Measurable residual disease assessment prior to allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndromes: a 20-year monocentric study.

Patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) who undergo allogeneic hematopoietic stem-cell transplantation (alloHSCT) can have divergent survival outcomes while all in morphological complete remission (CR). Techniques of measurable residual disease (MRD) have allowed us to refine their prognosis in two categories: MRD-positive and MRD-negative patients. We conducted a monocentric retrospective study (01/2000-12/2020) to assess the prognosis of pretransplant MRD status measured by multiparametric flow cytometry (MFC) and molecular biology assessed by PCR. 192 patients were included. The median follow-up period was 77 months. Among patients undergoing alloHSCT in CR, overall survival (median-OS: 130.6 vs. 16.0 months, P < 0.001), disease-free survival (median-DFS: 109.6 vs. 7.1 months, P < 0.001) and cumulative incidence of relapse (12-month CIR: 7.3% vs. 33.7%, P < 0.0001) were significantly different between MRD-negative and MRD-positive patients. Patients with discordant intermethod results had intermediate DFS. MRD-negative patients according to molecular PCR-based techniques, WT1 overexpression and MFC had longer median-DFS, compared to MRD-positive patients (P = 0.001, P < 0.001, P < 0.001, respectively). Looking into subgroups, MRD-positive patients among the ELN2017 adverse-category (P < 0.0001), myeloablative and reduced-intensity conditioning regimens (P < 0.0001, P = 0.005), < 60-year patients (P < 0.001) and AML patients (P < 0.001) were associated with lower DFS. This difference was not found in ≥ 60-year patients (P = 0.27) and MDS patients (P = 0.70). MRD-positive patients within the favorable/intermediate ELN2017 category trended toward lower DFS (P = 0.05). We confirmed that MRD status prior to alloHSCT is a strong prognostic factor for OS, DFS and CIR. Combining MFC and molecular-PCR techniques to assess MRD seems primordial as inter-method discordance can be consequential.

Beyond Chemotherapy: Present and Future Perspectives in the Treatment of Lymphoproliferative Disorders.

Over the past three decades, the treatment of lymphoproliferative disorders has undergone profound changes, notably due to the increasing availability of innovative therapies with the potential to redefine clinical management paradigms. A major impact is related to the development of monoclonal antibodies, checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cell therapies. This review discusses the current landscape of clinical trials targeting various hematological malignancies, highlighting promising early-phase results and strategies to overcome resistance. Lymphoproliferative disorders encompass a range of conditions: while in Hodgkin lymphoma (HL) the goal is to reduce chemotherapy-related toxicity by integrating immunotherapy into the frontline setting, peripheral T cell lymphoma (PTCL) lacks effective targeted therapies. The review emphasizes a shifting therapeutic landscape towards precision medicine and treatment modalities that are less toxic yet more effective.

Supportive Care in Older Lymphoma Patients to Reduce Toxicity and Preserve Quality of Life.

The treatment paradigm in older patients with malignant hemopathies is the choice between an effective conservative treatment that preserves quality of life and an intensive, potentially curative treatment with more toxicities. For each patient, it is important to determine the risk/benefit ratio. The patient should be involved in the discussion, sufficiently informed and able to express himself and his expectations in terms of quality of life. However, this informed consent is conditioned by the ability of the patient to understand the risks and benefits of the treatment. Decline in quality of life is an important parameter for older patients with cancer and many prospective trials have now confirmed the impact of different side effects of treatment, such as recurrent hospitalization, loss of autonomy in daily activities, loss of contact with grandchildren and loss of cognitive functions. Interventions oriented to vulnerabilities detected in the older patients (by comprehensive geriatric assessment) and an optimal approach, including preventive measures to reduce treatment-related toxicity and mortality, are directly correlated to improvement in quality of life.

Precision Medicine Approach Based on Molecular Alterations for Patients with Relapsed or Refractory Multiple Myeloma: Results from the MM-EP1 Study.

