Pulmonary infections in patients with acute myeloid leukemia receiving frontline treatment with hypomethylating agents.

Pulmonary infections (PIs) are a major complication of Acute Myeloid Leukemia (AML) treated with hypomethylating agents (HMA). We retrospectively evaluated 147 AML patients treated frontline with HMA in 2 Centers. Total number of HMA cycles was 1397. There were 88 episodes of PI in 64 patients (43.5%). Thirty-five/147 patients at risk (23.8%) developed at least 1 episode of early PI (during cycles 1-2). Median OS in patients who developed early PI was 3.3 months (95% CI 0.8 - 5.8) versus 10.5 months (95% CI 8.4 - 12.7) in patients without PI or with PI beyond the 2nd cycle (p < .001). Early PIs were an independent factor predicting lower survival (OR 1.94, 95% CI 1.28 - 2.93; p = .002). In conclusion, early PIs are common in AML patients receiving HMA and are associated with an unfavorable outcome. The results of our study raise the issue of a tailored infection prevention strategy.

Treatment in patients with acute myeloid leukemia/high-risk myelodysplastic syndrome with hypomethylating agents: Day-hospital management compared to home care setting.

OBJECTIVES: Aim of the study was to evaluate the role of a Domiciliary Hematologic Care Unit (DHCU) compared to standard DH setting in the active frontline treatment with hypomethylating agents (HMAs) +/- venetoclax of frail patients with acute myelogenous leukemia/high-risk myelodysplastic syndromes (AML/HR-MDS). METHODS: All patients with newly diagnosed AML/HR-MDS unfit for intensive care and treated frontline with HMAs from January 2010 to April 2021 were retrospectively included. RESULTS: Among 112 patients (62 AML/50 HR-MDS), 69 (61.6%) were treated in a standard DH setting and 43 (38.4%) were followed by DHCU, allocated to DH or DHCU by responsible physician. Overall response rate was 29/69 (42.0%) in DH versus 19/43 (44.1%) in DHCU (p = .797). Median response duration was 8.7 months (95%CI 7.0-10.3) in DH versus 13.0 months (95%CI 8.3-17.6) in DHCU (p = .460). Infections were also equally reported. Median overall survival of patients treated in DH was 13.7 months (95%CI 9.9-17.4) compared to 13.0 months (95%CI 6.7-19.3) of patients managed by DHCU (p = .753). CONCLUSIONS: Home care management of HMA is feasible and effective, with results similar to standard DH setting: this approach is thus adequate to offer active therapies in frail patients with AML/HR-MDS considered up to now ineligible.

Identification of Predictive Factors for Overall Survival and Response during Hypomethylating Treatment in Very Elderly (≥75 Years) Acute Myeloid Leukemia Patients: A Multicenter Real-Life Experience.

Elderly patients represent the most challenging and hard-to-treat patient population due to dismal characteristics of the disease, such as secondary-acute myeloid leukemia (AML), enrichment of unfavorable molecular genes (TP53) and comorbidities. We conducted a multicentric retrospective study to evaluate activity and safety in a real-life setting of hypomethylating drugs (HMAs) in patients older than 75 years with AML. Between September 2010 and December 2021, 220 patients were treated, 164 (74.5%) received AZAcitidine and 56 DECitabine; most patients (57.8%), received more than four cycles of HMAs. The best response obtained was CR in 51 patients (23.2%), PR in 23 (10.5%) and SD in 45 (20.5%); overall transfusion independence was obtained in 47 patients (34%), after a median of 3.5 months. The median OS (mOs) was 8 months (95% CI 5.9-10.2), with 1- and 2-years OS of 39.4% (95% CI 32.7-46) and 17.4% (95% CI 11.7-23.1), respectively; similar mOS was observed according to HMA treatment (AZA 8.3 vs. DEC 7.8 months, p = 0.810). A subset of 57 long survivors (44 in AZA group and 13 in DEC group) received at least 12 cycles of HMAs, their mOS was 24.3 months. In multivariate analysis, age (≥80), Charlson comorbidity index (≥3), creatinine clearance and the type of best response (≥PR) during treatment maintained independent significance in predicting survival. Infectious complications, most frequently pneumonia (35) and septic shock (12), were lethal in 49 patients (22.2%). Our data show that HMAs have similar efficacy compared to pivotal trials and are well tolerated in a setting of very elderly patients with several co-comorbidities.

