In recent years the management of patients (pts) with chronic lymphocytic leukemia (CLL) has benefited from a deeper knowledge of the mechanisms underlying the disease and from the development of ...novel therapeutic approaches. That notwithstanding, local and national accessibility to drugs and tests may lead to distinct “real-world” practices in terms of management of pts that are worth of being recorded and compared to understand the degree of reproducibility and applicability of international guidelines. This could also be relevant for the design of future clinical trials, more tailored to the true patient's needs. To this end, within the GIMEMA cooperative study group the observational retrospective and prospective CLL2121 study (NCT04867915) has been designed with the objective of evaluating the diagnosis and management of CLL in all hematological centers in Italy through the assessment of: 1) the methods and the actual diagnostic/prognostic work-up capacity; 2) the algorithms applied to define disease progression and treatment requirements with respect to national and international guidelines; 3) the clinical and biological variables not strictly associated with CLL, but capable of influencing the clinical course and overall survival; 4) the true incidence of some rarer complications associated with CLL. The study consists of a collection of clinico-biological data from all pts with newly diagnosed CLL, small lymphocytic lymphoma (SLL) or CLL-like monoclonal B-cell lymphocytosis (MBL), according to the iwCLL 2018 criteria in Italy. The retrospective part aims at including all cases followed at the participating centers with a diagnosis between January 2010 and September 2021, while the prospective part will include all pts with a documented diagnosis of CLL, SLL or MBL between September 2021 and September 2025. In this pilot analysis of the study, we examined pts' demographics, diagnosis, treatment line and type. Data were collected using the REDCap electronic data capture platform, analyzed using the SAS software v.9.4 and reported as numbers and frequencies. Between 2 November 2021 and 28 June 2023, 3294 eligible pts were enrolled in 75 hematology centers (out of the total of 110 centers who will be activated during the study) across the entire Italian territory. At the time of the present report, 3033 pts had clinical data available for our preliminary analysis. The vast majority of pts registered (N=2599, 85.7%) belonged to the retrospective cohort while only a minority (N=434, 14.3%) to the prospective cohort. Pts had a median age of 68 years ranging from 29 to 97; 60% of pts were males. 2630 pts (86.8%) had a diagnosis of CLL, 187 (6.2%) of SLL and 214 (7.0%) of MBL (2 missing information). Among those with available results 112 pts (12.6%) were TP53 mutated, 526 (45.6%) del(13q) positive, 174 (14.9%) del(11q) positive, 142 (11.9%) del(17p) positive and 226 (20.4%) presented a trisomy 12. The majority of pts (57.6%) were untreated, while 42.4% have been treated. Within the latter subset, 67.3% of pts have received one line of therapy, 21.4% 2 lines of therapy, 11.3% ≥3 lines of therapy. The most common therapeutic regimens were the combination of chemotherapy with an anti-CD20 antibody (39.3%), mainly rituximab, and those based on BTK inhibitors (33.3%), mainly ibrutinib. Chemotherapy alone was used in 12% of pts. Only 5% of pts was treated with the BCL2 inhibitor venetoclax. In the remaining 10% of pts, other approaches were used. This is the initial report of a nation-based real-world data collection aimed at describing the biological and clinical features of pts diagnosed with CLL in virtually all Italian hematology centers starting from 2010. The pattern of treatments highlighted in our preliminary analysis, with a wide use of the watch & wait policy and of chemoimmunotherapy, will help understand how the introduction of novel therapies impacted treatment habits also in light of the timing of the local reimbursement policy. The different time of drug access in Italy, typically delayed after the EU approval, may also have affected the limited use of venetoclax-based treatment. The continuous accrual of pts in this study will allow to obtain a close-to-registry vision of CLL management in Italy over time, in terms of coverage of the entire country but enriched with the granularity of the data and flexibility of the collection typical of a real-world study.
Background and aims
Anagrelide is a drug effective in reducing platelet counts in essential thrombocythemia (ET) and Ph1‐negative myeloproliferative neoplasms. The aim of this study was to evaluate ...the real‐life use of anagrelide in patients with ET followed over 25 years at the Haematological Institutes belonging to “Ph1‐negative Myeloproliferative Neoplasms Latium Group.”
Patients and methods
Eligibility criteria were diagnosis of ET and treatment with anagrelide. Data were collected through an ad hoc case report form.
Results
One hundred and fifty patients received anagrelide for a median time of 7.4 years (0.1‐23.2). Anagrelide was administered as first‐line therapy in 34.7% of patients, as second‐line in 52% and as third‐line in 13.3%: 85.4% responded to therapy. Sixty‐eight/136 evaluable patients reported side effects: palpitations, peripheral vasodilation, anaemia, diarrhoea and gastric distress. Fourteen thrombotic (arterial 10, venous 4) and 51 bleeding events (minor 48, major 3) occurred. Sixteen/150 (10.6%) patients developed secondary myelofibrosis and 3/150 (2%) an acute myeloid leukaemia.
