Gruppo Italiano Malattie Ematologiche Dell ' Adulto Research Articles

Gimema Seifem Real-Life Study VS Randomized CPX-351 Registrative Trial for Older Patients with Secondary ACUTE Myeloid Leukemia: An Unanchored Matching-Adjusted Indirect Comparison of Infection Rates and Survival Outcomes

Background: Unanchored MAIC (Matching-Adjusted Indirect Comparison) is an ITC (Indirect Treatment Comparison) method adjusting for cross-trial heterogeneity in patient demographic or disease that are believed to be either prognostic or treatment effect modifiers. In this analysis, two trials for adults with secondary acute myeloid leukemia (AML) were compared by an unanchored MAIC. Aims: The GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto)-SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) real-life study on the use of CPX-351 (Fianchi et al- Cancers 2023) was weighted for the aggregated patients characteristics from the standard arm(“7+3”) of the CPX-351 trial (cytarabine and daunorubicin Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia, Lancet et al - JCO 2018). This analysis aimed to test the feasibility to compare individual patients' data with aggregated published results and evaluate the rate of infections of CPX-351 in real life vs the “3+7” regimen and their impact on the survival outcomes. Methods: Patients-level data from GIMEMA-SEIFEM on the use of CPX-351 (n=202) and aggregated data from CPX-351 (“3+7” arm, n=156) trials were used to conduct an unanchored MAIC. GIMEMA-SEIFEM study included included all consecutive patients with AMLfrom 30 Italian hematologic centers who received at least 1 course of CPX-351 from July 2018 to June 2021 according to clinical practice. Patients from the GIMEMA-SEIFEM study were weighted to balance with baseline characteristics from the USA and Canada cohoort. Accordingly, weighted Overall and Event-free survival (w-OS, w-EFS) estimates, as well as rates of febrile neutropenia, pneumonia, CR, and the interval of PMN recovery, were computed. Results: Four potential effect modifiers were identified and used for adjustment: age, sex, AML subtype (tAML, sAML, MRC), and prior HMA exposure. Median w-OS and w-EFS were 14.2 (95%CI: 11.6-18.7) and 7.4 (95%CI: 3.0-10.6) months, respectively. These estimates were slightly lower than those documented in the most recent report of the GIMEMA-SEIFEM trial (median OS 17.7 months and median EFS 9.8 months) and higher than the results obtained by the standard arm of the CPX-351 trial (median OS 5.9 months, median EFS 1.3 months). Weighted rates of febrile neutropenia, pneumonia, CR, and interval of PMN recovery were comparable to the observed values and better than observed in the standard arm of the CPX-351 trial for all considered variables, except for febrile neutropenia (Table 1). Conclusions: The MAIC method allowed a robust comparison of two clinical trials for the treatment of AML patients. After adjustment, survival outcomes of the real-life cohort were slightly lower than the observed estimates and higher than the observed in the standard arm of the CPX-351 trial. Pneumonia risk was confirmed lower in GIMEMA-SEIFEM CPX-351 matched group than in “3+7” arm. This pilot analysis underlined the potentiality of this statistical method. Indeed, it could be useful to compare with high accuracy studies with strong differences in the selection of patients.

Neutralizing monoclonal antibodies in haematological patients paucisymptomatic for COVID-19: The GIMEMA EMATO-0321 study.

COVID-19 continues to be a relevant issue among patients with haematological malignancies (HM). Vaccines are frequently not effective in subjects on active treatment. In this multicentre retrospective study of Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA), we collected data from 91 paucisymptomatic HM patients treated with anti-spike neutralizing monoclonal antibodies (nMoAbs) to determine time to viral clearance, referencing it to the expected value of 28 days from an historical group of untreated paucisymptomatic patients. Secondary endpoints included rate of hospitalization, intensive care unit (ICU) admission, COVID-19 related death and safety. SARS-CoV-2 molecular swab negativity was obtained in 86 patients (95%), with a median time of 18 days (IQR 13-26; p< 0.0001). We did not find significant variations according to age, diagnosis, treatment type, vaccination status or nMoAbs type. Rate of hospitalization due to COVID-19 progression was 12% (11/91), with 2 patients (2.2%) requiring ICU admission. With a median follow-up of 2.33 months, the overall mortality was 5.5% (5/91), with 3 deaths due to COVID-19. Side effects were rare and self-limiting. Our data suggest that nMoAbs can limit the detrimental effect of immunosuppressive treatments on COVID-19 clinical progression and time to viral clearance. The original trial was registered at www.clinicaltrials.gov as #NCT04932967.

ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol

AbstractThe 2017 version of the European LeukemiaNet (ELN) recommendations, by integrating cytogenetics and mutational status of specific genes, divides patients with acute myeloid leukemia into 3 prognostically distinct risk categories: favorable (ELN2017-FR), intermediate (ELN2017-IR), and adverse (ELN2017-AR). We performed a post hoc analysis of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) AML1310 trial to investigate the applicability of the ELN2017 risk stratification to our study population. In this trial, after induction and consolidation, patients in complete remission were to receive an autologous stem cell transplant (auto-SCT) if categorized as favorable risk or an allogeneic stem cell transplant (allo-SCT) if adverse risk. Intermediate-risk patients were to receive auto-SCT or allo-SCT based on the postconsolidation levels of measurable residual disease as measured by using flow cytometry. Risk categorization was originally conducted according to the 2009 National Comprehensive Cancer Network recommendations. Among 500 patients, 445 (89%) were reclassified according to the ELN2017 criteria: ELN2017-FR, 186 (41.8%) of 455; ELN2017-IR, 179 (40.2%) of 445; and ELN2017-AR, 80 (18%) of 455. In 55 patients (11%), ELN2017 was not applicable. Two-year overall survival (OS) was 68.8%, 51.3%, 45.8%, and 42.8% for the ELN2017-FR, ELN2017-IR, ELN2017-not classifiable, and ELN2017-AR groups, respectively (P < .001). When comparing the 2 different transplant strategies in each ELN2017 risk category, a significant benefit of auto-SCT over allo-SCT was observed among ELN2017-FR patients (2-year OS of 83.3% vs 66.7%; P = .0421). The 2 transplant procedures performed almost equally in the ELN2017-IR group (2-year OS of 73.9% vs 70.8%; P = .5552). This post hoc analysis of the GIMEMA AML1310 trial confirms that the ELN2017 classification is able to accurately discriminate patients with different outcomes and who may benefit from different transplant strategies. This trial was registered as EudraCT number 2010-023809-36 and at www.clinicaltrials.gov as #NCT01452646.

ACUTE Lymphoblastic Leukemia (ALL) and COVID-19 Infection. a Campus ALL Report

▪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<0.001); likewise, also in T-ALL most patients suspended treatment (7/8).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.1.Foà R et al, Br J Haematol. 2020;190(1):e3-e5 DisclosuresChiaretti: 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.

Longitudinal Detection of DNMT3AR882H Transcripts in Patients with Acute Myeloid Leukemia

Introduction The DNMT3A gene is recurrently mutated in normal karyotype acute myeloid leukemia (NK-AML) and the most common alteration (65% of cases) is located at residue R882 of methyltransferase domain. DNMT3A mutations often occur in association with other mutations such as FLT3 and NPM1 and while it is now generally accepted that AML patients with NPM1 or FLT3 -ITD mutations have favourable and poor outcome respectively, the impact of DNMT3A mutations on survival remains controversial. Recent studies reported that DNMT3A -mutated cells are detectable in patients with AML in long-lasting complete remission, questioning whether quantification of DNMT3A levels could be used to minimal residual disease (MRD). To address this issue, we carried out sequential monitoring studies of DNMT3AR882H levels in AML patients and compared our results with those obtained with multiparametric flow-cytometry (MPFC) and NPM1 molecular status and expression levels.Methods The mutational analysis of DNMT3AR882, NPM1 and FLT3 (ITD/TKD) was assessed at diagnosis in 556 patients with de novo AML (median age: 49 years, range 16-89 years) enrolled in clinical trials conducted by the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) during the period 2012-2015. DNMT3AR882H molecular status was also studied in 100 patients with chronic myeloid leukemia (CML) and in 56 elderly healthy individuals. The expression levels of DNMT3AR882H and NPM1 Type_A mutation (NPM1mutA) were longitudinally analysed by qRT-PCR in 21 AML patients. For patients achieving complete morphologic remission (CR), DNMT3AR882Hlevels were compared with those of NPM1mutA and with MRD assessed by multiparametric flow cytometry (MPFC). W e then compared the levels of DNMT3AR882H and of MPFC-MRD in follow-up BM-samples from AML patients in CR , classified as MRDneg or MRDpos, according to threshold established based on previous work from our group (Buccisano et. al. Blood 2010). Finally, we evaluated the kinetics of DNMT3AR882H, NPM1mutA and FLT3 -ITD in 9 FLT3 -ITD+ve patients, using a FLT3 -ITD patient-specific qRT-PCR, and in 6 FLT3 -wt patients.Results Expression levels of DNMT3AR882H was also studied in sorted cell subpopulations from AML and CML patients and in healthy individuals. Distinct from NPM1mutA, DNMT3AR882H expression levels did not correlate with leukemic blast proportion assessed by MPFC (Figure 1) and decreased in AML samples only after induction treatment (Figure 2), while it was constantly detectable during remission and at relapse (Figure 3). Within FLT3 -ITD+ve AML, the kinetics of DNMT3AR882H paralleled that of NPM1mutA in 3 of 9 patients only. DNMT3AR882H expression levels were constant, independent from NPM1mutA in all 6 FLT3 -wt patients. Figure 4 shows 4 exemplary cases, with stable DNMT3AR882H levels during disease course in three of them. In CML patients, the DNMT3AR882H transcript was found only during follow-up in 4/100 patients, while it was undetectable at the time of CML diagnosis. DNMT3AR882H transcript levels were constantly low in all available CML samples. As previously reported, clonal hematopoiesis of indetermined potential (CHIP) was identified in 3/56 elderly healthy individuals. Similarly low expression levels of DNMT3AR882H were detected in blast and T-lymphocyte samples obtained from AML cases at CR and relapse phases, in CML patients and healthy individuals (Figure 5 and 6). There were no differences in DNMT3AR882H expression between MRDpos and MRDneg follow-up samples. DNMT3AR882H transcripts levels in MRDpos follow-up samples were significantly lower than those of samples harvested at diagnosis (Figure 6). These data show that DNMT3AR882H mutations probably arise in very early hematopoietic precursors in the context of CHIP. Interestingly, as reported in figure 6, DNMT3AR882H expression levels were similar in samples from CML patients, healthy individuals and AML follow-up samples.Conclusions In summary, the results of our study indicate that DNMT3AR882H quantification is unreliable as a tool for AML monitoring. In fact, together with its detection in CML and healthy subjects, the presence of DNMT3AR882H at constant levels detected in AML during active disease or CR clearly point to a lack of specificity of this abnormality for the leukemic AML blast population. [Display omitted] DisclosuresCicconi:TEVA: Speakers Bureau. Lo Coco:Lundbeck: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; TEVA: Honoraria, Speakers Bureau.

