Gilteritinib with or without venetoclax for relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Patients with FLT3-mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard-of-care for patients with R/R FLT3-mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt-ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt-ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt-ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem-cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt-ven (12-month OS 58.8% [95% CI 39.5%-87.6%]) versus gilteritinib (42.1% [95% CI 24.9%-71.3%] for gilteritinib). Early salvage with gilt-ven versus any other gilteritinib-based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt-ven did not improve remissions or HSCT-realization rates in patients with R/R FLT3-mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt-ven and a survival benefit was shown for gilt-ven approach when sequenced early for salvage.

Fluoroquinolone Prophylaxis during Conventional Chemotherapy or Hematopoietic Stem Cell Transplantation for Acute Leukemia - Pros and Cons.

BACKGROUND: Prophylaxis with fluoroquinolones (FQ) is commonly used in patients with acute leukemia (AL) during neutropenia. This practice is supported by an older meta-analysis reporting reduced mortality using FQ prophylaxis. Later meta-analyses have failed to reproduce this finding, presumably due to higher background FQ resistance rates limiting their effectiveness. SUMMARY: This article reviews the pros and cons of FQ prophylaxis mainly in patients with AL. Most current guidelines do not support universal prophylaxis but rather recommend a selective approach, weighing the benefits against the risks. This recommendation is based on the lack of mortality benefit reported in more recent meta-analyses. FQ prophylaxis was demonstrated to reduce bacteremia and febrile neutropenia episodes, although mostly in trials performed in low-resistance settings (<20%), whereas current FQ resistance rates may reach 30-60%. Other disadvantages of FQ include potential adverse events, antibiotic resistance development, cost, increase in Gram-positive infections and resistant Gram-negative infections following prophylaxis, Clostridioides difficile infection, and an effect on gut microbiota. KEY MESSAGES: Taking the above into consideration, alternative approaches other than universal FQ prophylaxis should be considered. Centers with high FQ resistance rates may consider either withholding prophylaxis or providing selective prophylaxis for high-risk patients screened negative for FQ-resistant bacteria.

The Effect of The Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes A Study by the Israeli MDS Working Group.

BACKGROUND: Most patients with lower risk myelodysplastic neoplasms (MDS) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron overloaded RBC transfusion-dependent patients with lower risk MDS. METHODS: Adult lower-risk MDS patients with a cumulative transfusion burden of >20 red blood cells units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side-effects were recorded as well. A paired t-test was applied for statistical analyses. RESULTS: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p<0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p<0.01 for all). The iron-overload marker, cellular labile iron pool, decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p<0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grade 1-2. CONCLUSIONS: Herein we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.

PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL.

BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options. METHODS: R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide. FINDINGS: We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin. INTERPRETATION: This immunotherapy combination was found to be active and safe in this clinically challenging patient population.

The occurrence of thrombosis during intensive chemotherapy treatment for acute myeloid leukemia patients does not impact on long-term survival.

Venous thromboembolism (VTE) is frequently seen in acute myeloid leukemia (AML) patients and presents a significant clinical challenge. The association of VTE during intensive chemotherapy with risk models such as the Medical Research Council (MRC) cytogenetic-based assessment and the European LeukemiaNet (ELN) 2017 molecular risk model have not been rigorously evaluated. Additionally, there is a paucity of data pertaining to the long-term prognostic impact of VTE in AML patients. We performed an analysis of baseline parameters of AML patients diagnosed with VTE during intensive chemotherapy and compared them with patients without VTE. The analyzed cohort consisted of 335 newly diagnosed AML patients with a median age of 55 years. Thirty-five patients (11%) were classified as MRC favorable risk, 219 (66%) patients as intermediate risk, 58 patients (17%) as adverse risk. Per ELN 2017, 132 patients (40%) had favorable risk disease, 122 patients (36%) intermediate risk, and 80 patients (24%) had adverse risk. VTE was seen in 33 patients (9.9%), occurring mostly during induction (70%), and required catheter removal in 9 patients (28%). Baseline clinical, laboratory, molecular, and ELN 2017 parameters were not significantly different groups. However, MRC intermediate-risk group patients were significantly more likely to experience thrombosis compared to favorable risk and adverse risk patients (12.8% versus 5.7% and 1.7%, respectively; p = 0.049). Median overall survival was not significantly impacted by the diagnosis of thrombosis (3.7 years versus 2.2 years; p = 0.47). VTE is tightly associated with temporal and cytogenetic parameters in AML but does not significantly impact on long-term outcomes.

