A real-world retrospective-prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience.

INTRODUCTION: Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE-MM1. OBJECTIVES AND METHODS: We conducted a retrospective-prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. RESULTS: At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high-risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)-exposed (including both Len-sensitive and Len-refractory pts), and 22% were Len-refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non-hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1-2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow-up of 38 m, median PFS (mPFS) was 16 m and the 1-year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len-naïve (NR), age ≥70 (20 m). In pts exposed to Len, non-refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len-refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). CONCLUSION: IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len-sensitive, independent of age, and cytogenetic risk.

A real-life study of daratumumab-bortezomib-dexamethasone (D-VD) in lenalidomide exposed/refractory multiple myeloma patients: a report from the Triveneto Myeloma Working Group.

Treatment of lenalidomide refractory (Len-R) multiple myeloma (MM) patients still represents an unmet clinical need. In the last years, daratumumab-bortezomib-dexamethasone (D-VD) combination was extensively used in this setting, even though only a small fraction of Len-R patients was included in the pivotal trial. This real-life study aimed to evaluate the efficacy and safety of the D-VD regimen in a cohort that exclusively enrolled Len exposed or refractory MM patients. The study cohort included 57 patients affected by relapsed/refractory MM. All patients were previously exposed to Len, with 77.2% being refractory. The overall response rate (ORR) was 79.6% with 43% of cases obtaining at least a very good partial response (VGPR). The D-VD regimen showed a favorable safety profile, with low frequency of grade 3-4 adverse events, except for thrombocytopenia observed in 21.4% of patients. With a median follow-up of 13 months, median progression-free survival (PFS) was 17 months. No significant PFS differences were observed according to age, ISS, LDH levels, type of relapse, and high-risk FISH. Len exposed patients displayed a PFS advantage as compared to Len refractory patients (29 vs 16 months, p = 0.2876). Similarly, patients treated after Len maintenance showed a better outcome as compared to patients who had received a full-dose Len treatment (23 vs 13 months, p = 0.1728). In conclusion, our real-world data on D-VD combination showed remarkable efficacy in Len-R patients, placing this regimen as one of the standards of care to be properly taken into account in this MM setting.

Refractory primary immune thrombocytopenia (ITP): current clinical challenges and therapeutic perspectives.

Chronic primary immune thrombocytopenia (ITP) can today benefit from multiple therapeutic approaches with proven clinical efficacy, including rituximab, thrombopoietin receptor agonists (TPO-RA), and splenectomy. However, some ITP patients are unresponsive to multiple lines of therapy with prolonged and severe thrombocytopenia. The diagnosis of refractory ITP is mainly performed by exclusion of other disorders and is based on the clinician's expertise. However, it significantly increases the risk of drug-related toxicity and of bleedings, including life-threatening events. The management of refractory ITP remains a major clinical challenge. Here, we provide an overview of the currently available treatment options, and we discuss the emerging rationale of new therapeutic approaches and their strategic combination. Particularly, combination strategies may target multiple pathogenetic mechanisms and trigger additive or synergistic effects. A series of best practices arising both from published studies and from real-life clinical experience is also included, aiming to optimize the management of refractory ITP.

Nuclear translocation of PKC-α is associated with cell cycle arrest and erythroid differentiation in myelodysplastic syndromes (MDSs).

PI-PLCß1 is involved in cell proliferation, differentiation, and myelodysplastic syndrome (MDS) pathogenesis. Moreover, the increased activity of PI-PLCß1 reduces the expression of PKC-α, which, in turn, delays the cell proliferation and is linked to erythropoiesis. Lenalidomide is currently used in low-risk patients with MDS and del(5q), where it can suppress the del(5q) clone and restore normal erythropoiesis. In this study, we analyzed the effect of lenalidomide on 16 patients with low-risk del(5q) MDS, as well as del(5q) and non-del(5q) hematopoietic cell lines, mainly focusing on erythropoiesis, cell cycle, and PI-PLCß1/PKC-α signaling. Overall, 11 patients were evaluated clinically, and 10 (90%) had favorable responses; the remaining case had a stable disease. At a molecular level, both responder patients and del(5q) cells showed a specific induction of erythropoiesis, with a reduced γ/ß-globin ratio, an increase in glycophorin A, and a nuclear translocation of PKC-α. Moreover, lenalidomide could induce a selective G0/G1 arrest of the cell cycle in del(5q) cells, slowing down the rate proliferation in those cells. Altogether, our results could not only better explain the role of PI-PLCß1/PKC-α signaling in erythropoiesis but also lead to a better comprehension of the lenalidomide effect on del(5q) MDS and pave the way to innovative, targeted therapies.-Poli, A., Ratti, S., Finelli, C., Mongiorgi, S., Clissa, C., Lonetti, A., Cappellini, A., Catozzi, A., Barraco, M., Suh, P.-G., Manzoli, L., McCubrey, J. A., Cocco, L., Follo, M. Y. Nuclear translocation of PKC-α is associated with cell cycle arrest and erythroid differentiation in myelodysplastic syndromes (MDSs).

