BMT for Myelodysplastic Syndrome: When and Where and How

Myelodysplastic syndromes (MDS) are a diverse group of hematological malignancies distinguished by a combination of dysplasia in the bone marrow, cytopenias and the risk of leukemic transformation. The hallmark of MDS is bone marrow failure which occurs due to selective growth of somatically mutated clonal hematopoietic stem cells. Multiple prognostic models have been developed to help predict survival and leukemic transformation, including the international prognostic scoring system (IPSS), revised international prognostic scoring system (IPSS-R), WHO prognostic scoring system (WPSS) and MD Anderson prognostic scoring system (MDAPSS). This risk stratification informs management as low risk (LR)-MDS treatment focuses on improving quality of life and cytopenias, while the treatment of high risk (HR)-MDS focuses on delaying disease progression and improving survival. While therapies such as erythropoiesis stimulating agents (ESAs), erythroid maturation agents (EMAs), immunomodulatory imide drugs (IMIDs), and hypomethylating agents (HMAs) may provide benefit, allogeneic blood or marrow transplant (alloBMT) is the only treatment that can offer cure for MDS. However, this therapy is marred, historically, by high rates of toxicity and transplant related mortality (TRM). Because of this, alloBMT is considered in a minority of MDS patients. With modern techniques, alloBMT has become a suitable option even for patients of advanced age or with significant comorbidities, many of whom who would not have been considered for transplant in prior years. Hence, a formal transplant evaluation to weigh the complex balance of patient and disease related factors and determine the potential benefit of transplant should be considered early in the disease course for most MDS patients. Once alloBMT is recommended, timing is a crucial consideration since delaying transplant can lead to disease progression and development of other comorbidities that may preclude transplant. Despite the success of alloBMT, relapse remains a major barrier to success and novel approaches are necessary to mitigate this risk and improve long term cure rates. This review describes various factors that should be considered when choosing patients with MDS who should pursue transplant, approaches and timing of transplant, and future directions of the field.

Lower risk but high risk

Risk stratification is crucial to the appropriate management of most cancers, but in patients with myelodysplastic syndromes (MDS), for whom expected survival can vary from a few months to more than a decade, accurate disease prognostication is especially important. Currently, patients with MDS are often grouped into higher-risk (HR) vs lower-risk (LR) disease using clinical prognostic scoring systems, but these systems have limitations. Factors such as molecular genetic information or disease characteristics not captured in the International Prognostic Scoring System–Revised (IPSS-R) can alter risk stratification and identify a subset of patients with LR-MDS who actually behave more like those with HR-MDS. This review describes the current identification and management of patients with LR-MDS whose condition is likely to behave in a less favorable manner than predicted by the IPSS-R.

Should be a Third Dose of BNT162b2 mRNA COVID-19-Vaccine Administered in Patients with Myelofibrosis Under Ruxolitinib?

