolled patients (approximately 70%) to remain on treatment with BOS 300 mg OAD or less, achieving a major molecular response (MR3) in 60% of the cases. These results trial showed that, in elderly patients intolerant to or failing a first-line TKI, BOS may be highly effective and better tolerated at a dose lower than 500 mg OAD, namely at 300 mg OAD. Disclosures Castagnetti: Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squiib: Consultancy, Honoraria. Gugliotta:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Trawinska:Novartis: Consultancy, Honoraria. Bonifacio:Novartis: Honoraria, Research Funding; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Elena:Novartis: Consultancy; Pfizer: Consultancy. Lucchesi:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Albano:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lunghi:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Stagno:BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Pregno:Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Incyte: Consultancy, Honoraria. Iurlo:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Ferrero:Novartis: Honoraria. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau. Saglio:BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jansen: Consultancy; Incyte: Consultancy. Pane:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: research founding; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Bosutinib is a second generation TKI already registered for the treatment of adult patients with chronic phase CML with resistance or intolerance to prior therapy. In the present study the initial dose is 200 mg instead of 500 mg OAD. A dose increase to 300 or 400 mg is scheduled according to molecular response and tolerabiliy

Background. Ponatinib is a third-generation tyrosine kinase inhibitor indicated for adult patients with resistant or intolerant chronic phase (CP), accelerated phase (AP) or blast phase (BP) chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia, or for those carrying the T315I mutation. In the real-world setting, there is a paucity of data regarding the use of ponatinib. The goal of the Observational study of Iclusig® (ponatinib) Treatment in patients with CML in Italy (OITI) is to evaluate treatment patterns and outcomes, including the safety and efficacy of ponatinib, in patients with CML treated in hematology centers in Italy since January 2015, when ponatinib became commercially available. Methods. This ongoing, non-interventional study includes patients aged ≥18 years with CP, AP or BP CML who initiated ponatinib treatment in routine clinical practice across 40 centers (academic and hospital settings) as of October 2018. The study population consists of a prospective cohort, including patients who started treatment with ponatinib after site activation during the ongoing enrolment period; a retrospective cohort, including patients who started treatment with ponatinib but who died or were lost to follow-up prior to site activation; and a retrospective/prospective cohort, including patients who started treatment with ponatinib prior to site activation and are still on treatment. Demographic, efficacy and safety data are collected from patient medical charts at study entry and at routine care visits. The primary endpoint is complete cytogenetic response (CCyR) rate in patients with CP CML 6 months after starting ponatinib treatment. Here, the first interim analysis after ≥6 months' observation is presented for the retrospective and retrospective/prospective cohorts. Results. At time of data analysis (02 July 2019), 56 patients (53 CP, 1 AP and 2 BP CML) had been enrolled across 21 Italian centers. Twenty-eight (50.0%) patients had received ponatinib as second-line (2L) treatment and 33.9% received ponatinib in third-line (3L). Twenty (35.7%) patients had a history of cardiovascular events and 23 (41.1%) had a history of hypertension. Among patients with CP, AP and BP CML, median age at study entry was 59.1, 33.7 and 48.5 years, respectively; among 37 evaluable patients, 12 (32.4%), 1 (2.7%) and 1 (2.7%) patient(s) had a confirmed BCR-ABL1 mutation. Of evaluable patients, 4 (10.8%) had the T315I mutation. The starting dose of ponatinib for patients with CP CML was 45 mg once daily in 41.5% of patients, 30 mg in 39.6% of patients and 15 mg in 17.0% of patients; 1 (1.9%) patient started ponatinib at another dose. Median treatment duration was 23.9 months (range, 3.3-49.9 months) at the time of analysis. At Month 6, 88.6% of patients with CP CML achieved a CCyR. Additionally, 37.5% and 15.0% of evaluable patients with CP CML achieved a major molecular response (MMR; MR3.0) and a deep molecular response (MR4.5), respectively (Table 1). Estimated progression-free survival rates for patients with CP CML at Months 12 and 24 were 86.6% (95% CI, 77.8-96.4%) and 83.7% (95% CI, 73.8-94.9%), respectively. Corresponding overall survival rates were 96.2% (95% CI, 91.1-100.0%) and 93.1% (95% CI, 85.6-100.0%), respectively. Thirty (53.6%) patients had treatment-related adverse events (TRAE). The most frequent TRAEs were hypertension (n=6), skin lesion (n=2), increased lipase (n=2), rash (n=2) and pain in extremity (n=2). The only hematologic TRAE reported was thrombocytopenia (n=1). Dose interruptions occurred in 13 patients: for TRAEs (n=5, 38.5%), medical decision (n=4, 30.8%) or other causes (n=4, 30.8%; comprising death in 3 cases and 1 attempt at treatment-free remission). Conclusions. Data show that ponatinib has a favorable efficacy and safety profile in patients with CML treated in standard clinical practice in Italy. By Month 6, most patients had achieved CCyR and 44% of patients achieved MMR in 2/3L. Furthermore, the probability of survival at 2 years was more than 90%. No new safety signals emerged with ponatinib treatment than those previously reported. The early use of ponatinib (84% of patients received it as 2/3L treatment) as well as careful dose selection appear key to the safety and efficacy outcomes observed in this preliminary study evaluation. Disclosures Iurlo: Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria. Annunziata:Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Albano:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Spadano:Incyte: Speakers Bureau; Pfizer: Speakers Bureau. Bonifacio:BMS: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Pellegrino:Inycte Biosciences Italy S.R.L: Employment. Galimberti:Inycte Biosciences Italy S.R.L: Employment. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees. Breccia:Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