Myelodysplastic Syndromes with Isolated 20q Deletion: A New Clinical-Biological Entity?

Aims: To define the peculiar features of patients with the deletion of the chromosome 20 long arm (del20q), data from 69 patients with myelodysplastic syndromes (MDSs) and isolated del20q, followed by the Gruppo Romano-Laziale Sindromi Mielodisplastiche (GROM-L) and Ospedale Torrette of Ancona, were collected and compared with those of 502 MDS patients with normal karyotype (NK-MDS). Results: Compared to the NK-MDS group, patients with del20q at diagnosis were older (p = 0.020) and mainly male (p = 0.006). They also had a higher rate of bone marrow blast < 5% (p = 0.004), a higher proportion of low and int-1 risk according to IPSS score (p = 0.023), and lower median platelet (PLT) count (p < 0.001). To date, in the del20q cohort, 21 patients (30.4%) received no treatment, 42 (61.0%) were treated with erythropoiesis-stimulating agents (ESA), 3 (4.3%) with hypomethylating agents, and 3 (4.3%) with other treatments. Among 34 patients evaluable for response to ESA, 21 (61.7%) achieved stable erythroid response according to IWG 2006 criteria and 13 (38.2%) were resistant. Nine patients (13.0%) progressed to acute myeloid leukaemia (AML) after a median time from diagnosis of 28 months (IR 4.1−51.7). The median overall survival (OS) of the entire cohort was 60.6 months (95% CI 54.7−66.4). the 5-year cumulative OS was 55.9% (95% CI 40.6−71.2). Conclusion: According to our results, we hypothesize that MDSs with isolated del 20q may represent a distinct biological entity, with peculiar clinical and prognostic features. The physio-pathological mechanisms underlying the deletion of the chromosome 20 long arm are still unclear and warrant future molecular analysis.

Safety and effectiveness of ruxolitinib in the real-world management of polycythemia vera patients: a collaborative retrospective study by pH-negative MPN latial group.

Ruxolitinib is approved for polycythemia vera (PV) patients after failure to previous cytoreductive therapy, based on durable results observed in phase 3 trials. We report a multicenter retrospective study demonstrating the efficacy and safety of ruxolitinib in real-life setting. Eighty-three patients were evaluated. Median follow-up was 24.5 months (IQR 14.0-29.3). At a 3-month response assessment, ruxolitinib provided significant benefit in reducing hematocrit (HCT) level (p < 0.001), phlebotomy requirement (p < 0.001), leucocytes (p = 0.044), and disease-related symptoms (p < 0.001). The exposure-adjusted rates (per 100 patient-years) of infectious complications, thromboembolic events, and secondary malignancies were 6.9, 3, and 3.7, respectively. Non-melanoma skin cancers (NMSC) were the most frequent (40%) SM type. Lymphoproliferative disorders were not detected. Five (6%) patients permanently discontinued ruxolitinib treatment and four (5%) evolved in myelofibrosis (MF), but none in acute leukemia. The rate of MF evolution per 100 patient-years of exposure was 2.8. In our experience, ruxolitinib confirmed its efficacy and safety outside of clinical trials.

Deferasirox in the management of iron overload in patients with myelofibrosis treated with ruxolitinib: The multicentre retrospective RUX-IOL study.

Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX-DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1-71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX-DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.

Bosutinib in the real-life treatment of chronic myeloid leukemia patients aged >65 years resistant/intolerant to previous tyrosine-kinase inhibitors.