BACKGROUND: Despite that cytogenetic and molecular analysis of tumor cells can rapidly identify recurring molecular abnormalities, no personalized therapy is currently available in the setting of relapsed/refractory multiple myeloma (r/r MM). METHODS: MM-EP1 is a retrospective study aimed at comparing a personalized molecular-oriented (MO) versus a non-molecular-oriented (no-MO) approach in r/r MM. Actionable molecular targets and their associated therapies were the BRAF V600E mutation and BRAF inhibitors; t(11;14)(q13;q32) and BCL2 inhibitors; and t(4;14)(p16;q32) with FGFR3 fusion/rearrangements and FGFR3 inhibitors. RESULTS: One hundred three highly pretreated r/r MM patients with a median age of 67 years (range 44-85) were included. Seventeen (17%) patients were treated using an MO approach with BRAF inhibitors (vemurafenib or dabrafenib, n = 6), BCL2 inhibitor (venetoclax, n = 9), or FGFR3 inhibitor (erdafitinib, n = 2). Eighty-six (86%) patients received non-MO therapies. Overall response rate was 65% in MO patients versus 58% in the non-MO group (p = 0.053). Median PFS and OS were 9 and 6 months (HR = 0.96; CI95 = 0.51-1.78; p = 0.88) and 26 and 28 months (HR = 0.98; CI95 = 0.46-2.12; p = 0.98), respectively, in MO and no-MO patients. CONCLUSION: Despite the low number of patients treated with an MO approach, this study highlights the strengths and weakness of a molecular-targeted approach for the treatment of multiple myeloma. Widespread biomolecular techniques and improvement of precision medicine treatment algorithms could improve selection for precision medicine in myeloma.

New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy.

For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible for IC or who have had failed IC. Over the last few years, several new drugs have enriched the therapeutic arsenal of AML treatment for both fit and unfit patients, raising new opportunities but also new challenges. These include the already approved venetoclax, the IDH1/2 inhibitors enasidenib and ivosidenib, gemtuzumab ozogamicin, the liposomal daunorubicin/cytarabine formulation CPX-351, and oral azacitidine. Venetoclax, an anti BCL2-inhibitor, in combination with hypomethylating agents (HMAs), has markedly improved the management of unfit and elderly patients from the perspective of improved quality of life and better survival. Venetoclax is currently under investigation in combination with other old and new drugs in early phase trials. Recently developed drugs with different mechanisms of action and new technologies that have already been investigated in other settings (BiTE and CAR-T cells) are currently being explored in AML, and ongoing trials should determine promising agents, more synergic combinations, and better treatment strategies. Access to new drugs and inclusion in clinical trials should be strongly encouraged to provide scientific evidence and to define the future standard of treatment in AML.

Obstructive Sleep Apnea Syndrome Phenotyping by Cluster Analysis: Typical Sleepy, Obese Middle-aged Men with Desaturating Events are A Minority of Patients in A Multi-ethnic Cohort of 33% Women.

OBJECTIVE: Several clinical obstructive sleep apnea syndrome (OSAS) phenotypes associated with heterogeneous cardiovascular risk profiles have been recently identified. The purpose of this study was to identify clusters amongst these profiles that allow for the differentiation of patients. METHODS: This retrospective study included all moderate-to-severe OSAS patients referred to the sleep unit over a 5-year period. Demographic, symptom, comorbidity, polysomnographic, and continuous positive airway pressure (CPAP) adherence data were collected. Statistical analyses were performed to identify clusters of patients. RESULTS: A total of 567 patients were included (67% men, 54±13 years, body mass index: 32±7 kg/m2, 65% Caucasian, 32% European African). Five clusters were identified: less severe OSAS (n=172); healthier severe OSAS (n=160); poorly sleeping OSAS patients with cardiometabolic comorbidities (n=87); younger obese men with sleepiness at the wheel (n=94); sleepy obese men with very severe desaturating OSAS and cardiometabolic comorbidities (n=54). Patients in clusters 3 and 5 were older than those in clusters 2 and 4 (P=0.034). Patients in clusters 4 and 5 were significantly more obese than those in the other clusters (P=0.04). No significant differences were detected in terms of symptoms and comorbidities. Polysomnographic profiles were very discriminating between clusters. CPAP adherence was similar in all clusters but, among adherent patients, daily usage was more important in cluster 1 (less severe patients) than in cluster 5. CONCLUSION: This study highlights that the typical sleepy obese middle-aged men with desaturating events represent only a minority of patients in our multi-ethnic moderate-to-severe OSAS cohort of 33% females.

