Overall survival of myelodysplastic syndrome patients after azacitidine discontinuation and applicability of the North American MDS Consortium scoring system in clinical practice.

BACKGROUND: Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome. METHODS: The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting. RESULTS: At treatment discontinuation, 20.3% of the patients were still responding to AZA, 35.4% of the cases had primary resistance, and 44.3% developed adaptive resistance. Overall survival (OS) was better for patients who discontinued treatment while in response because of planned allogeneic hematopoietic stem cell transplantation (HSCT; median OS, not reached) in comparison with patients with primary resistance (median OS, 4 months) or adaptive resistance (median OS, 5 months) or patients responsive but noncompliant/intolerant to AZA (median OS, 4 months; P = .004). After AZA discontinuation, 309 patients (77%) received best supportive care (BSC), 60 (15%) received active treatments, and 33 (8%) received HSCT. HSCT was associated with a significant survival advantage, regardless of the response to AZA. The North American MDS Consortium scoring system was evaluable in 278 of the 402 cases: patients at high risk had worse OS than patients at low risk (3 and 7 months, respectively; P < .001). The score was predictive of survival both in patients receiving BSC (median OS, 2 months for high-risk patients vs 5 months for low-risk patients) and in patients being actively treated (median OS, 8 months for high-risk patients vs 16 months for low-risk patients; P < .001), including transplant patients. CONCLUSIONS: Real-life data confirm that this prognostic scoring system for MDS patients failing a hypomethylating agent seems to be a useful tool for optimal prognostic stratification and for choosing a second-line treatment after AZA discontinuation.

Carfilzomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma patients: the real-life experience of Rete Ematologica Pugliese (REP).

Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness and safety profile in real clinical practice should be further assessed. We retrospectively evaluated 130 consecutive RRMM patients treated with KRd between December 2015 and August 2018, in 9 Hematology Departments of Rete Ematologica Pugliese (REP). The overall response rate (ORR) was 79%, with 37% complete response (CR). Treatment with KRd led to an improvement in response regardless of age, refractory disease, and number and type of previous therapies. After a median follow-up of 18 months, median PFS was 24 months and 2y-PFS was 54%. PFS was longer in patients achieving a very good partial response (VGPR) with median PFS of 32.4 months. The relapses after prior autologous transplant (ASCT) positively impact median PFS. Several baseline disease characteristics, such as III ISS scoring or elevated LDH, and prior exposure to lenalidomide were found to negatively impact PFS. Primary refractory or relapsed myeloma patients have been treated with KRd as bridge to ASCT with a great benefit. Thirty-four (83%) reached at least a partial response after KRd and 21 (61%) performed ASCT. In transplanted patients, median PFS was not reached and 2y-PFS was 100%. The treatment discontinuation rate due to adverse events (AEs) was 18%, most commonly for lenalidomide (11%). Overall, in 10% of patients, a KRd dose reduction was necessary at least once (2.5% for carfilzomib and 8% for lenalidomide). The most frequent AE was neutropenia (44%) and anemia (41%). Infections occurred in 14% of patients. Cardiovascular events occurred in 11% of patients. Elderly patients have tolerated therapy very well, without additional side effects compared to younger patients, except for cardiac impairment. Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients achieving VGPR, in those lenalidomide naïve and in patients relapsing after previous ASCT. Previous ASCT should not hamper the option for KRd therapy. Accordingly, KRd should be used as bridge regimen to ASCT with remarkable improvement in response and PFS rates. Further clinical studies are needed.