Patient-reported fatigue refines prognosis in higher-risk myelodysplastic syndromes (MDS): a MDS-CAN study.

The incorporation of patient-reported outcomes with traditional disease risk classification was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). In the present Canadian MDS registry analysis, we validate a recently reported prognostic model, the Fatigue-International Prognostic Scoring System among higher-risk patients [FA-IPSS(h)], which incorporates patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), with a threshold of ≥45 points, in higher IPSS score, stratifying them into distinct subgroups with different survival outcomes. We further validated this concept, using the Revised IPSS >3·5 as cut-off for the definition of higher-risk MDS, and patients' reported fatigue according to Edmonton Symptom Self-Assessment Scale (ESAS) Global Fatigue Scale (GFS), a single-item fatigue rating scale, which is easier to deploy. This emphasises the power of self-reported fatigue at refining overall survival predictions in higher-risk MDS and further bolsters the importance of considering patient-related outcomes in global assessments.

Obinutuzumab-related adverse events: A systematic review and meta-analysis.

Rituximab, the first anti-CD20 monoclonal antibody, has dramatically improved outcomes for patients with B-cell lymphoproliferative disorders. Obinutuzumab was developed to potentiate activity and overcome resistance to rituximab. Clinical data suggest that obinutuzumab is superior to rituximab in follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Yet, it has increased toxicity. This systematic review and meta-analysis compiled all randomized controlled trials (RCTs) comparing obinutuzumab-based regimens with rituximab-based regimens to better assess their toxicity profile. Primary outcome was grade 3-4 infections; secondary outcomes included any adverse events (AE), grade 3-4 AE, drug discontinuation rate, and 3-years mortality. Relative risks (RRs) were estimated and pooled using a fixed-effect model, unless there was significant heterogeneity, in which case a random-effects model was used. Our comprehensive search yielded five RCTs conducted between 2009 and 2014, including 4247 patients. The trials included FL patients, CLL and diffuse large B cell lymphoma. Monoclonal antibodies were given with different chemotherapy regimens (in four trials) or as monotherapy (in one trial). The point estimate favored increase in both grade 3-4 infections rate (RR 1.17 [95% CI, 1.0-1.36]) and any AE rate (RR 1.05 [95% 1-1.1]) with obinutuzumab, although this was not statistically significant. There was a significantly increased rate of grade 3-4 AE (RR 1.15 [95% CI, 1.09-1.2]), as well as grade 3-4 toxicities including thrombocytopenia (RR 2.8 [95% CI, 1.92-4.06]), infusion related reactions (RR 2.8 [95% CI, 2.16-3.64]) and cardiac events (RR 1.65 [95% CI, 1.11-2.46]). There was no significant difference in grade 3-4 anemia and neutropenia nor in the 3-year mortality rate. The point estimate favored increase in discontinuation rate due to AE with obinutuzumab, although without statistical significance (RR 1.24 [95% CI, 1.0-1.54]). In conclusion, physicians need to weigh the clinical benefits of this agent against higher toxicity.

Chronic myeloid leukemia in solid organ transplant patients: a case series.