Iron-chelating therapy with deferasirox in transfusion-dependent, higher risk myelodysplastic syndromes: a retrospective, multicentre study.

Iron chelation is controversial in higher risk myelodysplastic syndromes (HR-MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion-dependent, intermediate-to-very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty-six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375-2500 mg) for a median of 11 months (range 0·4-75). Eight patients (16%) showed grade 2-3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 µg/l at baseline to 1100 µg/l after 12 months of treatment (P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR-MDS are comparable, in terms of safety and efficacy, with those observed in lower-risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR-MDS patients.

Clinical Impact of Hypomethylating Agents in the Treatment of Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic diseases, mainly affecting the elderly, characterized by unilinear or multilinear peripheral cytopenia, bone marrow ineffective haemopoiesis, and a varying risk of progression to acute myeloid leukemia (AML). On the basis of the prognostic score systems currently used, MDS patients are generally classified as having higher risk (HR) or lower risk (LR) MDS. Two drugs, azacitidine (AZA) and decitabine (DAC), defined, because of their proven mechanism of action, as DNA methyltransferase inhibitors (DNMTIs), or hypomethylating agents (HMAs), have proven effective in improving peripheral cytopenias and quality of life, reducing or eliminating transfusion need, delaying leukemic evolution, and (only for AZA) prolonging overall survival (OS). HMAs are currently the first therapeutic choice for MDS patients who are not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT). HMAs have also been used before and after allo-HSCT, but their role in this setting needs to be confirmed by larger studies. Although data from several clinical and biological studies might help to identify patients with a higher probability to respond to HMAs, to date this treatment should not be denied to any HR MDS patient. Several attempts have been made to combine HMAs with other therapeutic agents, and these results await confirmation by further studies.

Inositide-dependent signaling pathways as new therapeutic targets in myelodysplastic syndromes.

INTRODUCTION: Nuclear inositide signaling pathways specifically regulate cell proliferation and differentiation. Interestingly, the modulation of nuclear inositides in hematological malignancies can differentially affect erythropoiesis or myelopoiesis. This is particularly important in patients with myelodysplastic syndromes (MDS), who show both defective erythroid and myeloid differentiation, as well as an increased risk of evolution into acute myeloid leukemia (AML). AREAS COVERED: This review focuses on the structure and function of specific nuclear inositide enzymes, whose impairment could be linked with disease pathogenesis and cancer. The authors, stemming from literature and published data, discuss and describe the role of nuclear inositides, focusing on specific enzymes and demonstrating that targeting these molecules could be important to develop innovative therapeutic approaches, with particular reference to MDS treatment. EXPERT OPINION: Demethylating therapy, alone or in combination with other drugs, is the most common and current therapy for MDS patients. Nuclear inositide signaling molecules have been demonstrated to be important in hematopoietic differentiation and are promising new targets for developing a personalized MDS therapy. Indeed, these enzymes can be ideal targets for drug design and their modulation can have several important downstream effects to regulate MDS pathogenesis and prevent MDS progression to AML.

Advancement in high dose therapy and autologous stem cell rescue in lymphoma.

Although advanced stage aggressive non-Hodgkin's lymphomas and Hodgkin's disease are thought to be chemotherapy-responsive cancers, a considerable number of patients either relapse or never attain a remission. High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is often the only possibility of cure for most of these patients. However, many controversial issues still remain with respect to HDT/ASCT for lymphomas, including its role for, the optimal timing of transplantation, the best conditioning regimen and the potential use of localized radiotherapy or immunologic methods to decrease post-transplant recurrence. Recently, mainly due to the unavailability of carmustine, several novel conditioning protocols have been clinically developed, with the aim of improving the overall outcome by enhancing the anti-lymphoma effect and, at the same time, by reducing short and long-term toxicity. Furthermore, the better safety profiles of novel approaches would definitively allow patients aged more than 65-70 years to benefit from this therapeutic option. In this review, we will briefly discuss the most relevant and recent data available regarding HDT/ASCT in lymphomas.

An increased expression of PI-PLCß1 is associated with myeloid differentiation and a longer response to azacitidine in myelodysplastic syndromes.