Early diagnosis, clinical management, and follow-up of cardiovascular events with ponatinib.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by neoplastic transformation of pluripotent cells due to a typical cytogenetic and molecular mutation known as Philadelphia (Ph) chromosome. In 2001, the introduction of the tyrosine kinasis inhibitor (TKI) imatinib as a therapeutic strategy for CML with PH chromosome mutation represented an important step towards treatment of these patients, and nowadays, this drug represents the gold therapeutic standard in this clinical setting. A second generation of TKIs (dasatinib, nilotinib, and bosutinib) showed an effective action in all patients with mutations resistant to imatinib. Ponatinib is a third-generation TKI and is the only inhibitor with activity against T3151 mutation. The impact of ponatinib on cardiovascular events was first evaluated in the PACE trial. We therefore report and discuss most relevant evidence currently available on cardiovascular events associated with the use of ponatinib. Though many exams can be used for diagnosis and follow-up of this kind of cardiotoxicity, echocardiography seems to have a pivotal role thanks to its feasibility, availability, and low cost.

Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib.

BACKGROUND: Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. METHODS: This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. RESULTS: The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P = .013), Role Functioning (P = .004), and Fatigue (P < .001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P = .005). CONCLUSIONS: For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society.

Brentuximab vedotin as salvage treatment in Hodgkin lymphoma naïve transplant patients or failing ASCT: the real life experience of Rete Ematologica Pugliese (REP).

Brentuximab vedotin (BV) shows a high overall response rate (ORR) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) after autologous transplant (ASCT). The aim of this multicenter study, conducted in nine Hematology Departments of Rete Ematologica Pugliese, was to retrospectively evaluate the efficacy and safety of BV as salvage therapy and as bridge regimen to ASCT or allogeneic transplant (alloSCT) in R/R HL patients. Seventy patients received BV. Forty-five patients (64%) were treated with BV as bridge to transplant:16 (23%) patients as bridge to ASCT and 29 (41%) as bridge to alloSCT. Twenty-five patients (36%), not eligible for transplant, received BV as salvage treatment. The ORR was 59% (CR 26%). The ORR in transplant naïve patients was 75% (CR 31%). In patients treated with BV as bridge to alloSCT, the ORR was 62% (CR 24%). In a multivariate analysis, the ORR was lower in refractory patients (p < 0.005). The 2y-OS was 70%. The median PFS was 17 months. Ten of the 16 (63%) naïve-transplant patients received ASCT, with 50% in CR before ASCT. In the 29 patients treated with BV as bridge to alloSCT, 28 (97%) proceeded to alloSCT with 25% in CR prior to alloSCT. The most common adverse events were peripheral neuropathy (50%), neutropenia (29%) and anemia (12%). These data suggest that BV is well tolerated and very effective in R/R HL, producing a substantial level of CR. BV may also be a key therapeutic agent to achieve good disease control before transplant, improving post- transplant outcomes, also in refractory and heavily pretreated patients, without significant overlapping toxicities with prior therapies.

Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients.

The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR4.0) and 17% (MR4.5) of patients at 2 years; 58% of the enrolled patients achieved a MR4.0 at least once, with a sustained MR4.0 in 52% of them. With a median observation of 29 months (range 24-37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non-hematologic and metabolic adverse events (clinicaltrials.gov identifier: 01535391).

Personal history and quality of life in chronic myeloid leukemia patients: a cross-sectional study using narrative medicine and quantitative analysis.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) drastically changed the outcome of patients diagnosed with chronic myeloid leukemia (CML). Several reports indicated the advantage of continue long-term adherence associated with positive outcome. Therefore, it is important to better understand from the patient's standpoint the experience of living with the disease and the related treatment. OBJECTIVES: In this study, quantitative analysis and narrative medicine were combined to get insights on this issue in a population of 257 patients with CML in chronic phase treated with TKIs (43 % men, with a median age of 58 years, 27 % aged 31-50 years), followed for a median time of 5 years. Sixty-one percent of patients enrolled were treated in first line, whereas 37 % were treated in second line. RESULTS: The results showed more positive perceptions and acceptance in males compared to females, without impact of disease on relationships. Level of positive acceptance was more evident in elderly compared to younger patients, with a close connection with median time from diagnosis. Overall, female patients reported negative perceptions and an impact of disease on family daily living. The majority of patients understood the importance of continue adherence to treatment, with 27 % resulting less adherent (60 % for forgetfulness), even if well informed and supported by his/her physician. DISCUSSION AND CONCLUSIONS: Narrative medicine, in association to quantitative analysis, can help physicians to understand needs of their patients in order to improve communication.