Solid organ transplant (SOT) has transformed the survival and quality of life of patients with end-organ dysfunction. Lifelong need for immunosuppressive medications prolongs life expectancy, but results in altered immune function and is associated with a higher risk of certain malignancies, including chronic myeloid leukemia (CML). In this article, we report on six patients, aged 41-79 years, diagnosed with CML, from 3 to 132 months post-various organ transplants and treated with different tyrosine kinase inhibitors (TKI), including first generation (i.e., imatinib) and second generation (i.e., dasatinib and nilotinib). Use of second-generation TKIs has not been previously reported in this population. In these six cases, treatment with different TKIs in SOT patients was feasible, well tolerated and achieved good efficacy, which was maintained in extended follow-up, as well.

Risk factors for high-dose methotrexate associated acute kidney injury in patients with hematological malignancies.

High dose methotrexate (HDMTX)-induced acute kidney injury (AKI) is a well-known adverse event in hemato-oncology patients. Our purpose was to define factors and setup cut-offs that may help better identify patients at-risk for developing AKI following HDMTX. All consecutive patients who received MTX dose ≥1 g were retrospectively reviewed. We compared patients with or without renal toxicity. We used a logistic regression model to define baseline variables associated with AKI. Overall survival (OS) was estimated by the Kaplan-Meier method employing log-rank test. Between 2012 and 2017, 160 patients were included with a total of 265 courses. Indications included: primary central nervous system (CNS) lymphoma, CNS prophylaxis in other lymphoma types, acute lymphatic leukemia and others. Median age at diagnosis was 58 years (range, 18-84), 54% were males, median MTX dose was 1941 mg/m2 (range, 743-5442) and AKI developed in 9% of drug administrations (n = 24). In univariate analysis: age > 40, LDH > 380 units/L, eGFR < 112 mL/min, albumin <3.6 mg/dL at baseline and Charlson comorbidity index (CCI) were associated with AKI. In multivariable analysis, only LDH > 380 units/L (OR = 4.1, 95% confidence interval [CI] 1.04-20.9, P = .04) and albumin levels <3.6 g/dL (OR = 4.17, 95% CI 1.04-6.5, P = .04) remained significant. In patients with AKI, median drug elimination was longer (8 days vs 5 days). In 80% of cases, the creatinine levels returned to normal within 1 month. Yet, the median survival of patients who developed AKI was 37 months, compared to 145 months in patients without AKI (Log rank = 0.015). In conclusion, LDH > 380 units/L and albumin <3.6 g/dL were the strongest factors associated with AKI in patients receiving HDMTX. Although the rise in creatinine levels was almost uniformly reversible, AKI was associated with increased mortality rates.

Changes in primary outcome and sample size measures after initiation of accrual among trials supporting approval of drugs for hematological malignancies by the US food and drug administration.

Changes in primary outcome and sample size measures after onset of patient accrual affects the scientific basis of evidence-based medicine. The FDA website was searched for trials supporting new hemato-oncology drug approvals from January 2010 to December 2017. Matching ClinicalTrials.gov entries were compared to identify modifications. Associated publications were reviewed for reporting of these changes. Of 69 included trials, five (7%) had post accrual modifications in primary outcome and 30 (43%) had modifications in planned sample size. Sample size was increased in 24 trials (median 66 patients, IQR 35-95, median relative increase of 40% from initial sample size) and was decreased in 6 trials (median 38 patients, IQR 27-60, median relative decrease of 25%). None of the primary outcome modifications and only 53% of the sample size modifications were reported in the related publications. Further improvement is warranted in order to achieve complete transparency in reporting landmark studies.

Anthracycline-Induced Cardiotoxicity in Acute Myeloid Leukemia Patients Who Undergo Allogeneic Hematopoietic Stem Cell Transplantation.

INTRODUCTION: There is paucity of data regarding the cardiotoxic effects of anthracycline treatment in the context of acute myeloid leukemia (AML) patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT). Even a transient decrease in cardiac function might affect transplantation outcome. PATIENTS AND METHODS: We reviewed the clinical records and echocardiography examinations of 78 patients with AML who received induction therapy and underwent HSCT. RESULTS: Twenty-two patients (28%) received daunorubicin at a dose of 90 mg/m2 per day and 53 patients (68%) received 60 mg/m2 per day or an equivalent dose of idarubicin. In 14 patients (18%) the postinduction ejection fraction declined by at least 10%. This change was temporary in 6 patients and longstanding in the remainder. Patients who developed systolic dysfunction had inferior overall survival (13 months compared with 27 months; P = .013). Patients whose diastolic function deteriorated had improved survival outcome (38 months compared with 17 months; P = .048). CONCLUSION: Although even transient reduction in systolic function might compromise survival outcome, diastolic dysfunction predicts improved survival in patients with AML who undergo HSCT.