This study tested the hypothesis that PI-PLCß1 is associated with myeloid differentiation and that its expression could be useful for predicting the response of MDS patients to azacitidine, as the clinical effect of epigenetic treatments is often detectable only after several cycles of therapy. To this end, PI-PLCß1 was quantified on 70 MDS patients (IPSS risk: 13 Low, 20 Int-1, 31 Int-2, 6 High) at baseline and during the first 3 cycles of azacitidine. Results were then compared with the hematologic response, as assessed after the sixth cycle of azacitidine therapy. Overall, 60 patients completed 6 cycles of azacitidine, and for them, a clinical and molecular evaluation was possible: 37 of these patients (62%) showed a specific increase of PI-PLCß1 mRNA within the first 3 cycles, which was associated with a longer duration of response and with an increased myeloid differentiation, as evidenced by PI-PLCγ2 induction and the recruitment of specific myeloid-associated transcription factors to the PI-PLCß1 promoter during azacitidine response. Moreover, the increase of cyclin D3 gene expression throughout all of the therapy showed that PI-PLCß1-dependent signaling is indeed activated in azacitidine responder patients. Taken together, our results show that PI-PLCß1 quantification in MDS predicts the response to azacitidine and is associated with an increased myeloid differentiation.

Strategic Role of Nuclear Inositide Signalling in Myelodysplastic Syndromes Therapy.

Nuclear inositide signalling is implicated in normal and pathological cell proliferation and differentiation in several distinct models. Among the key molecules of nuclear inositide pathways, phosphoinositide-phospholipase (PI-PLC) C β1 is essential for regulating hematopoiesis, particularly along myeloid and erythroid lineage. Moreover, Akt activation is associated with protein synthesis, via mTOR pathway, and with erythroid induction, through PI-PLCγ1 activation. Myelodysplastic syndromes (MDS) are a series of heterogeneous diseases characterized by ineffective hemopoiesis, with a variable risk of evolution into acute myeloid leukemia (AML). Therapeutic approaches for MDS include demethylating agents, such as azacitidine, aiming at reducing cell proliferation, and erythropoietin, useful for sustaining a normal erythropoiesis. In the last few years, a role for nuclear inositide signalling as a therapeutic target in MDS has been disclosed, in that PI-PLCβ1 increase is associated with azacitidine responsiveness, even when this drug is used in combination with other agents, and Akt is specifically activated in MDS at higher risk of AML evolution. On the other hand, recent data demonstrated that inositide signalling can also be involved in erythroid therapy, given the inhibitory effect of erythropoietin on PI-PLCβ1 and the activation of Akt/PI-PLCγ1 pathway, following the administration of erythropoietin. Here, we review the strategic role of nuclear inositide signalling in MDS, in pathogenesis and therapy.

The role of the immunosuppressive microenvironment in acute myeloid leukemia development and treatment.

Functional interplay between acute myeloid leukemia (AML) cells and the bone marrow microenvironment is a distinctive characteristic of this hematological cancer. Indeed, a large body of evidence suggests that proliferation, survival and drug resistance of AML are sustained and modulated by the bone marrow immunosuppressive microenvironment, where both innate and adaptive immune responses are profoundly deregulated. Furthermore, the presence of a number of different immunosuppressive mechanisms results in massive immune deregulation, which causes the eventual escape from natural immune control. Modulating the immune system, as documented by 40 years of stem cell transplantation, may improve survival of AML patients, as the immune system is clearly able to recognize and attack leukemic cells. The understanding of the factors responsible for the escape from immune destruction in AML, which becomes more prominent with disease progression, is necessary for the development of innovative immunotherapeutic treatment modalities in AML.

[Molecular biology in myelodysplastic syndromes and acute myeloid leukemias "smoldering"]. / Biologia molecolare nelle sindromi mielodisplastiche e nelle leucemie acute mieloidi "smoldering"

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders of the myeloid lineage characterized by peripheral cytopenias and frequent leukemic evolution. MDS differ for clinical presentation, disease behavior and progression and this is the reflection of remarkable variability at molecular level. To this moment disease diagnosis is still dependent on bone marrow morphology that, although high concordance rates among experts are reported, remains subjective. Karyotype analysis is mandatory but diagnosis may be difficult in presence of normal karyotype or non-informative cytogenetics. Standardized molecular markers are needed to better define diagnosis, prediction of disease progression and prognosis. Furthermore, a molecular biology analysis could provide an important therapeutic tool towards tailored therapy and new insights in the disease's biology.

[The role of iron metabolism in myelodysplastic syndromes]. / Il ruolo del metabolismo del ferro nelle sindromi mielodisplastiche.

