Semra Aydin

Recent implementations with novel target drugs of the hypomethylating agent/venetoclax doublet challenge our treatment approach in acute myeloid leukemia patients ineligible for intensive chemotherapy. Given the doublets’ efficacy, associations of agents based on the disease’s biology to the doublet backbone are leading to novel triplet (or more) combinations. In the present review mainly FLT3, IDH and KMT2A are discussed as possible targets in this context. These triplets do not only have efficacy in relapsed/refractory patients but also in treatment-naïve patients. Results from concluded and ongoing clinical trials, as well as real-world experiences, report high efficacies competing with intensive chemotherapy. For instance, the azacytidine/venetoclax/gilteritinib triplet as first-line is reported to induce a complete remission rate with and without incomplete recovery (CR/CRi) of 96%, with 90% of responders achieving minimal residual negativity. Once a stable CR was obtained, 47% of patients who were initially considered too frail for intensive chemotherapy were able to undergo allogeneic stem cell transplantation. However, there are still open questions and challenges regarding toxicity, post-remission therapy, and overall treatment duration. The present review will not only present the specific potency of these arising triplets, but also discuss their challenges and limitations, based on currently available data. Besides regimens containing approved inhibitors, triplets with next-generation inhibitors, including completely orally administered triplet regimens, are also summarized. Their promising results are leading to advanced phase clinical studies by international consortia and collaborative groups, aiming to further refine their clinical management.

Background: Accurate assessment of elderly acute myeloid leukemia (AML) patients is essential before intensive induction chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation. In this context, we investigated the capacity of three scores for frailty prediction. Methods: At diagnosis, 197 patients were clinically evaluated for appropriate treatment intensity. In parallel and independently, the G8-score, the Hematopoietic Stem Cell Index (HCT-CI) and the AML-score for CR were determined for each patient and analyzed with respect to overall survival (OS). Results: The G8-score and the HCT-CI were able to significantly separate “fit” from “unfit” patients, p = 0.008. In univariate Cox models, the predictive role for OS was confirmed: for the G8-score (HR: 2.35, 95% CI 1.53–3.60, p < 0.001), the HCT-CI (HR: 1.91, 95% CI 1.17–3.11, p = 0.009) and the AML-score (HR: 5.59, 95% CI 2.04–15.31, p = 0.001), the latter was subsequently used to verify the cohort. In the multivariate Cox model, the results were confirmed for the G8- (HR: 2.03, p < 0.001) and AML-score (HR: 3.27, p = 0.001). Of interest, when combining the scores, their prediction capacity was significantly enhanced, p < 0.001. Conclusions: The G8-, the HCTCI and the AML-score represent valid tools in the frailty assessment of elderly AML patients at diagnosis.

In a retrospective analysis, 21 acute myeloid leukemia patients receiving single-agent sorafenib maintenance therapy in complete remission (CR) after hematopoietic stem cell transplantation (HSCT) were compared with a control group of 22 patients without maintenance. Sorafenib was initiated a median of 3 months (IQR: 2.3–3.5) after allogeneic HSCT with a median daily dosage of 400 mg (range: 200–800) orally, and lasted a median of 11.3 months (IQR: 3.3–24.4). No significant increase in graft versus host disease or toxicity was observed. Adverse events were reversible with dose adjustment or temporary discontinuation in 19/19 cases. With a median follow-up of 34.7 months (IQR: 16.9–79.5), sorafenib maintenance significantly improved cumulative incidence of relapse (p = 0.028) as well as overall survival (OS) (p = 0.016), especially in patients undergoing allogeneic HSCT in CR1 (p < 0.001). In conclusion, sorafenib maintenance after allogeneic HSCT is safe and may improve cumulative incidence of relapse and OS in FLT3–ITD-mutated AML.