The GIMEMA-ALLIANCE Digital Health Platform for Patients With Hematologic Malignancies in the COVID-19 Pandemic and Postpandemic Era: Protocol for a Multicenter, Prospective, Observational Study.

BackgroundThe COVID-19 pandemic has raised unprecedented challenges in the management of patients with cancer and has increased the demands for digital health tools that, for example, could facilitate remote monitoring of patients. Based on this, the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) has recently developed a digital health tool dedicated to patients with hematologic malignancies: the GIMEMA-ALLIANCE platform.ObjectiveThe main objectives of this web-based platform are to generate relevant data to better understand quality of life, symptoms, and medication adherence during the COVID-19 pandemic and postpandemic era; to develop a prospective real-life registry on outcomes of patients with hematologic cancer, with or without a diagnosis of COVID-19; and to facilitate patient-centered care in routine practice.MethodsThe platform consists of physician- and patient-secure portals and enables electronic patient-reported outcome (ePRO) assessments with real-time graphical presentation to physicians of individual patient symptoms and quality-of-life outcomes. Automated alerts are sent to treating hematologists based on the following predetermined criteria: presence of clinically important problems and symptoms, problems with adherence to therapy, and risk of COVID-19 diagnosis. The platform also allows physicians to set up video consultations. Clinical information regarding disease and treatment as well as clinical and survival outcomes are also prospectively collected.ResultsRecruitment of participants started in December 2020. As of April 2021, a total of 116 patients have been enrolled in this study. Use of this platform may help to improve patient-physician communication and help hematologists in the early recognition of clinically important problems and symptoms of their patients. More than 20 community and university-based hospitals have currently agreed to participate. In addition to patient-reported outcome data, the prospective collection of disease- and treatment-related information, as well as data on possible COVID-19 diagnosis and COVID-19 vaccination, will allow the development of a large database to also identify subgroups of patients at risk of poor outcomes.ConclusionsData generated via this platform will help to answer clinically relevant questions for patients with hematologic malignancies during the COVID-19 pandemic and postpandemic era. The use of the GIMEMA-ALLIANCE platform in routine practice may also contribute to enhancing patient-centered care.Trial RegistrationClinicalTrials.gov NCT04581187; https://clinicaltrials.gov/ct2/show/NCT04581187International Registered Report Identifier (IRRID)PRR1-10.2196/25271

Prognostic Impact of t(4;11)(q21;q23)/KMT2A-AFF1-Positivity in 926 BCR-ABL1-Negative B-Lineage Acute Lymphoblastic Leukemia Patients Treated in Gimema Clinical Trials Since 1996