Conclusions
In our experience, anagrelide is an effective drug in reducing platelet levels in a high percentage of patients with ET. It is especially addressed to younger people. A careful assessment of the thrombotic risk and monitoring of cardiac function, at diagnosis and during follow‐up, is mandatory.
Summary
Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute ...promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher‐than‐normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low‐risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.
Background: Cold agglutinin disease (CAD) is a chronic hemolytic disorder caused by the presence of an IgM autoantibody with specificity towards red cell antigens. The autoantibody is produced by a ...B-cell clone, which can often be detectable with standard diagnostic work-up. Some patients with CAD require transfusions to compensate for the chronic red cell destruction. There are few therapeutic modalities of proven efficacy which include alkylating agents, rituximab alone or in combination with fludarabine or bendamustine. Bortezomib is a proteasome inhibitor which has been successfully used in Ig-producing diseases, like amyloidosis and Waldenstrom macroglobulinemia (WM). Protein metabolism is a tightly regulated process, and inhibition of its turnover using proteasome inhibitors may lead to apoptosis in protein secreting B-cell malignancies, including multiple myeloma (MM) and WM. Aim: We have conducted a prospective multicenter, phase II, open label study (ClinicalTrials.gov NCT01696474) to evaluate the potential efficacy of a short course of bortezomib in anemic patients with CAD requiring transfusion or with a hemoglobin concentration below 100 g/L determined at least monthly during the two months before entering the trial. Patients and Methods: Patients had to be refractory to at least one previous treatment. The primary endpoint was the achievement of transfusion independence or a significant rise (>20 g/L) of hemoglobin concentration. A single course of bortezomib was given at the dose of 1,3 mg/sqm iv on days 1, 4, 8, 11. Safety evaluation, duration of transfusion independence, and the effects of treatment on the underlying clonal B-cell disorder were secondary objectives of the trial. Patients with a concomitant lymphoproliferative disorder requiring specific treatment for reasons other than CAD or with preexisting peripheral neuropathy were excluded. Results: Between 12-04-2012 and 03-14-2016, 21 patients have been enrolled by 6 Gimema italian centers. Their characteristics were as follows: median age 70 years (range 53 to 85); M/F ratio: 1/2; 6 patients had concomitant or previous clonal B-cell disorder (3 CLL, 3 B-cell lymphoma) not requiring specific therapy. Previous treatments included corticosteroids, rituximab, cyclophosphamide, azathioprine or combinations of them. Median Hb concentration at study entry was 87 g/dL (range 78-102). Ten patients were transfusion-dependent. Treatment response was evaluated at three months. Two patients stopped treatment early, one at day 4 because of pulmonary embolism and the other at day 8 because of headache, respectively, and were excluded from efficacy analysis. One of them actually achieved transfusion independence in spite of treatment stop. Of 19 evaluable patients, 3 achieved complete remission, defined as normalization of hemoglobin levels and absence of symptoms or signs of hemolysis and 3 partial remission, defined as the achievement of transfusion independence or of a stable increase of > 20g/L of hemoglobin concentration in untransfused patients, for an overall response rate of 31,6%. Four of the 6 responding patients achieved transfusion independence. The small number of patients studied precluded an analysis of factors associated with response. Five grade 3 adverse events, including headache, diarrhea, increased bilirubin levels, anemia and upper respiratory tract infection (URTI) in one patient each, and one grade 4 pulmonary embolism. They were considered not related to study drug, except for URTI. Four of 6 responding patients maintained the response after 12 months from study entry (66,7%; 95% CI: 37.9-100). All patients were alive at last follow up except for one who died of septic shock during off treatment follow up, 10 months after study entry. The effects of bortezomib on underlying B-cell lymphoproliferative disorder are being evaluated. Conclusions: The data demonstrate that a short course of bortezomib may be effective in a subset of patients with symptomatic CAD failing previous treatments, with acceptable toxicity. Responses seem to be long-lasting in the majority of responding patients. These data provide a rational for further investigating the potential benefits of bortezomib either by using a more prolonged treatment schedule or in combination with other active agents. The study has been supported by JANSSEN-CILAG Spa which provided bortezomib and a grant for study monitoring.
Rossi:Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Zaja:Celgene: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria, Research Funding; Janssem: Honoraria; Abbvie: Honoraria; Roche: Honoraria, Research Funding; Gilead: Honoraria. Mauro:Janssen: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Gilead: Honoraria. Barcellini:Alexion: Honoraria; Agios: Honoraria, Research Funding; Novartis: Honoraria.
Highlights • 34% of adult B-lineage ALL without aberrations have high CRLF2 expression levels. • In adult B-ALL, CRLF2 expression has prognostic significance. • Also in adult B-ALL, CRLF2 is ...associated with JAK/STAT and IKZF1 lesions.