Acute myeloid leukemia (AML) in older patients is characterized by unfavorable prognosis due to adverse disease features and a high rate of treatment-related complications. Classical therapeutic options range from intensive chemotherapy in fit patients, potentially followed by allogeneic hematopoietic cell transplantation (allo-HCT), to hypomethylating agents or palliative care alone for unfit/frail ones. In the era of precision medicine, the treatment paradigm of AML is rapidly changing. On the one hand, a plethora of new targeted drugs with good tolerability profiles are becoming available, offering the possibility to achieve a prolonged remission to many patients not otherwise eligible for more intensive therapies. On the other hand, better tools to assess patients’ fitness and improvements in the selection and management of those undergoing allo-HCT will hopefully reduce treatment-related mortality and complications. Importantly, a detailed genetic characterization of AML has become of paramount importance to choose the best therapeutic option in both intensively treated and unfit patients. Finally, improving supportive care and quality of life is of major importance in this age group, especially for the minority of patients that are still candidates for palliative care because of very poor clinical conditions or unwillingness to receive active treatments. In the present review, we discuss the evolving approaches in the treatment of older AML patients, which is becoming increasingly challenging following the advent of new effective drugs for a very heterogeneous and complex population.

COVID-19 pandemic has raised several concerns regarding patients with hematologic and immune-mediated diseases. It can be assumed that Paroxysmal nocturnal hemoglobinuria (PNH), both classic hemolytic and associated with aplastic anemia, particularly on treatment with complement inhibitors, may be more susceptible and have higher morbidity and mortality rates from COVID-19 than the general population. Italy has been heavily affected from the COVID-19 outbreak with the peak of contagions at the end of March 2020. As of July, 23 2020 the cumulative incidence of COVID-19 in Italy was 0.4% (1 case every 246 residents) (ranging from 0.06% - 1/1621- in Calabria to 0.9% - 1/106 - in Lombardy). We conducted a survey on 126 patients with PNH (77 females/49 males, median age 48 years, range 19-86) among 7 reference Italian centers in order to evaluate the occurrence and clinical characteristics of COVID-19 infection from the outbreak until the time of writing. According to International PNH Interest Group (IPIG) classification, 95 patients suffered from classic hemolytic PNH, 24 had associated bone marrow failures (aplastic anemia or myelodysplastic syndrome), and 7 had subclinical PNH (clone size <10%). Sixty-nine cases were on complement fraction 5 (C5) inhibition (72 eculizumab and 19 ravulizumab). Comorbidities were present in 33 patients, including arterial hypertension (N=14), ischemic cardiomyopathy (N=3), atrial fibrillation (N=2), diabetes mellitus (N=2), breast cancer (N=3), colon cancer (N=1), prostate cancer (N=1), Crohn disease (N=1), and Hashimoto thyroiditis (N=1). During the observation period, only one patient (55 years female), from Milan, Lombardy, not on C5-inhibitor was diagnosed with COVID-19 infection (positive swab, ageusia, and mild fever for few days). No hemolytic flare occurred, nor hospital admission was required. She received azithromycin and low molecular heparin. Other 6 patients, all on C5-inhibitors, experienced fever (N=5) and cough (N=2), and/or dysgeusia (N=1), of whom 2 experienced breakthrough hemolysis (BTH), but swabs and CT scans (N=2) were negative. At variance, 6 patients (4 on eculizumab and 2 on ravulizumab) experienced BTH without COVID-19 symptoms. Interestingly, a young male patient on eculizumab, working as medical doctor in a COVID-19 ward, did not contract the infection. In conclusion, this survey suggests that PNH subjects, either on complement inhibition or not, are not at significantly higher risk of COVID-19 infection as compared with the general population. As a matter of fact, the basic protective measures against COVID-19 have always been advised to PNH patients particularly during treatment and were presumably carefully followed during the pandemic. On the other hand, immune activation and inflammation are thought to play an important role in the clinical severity of COVID-19 pneumonia. Complement inhibition, which is under investigation in COVID-19 disease, seems at least not disadvantageous in PNH.