Chronic lymphocytic leukemia-associated immune thrombocytopenia treated with rituximab: a retrospective study of 21 patients.

INTRODUCTION: There are no standard therapies for chronic lymphocytic leukemia (CLL)-associated immune thrombocytopenia (IT) so far. PATIENTS AND METHODS: We report the results of therapy with single agent rituximab in 21 patients with CLL-associated IT. The mean age at CLL and IT diagnosis was 64 and 68 yr, respectively. IT developed at a mean time of 44 months from the diagnosis of CLL. In four cases, IT was diagnosed at the same time as CLL. For three patients, IT was considered fludarabine-related and two patients showed autoimmune hemolysis also. All patients but one received steroids as first-line treatment for IT. Some patients received intravenous high-dose Ig, vincristine, and Cytoxan also, without beneficial effect. After a mean time of 43 d from the diagnosis of IT, all patients were scheduled to receive rituximab at a dosage of 375 mg/mq/weekly. RESULTS: Eighteen (86%) patients completed the scheduled four cycles of rituximab. Irrelevant first infusion side effects were seen only in one patient. Twelve (57%) patients showed a complete response (CR), six (29%) patients a partial response (PR), and three (14%) patients did not respond. In responding patients, the mean duration of response was 21 months (4-49 months). At a mean follow-up of 28 months, 14 (66%) patients were still alive, 10 (48%) of them in CR and three (14%) in PR. CONCLUSIONS: This retrospective analysis prove that rituximab is an effective and well-tolerated alternative treatment for CLL-associated IT.

Parachute mitral valve assessed by cardiac magnetic resonance.

Parachute mitral valve (PMV) is a congenital cardiac malformation where typically all tendons chordae converge and insert into one major papillary muscle. We report the case of 27-year-old man affected by Hodgkin's lymphoma-mixed cellularity subtype with polychemotherapy treatment and Barrett's esophagus who came to our attention for routine echocardiographic exam and evaluation of left ventricular function. In the presence of normal left ventricular systolic function and mild-moderate mitral regurgitation, a careful examination of mitral apparatus showed a single papillary muscle suspected for PMV. In the presence of Barrett's esophagus, the patient was further assessed cardiac magnetic resonance (CMR) that confirmed the diagnosis of PMV and excluded other associated congenital anomalies. Despite the rare incidence of PMV and a diagnosis generally based on transesophageal echocardiography, CMR could represent a useful tool, in selected cases, to confirm the diagnosis of PMV, identify other possible congenital anomalies, and assess ventricular and valvular function.

Osteonecrosis of the myeloma patients treated with bisphosphonates.

Osteonecrosis of the jaw (ONJ) has been reported as uncommon but well recognised complication associated with bisphosphonate treatment. Multiple Myeloma (MM) is the pathology most frequently associated with ONJ in the medical and dental papers published over the last years (45% of the ONJ published cases). ONJ appears to be time-dependent with higher risk after long-term use of intravenous (i.v.) nitrogen containing bisphosphonates (eg, pamidronate, zoledronate) in older MM patients. The most frequent site of ONJ is the mandible and previous dental procedures may be a precipitating factor. Most of the ONJ cases presented clinical evidence of bone exposure and pain. There was no significant association between the occurrence of ONJ and the presence of osteolytic lesions, disease status and the use of thalidomide. Different treatments have been proposed, associated or not: medical therapy (eg, antimicrobial oral rinses, antibiotic and antimicotic), surgical therapy (eg, curettage or sequestrectomy) showing low healing rates and uncertain impact on the prognosis and on the outcome.

Ruxolitinib - better prognostic impact in low-intermediate 1 risk score: evaluation of the 'rete ematologica pugliese' (REP) in primary and secondary myelofibrosis.