Background and aims. B-lineage acute lymphoblastic leukemia (B-ALL) carrying t(4;11)(q21;q23)/KMT2A-AFF1 accounts for roughly 10% of adult B-ALL, it is associated to pro-B immunophenotype and aggressive clinical features. However, the role of KMT2A-AFF1 in pediatric-like, minimal residual disease (MRD)-driven clinical trials and the impact of transplant in this poor prognostic subgroup are still debated. To address these issues we investigated the incidence, clinical features and outcome of KMT2A-AFF1-positive ALL treated in 6 consecutive GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) clinical trials. Materials and methods. Between November 1996 and September 2016, 926 BCR-ABL1-negative B-ALL patients were enrolled in the GIMEMA clinical trials LAL0496, LAL2000, LAL0904, LAL1104, LAL1308, LAL1913. The median follow-up is 25.4 months (range: 0.1-146.9). Starting from LAL2000, KMT2A-AFF1-positive patients were classified as high-risk and managed more intensively. LAL1308 and LAL1913 adopted a similar pediatric-like backbone, at variance from LAL0496, LAL2000 and LAL0904. Overall, median age was 34.3 (range, 14.1 - 81.9), there were 502 males (54.2%) and 424 females (45.8%) and the median WBC count was 8.80 x 109/L (range, 0.4- 872.3). Incidence, clinical features and outcome of KMT2A-AFF1-positive were analyzed in comparison with KMT2A-AFF1-negative B-ALL. MRD evaluation after induction treatment was available in 197 patients enrolled in the more recent protocols. Results. Overall, 97/926 (10.5%) samples harbored KMT2A-AFF1 fusion gene. The comparison between KMT2A-AFF1-positive and the 829 KMT2A-AFF1-negative B-ALL patients revealed that KMT2A-AFF1-positive patients had a higher median age (42 vs 32.5 years old, p&amp;lt;0.001), were more likely to be female (60/97 vs 364/829, p=0.001) and had a significantly higher median WBC count (70.7 vs 7.2 x 109/L, p&amp;lt;0.001). The complete remission (CR) rate did not differ between KMT2A-AFF1-positive and -negative patients (87.5% vs 81.5%, p=0.188). Notwithstanding, at 24 months, KMT2A-AFF1-positive patients had a significantly shorter survival than KMT2A-AFF1-negative in terms of median overall (OS, 20.3% vs 45.5%, p=0.003, Figure 1A), disease-free (DFS, 9.2% vs 34.3%, p&amp;lt;0.0001) and event-free survival (EFS, 9.5% vs 21.9%, p=0.03, Figure 1B). Of the KMT2A-AFF1-positive patients, 25 underwent transplant (18 received an allograft, 7 an autograft) and - in keeping with this - survival analyses were repeated after censoring for transplant and we found that KMT2A-AFF1-positive patients maintained a significantly worse OS (p&amp;lt;0.0001), DFS (p&amp;lt;0.0001), EFS (p=0.036). Similarly, the effect of KMT2A-AFF1-positivity was adjusted for treatment received and retained statistical significance (HR: 1.3, 95%CI: 1.0-1.7, p=0.050). Moreover, when survival analyses were restricted to the only KMT2A-AFF1-positive patients, we did not observe significant differences among the median survival across the various clinical trials (p=0.581). MRD quantification, with the caveat that the number of patients evaluated for MRD is small, showed that KMT2A-AFF1-positive and negative patients did not differ in the achievement of MRD-negativity: indeed, 8/26 (30.8%) KMT2A-AFF1-positive and 71/171 (41.5%) KMT2A-AFF1-negative patients were MRD-negative post-induction. Conclusions. The present study examined a cohort of 926 BCR-ABL1-negative B-ALL treated in Italian multicenter clinical trials. Overall, though not differing in the achievement of CR and MRD negativity, the analysis of survival curves confirms that KMT2A-AFF1-positive patients have a significantly shorter survival than KMT2A-AFF1-negative patients. This result holds true also when censoring for transplant, thus suggesting that allograft does not confer a survival advantage to KMT2A-AFF1-positive patients. Moreover, KMT2A-AFF1-positive patients perform poorly also in more intensive regimen, as emerged from the analysis of the GIMEMA LAL1913 clinical trial. These findings encourage the adoption of alternative strategies: among the available targeted therapies, preclinical models of KMT2A-leukemia show sensitivity to BCL2-inhibitors, thus providing the rationale for testing this approach in upcoming clinical trials for KMT2A-AFF1-positive patients. Figure Disclosures Chiaretti: Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy. Bassan:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: 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; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. 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.