Introduction. Patients with Myelofibrosis (MF) are considered fragile and thus eligible in Italy for COVID-19 BNT162b2 mRNA vaccination. According to the International Prognostic Scoring System (IPSS), patients with intermediate and high MF, may receive clinical benefits from ruxolitinib, the first approved JAK1/JAK2 inhibitor. Given the potent anti-inflammatory properties of ruxolitinib against immunocompetent cells, we previously reported a lower but non-statistically absolute IgG anti-Spike humoral response in vaccinated MF patients treated with ruxolitinib. In the present report we extended the cohort of MF patients. Methods. All MF patients received 2 injections of 30 ug per dose of BNT162b2 mRNA COVID-19 vaccine 3 weeks apart, according to the standard protocol. After injection, mild pain at the injection site was frequently reported. No serious adverse events were registered. The serum level of IgG anti-Spike glycoprotein was tested after a median time of 45 days (range 40-60) from the second vaccine dose, using the approved anti-SARS-CoV-2 IgG CLIA (LIAISON® SARS-CoV-2 TrimericS IgG assay, Diasorin, Saluggia, Italy). An Arbitrary Units per milliliter (AU/mL) ratio of <12.0 was considered to be negative, 12.0-15.0 AU/mL to be borderline and >15 AU/mL to be positive. A conversion of AU/mL to binding antibody units (BAU/mL) as recommended by the World Health Organization (WHO) guidelines was achieved considering the following equation: BAU/mL = 2.6*AU/mL. Results. Overall, 30 MF patients (median age 65 years, range 48-83) were vaccinated. A diagnosis of primary MF was reported in 21 cases (70%), post essential thrombocythemia-MF in 6 (20%) patients and post polycythemia vera-MF in 3 (10%) patients; 23 out of 30 patients (76.6%) were positive for the JAK2V617F, 5 (16.6%) for CALR mutation, 1 (3.3%) for MPL mutation and 1 patient (3.3%) resulted triple negative. Splenomegaly was observed in 14 patients (46%) and 19 (63.3%) reported comorbidities. Nineteen patients (63.3%) were classified as DIPSS low or intermediate-1 risk, and 11 (36.6%) as intermediate-2 or high risk. Fifteen patients (50%) were receiving ruxolitinib, at a median total dose of 20 mg/die (range 20-40 mg) and the remaining 15 patients other treatments (8 patients hydroxyurea and 7 only supportive therapy). None of the patients reported COVID-19 infection neither previous nor subsequently to vaccination. Overall, a positive immune response against COVID-19 was observed in 8 out of 15 patients (53.3%) in the ruxolitinib group, in comparison with 13 out 15 patients (86.6%) in the other treatment group (p=0,046). The absolute IgG anti-Spike value was lower in the ruxolitinib group (median 35.2±49.81) in comparison with the other group (median 226.1±163.9; p=<0.001), Figure 1. In univariate analysis, only ruxolitinib treatment was found associated with a lower humoral immune response to the vaccine. Conclusions. MF patients under ruxolitinib achieved a lower humoral immune response in comparison with MF patients who underwent other treatments. No COVID-19 infection was observed in both groups after vaccination, after a median follow up of 3 months since the second dose. Whether patients with a potential insufficient humoral response to vaccine will benefit from a third dose of BNT162b2 mRNA COVID-19 vaccine is a matter of further investigation. Our preliminary data need to be confirmed in larger cohort of MF patients. Figure 1 Figure 1. Disclosures Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria.

Myelodysplastic Syndromes: Have You Seen Your Patient Beyond His Hemoglobin?