Patients with post-transplant cytopenias due to poor graft function or primary engraftment failure show poor prognosis with a high mortality rate mainly because of graft versus host disease (GVHD), infection and/or bleeding. Treatment options are scarce and a CD34+ stem cell boost or a second bone marrow transplantation may be required to restore adequate haematopoiesis. In the present study patients with primary engraftment failure (n = 1) and refractory poor graft function (n = 11) were treated with eltrombopag in a single centre. The reason for eltrombopag treatment was trilineage cytopenia in six patients, bilineage cytopenia in three patients and single lineage cytopenia in three patients. Eltrombopag was initiated at a median of 214 (range: 120–877) days after haematopoietic stem cell transplantation (HCST) and administered for a median time of 114 (range: 12 days to >490) days. In 8/12 patients eltrombopag was introduced at a dose of 75 mg/day and then increased to 150 mg/day after 1 week; 1 patient was given 50 mg eltrombopag per day, and 3 patients received 75 mg daily. In 10/12 patients eltrombopag significantly enhanced blood count values and patients became transfusion independent. Once stable haematological response was obtained, treatment was tapered until final discontinuation in 9/10 responding patients. No grade 3 or 4 toxicities were observed. At time of last follow up, 3/12 patients were dead, 2 due to disease relapse, 1 due to GVHD and pneumonia. All patients except one maintained their complete response and remain transfusion independent at a median of 858 (range: 429–1119) days. These preliminary data confirm that eltrombopag is able to rescue multilineage haematopoiesis in patients with treatment-refractory cytopenias after allogeneic HSCT.

Background: Although acute myeloid leukemia (AML) occurs most commonly in adults ≥60 years, the treatment of AML in older patients remains a significant challenge due to both, more aggressive disease biology as well as patient-related risk factors that limit tolerance of intensive chemotherapy. Several studies demonstrated improved survival for older patients receiving intensive induction chemotherapy. Therefore intensive chemotherapy, as long as patient fitness allows, is aimed. Defining the subset of patients that is eligible or "fit" for intensive chemotherapy involves a great deal of subjectivity. Criteria yet have to be standardized across or within institutions. Aim: The aim of the present study was to investigate the power of three validation scores in assessing patient fitness at diagnosis in parallel to physician evaluation. Further patient outcome according the respective assessment was compared. Methods: A total of 130 clinically and molecularly well characterized consecutive elderly (≥60 years) patients with newly diagnosed AML were treated from 2012 to 2018 according to age, performance status and co-morbidities in a single hematology center. Initial haematologist evaluation followed by discussion of the patient case in an interdisciplinary board led to decision of therapy intensity of each patient. In parallel, independently from the medical board decision, three scores were performed: i) a local geriatric G8 screening tool, consisting of seven items from the Mini Nutritional Assessment (MNA) questionnaire and age, ii) the Sorror Index used for hematopoietic stem cell transplantation (HSCT) evaluation as well as iii) the AML score proposed by the German Acute Myeloid Leukemia Cooperative Group, predicting the probability of complete remission (CR) and early death (ED). Therapy response was defined according to ELN criteria. Overall survival from diagnosis was compared between groups using the Cox model. Results: Median age was 71,2 (range: 60-86) years. A total of 75 (57,7%) patients were evaluated "fit" by the medical board and treated by intensive chemotherapy ("7+3" regimen), whereas 41 patients (31,5%) underwent semi-intensive therapy (based on hypomethylating agents or low-dose Cytarabine s.c.) and 14 patients (10,7%) received best supportive care. Fifty patients (38,5%) achieved a complete remission after induction chemotherapy, could follow consolidation chemotherapy and ten of them underwent allogeneic HSCT. Sixty-four (49,2%) were non responders and 16 patients (12,3%) died during the first cycle. Overall, the median survival time was 11,2 months (95% CI 7,9-17,8). Primary physician care evaluation was able to define a "fit" from an "unfit" patient in a statistically significantly way. Median survival time from the "fit" patients was 17,6 months (95%CI 9-28,9) compared to the "unfit" evaluated patients with 3,6 months (95%CI 1,8-8,8), pConclusion: In conclusion, the frailty scores G8, Sorror Index and the AML Score, that have been applied to elderly patients at AML diagnosis seem to discriminate patients quite well in terms of overall survival in this single centre patient cohort and may represent objective instruments for the haematologist in the validation of the fitness of the elderly AML patients for intensive chemotherpy. In order to validate the discrimination ability arising from the performed analysis, a multi-centre study is planned.

Pure red blood cell aplasia (PRCA) is a complication of ABO major-incompatible stem cell transplantation, likely due to the persistence of memory B lymphocytes of recipient origin, which produce hemagglutinins against ABO antigens on donor RBCs. At present no standard of care is established for this complication. We report a case of PRCA after allogeneic bone marrow transplantation, successfully treated with plasma exchange (PEX) after failing erythropoietin administration. The patient fully recovered from RBC aplasia. This case suggests a role for PEX in the treatment of PRCA after allogeneic stem cell transplantation.