To evaluate the role of bosutinib in elderly patients aged >65 years with chronic myeloid leukemia (CML), a real-life cohort of 101 chronic-phase CML patients followed up in 23 Italian centers and treated with bosutinib in second or a subsequent line was retrospectively evaluated. Starting dose of bosutinib was 500 mg/day in 25 patients (24.8%), 400 mg/day in 7 patients (6.9%), 300 mg/day in 33 patients (32.7%), 200 mg/day in 34 patients (33.6%), and 100 mg/day in 2 patients (2.0%). Grade 3/4 hematological toxicity occurred in 7/101 patients (6.9%) and grade 3/4 extra-hematological toxicity in 19/101 patients (18.8%). Permanent bosutinib discontinuation due to toxicity was needed in 12 patients (11.9%). Among the 96 patients evaluable for response, 74 (77.0%) achieved a complete cytogenetic response (CCyR), while 64 of these 74 patients in CCyR (66.6% of all 96 evaluable patients) also achieved a molecular response (MR) (major MR [MR 3.0] in 21 [21.8%], deep MR [MR 4.0/4.5] in 43 [44.8%]). The 3-year event-free survival and overall survival of the whole patients' cohort from bosutinib start were 60.9% (CI 95% 49.3-72.5) and 86.4% (CI 95% 77.2-95.6), respectively. Our real-life data show that bosutinib is effective, with a favorable safety profile, also in elderly patients with important comorbidities and resistance and/or intolerance to previous tyrosine-kinase inhibitor treatments. As a consequence, it could play a significant role in current clinical practice for frail patients.

Anagrelide in Essential Thrombocythemia (ET): Results from 150 patients over 25 years by the "Ph1-negative Myeloproliferative Neoplasms Latium Group".

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.

Second cancers in MPN: Survival analysis from an international study.

One out of ten patients with Philadelphia-negative myeloproliferative neoplasms (MPN) develop a second cancer (SC): in such patients we aimed at assessing the survival impact of SC itself and of MPN-specific therapies. Data were therefore extracted from an international nested case-control study, recruiting 798 patients with SC diagnosed concurrently or after the MPN. Overall, 2995 person-years (PYs) were accumulated and mortality rate (MR) since SC diagnosis was 5.9 (5.1-6.9) deaths for every 100 PYs. A "poor prognosis" SC (stomach, esophagus, liver, pancreas, lung, ovary, head-and-neck or nervous system, osteosarcomas, multiple myeloma, aggressive lymphoma, acute leukemia) was reported in 26.3% of the patients and was the cause of death in 65% of them (MR 11.0/100 PYs). In contrast, patients with a "non-poor prognosis" SC (NPPSC) incurred a MR of 4.6/100 PYs: 31% of the deaths were attributed to SC and 15% to MPN evolution. At multivariable analysis, death after SC diagnosis was independently predicted (HR and 95% CI) by patient age greater than 70 years (2.68; 1.88-3.81), the SC prognostic group (2.57; 1.86-3.55), SC relapse (1.53; 10.6-2.21), MPN evolution (2.72; 1.84-4.02), anemia at SC diagnosis (2.32; 1.49-3.59), exposure to hydroxyurea (1.89; 1.26-2.85) and to ruxolitinib (3.63; 1.97-6.71). Aspirin was protective for patients with a NPPSC (0.60; 0.38-0.95). In conclusion, SC is a relevant cause of death competing with MPN evolution. Prospective data are awaited to confirm the role of cytoreductive and anti-platelet drugs in modulating patient survival after the occurrence of a SC.

Arterial thrombosis in Philadelphia-negative myeloproliferative neoplasms predicts second cancer: a case-control study.

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.

Cytotoxicity and Differentiating Effect of the Poly(ADP-Ribose) Polymerase Inhibitor Olaparib in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are highly heterogeneous myeloid diseases, characterized by frequent genetic/chromosomal aberrations. Olaparib is a potent, orally bioavailable poly(ADP-ribose) polymerase 1 (PARP1) inhibitor with acceptable toxicity profile, designed as targeted therapy for DNA repair defective tumors. Here, we investigated olaparib activity in primary cultures of bone marrow mononuclear cells collected from patients with MDS (n = 28). A single treatment with olaparib induced cytotoxic effects in most samples, with median IC50 of 5.4 µM (2.0-24.8 µM), lower than plasma peak concentration reached in vivo. In addition, olaparib induced DNA damage as shown by a high proportion of γH2AX positive cells in samples with low IC50s. Olaparib preferentially killed myeloid cells causing a significant reduction of blasts and promyelocytes, paralleled by an increase in metamyelocytes and mature granulocytes while sparing lymphocytes that are not part of the MDS clone. Consistently, flow cytometry analysis revealed a decrease of CD117+/CD123+ immature progenitors (p < 0.001) and induction of CD11b+/CD16+ (p < 0.001) and CD10+/CD15+ (p < 0.01) neutrophils. Morphological and immunophenotypic changes were associated with a dose-dependent increase of PU.1 and CEBPA transcription factors, which are drivers of granulocytic and monocytic differentiation. Moreover, the combination of olaparib with decitabine resulted in augmented cytotoxic and differentiating effects. Our data suggest that olaparib may have therapeutic potential in MDS patients.