Background: Palliative care (PC) is a patient-centered care model that aims to relief suffering by establishing a plan of care that integrates physical, psychosocial, cultural, familial and spiritual issues during the course of disease's evolution. Thus, PC applies not only to patients who face a diagnosis beyond the possibility of cure, but to all those who experience significant symptoms throughout the course of the disease. Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by cytopenias and an elevated risk of developing acute leukemia. As MDS display a wide genetic heterogeneity, patients have a variable clinical presentation, ranging from asymptomatic patients to individuals with severe cytopenias and high-risk disease. MDS are more prevalent in the elderly population, which usually experience several morbidities; thus, MDS frequently lead to notable symptoms and deterioration of quality-of-life, making most of them eligible to PC in addition to standard hematologic care. In spite of that, previous studies demonstrated that patients with hematologic malignancies appear to have restricted access to PC services and receive more aggressive therapies at the end of life. Aims: To evaluate eligibility criteria for PC in a cohort of MDS patients and correlate with clinical and laboratory data. Methods: Clinical and demographic data of MDS patients were collected through interviews using a standardized questionnaire: time from diagnosis, number of morbidities, need for seeking the emergency during the last 12mo, delirium events, wounds, dysphagia, recurrent falls, adverse events to medication, quality of communication with the medical team, fears regarding the disease and its complications, religious support, age, gender, monthly household income and level of schooling. Specific PC scores were also applied: Edmonton Symptom Assessment Scale (ESAS) and Palliative Performance Scale (PPS). Clinical and laboratory data were collected: hemoglobin (Hb), platelet and neutrophil counts, Revised International Prognostic Scoring System (IPSS-R) and transfusion burden. Statistical univariate and multivariate analysis were performed. P value <.05 was considered statistically significant. This research was approved by the Institutional and National Review Board; written informed consent was obtained from all subjects. Results:Thirty-six patients were evaluated: median age 68y (21-90), sex 16F/20M. According to ESAS, tiredness and anxiety were the most relevant symptoms in MDS patients [median (min-max)]: pain 0 (0-10), tiredness 4.5 (0-10), drowsiness 1.5 (0-10), nausea 0 (0-7), lack of appetite 0 (0-10), shortness of breath 0 (0-10), depression 0 (0-10), anxiety 3.5 (0-10), best wellbeing 2.5 (0-8). Younger patients (<60y, n=10) had a worse ESAS for best wellbeing (5 (2-8)) when compared to older individuals (≥60y, n=26): (2 (0-7)), p=.007, and tended to have worse ESAS scores for tiredness: 8.5 (0-10) vs 3.5 (0-10), p=.56. Importantly, ESAS for tiredness was not correlated to Hb levels, the number of red blood cell transfusions nor with IPSS-R (all p>.05). ESAS for drowsiness was significantly higher in patients with two (5 (0-10)) and ≥three morbidities (3 (0-8) vs those with only one morbidity (0 (0-10)): p=.01 and p=.03, respectively. ESAS for best wellbeing was better in individuals with higher household income 0 (0-0) vs patients with lower financial resources 3 (0-7), p=.04). PPS median was 90% (60-100%) and negatively correlated with transfusion burden (r=0.407, p=.01) and with the need for seeking the emergency in the past 12mo (r=-0.332, p=.04). Finally, despite facing a potential life-threatening disease, 94.4% of the patients reported that their doctors had never talked to them about aspects related to end-of-life care. Conversely, 75% of them reported fears and doubts regarding this phase. Conclusions: In our casuistic of MDS patients, tiredness was the most important symptom observed. Surprisingly, it was not correlated with Hb levels and transfusion burden, suggesting that Hb levels alone should not be used to justify symptoms. The number of morbidities and lower household income also impacted ESAS scores. Finally, a great part of the patients revealed miscommunication with their hematologists regarding end-of-life planning. Our data indicate that MDS patients might benefit from a PC multidisciplinary team approach. Disclosures Costa: Novartis: Consultancy.

Monitoring of Plasma Ferritin Levels after Blood Transfusions in Patients with Myelodysplastic Syndromes