PF802 ANTICOAGULANT THERAPY IN THROMBOCYTOPENIC PATIENTS WITH BLOOD CANCER AND CATHETER‐RELATED VTE: RESULTS FROM A DELPHI CONSENSUS ON PLATELETS COUNT BELOW 50 X 109L

Background:Management of venous thromboembolism (VTE) in patients with haematological malignancies (HM) and thrombocytopenia challenges clinicians because this scenario is encumbered with several risks. Our panel, composed by elected members of the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) Working Party on Thrombosis and Haemostasis (WPHT). has recently published a consensus,reached by RAND method, focused on the platelet cut‐off for safely administering Low Molecular Weight Heparin (LMWH) in adult patients with hematological malignancies, acute (no later than 1 month) or non‐acute VTE and thrombocytopenia (PLT&lt; 100 × 109/L).Aims:Aim of the current study was to produce a formal consensus, not achieved by the previous method, focused on anticoagulant treatment with LMWH in adult patients with HM affected by acute or non‐acute catheter‐related VTE and severe thrombocytopeniaMethods:Delphi methodology was adopted to allow members of the GIMEMA‐WPHT to achieve consensus on the above reported issue, starting from available scientific data. For each indication, the panel members (N = 21, 3 validators and 18 participants) rated the benefit‐to‐harm ratio of the indication on a scale of 1 to 5, where 1 means that the expected harms greatly outweigh the expected benefits, and 5 means that the expected benefits greatly outweigh the expected harms. The first survey consisted of 7 different statement; after analysis of the first results, it was decided to discuss and re‐formulate 3 items, panel members were then asked to rate again items for which no consensus had been achieved. The interventions considered were the administration of different doses of LMWH (therapeutic, reduced dose at 50% of full therapeutic dose, prophylactic dose) and PLT transfusions, according to platelet counts &gt;30 &lt;50 × 109/L, in patients with catheter‐related VTE. LMWH doses were defined according to the datasheet for each LMWH molecule.Results:After the first round, an agreement &gt;80%was reached for 4 out of the initial 7 items. Three items were thus reformulated nd partecipants were asked to reasses them After the second round, an agreement was reached for all items. The panel of experts expressed the following consensus: for the management of acute‐catether related VTE with platelet counts &gt;30 &lt;50 × 109/L in patients with HM, anticoagulant treatment with reduced dose to 50% of LMWH is appropriate (90%agreement); for the management of non‐acute catheter‐related VTE, treatment with reduced dose to 50% of LMWH is also appropiate. PLTs transfusions were deemed inappropriate in both,acute (90% agreement) and non‐acute (100% agreement) catheter‐related VTE. The administration of prophylactic dose of LMWH was deemed inappropriate with an agreement of 90% in patients with acute catheter‐related VTE and 80% in subjects with non‐acute catheter‐related VTE.Summary/Conclusion:Delphi method has allowed to reach consensus on a still debated issue, where scientific evidences are lacking.GIMEMA‐WPHT suggests anticoagulant treatment with reduced dose to 50% of LMWH for platelet counts &gt;30 &lt;50 × 109/L in patients with haematological malignancies and either acute or non‐acute catheter‐related VTE.

Outcome of Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib within a Named Patient Program (NPP) in Italy. a Real-Life Retrospective Study

Outcome of Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib within a Named Patient Program (NPP) in Italy. a Real-Life Retrospective Study

Clinical and Serological Characteristics of Cold Autoimmune Hemolytic Anemia with Concomitant Cold Agglutinin and Donath-Landsteiner Antibodies