We evaluated ruxolitinib in 65 patients with myelofibrosis according to age, sex, time of diagnosis, grade of fibrosis, prognostic score risk, Janus kinase (JAK) status, primary or secondary myelofibrosis, previous treatment, and dosage. Outcome measures were response rate, time to response, duration of response, and event-free survival and survival. Kaplan and Meier curves show a significant difference in event-free survival according to the prognostic score, in favor of patients with low int1 (p = 0.0009). The Cox stepwise model confirmed the result, the int2 high-risk score being the most powerful negative independent parameter (0.001), followed by JAK (0.008); other parameters, such as diagnosis more than 5 years earlier, grade III-IV fibrosis, and ruxolitinib dose have a negligible impact. Time to response was shorter (p = 0.001) in primary myelofibrosis. In conclusion, ruxolitinib is effective, with a better outcome in patients with a low-int1 risk score. This may suggest considering an earlier administration in the disease course.

Common variable immunodeficiency patient with large granular lymphocytosis developing extranodal diffuse large B-cell lymphoma: a case report.

Here we describe a Common Variable Immunodeficiency (CVI) patient with large granular (LG) lymphocytosis and systemic non-malignant lymphadenopathy who developed diffuse large B-cell lymphoma of the stomach. This is the first report of gastric high-grade lymphoma with widespread lymphadenopathy in a patient with LG lymphocytosis associated with CVI.

Relationship between autoimmune phenomena and disease stage and therapy in B-cell chronic lymphocytic leukemia.

The aim of this multicenter GIMEMA study was to correlate autoimmune complications (AIC) in B-cell chronic lymphocytic leukemia (B-CLL) with stage and therapy. Autoimmune hemolytic anemia (129/194 cases) and autoimmune thrombocytopenia (35/194 cases) were typically present in advanced and multi-treated disease. Age over the median, stage C and first and second line therapy were identified as independent risk factors by multivariate analysis. In contrast, non-hematologic AIC (30/194 cases) and the presence of serological markers of autoimmunity were mostly observed in early B-CLL, suggesting different pathogenic mechanisms underlying hematologic and non-hematologic autoimmune phenomena in B-CLL.

Jaw osteonecrosis associated with use of bisphosphonates and chemotherapy: paradoxical complication of treatment of bone lesions in multiple myeloma patients.

It has been demonstrated that bisphosphonate-based supportive therapy (pamidronate or zoledronate) reduces skeletal events (onset or progression of osteolytic lesions) both in patients with multiple myeloma (MM) and in cancer patients with bone metastasis. Bisphosphonates (eg, alendronate) are also indicated in the treatment of osteoporosis. Nevertheless, osteonecrosis of the jaw (ONJ) has been reported in some patients being treated with bisphosphonates. We present a series of 9 MM patients who developed ONJ after treatment with bisphosphonates and chemotherapy. All the patients in this case series had undergone tooth extraction for recurrent dental abscesses while taking bisphosphonates. We also review the diagnostic and therapeutic implications of this paradoxical complication associated with treatment of bone lesions in MM.

Azacitidine in the treatment of older patients affected by acute myeloid leukemia: A report by the Rete Ematologica Pugliese (REP).

The optimal treatment of older patients (>65 years) with acute myeloid leukemia (AML) remains challenging in daily clinical practice; a choice has to be made between intensive chemotherapy and best supportive care. To guide physicians, several prognostic factors have been identified and risk scores developed. Recently, the DNA methyltransferase inhibitor azacitidine has become available for use in MDS and AML patients with up to 30% bone marrow blasts. However, limited data are available on the outcome of older unfit AML patients, regardless of their bone marrow blast count. We retrospectively analyzed the outcome of 90 newly diagnosed older unfit AML patients in 9 Institutions from the Apulia Region (REP). Responder patients (evaluation performed after 4 cycles of treatment even in cases of primary failure) showed a better overall survival than non responders (23 vs 6 months, p<.001). ECOG PS≥2 seems to be correlated with OS in multivariate analysis, while neither primary treatment failure (documented after 2 cycles) nor bone marrow blast count were correlated with a worse overall survival either at univariate (22 vs 29 months, p=.ns; 16 vs 19 months, p=.ns) or multivariate analysis. Overall, the results of our retrospective analysis seem to confirm the efficacy of AZA treatment for this unfit AML patients setting, in terms of both CR and OS, regardless of the bone marrow blasts count, while primary treatment failure should not lead to a discontinuation of treatment.