Background: The majority of patients with myelodysplastic syndromes (MDS) needs regular blood transfusions and becomes transfusion dependent. Blood transfusions temporarily alleviate anemia-related symptoms, but can be accompanied by adverse events, like iron overload. In MDS patients with >20 blood transfusions and plasma ferritin levels >1000 µg/L, (inter)national guidelines advise iron chelation therapy (ICT) to reduce potential organ damage due to transfusion-mediated iron overload. The aim of this study was to determine the adherence to these guidelines, to determine to what extent plasma ferritin levels were monitored in daily practice and which patient-related factors contributed to monitoring plasma ferritin levels during the transfusion period. Methods: We performed an observational, retrospective, population-based study, using the Hemobase registry, in MDS patients diagnosed between 2005 and 2017. The Hemobase registry is a population-based registry for all hemato-oncological patients diagnosed since 2005 in Friesland, a province of the Netherlands with approximately 650.000 inhabitants. It provides detailed clinical information on diagnosis and follow-up in daily clinical practice. Clinical information on blood transfusions, plasma ferritin measurements, treatment with ICT, and patient-related factors as age, comorbidities (according to the Charlson Comorbidity Index (CCI)) and revised international prognostic scoring system (IPSS-R) risk category was collected from electronic health records. Information about all distributed blood transfusions was available from the laboratory systems. RBC units were administered to patients according to and following national guidelines. Transfusion dependence was defined according to the International Working Group (IWG) 2018 guidelines: low transfusion burden (LTB) or high transfusion burden (HTB). LTB was defined as 3-7 transfusions in a period of 16 weeks; HTB was defined as ≥8 transfusions in a period of 16 weeks. MDS patients with International Prognostic Scoring System (IPSS-R) (very) low and intermediate were categorized as low-risk MDS, and patients with IPSS-R (very) high as high-risk MDS. Logistic regression analyses were performed to analyze the likelihood of monitoring plasma ferritin levels for patients of different subgroups: age >80 years vs. ≤80 y, CCI score ≥2 vs. <2, and IPSS-R high vs. low risk MDS. Results: A total of 237 out of 292 MDS patients (81.1%) received at least one transfusion. Plasma ferritin levels were measured at least once in 55.3% (n=131) of these patients (Table 1 and Figure 1). During the first 20 transfusions, plasma ferritin measurements were present in 114 of 237 patients (48.1%). After >20 transfusions, plasma ferritin measurements were present in 51 of 121 patients (42.1%). Age, comorbidities and IPSS-R score were not associated with the likelihood of monitoring plasma ferritin levels. 112 patients were eligible for ICT (i.e. plasma ferritin levels >1000 µg/L or >20 transfusions). ICT was given to 22.3% (n=25) of these patients. Five patients received ICT whilst not fulfilling the criteria according to the guideline. During ICT, plasma ferritin levels were monitored in 60.0% of patients with ICT. Conclusions: In conclusion, in this population-based study, plasma ferritin levels were measured, irrespective of age, comorbidities and IPSS-R score, in 55% of MDS patients with transfusions. ICT was not given to all eligible patients and during ICT, monitoring of plasma ferritin levels was not performed in all cases. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

TP53 in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDSs) are heterogeneous for their morphology, clinical characteristics, survival of patients, and evolution to acute myeloid leukemia. Different prognostic scoring systems including the International Prognostic Scoring System (IPSS), the Revised IPSS, the WHO Typed Prognostic Scoring System, and the Lower-Risk Prognostic Scoring System have been introduced for categorizing the highly variable clinical outcomes. However, not considered by current MDS prognosis classification systems, gene variants have been identified for their contribution to the clinical heterogeneity of the disease and their impact on the prognosis. Notably, TP53 mutation is independently associated with a higher risk category, resistance to conventional therapies, rapid transformation to leukemia, and a poor outcome. Herein, we discuss the features of monoallelic and biallelic TP53 mutations within MDS, their corresponding carcinogenic mechanisms, their predictive value in current standard treatments including hypomethylating agents, allogeneic hematopoietic stem cell transplantation, and lenalidomide, together with the latest progress in TP53-targeted therapy strategies, especially MDS clinical trial data.

New Markers of Disease Progression in Myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm due to the clonal proliferation of a hematopoietic stem cell. The vast majority of patients harbor a somatic gain of function mutation either of JAK2 or MPL or CALR genes in their hematopoietic cells, resulting in the activation of the JAK/STAT pathway. Patients display variable clinical and laboratoristic features, including anemia, thrombocytopenia, splenomegaly, thrombotic complications, systemic symptoms, and curtailed survival due to infections, thrombo-hemorrhagic events, or progression to leukemic transformation. New drugs have been developed in the last decade for the treatment of PMF-associated symptoms; however, the only curative option is currently represented by allogeneic hematopoietic cell transplantation, which can only be offered to a small percentage of patients. Disease prognosis is based at diagnosis on the classical International Prognostic Scoring System (IPSS) and Dynamic-IPSS (during disease course), which comprehend clinical parameters; recently, new prognostic scoring systems, including genetic and molecular parameters, have been proposed as meaningful tools for a better patient stratification. Moreover, new biological markers predicting clinical evolution and patient survival have been associated with the disease. This review summarizes basic concepts of PMF pathogenesis, clinics, and therapy, focusing on classical prognostic scoring systems and new biological markers of the disease.