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Background. Minimal residual disease (MRD) is the strongest prognostic factor in both children and adults with acute lymphoblastic leukemia (ALL). Currently, it is most widely monitored by ...molecular methods based on real-time-quantitative-PCR (RQ-PCR). Digital-droplet-PCR (ddPCR) and next-generation-sequencing (NGS) represent advanced tools that have the potential to overcome some limitations of standard approaches and potentially provide additional benefits. We analyzed adult ALL follow-up (FU) samples by RQ-PCR, ddPCR and NGS in order to better define the discriminating power of these novel methods.
Patients and Methods. Thirty adult ALL patients enrolled in the GIMEMA LAL 1913 protocol and their 83 FU bone marrow (BM) samples were studied. All patients received homogeneous induction/early consolidation chemotherapy, with concurrent MRD analysis at four time-points, to optimize risk classification and support risk/MRD-oriented therapy. RQ-PCR analyses followed the EuroMRD Consortium guidelines (van der Velden, 2007), ddPCR was performed as published (Della Starza, 2016; Cavalli, 2017) and NGS, as previously described (Faham, 2012; Kotrova M, 2017).
Results. By MRD RQ-PCR analysis, 19/83 samples were positive and quantifiable (Q), 9/83 were positive not-quantifiable (PNQ) and 55/83 were negative (NEG). By MRD ddPCR analysis, 27/83 samples were Q, 1/83 sample was PNQ and 55/83 proved NEG. Comparing the results of the two methods, we observed that MRD detection was concordantly positive or negative in 81% (67/83) of FU samples, while 19% (16/83) samples were classified as discordant. Most of the discordances occurred in samples with low levels of disease, i.e. PNQ or NEG: 9/83 were RQ-PCR PNQ, 4 of which were Q by ddPCR and 5 were ddPCR NEG. In the remaining 7 discordant FU samples, 5 were RQ-PCR NEG/ddPCR Q, 1 sample was RQ-PCR Q /ddPCR NEG and 1 sample was RQ-PCR NEG/ddPCR PNQ. The use of ddPCR significantly reduced the proportion of PNQ samples if compared to RQ-PCR - 1/83 (3%) vs 9/83 (15%) - respectively (p=0.0179), increasing the proportion of Q samples: 27/83 (33%) vs 19/83 (23%). It is worth noting that ddPCR also quantified the levels of disease in 9% (5/55) of samples, that were RQ-PCR NEG (Table 1).
MRD analysis was also performed by NGS in 41 samples from 15 patients: 18/41 samples proved Q and 23/41 were NEG. Comparing the MRD detection obtained by both ddPCR and NGS, we observed a concordant result in 98% (40/41) of samples; only 1 sample was ddPCR NEG and NGS Q with a MRD level of 1x10-5. The concordance between RQ-PCR and NGS was 78% (32/41 samples). Moreover, among these 41 samples 9 (from 7 patients) were discordant between RQ-PCR and ddPCR in the first comparative analysis: in 4 RQ-PCR-NEG FU samples, 3 were Q by both ddPCR and NGS, 1 was ddPCR NEG and NGS Q, with a MRD level of 10- 5; 1 subsequent relapse was observed; 4 FU samples that were RQ-PCR-PNQ/ddPCR-Q, were Q also by NGS; 1 subsequent relapse was observed. Finally, 1 RQ-PCR-PNQ sample was negative by both ddPCR and NGS, and no recurrence has so far been observed. Moreover, in the cohort of samples analyzed only by RQ-PCR and ddPCR, in 1 RQ-PCR NEG/ddPCR Q sample a relapse was observed, while the only case that was RQ-PCR Q/ddPCR NEG has so far not relapsed. Notably, 2 of the 3 relapses were documented in patients who were, at decisional treatment TPs, RQ-PCR PNQ or NEG and ddPCR/NGS Q.
Conclusions. When MRD levels are very low, it can be difficult to dissect if the not-quantifiable signal observed by PCR is due to few residual leukemic cells or to a non-specific amplification of normal DNA. The superior sensitivity and accuracy of ddPCR and NGS could be instrumental to univocally define these samples, which presently represent a problematic gray area in the clinical practice of MRD-driven protocols and might be associated with clinical relapse: indeed, among 83 FU samples analyzed we observed 3 relapses, whose FU samples were classified as PNQ or NEG by RQ-PCR, but proved Q by ddPCR and/or NGS. At variance, no relapses were recorded in patients whose FU samples were defined RQ-PCR-PNQ, but proved ddPCR/NGS NEG. Moreover, in 2/3 relapsed cases the change of MRD status (PNQ or NEG vs Q) could have led to a switch in risk classification and therefore in a treatment change. Further studies with a larger number of discrepant cases and a longer FU time will allow to conclusively define the clinical application and implication of these new methods.
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Chiaretti:Shire: Consultancy; Pfuzer: Consultancy; Amgen: Consultancy; Incyte: Consultancy. Foà:NOVARTIS: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau.
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.
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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.
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