Optimal time-points for minimal residual disease monitoring change on the basis of the method used in patients with acute myeloid leukemia who underwent allogeneic stem cell transplantation: a comparison between multiparameter flow cytometry and Wilms' tumor 1 expression.

Minimal residual disease (MRD) of 30 adult AML patients was monitored by multiparameter flow cytometry (MFC) and WT1 expression before and after allogeneic stem cell transplantation (allo-SCT). Diagnostic performance of pre-transplant MRD measured by MFC was higher than that obtained by WT1 expression. Comparable results were displayed at day +30 post-transplant, while better values by WT1 compared to MFC were found at day +90. Positive MRD by MFC predicted a shorter disease free survival (DFS) before and 1 month after transplant (p=0.006 and p=0.005), while only high WT1 levels at 1 month from the transplant significantly impacted on DFS (p=0.010). Our results support the idea that MRD monitoring by MFC should be suggested before and 30 days after the transplant, while WT1 expression should be preferred after this procedure. The assessment of MRD at day +30 from allo-SCT is recommended as post transplant check-point for the predictive role displayed, independently of the method used.

Familial B-cell chronic lymphocytic leukemia in a population of patients from Southern Italy.

We investigated the prevalence of chronic lymphocytic leukemia (CLL) in 9650 relatives of 510 CLL patients from 5 different regions (Apulia, Basilicata, Campania, Calabria, and Sicily) of Southern Italy. Data collection included a family history questionnaire. In our series of 510 CLL patients, 53 families with 2 or more individuals who had chronic lymphoproliferative disease (CLD) or other hematological malignancies were identified. In these families, 27 cases of CLL, 10 of indolent non-Hodgkin's lymphoma, and 7 of multiple myeloma were identified in relatives of CLL probands. Twenty-two relatives developed hematological malignancies other than CLD (19, acute leukemia; 3, chronic myeloid leukemia). In this study the prevalence of CLD in relatives of 510 CLL patients was 8.6% (44/510), and the prevalence of CLL in the same series was 5.2% (27/ 510). Considering the presence of clusters of individuals with hematological malignancies, overall our series contained 4 families showing a cluster with more than 2 cases. The most frequent pattern of affected family members was represented by 39 families (39/53 [73%]) with affected siblings or cousins only. Twenty siblings had CLL. The other families showed a multigenerational pattern with an affected parent-offspring relationship in only 11 (21%) of the cases and with a combination of the first 2 categories in 3 (6%) of the families. In 8 families belonging to both the last 2 mentioned groups, the affected offspring had an earlier disease onset than their parents, suggesting anticipation. We estimated the size and examined the pattern of familial aggregation of hematological malignancies, in particular CLL/CLD, in a specific geographical area. CLL was the most frequent disease in relatives, mainly siblings, of our CLL patients. Our results may be a contribution to the characterization of the epidemiological distribution pattern of CLL.

Concomitant tetrasomy 3q and trisomy 18 in CD5(-), CD13(+) chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) associated with myeloid antigens on the surface of B neoplastic cells is a recently identified immunologic variant confined to patients with CD5 negative B-CLL. We describe the case of a 61-year-old female diagnosed with CD5(-), CD13(+) B-CLL with a tetrasomy 3q revealed by fluorescence in situ hybridization analysis, in addition to trisomy 18. To our knowledge, this is the first reported case of B-CLL with this kind of cytogenetic abnormality.