Patients affected by myelodysplastic syndromes (MDS) with transfusion-dependent anemia are destined to develop iron overload. The main diagnostic tools for the diagnosis of transfusional iron overload are serum ferritin and transfusion history. In MDS several studies showed that iron overload is an independent negative prognostic factor. Deferasirox, an oral iron chelator, has shown efficacy and acceptable tolerability in MDS setting, and has also been shown to improve peripheral cytopenia in 10-20% of patients. Iron chelation therapy is recommended, after the transfusion of 20 red cell units, in low-risk MDS patients, and also in high-risk patients responding to treatment of the disease and/or candidates to receive allogeneic hematopoietic stem cell transplantation.

Prospective phase II Study on 5-days azacitidine for treatment of symptomatic and/or erythropoietin unresponsive patients with low/INT-1-risk myelodysplastic syndromes.

PURPOSE: This phase II prospective study aimed to evaluate the efficacy and safety of 5-days azacytidine (5d-AZA) in patients with low-risk myelodysplastic syndromes (MDS). Second, single-nucleotide polymorphism (SNP) genetic profile and phosphoinositide-phospholipase C (PI-PLC) ß1 levels were studied to evaluate possible biologic markers able to predict the hematologic response. EXPERIMENTAL DESIGN: The study tested a lower intensity schedule of azacytidine. The treatment plan consisted of 75 mg/sqm/d subcutaneous administered for 5 days every 28 days, for a total of 8 cycles. RESULTS: Thirty-two patients were enrolled in the study. The overall response rate was 47% (15 of 32) on intention-to-treat and 58% (15 of 26) for patients completing the treatment program. In this latter group, 5 (19%) achieved complete remission (CR) and 10 (38%) had hematologic improvement, according to the International Working Group (IWG) criteria. Three patients have maintained their hematologic improvement after 37, 34, and 33 months without other treatments. Moreover, 21 and 2 of 26 cases completing 8 cycles were transfusion-dependent for red blood cells and platelets at baseline, respectively. Of these, 7 (33%) and 2 (100%) became transfusion-independent at the end of the treatment program, respectively. Grade 3-4 neutropenia occurred in 28% of patients and 4 patients died early due to infections or hemorrhage. SNP results were not significantly correlated to the clinical outcome, whereas PI-PLCß1 level anticipated either positive or negative clinical responses. CONCLUSIONS: 5d-AZA is safe and effective in a proportion of patients with low-risk MDS. PI-PLCß1 gene expression is a reliable and dynamic marker of response that can be useful to optimize azacytidine therapy.

Nuclear PI-PLC ß1 and Myelodysplastic syndromes: from bench to clinics.

Myelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. A number of MDS progresses to acute myeloid leukemia (AML) with the involvement of genetic and epigenetic mechanisms affecting PI-PLC ß1. The molecular mechanisms underlying the MDS evolution to AML are still unclear, even though it is now clear that the nuclear signaling elicited by PI-PLC ß1, Cyclin D3, and Akt plays an important role in the control of the balance between cell cycle progression and apoptosis in both normal and pathologic conditions. Moreover, a correlation between other PI-PLCs, such as PI-PLC ß3, kinases and phosphatases has been postulated in MDS pathogenesis. Here, we review the findings hinting at the role of nuclear lipid signaling pathways in MDS, which could become promising therapeutic targets.

Quality of life and physicians' perception in myelodysplastic syndromes.

To detect factors associated with quality of life (QOL) of patients with myelodysplastic syndrome (MDS) and to compare the MDS patients' self-assessed QOL with that perceived by their physicians. In an observational, non-interventional, prospective, multicentre study, QOL was evaluated in 148 patients with newly diagnosed low- and intermediate-risk IPSS MDS. QOL measures (QOL-E v.2, LASA and EQ-5D) and patient-related candidate determinants of QOL were assessed for up to 18 months. Patients' QOL scores were compared with those obtained by appointed hematologists' assessment and with ECOG performance status (PS). Fatigue was not prevalent at diagnosis, though physical QOL and energy levels were low. Transfusion-dependent patients had worse QOL scores. In multivariate analysis, Hb levels and comorbidities were a major determinant of QOL. Physicians' perception of patients' well-being correlated with patients' QOL. Physicians underestimated the impact of disturbances on patients' QOL, mainly in the MDS-specific components. ECOG PS did not discriminate patients according to QOL status. In conclusion, the association of anemia with QOL is confirmed, while co-morbidities emerge as an independent predictor of QOL in MDS. Fatigue is not a major concern. ECOG PS is not a valuable surrogate of patient's QOL, thus highlighting that physician's judgment of patient's well-being must not substitute patient-reported outcomes. Appropriate questionnaires should be used to assess MDS patients' QOL in order to improve communication and therapeutic choice.