A CIBERSORTx-based immune-cell scoring system could independently predict prognosis of myelodysplastic syndrome patients

Aside from the cell-intrinsic factors such as genetic alterations, immune dysregulation in the bone marrow (BM) microenvironment plays a role in the development and progression of myelodysplastic syndromes (MDS). However, the prognostic implications of various immune cells in MDS patients remain unclear. We adopted CIBERSORTx to estimate the relative fractions of 22 subtypes of immune cells in the BM of 316 MDS patients and correlated the results with clinical outcomes. A lower fraction of unpolarized M0 macrophages and higher fractions of M2 macrophages and eosinophils were significantly associated with inferior survival. An immune cell scoring system (ICSS) was constructed based on the proportion of these three immune cells in the BM. The ICSS high-risk patients had higher BM blast counts, higher frequencies of poor-risk cytogenetics, and NPM1, TP53, and WT1 mutations than intermediate- and low-risk patients. The ICSS could stratify MDS patients into three risk groups with distinct leukemia-free survival and overall survival among the total cohort and in the subgroups of patients with lower and higher disease risk based on the revised International Prognostic Scoring System (IPSS-R). The prognostic significance of ICSS was also validated in another independent cohort. Multivariable analysis revealed that ICSS independently predicted prognosis, irrespective of age, IPSS-R, and mutation status. Bioinformatic analysis demonstrated a significant correlation between high-risk ICSS and nuclear factor kappa B signaling, oxidative stress, and leukemic stem cell signature pathways. Further studies investigating the mechanistic insight into the crosstalk between stem cells and immune cells are warranted.

Should We Look beyond Revised International Prognostic Scoring System: A Retrospective Observational Study of Progression of Myelodysplastic Syndrome to Acute Leukemia

Introduction Myelodysplastic syndrome (MDS) is a clonal stem cell disorder and heterogeneous condition resulting in peripheral cytopenias with marrow dysplasia due to ineffective hematopoiesis. The revised International Prognostic Scoring System (IPSS-R) predicts the risk of progression to acute leukemia (AL). Indian data on MDS and its progression to AL are limited. Additionally, the cytogenetic findings are dictated by patients' racial background. Study intended to analyze the cytogenetic profile of the patients with MDS. Objectives This study aimed to (1) evaluate the clinicohematologic and morphologic spectrum of newly diagnosed MDS cases, (2) evaluate the cytogenetic profile of these cases, and (3) study the cases progressed to AL. Materials and Methods MDS cases diagnosed and followed-up during a 5-year study period, from January 2015 to December 2019, were included in the study and the study was conducted at regional cancer center in Western India. De novo diagnosed MDS cases with complete workup were considered and MDS due to secondary causes were excluded. Baseline clinical, hematologic findings were tabulated along with cytogenetics and risk stratified as per IPSS-R, and their progression was studied. Results A total of 63 cases of de novo MDS were diagnosed over a period of 5 years with 45 cases on follow-up and 15 cases (33.3%) progressed to AL. Maximum number of cases belonged to MDS-excess blast (EB) category accounting to 48 cases (76.1%). Apparently normal karyotyping was the commonest cytogenetic finding in 33 MDS cases (61.2%) and in 8 cases that progressed to AL (53.4%). Conclusion MDS cases diagnosed at relatively early age were at higher risk of progression to AL. Majority of the cases that progressed to AL were risk stratified in high and very high risk groups and 10 cases which progressed to AL belonged to good category, interestingly apparent normal karyotyping was the commonest cytogenetic finding in more than 50% of the cases progressed to AL. Molecular mutations could only explain this progression and studies integrating molecular mutations with present IPSS-R scoring system should be conducted, as it could translate into better risk stratification and help in early identification and better management of cases at risk in progression to AL.