A defective switching off of the immune response is involved in several autoimmune diseases. This switching off involves Fas-mediated apoptosis, perforin-mediated fratricide of activated lymphocytes, and the suppressive activity of regulatory T (Treg) cells. These mechanisms are altered in autoimmune lymphoproliferative syndrome that often displays autoimmune thrombocytopenia. The aim of this research was to evaluate these mechanisms in adult patients with primary immune thrombocytopenia (ITP), compared with healthy controls. The results show that a substantial subgroup of the ITP patients displayed a defective Fas function; most of them displayed decreased Fas expression in T cells activated in vitro. Moreover, ITP patients displayed an increased frequency of rare missense variations of the PRF1 gene and decreased levels of Treg. Immunological analysis showed that levels of Interleukin (IL)10 and IL17 were decreased and marginal zone B cells were increased. Moreover, myeloid and plasmacytoid dendritic cells were decreased in ITP patients. In conclusion, in adult ITP patients, several mechanisms involved in shutting off the immune response are defective and several immunological parameters are dysregulated; these alterations may play a role in the clinical heterogeneity of the disease.

The objective of this study was to evaluate the clinical features, prognostic factors, and efficacy of treatments in patients with blastic plasmacytoid dendritic cell neoplasm with a leukemic presentation at onset of the disease. In order to do this, a retrospective multicenter study was performed from 2005-2011 in 28 Italian hematology divisions in which 43 cases were collected. Forty-one patients received an induction therapy, consisting of an acute myeloid leukemia-type regimen in 26 patients (60%) and acute lymphoid leukemia/lymphoma-type regimen in 15 patients (35%). Six patients (14%) underwent allogeneic hematopoietic stem cell transplantation. Seventeen patients (41%) achieved a complete remission: seven after acute myeloid leukemia-type treatment and 10 after an acute lymphoid leukemia/lymphoma-type regimen, with a significant advantage for acute lymphoid leukemia/lymphoma-type chemotherapy (P=0.02). Relapse occurred in six of the 17 patients (35%) who achieved complete remission, more frequently after acute lymphoid leukemia/lymphoma-type chemotherapy. The median overall survival was 8.7 months (range, 0.2-32.9). The patients treated with an acute myeloid leukemia-type regimen had an overall survival of 7.1 months (range, 0.2-19.5), whereas that of the patients receiving acute lymphoid leukemia/lymphoma-type chemotherapy was 12.3 months (range, 1-32.9) (P=0.02). The median overall survival of the allogeneic hematopoietic stem cell transplant recipients was 22.7 months (range, 12-32.9), and these patients had a significant survival advantage compared to the non-transplanted patients (median 7.1 months, 0.2-21.3; P=0.03). In conclusion, blastic plasmacytoid dendritic cell neoplasm with bone-marrow involvement is an aggressive subtype of high-risk acute leukemia. The rarity of this disease does not enable prospective clinical trials to identify the better therapeutic strategy, which, at present, is based on clinicians' experience.