Human herpes virus 6 reactivation following autologous hematopoietic cell transplantation - a single-center experience.

Data regarding presentation and management of human herpes virus 6 (HHV-6) reactivation among autologous hematopoietic cell transplantation (HCT) recipients are limited. We retrospectively reviewed medical charts of all autologous HCT patients tested for HHV-6 reactivation due to suspected clinical presentation between 1/2012 and 8/2017. Among 328 autologous HCT recipients, 44 patients were tested for HHV-6 reactivation. Thirty patients tested positive; 29 (97%) had sustained fever, six (20%) had rash and four (13%) had pneumonia. Median C-reactive protein was significantly lower in HHV-6 positive patients compared to negative patients (3.6 (range, 0.4-11) vs. 9.6 (range, 3.2-30) mg/dL, respectively, p = .004). Ganciclovir formulations were administrated in 29 (97%) patients with median time to fever resolution of one (range, 1-2) day. HHV-6 should be considered as an important cause of post engraftment fever in autologous HCT. Larger studies are warranted to evaluate incidence of HHV-6 reactivation and optimal treatment regimen.

PET-adapted therapy for advanced Hodgkin lymphoma - systematic review.

INTRODUCTION: Positron emission tomography-computed tomography (PET-CT) performed after two chemotherapy cycles (PET-2) has become an accepted prognostic tool in Hodgkin lymphoma (HL). We evaluated the effect of PET-adapted strategy on outcome in advanced stage HL. METHODS: In August 2017, we searched electronic databases, conference proceedings and ongoing trials. We included all studies in which treatment modification for advanced HL was performed based on the results of the interim PET scan. The primary analysis included randomized controlled trials (RCTs). Outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: We identified 13 studies (4 RCTs, 7 phase II and 2 retrospective studies), conducted between 1999 and 2014, including 6856 patients. Of the four RCTS: one used therapy escalation, one did de-escalation and two trials performed both. Outcomes were assessed at different time point between 2 and 5 years. Three RCTs for de-escalating therapy, obtained similar outcomes despite reducing therapy, with a 2-year PFS of 88-92% (6 escalated BEACOPP (EB) vs. 4 ABVD cycles), a 5-year PFS of 91-92% (6/8 EB vs. 4 EB cycles) and a 5-year PFS of 80-82% (6 ABVD vs. omitting bleomycin after two successful ABVD cycles). Two RCTs implemented escalation. The randomization was between adding rituximab or not. In both trials, it did not affect outcome, with a 4-year PFS of 68-69% (addition of rituximab to BEACOPP after 2 ABVD cycles) and 5-year PFS of 88-90% (addition of rituximab to EB after 2 EB cycles). Performing true randomization between PET-adapted and a standard ABVD control arm was not feasible, given historical data. CONCLUSIONS: This systematic review of PET-adapted therapy, mainly based on RCTs, suggests that a change to the treatment paradigm is appropriate in advanced HL.

Current challenges and opportunities in treating adult patients with Philadelphia-negative acute lymphoblastic leukaemia.