Cardiometabolic comorbidities in obstructive sleep apnea patients are related to disease severity, nocturnal hypoxemia, and decreased sleep quality.

BACKGROUND: Obstructive sleep apnea syndrome (OSA) is currently recognized as an independent risk factor for hypertension, arrhythmia, coronary heart disease, stroke, and metabolic disorders (e.g. diabetes, dyslipidemia). In clinical practice, apnea-hypopnea index (AHI) is the marker used to classify disease severity and guide treatment. However, AHI alone does not sufficiently identify OSA patients at risk for cardiometabolic comorbidities. With this in mind, the aim of this retrospective study was to determine whether some polysomnographic parameters (e.g. apnea-hypopnea duration, sleep structure, nocturnal hypoxemia) are specifically associated with cardiometabolic comorbidities in OSA. METHODS: In this retrospective study, 1717 patients suffering from moderate/severe OSA were included between 2013 and 2017. Data on demographics, comorbidities, and polysomnographic characteristics were collected and analyzed to identify factors associated with cardiometabolic complications. RESULTS: The medical files of 1717 patients (68% male) were reviewed. The mean AHI was 43.1 +/- 27.7 with 57.3% of patients suffering from severe OSA, and 52% from at least one cardiovascular comorbidity (CVCo). Diabetes affected 22% of the patients and 27% exhibited dyslipidemia. Patients affected by CVCos were older, and more often women and non-smokers. These patients also had worse sleep quality, and a more marked intermittent/global nocturnal hypoxemia. With regard to diabetes, diabetics were older, more often non-smoker, non-drinker women, and were more obese. These patients also exhibited more severe OSA, especially in non-REM (NREM) sleep, worse sleep quality, and a more marked intermittent/global nocturnal hypoxemia. Dyslipidemia was more frequent in the absence of alcohol consumption, and was associated with OSA severity, decreased sleep quality, and longer AH in REM sleep. CONCLUSIONS: This study identifies demographic and polysomnographic factors associated with cardiometabolic comorbidities. Patients (especially women) suffering from more severe OSA, longer sleep apneas and hypopneas, worse sleep quality, and marked intermittent/global nocturnal hypoxemia are more likely to develop cardiometabolic comorbidities. This should stimulate clinicians to obtain adequate treatment in this population.

African ethnicity is associated with a higher prevalence of diabetes in obstructive sleep apnea patients: results of a retrospective analysis.

PURPOSE: Obstructive sleep apnea (OSA) syndrome is a well-recognized independent risk factor for cardiovascular disease and its prevalence is increasing. OSA symptomology, polysomnographic features, and comorbidities are heterogeneous among patients. Ethnicity is thought to influence OSA phenotypes, but extensive knowledge of OSA ethnic patterns is lacking. The primary aim of the present study was to compare comorbidities in Caucasian and African OSA. Secondary aims were to observe OSA symptomatology, polysomnographic characteristics, and CPAP adherence in these two ethnic groups. METHODS: In this retrospective study, 1717 patients suffering from moderate/severe OSA were included between 2013 and 2017. Data on demographics, symptomatology, comorbidities, polysomnographic characteristics, and CPAP adherence were collected. Data were analyzed to identify potential differences between Caucasians and Africans. RESULTS: Despite healthier lifestyles and lower BMI, a higher prevalence of diabetes but less cardiac comorbidities and dyslipidemia was observed in the African population. Younger African patients (< 56 years) suffered more from cognitive impairment than Caucasians and both younger and older Africans complained more of nighttime choking than Caucasians. In analysis of polysomnographic data, Africans had higher apnea-hypopnea index (AHI) in REM sleep, lower supine AHI, lower desaturation time, and lower periodic leg movements index. CONCLUSIONS: Compared with Caucasians, African OSA showed a particular comorbidity profile. There are younger patients who exhibit more diabetes but less cardiac comorbidities than the Caucasians. African diabetics should be more promptly referred for OSA testing. Moreover, as they suffer more often from choking and cognitive impairment, OSA treatment could positively impact their quality of life.