BackgroundThe two major types of cold autoimmune hemolytic anemias are cold agglutinin disease (CAD) and paroxysmal cold hemoglobinuria (PCH). In CAD, the cold agglutinin is usually IgM with anti-I specificity. In PCH, the Donath-Landsteiner (DL) antibody is a cold reacting IgG with anti-P specificity. In this study, we describe the clinical and serological characteristics of patients with autoimmune hemolytic anemia positive for both cold agglutinin and DL antibodies.MethodsOn review of our immunohematology reference laboratory database, we identified patients over a 16-year period (January 2000- March 2016) with the following: i) age ≥18 years, ii) hemoglobin (Hb) <12g/dL, iii) positive direct antiglobulin test (DAT) with hemolysis (increased lactate dehydrogenase/low serum haptoglobin/ elevated indirect bilirubin), and iv) tested for both CAD and DL antibodies. We classified the patients into 3 cohorts. Cohort 1 included patients positive for both cold agglutinin (titer ≥1:64) and DL antibodies. Cohort 2 consisted of patients with DL antibody but no cold agglutinin (titer <1:64), while Cohort 3 was comprised of patients with cold agglutinin but no DL antibody. We evaluated the clinical response based on the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) criteria (Barcellini W, et al . Blood 2014) defined as i) complete (CR): hemoglobin ≥12 g/dL with normalization of at least one previously abnormal hemolytic marker; ii) partial (PR): hemoglobin 10-12 g/dL with hemolysis; or iii) none (NR): if any of the above criteria were not met.ResultsSeven patients had cold autoimmune hemolytic anemia with concomitant cold agglutinin and DL antibodies (Cohort 1). The clinical and serological characteristics are described in table 1. The median age at diagnosis was 68 years (range: 59-78) and the median hemoglobin at onset was 10.3 g/dL (range: 8.2-10.6). Six had red cell agglutination in the blood smear. Two patients had a recent history of infection (1 with Mycoplasma pneumoniae and 1 with upper respiratory tract infection). The median follow-up was 4.8 months (range: 1.0-166.4). Five patients received steroid/other immunosuppressants and two were managed conservatively. The clinical response to treatment was CR in 28.6% patients, PR in 42.9%, and NR in 14.3%. In comparison, Cohort 2 had a 20% CR, 20% PR and 40% NR, while Cohort 3 had a 50% CR, 25% PR and 25% NR, respectively.ConclusionOur study is the first series describing patients with cold autoimmune hemolytic anemia with concomitant cold agglutinin and DL antibodies. In terms of clinical response, patients with negative DL antibodies and cold agglutinin titers >1:64 had better response (50% CR, Cohort 3) to immunosuppressants compared to patients with positive DL antibody (20-30% CR, Cohorts 1 and 2). Large scale studies may be warranted to determine the treatment strategies among patients with concomitant DL and high cold agglutinin titers. [Display omitted] DisclosuresKay:Agios: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Tolero Corporation: Research Funding; Gilead: Research Funding. Winters:Fresenius Kabi USA: Consultancy; Eliaz Therapeutics Inc: Membership on an entity's Board of Directors or advisory committees; Sanofi Inc: Other: Moderated opinion leader's forum; Wiley Blackwell: Employment; Regional Health Inc: Consultancy; Mayo Clinic: Employment; Grifols International SA: Consultancy.

Outcome of Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and/or 17p Deletion/TP53 Mutations Treated with Ibrutinib According to a Named Patient Program (NPP) in Italy: Preliminary Analysis of a Real Life Retrospective Study

Outcome of Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and/or 17p Deletion/TP53 Mutations Treated with Ibrutinib According to a Named Patient Program (NPP) in Italy: Preliminary Analysis of a Real Life Retrospective Study

Phase 1, multicenter, open-label, dose-escalation, combination study (NCT02103335) of pomalidomide (POM), marizomib (MRZ, NPI-0052), and dexamethasone (DEX) in patients with relapsed and refractory multiple myeloma (MM); study NPI-0052-107 preliminary results

toxic deaths. Methods: 1173 newly diagnosed MM patients entered the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) and European Myeloma Network (EMN) trials from May 2006 to September 2012. Overall, 511 patients received bortezomiband 662 patients lenalidomide-containing regimens. Results: 1146 patients started therapy and could be evaluated for this analysis. Death within 24 months of start of therapy occurred in 207 patients (18%). Among them, 61 patients (5%) died due to adverse events. Toxic deaths within 60 days occurred in 12 patients (1%) with a linear increase over time of 1% every 6 months. Thirty percent of deaths were attributable to cardiac complications (18 pts), 28% to infections (17 pts) and 15% to vascular complications (9 pts). There was no difference in the incidence of toxic deaths between patients receiving bortezomib (31 pts, 6%) or lenalidomide-containing regimens (30 pts, 5%, p1⁄40.32), nor in the proportions of toxic events. The incidence of toxic deaths was significantly higher in patients older than 80 years (11/107 [10%], p1⁄40.005). In multivariate analysis, factors associated with increased risk of early mortality were age (HR 1.09 per 1 year increase, p1⁄40.002) and ISS stage (HR 3.81, p1⁄40.01 ISS 2 vs ISS 1; HR 5.69, p1⁄40.002 ISS 3 vs ISS 1). Poor performance status was not a predictor of early death (HR 1.25, p1⁄40.59). By analyzing the impact of response, toxic deaths within 6 months occurred in patients with a suboptimal response (overall response rate 29%). Conclusions: Novel agents have substantially reduced the risk of toxic deaths as compared to conventional therapy. Nevertheless one-third of early deaths occurred due to cumulative specific drug-related toxicities. Cardio-vascular events and infections are the main causes. Greater tumor burden and activity (defined by ISS stage) increased the risk of death. The 2-fold higher risk of toxic mortality in octogenarians indicates the need for a careful assessment of frailty to identify patients who may benefit from a gentler approach.