Second cancer in Philadelphia negative myeloproliferative neoplasms (MPN-K). A nested case-control study.

We conducted a large international nested case-control study including 1881 patients with Philadelphia-negative myeloproliferative neoplasms (MPN). Cases (n = 647) were patients with second cancer (SC: carcinoma, non-melanoma skin cancer, hematological second cancer, and melanoma) and controls (n = 1234) were patients without SC, matched with cases for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. The aim was to evaluate the risk of SC after exposure to cytoreductive drugs. Patients exposed to hydroxyurea (HU) (median: 3 years) had a risk of SC similar to unexposed patients (OR = 1.06, 95% CI 0.82-1.38). In contrast, in cancer-specific stratified multivariable analysis, HU had two-fold higher risk of non-melanoma (NM) skin cancer (OR = 2.28, 95% CI 1.15-4.51). A significantly higher risk of NM-skin cancer was also documented for pipobroman (OR = 3.74, 95% CI 1.00-14.01), ruxolitinib (OR = 3.87, 95% CI 1.18-12.75), and for drug combination (OR = 3.47, 95% CI 1.55-7.75). These three drugs did not show excess risk of carcinoma and hematological second cancer compared with unexposed patients. Exposure to interferon, busulfan, and anagrelide did not increase the risk. In summary, while it is reassuring that no excess of carcinoma was documented, a careful dermatologic active surveillance before and during the course of treatments is recommended.

Treatment of Philadelphia-negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors.

There have been some reports on a possible role of azacytidine (AZA) in the treatment of accelerated/blastic phase evolved from Philadelphia-negative myeloproliferative neoplasms (MPN-AP/BP), but results are conflicting. In this study, we analyzed a cohort of 39 patients with MPN-AP/BP treated frontline with AZA at the standard dosage (75 mg/m2 ). Median time from diagnosis to AP/BP evolution was 92.3 months (IR 29.9-180.1). All patients were evaluable for hematologic response: two patients (5.2%) died early after AZA initiation, 13 patients (33.3%) had a progressive or stable disease, nine (23.1%) had a hematologic improvement (HI), seven (17.9%) achieved a partial response (PR), and eight (20.5%) a complete response (CR). Overall, 24 patients achieved a clinical hematologic response (HI + PR + CR), with an overall response rate of 61.5%. Median overall survival (OS) from AZA start of the whole cohort was 13.5 months (95% CI, 8.2-18.7). There was no difference in median OS among patients with HI, PR, or CR (P = .908). These three subgroups as "responders" having been considered, a significantly better OS was observed in responder compared with nonresponder patients, with a median OS of 17.6 months (95% CI, 10.1-25.0) versus 4.1 months (95% CI, 0.4-10.0) (P = .001) Only female gender was significant for both achievement of response (.010) and OS duration (P = .002). In conclusion, AZA is useful for the management of MPN-AP/BP, with an overall response rate (HI + PR + CR) of 61.5% and a longer OS in responders.

Deferasirox in the treatment of iron overload during myeloproliferative neoplasms in fibrotic phase: does ferritin decrement matter?

Few data are available on the treatment with DFX in patients with transfusion dependent Ph- Myeloproliferative Neoplasms in fibrotic phase. Here we report 48MPNpatients and iron overload treated with DFX. Starting DFX dose was 20 mg/Kg in 23 patients, 15 mg/Kg in 20 patientsand 10 mg/Kg in 5 patients. After a median treatment of 27.6 months, 5 patients achieved ferritin<500 ng/ml, 11 < 1000 ng/ml and 3 a reduction >50% of basal ferritin with a global response rate of 41%. As to hematological improvement, 9/47 patients (19.1%) showed a persistent rise of Hb>1.5 g/dl, with disappearance of transfusion requirement in 6 cases. The median OS from DFX initiation in patients with chelation response was 61.0 months compared to 15.8 months in patients without chelation efficacy. Treatment with DFX is feasible and effective in MPN with iron overload and a hematological improvement can occur in a sizeable rate of patients.