Significant advances have been made in recent years in the field of Philadelphia-negative acute lymphoblastic leukaemia (ALL). New insights into the biology and genetics of ALL as well as novel clinical observations and new drugs are changing the way we diagnose, risk-stratify and treat adult patients with ALL. New genetic subtypes and alterations refine risk stratification and uncover new actionable therapeutic targets. The incorporation of more intensive, paediatric and paediatric-inspired approaches for young adults seem to have a positive impact on survival in this population. Minimal residual disease at different time points can assist in tailoring risk-adapted interventions for patients based on individual response. Finally, novel targeted approaches with monoclonal antibodies, immunotherapies and small molecules are moving through clinical development and entering the clinic. The aim of this review is to consolidate the abundance of emerging data and to review and revisit the concepts of risk-stratification, choice of induction and post-remission strategies as well as to discuss and update the approach to specific populations with ALL, such as young adult, elderly/unfit and relapsed/refractory patients with ALL.

Bone mineral density utilization in patients with newly diagnosed multiple myeloma.

Bone disease is a major cause for morbidity in multiple myeloma (MM), with the main focus concerning the manifestation as osteolytic lesions. Bone mineral loss is another reflection of myeloma bone involvement. Recently, osteoporosis has been omitted as a defining criterion for symptomatic disease in MM. We conducted a retrospective study to evaluate the use of bone mineral density (BMD) exams by dual-energy X-ray absorptiometry (DXA) among MM patients in a tertiary medical care centre. One-hundred seventy three patients were included. The T-scores of lumbar spine (LS), left femur neck (FN) and left total hip (TH) were obtained and analysed. The extent of osteolytic disease was categorized based on six bony areas. There was a strong correlation between spine and femur's T-scores (r = 0.56-0.61, p < 0.0001), although different sets of variables were correlated with LS and femur's T-scores. There was no correlation between BMD measurements and osteolytic disease extent. Patients with vertebral fracture(s) had significant lower T-scores of the spine in comparison to patients without vertebral fractures. Sixty-three patients (36.4% of the cohort) had follow-up DXA exam. In general, there was an increase in the LS T-scores, while femoral values decreased. However, in patients who achieved complete response (CR) and in those who retained CR during follow-up, femoral BMD increased as well. Because correlation between BMD and the extent of osteolytic lesions was not seen, our data support the recent exclusion of BMD assessment from the definition of symptomatic myeloma. Still, its use should be considered for evaluation of age- or therapy-related osteoporosis. Copyright © 2016 John Wiley & Sons, Ltd.

[THE EFFECT OF PLACENTAL SOLUBLE FACTORS AND STEROID HORMONES ON OVARIAN CANCER PHENOTYPE].

UNLABELLED: Estrogen is involved in ovarian cancer etiology. Crosstalk exists between estrogen and progesterone ending with the inhibition of estrogen effects. While estrogen induces ovarian cancer cell proliferation, progesterone protects women from ovarian cancer. The placenta facilitates estrogen and progesterone production. Moreover, during pregnancy epithelial ovarian cancer is more common than in young non-pregnant women and borderline ovarian tumors exhibit aggressive behavior These data suggest that pregnancy changes ovarian cancer characteristics. AIM: Analyzing the effect of placental soluble factors and estrogen+progesterone [E+P, in placental supernatant level) on epithelial ovarian cancer cell phenotype. METHODS: Ovarian epithelial cancer cells (OVCAR-3, SKOV-3) were exposed to 1) supernatants collected from first trimester human placental explant culture; 2) E+P in levels equivalent to those measured in the placental supernatants. As a control OVCAR-3 and SKOV-3 were exposed to their supernatants or to the hormones solvent. Then we tested ovarian cancer cells proliferation, death, cell-cycle and migration. RESULTS: Placental supernatants facilitated cancer cells migration and SKOV-3 proliferation. E+P facilitated SKOV-3 migration and elevated OVCAR-3 cell-number and apoptotic rate. CONCLUSION: Placental soluble factors and E+P affect ovarian cancer cells phenotype. Discussion: The elevated aggressiveness observed following exposure of ovarian cancer cells to placental supernatant and to E+P may contribute to the special phenomena observed in ovarian cancer during pregnancy. During pregnancy, ovarian cancer is usually discovered at an early stage, which improves patients' prognosis. Nevertheless, our results suggest that physicians should closely follow ovarian tumors during pregnancy as they might be affected by pregnancy-related factors.