Electrolyte Disorders as Triggers for Takotsubo Cardiomyopathy.

A 56-year-old woman presented with cognitive impairment, confusion and slowed speech, muscle cramps and peripheral paraesthesia preceded by vomiting. Blood tests revealed severe hypokalaemia, hyponatremia, hypomagnesemia and hypocalcaemia. Following a diagnosis of Takotsubo cardiomyopathy based on ultrasonography, the patient was treated with electrolyte supplementation and recovered within 48h. When heart failure is suspected, electrolyte abnormalities should be carefully ruled out as they can affect cardiac function. LEARNING POINTS: The association between electrolyte abnormalities and Takotsubo cardiomyopathy has still not been well established in the literature.Hypomagnesemia and hypocalcaemia can contribute to cardiac akinesia and so should be ruled out in heart failure.Correction of hypomagnesemia and hypocalcaemia is an important and an under-estimated part of the optimal treatment of cardiac failure.

The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment.

Iron refractory iron deficiency anemia (IRIDA) is a rare hereditary disease caused by mutations in TMPRSS6 gene encoding Matriptase-2, a negative regulator of hepcidin transcription. Up to now, 53 IRIDA patients from 35 families with different ethnic origins have been reported and 41 TMPRSS6 mutations have been identified. TMPRSS6 polymorphisms are more frequent than mutations, and have been associated with variation in iron and hematologic parameters. Our study evaluated their presence in 113 subjects with iron deficiency anemia (IDA) partially responsive to oral iron therapy and in 50 healthy blood donors. Thalassemic trait was diagnosed in 38 patients. Sequencing analysis of TMPRSS6 gene revealed that the frequency of several polymorphisms was markedly different between IDA subjects and controls. In particular, the V736A TMPRSS6 polymorphism was associated to moderately lower hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin levels, and in thalassemia carriers with marked anemia and microcytosis. A new variant-H448R- and two uncommon polymorphisms -A719T and V795I- were also identified. These results indicate that TMPRSS6 polymorphisms are more frequent in subjects with persistent IDA than in healthy controls, and in thalassemia carriers V736A variant may account for lower hemoglobin and MCV levels. Further studies in larger court of patients are necessary to identify potential haplotypes and polymorphisms responsible for low response to oral iron treatment and may be useful for planning a correct iron supplementation.

Acute coronary syndrome and decompression illness: a challenge for the diving physician.

Decompression illness (DCI) is a syndrome with diverse clinical manifestations but in which cardiac symptoms are rare. In the presence of cardiac symptoms, the necessity to rule out an acute coronary syndrome (ACS) which requires prompt treatment may result in delay to appropriate recompression treatment. We describe three cases with cardiologic symptoms referred to our centre by the Emergency Department (ED) of our facility. The first was a 48-year-old woman who lost consciousness during a dive and required cardiopulmonary resuscitation. The final diagnosis was acute myocardial infarction and the patient did not undergo recompression treatment. The second case was that of a 27-year-old man who complained of tachycardia, dyspnoea and vertigo soon after a dive. He was referred by helicopter ambulance and in the ED was diagnosed with new-onset atrial fibrillation. Recompression resulted in disappearance of his vertigo, and sinus rhythm was restored pharmacologically. The third case was a 43-year-old man, with a history of coronary artery disease, who had undergone coronary artery bypass grafting three years previously. After a repetitive dive without adequate decompression, he complained of crushing retrosternal pain and numbness in the upper left arm. All cardiovascular examinations were negative and the patient was recompressed, with resolution of his symptoms. Features to consider in arriving at the correct differential diagnosis in divers presenting with cardiac symptoms are discussed in the light of these three illustrative cases.