The Genomic and Transcriptional Landscape of Waldenström’s Macroglobulinemia Impacts Disease Presentation, Overall Survival, and Therapeutic Response

toxic deaths. Methods: 1173 newly diagnosed MM patients entered the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) and European Myeloma Network (EMN) trials from May 2006 to September 2012. Overall, 511 patients received bortezomiband 662 patients lenalidomide-containing regimens. Results: 1146 patients started therapy and could be evaluated for this analysis. Death within 24 months of start of therapy occurred in 207 patients (18%). Among them, 61 patients (5%) died due to adverse events. Toxic deaths within 60 days occurred in 12 patients (1%) with a linear increase over time of 1% every 6 months. Thirty percent of deaths were attributable to cardiac complications (18 pts), 28% to infections (17 pts) and 15% to vascular complications (9 pts). There was no difference in the incidence of toxic deaths between patients receiving bortezomib (31 pts, 6%) or lenalidomide-containing regimens (30 pts, 5%, p1⁄40.32), nor in the proportions of toxic events. The incidence of toxic deaths was significantly higher in patients older than 80 years (11/107 [10%], p1⁄40.005). In multivariate analysis, factors associated with increased risk of early mortality were age (HR 1.09 per 1 year increase, p1⁄40.002) and ISS stage (HR 3.81, p1⁄40.01 ISS 2 vs ISS 1; HR 5.69, p1⁄40.002 ISS 3 vs ISS 1). Poor performance status was not a predictor of early death (HR 1.25, p1⁄40.59). By analyzing the impact of response, toxic deaths within 6 months occurred in patients with a suboptimal response (overall response rate 29%). Conclusions: Novel agents have substantially reduced the risk of toxic deaths as compared to conventional therapy. Nevertheless one-third of early deaths occurred due to cumulative specific drug-related toxicities. Cardio-vascular events and infections are the main causes. Greater tumor burden and activity (defined by ISS stage) increased the risk of death. The 2-fold higher risk of toxic mortality in octogenarians indicates the need for a careful assessment of frailty to identify patients who may benefit from a gentler approach.

Combination of international scoring system 3, high lactate dehydrogenase, and t(4;14) and/or del(17p) identifies patients with multiple myeloma (MM) treated with front-line autologous stem-cell transplantation at high risk of early MM progression-related death.

To construct and validate among patients with multiple myeloma (MM) who were treated with intensive therapy a prognostic index of early MM progression-related death. Patient-level data from the Intergroupe Francophone du Myélome (IFM) 2005-01 trial (N = 482) were used to construct the prognostic index. The event was MM progression-related death within 2 years from treatment initiation. The index was validated using data from three other trials: the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) 26866138-MMY-3006 trial (N = 480), the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA)-GEMMENOS65 trial (N = 390), and the Hemato-Oncologie voor Volwassenen Nederland (HOVON) -65/German-Speaking Myeloma Multicenter Group (GMMG) -HD4 trial (N = 827). The risk of early MM progression-related death was related to three independent prognostic variables: lactate dehydrogenase (LDH) higher than than normal, International Staging System 3 (ISS3), and adverse cytogenetics [t(4;14) and/or del(17p)]. These three variables enabled the definition of an ordinal prognostic classification composed of four scores (0 to 3). Patients with a score of 3, defined by the presence of t(4;14) and/or del(17p) in addition to ISS3 and/or high LDH, comprised 5% (20 of 387 patients) to 8% (94 of 1,139 patients) of the patients in the learning and validation samples, respectively, and they had a very poor prognosis. When applied to the population of 855 patients who had received bortezomib-based induction therapy in the four trials, the prognostic classification was also able to segregate patients into four categories, with a very poor prognosis attributed to patients with a score of 3. Our model allows the simple definition of a subgroup of MM patients at high risk of early MM progression-related death despite the use of the most modern and effective strategies.

Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial.

We assessed the prognostic impact of TET2 mutations and mRNA expression in a prospective cohort of 357 adult AML patients < 60 years of age enrolled in the European Organization For Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) AML-12 06991 clinical trial. In addition the co-occurrence with other genetic defects and the functional consequences of TET2 mutations were investigated. TET2 mutations occurred in 7.6 % of the patients and were an independent marker of poor prognosis (p = 0.024). TET2 and IDH1/2 mutations strongly associated with aberrations in the DNA methyltransferase DNMT3A. Functional studies confirmed previous work that neither nonsense truncations, nor missense TET2 mutations, induced 5-hydroxymethylcytosine formation. In addition, we now show that mutant TET2 forms did not act in a dominant negative manner when co-expressed with the wild-type protein. Finally, as loss-of-function TET2 mutations predicted poor outcome, we questioned whether low TET2 mRNA expression in cases of AML without TET2 mutations would affect overall survival. Notably, also AML patients with low TET2 mRNA expression levels showed inferior overall survival.

NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukemia undergoing first-line treatment: correlation with biological parameters and response to treatment

In chronic lymphocytic leukemia, NOTCH1, SF3B1, BIRC3 and TP53 disruptions are recurrent and affect survival. To define their incidence and clinical impact in patients undergoing first-line treatment, we evaluated 163 cases enrolled in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) LLC0405 protocol (fludarabine plus alemtuzumab or fludarabine plus cyclophosphamide), for young patients, or in the ML21445 protocol (chlorambucil plus rituximab), for elderly patients. NOTCH1, SF3B1, BIRC3 and TP53 disruptions were detected in 15.9%, 12.2%, 8.6% and 10.4% of cases. NOTCH1 mutations correlated with a shorter treatment-free interval (p = 0.058), an unmutated immunoglobulin heavy variable gene (IGHV) status (p < 0.0001), CD38 and ZAP-70 expression (p = 0.0025 and 0.026, respectively) and trisomy 12 (p = 0.0028), SF3B1 mutations with an unmutated IGHV status (p = 0.02), and BIRC3 disruptions with an unmutated IGHV configuration (p = 0.01) and 11q deletion (p < 0.0001). NOTCH1 and SF3B1 did not appear to impact on overall response, while an inferior response was observed for BIRC3- and TP53-disrupted cases in the LLC0405 and ML21445 protocols, respectively. Progression-free survival, evaluable in the LLC0405 protocol – not affected by NOTCH1, SF3B1 and TP53 – appeared inferior for BIRC3 disruption. NOTCH1 and SF3B1 mutations may be overcome by aggressive regimens, while BIRC3 might impact on outcome also in intensive regimens.

High-Dose Cytarabine in Induction Treatment Improves the Outcome of Adult Patients Younger Than Age 46 Years With Acute Myeloid Leukemia: Results of the EORTC-GIMEMA AML-12 Trial

Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission induction. Consensus has not been reached on the benefit of higher dosages of cytarabine. The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival. At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine. HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.

Bendamustine in combination with Ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m(2)) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.

Chronic Lymphocytic Leukemia: Past, Present and Future

Stefano Molica is Chief of the Department of Hematology–Oncology at the Azienda Ospedaliera “Pugliese-Ciaccio” (Catanzaro, Italy). He is a member of the American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH) and European Hematology Association, and is actively involved in the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) lymphoproliferative working group as a member of the working party. His current research is focused on investigating the impact of novel laboratory parameters useful for assessing the prognosis of chronic lymphocytic leukemia (CLL) and studying the role of angiogenesis in the disease. From a clinical standpoint he is actively involved in the management and treatment of patients with hematological malignancies and, particularly, those suffering from lymphoproliferative disorders. He has published 138 peer-reviewed papers primarily in the field of CLL and CLL-related disorders. He is a member of the editorial board of International Journal of Hematologic Oncology, as well as Leukemia &amp; Lymphoma, BMC Medicine and ISRN Hematology. Molica currently serves or has served as a referee for several hematology–oncology journals, such as Journal of Clinical Oncology, Blood, Haematologica, British Journal of Haematology, Leukemia Research, Leukemia, Leukemia &amp; Lymphoma, European Journal of Haematology and Cancer.

Prognostic factors associated with progression of smoldering multiple myeloma to symptomatic form

Smoldering multiple myeloma (SMM) presents a high risk of progression to symptomatic MM (sy-MM). Herein, we analyzed some predictors of development of sy-MM. In 144 patients with SMM, we also compared the risk of progression predicted by bone marrow plasma cell (BMPC) involvement on the bone marrow biopsy (BMB) versus bone marrow aspirates (BMA). From January 1980 to July 2010, 397 patients with SMM observed in 12 centers of the Multiple Myeloma GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) Latium Working Group have been analyzed. At progression to sy-MM, the severity of clinical presentation was graded according to the need of intensive supportive care. After a median follow-up of 135 months, the cumulative incidence of progression rates to sy-MM were 45%, 55%, and 75% at 10, 15, and 20 years, respectively. Hemoglobin ≤12.5 g/dL, monoclonal component ≥2.5 g/dL, and BMPC ≥60% were the only parameters negatively affecting the cumulative incidence of progression. In particular, 10 of 397 (2.5%) patients with BMPC ≥60% had a 5.6-fold increased risk of fast progression (within 2 years), which occurred with severe clinical manifestations in 62% of cases. BMB was more sensitive for the detection of BMPC involvement, even though BMA was a more reliable indicator of a rapid progression to sy-MM. The highest risk of rapid evolution to sy-MM and the severity of clinical manifestation at the progression suggest that SMM patients with a BMPC ≥60% should be treated soon after diagnosis. Moreover, BMPC is a more reliable index for progression to sy-MM if assessed by BMA.