Summary The mammalian target of rapamycin (mTOR) signalling pathway has emerged as an important therapeutic target for acute myeloid leukaemia (AML). This study assessed the combination of temsirolimus, an mTOR inhibitor, and lower-dose clofarabine as salvage therapy in older patients with AML. Induction consisted of clofarabine 20 mg/m2 on days 1–5 and temsirolimus 25 mg (flat dose) on days 1, 8 and 15. Patients achieving complete remission with (CR) or without (CRi) full haematological recovery could receive monthly temsirolimus maintenance. In 53 evaluable patients, the overall remission rate (ORR) was 21% (8% CR, 13% CRi). Median disease-free survival was 3·5 months, and median overall survival was 4 months (9·1 months for responders). The most common non-haematological severe adverse events included infection (48%), febrile neutropenia (34%) and transaminitis (11%). The 30-d all-cause induction mortality was 13%. Laboratory data from 25 patients demonstrated that a >50%in vivo inhibition of S6 ribosomal protein phosphorylation was highly correlated with response rate (75% with inhibition versus 0% without inhibition; P = 0·0001), suggesting that targeting the mTOR pathway is clinically relevant. The acceptable safety profile and the predictive value of target inhibition encourage further investigation of this novel regimen.

Glivec was the first tyrosine kinase inhibitor (TKI) approved for chronic myeloid leukemia (CML) treatment and its efficacy has been demonstrated in a large number of trials. Generic formulations have been used recently as a more cost effective treatment, but there are few studies that have prospectively evaluated the efficacy and safety of these drugs.Aims: The present study aimed to evaluate the efficacy and safety of generic imatinib in CP-CML in first line therapy. Methods: This is a multicenter, observational, cohort-type study. The prospective cohort consisted of patients who initiated treatment with generic imatinib between January 2015 and September 2017; whereas the retrospective cohort was treated with Glivec between January 2010 and December 2011. All patients started imatinib in CP, less than six months from diagnosis. Patients were managed according to European Leukemia Net (ELN) 2009 and 2013 recommendations. The definition of the responses followed the ELN 2013 criteria. Adverse events were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.3, 2010. Event-free survival (EFS) was measured from starting date of treatment until loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated (AP) or blast crisis (BC) or death from any cause at any time during initial therapy or discontinuation of imatinib by any cause. Patients that switched from Glivec to generic where censored. Overall survival (OS) was measured from starting date of imatinib until to the date of death from any cause while on therapy or last seen. Progression-free survival (PFS) was measured from starting date of imatinib to transformation to AP or BC or deaths while on therapy. Survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Cox regression was used with Backward Wald Method. SPSS version 21.0 was used applying the chi-square and t-test, when adequate. All analysis considered p-value Results: A total of 445 patients were analyzed (Glivec=285; Generic=160). The median age was 54 years (18-87) in Glivec and 50 (18-89) in the Generic group (P=0.027). Sokal score stratification in Glivec and generic groups, was respectively: low risk 14.4%/25.7%; intermediate risk 42.3%/38.2% and high risk 43.3%/36.1% (P=0.02). B3a2 frequency was 51.5% vs. 37.7% in Glivec and Generic group, respectively, and b2a2 41.4% vs. 53.8% (P=0.017). There was no significant difference in gender, Hasford, EUTOS scores and ECOG. The median follow-up was 25 months (0-71) and 11 months (0-31) for Glivec and Generic groups, respectively (P Conclusion: The group treated with generic imatinib presented higher rate of failure at 3 months and lower OS, PFS and EFS at 24 months. Differences between the groups included a longer time to initiate treatment in the Generic group, a higher proportion of patients with b2a2 transcripts, which were related to an inferior rate of molecular responses and survival in other studies. There was no difference in the safety profile. The long-term impact in prognosis will be evaluated after a longer follow-up. Disclosures Pagnano: Shire: Other: Lecture; Abbvie: Consultancy; EMS: Other: Financial support for participation in congress; Novartis: Consultancy. Magalhaes:Novartis: Consultancy, Other: Lecture. Clementino:EMS: Other: Financial support for congress. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Centrone:EMS: Other: Financial support for congress, Speakers Bureau; Bristol Meiers-Squibb: Other: Financial support for congress, Speakers Bureau; Novartis: Other: Financial support for congress, Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Other: Financial support for congress, Speakers Bureau. Fogliatto:Novartis: Consultancy; Roche: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding. Giai:Pfizer: Consultancy; Novartis: Consultancy. Bortolheiro:Abbvie: Consultancy, Speakers Bureau; Sanoffi: Speakers Bureau; Novartis: Consultancy, Speakers Bureau.