RNA methylation sequencing shows different gene expression signatures for response to azacytidine therapy in high-grade myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are myeloid malignancies with heterogeneous genotypes and phenotypes, characterized by ineffective haematopoiesis and a high risk of progression towards acute myeloid leukaemia (AML). Prognosis for patients treated with hypomethylating agents (HMAs), as is azacytidine, the main drug used as frontline therapy for MDS is mostly based on cytogenetics and next generation sequencing (NGS) of the initial myeloid clone. Although the critical influence of the epigenetic landscape upon cancer cells survival and development as well on tumour environment establishment is currently recognized and approached within current clinical practice in MDS, the heterogenous response of the patients to epigenetic therapy is suggesting a more complex mechanism of action, as is the case of RNA methylation. In this sense, the newly emerging field of epitranscriptomics could provide a more comprehensive perspective upon the modulation of gene expression in malignancies, as is the proof-of-concept of MDS. We initially did RNA methylation sequencing on MDS patients (n = 6) treated with azacytidine and compared responders with non-responders. Afterwards, the genes identified were assessed in vitro and afterwards validated on a larger cohort of MDS patients treated with azacytidine (n = 58). Our data show that a more accurate prognosis could be based on analysing the methylome and thus we used methylation sequencing to differentially split high-grade MDS patients with identical demographical and cytogenetic features, between azacytidine responders and non-responders.

"Lazarus Response" When Feto-Maternal Microchimerism Kicks in: Spontaneous Remission in Refractory Primary Mediastinal B Cell Lymphoma Following Twin Pregnancy.

Background: Spontaneous remission of cancer is a rare and poorly understood phenomenon characterized by complete or partial remission of a malignancy in the absence of or with inadequate treatment. The underlying mechanism for such occurrences is poorly understood, however, immune mechanisms seem to play an important role in such cases. In recent years increasingly more data have become available in favor of the clinical benefit of low levels of chimerism in hematologic malignancies. One such instance of naturally occurring low-level chimerism is feto-maternal microchimerism which has been shown to influence cancer progression and, in some instances, to be a protective factor against malignancy. Case report: We report a case of a young female patient with aggressive primary mediastinal large B cell lymphoma refractory to two lines of chemo-immunotherapy achieving sustained complete metabolic remission of tumor while pregnant with twins. Results: A focus on feto-maternal microchimerism during and after pregnancy revealed transient levels of feto-maternal microchimerism in the peripheral blood of the patient as measured by quantifying the Y-chromosome-linked SRY gene. Conclusions: Microchimerism presents significant potential for enhancing our comprehension of disease mechanisms, uncovering novel therapeutic targets, and refining diagnostic and treatment approaches, especially concerning cancer.

Switching from salvage chemotherapy to immunotherapy in adult B-cell acute lymphoblastic leukemia.

About one-half of adults with acute B-cell lymphoblastic leukemia (B-ALL) who do not achieve molecular complete remission or who subsequently relapse are not cured by current chemo- or targeted therapies. Previously, the sole therapeutic option for such persons was a hematopoietic stem cell transplant. Recently, several immune therapies including monoclonal antibodies, bispecific T-cell engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cells (CARs) have been shown safe and effective in this setting. In this manuscript, we summarize data on US FDA-approved immune therapies of advanced adult B-ALL including rituximab, blinatumomab, inotuzumab ozogamicin, tisagenlecleucel and brexucabtagene autoleucel. We consider the results of clinical trials focusing on efficacy, safety, and quality of life (QoL). Real-world evidence is presented as well. We also briefly discuss pharmacodynamics, pharmacokinetics, and pharmacoeconomics followed by risk-benefit analyses. Lastly, we present future directions of immune therapies for advanced B-ALL in adults.

Unexplained hemorrhagic syndrome? Consider acquired hemophilia A or B.

There is a dire need to develop an algorithm to improve the recognition of acquired hemophilia A and B (AHA and AHB) in clinical practice. Initial and intensive care unit (ICU) management of the disorder is particular and represents a challenge for the internist/hematologist and the ICU physician. A delay in the proper treatment of bleeding episodes can lead to a life-threatening event. Expert advice should be sought as soon as possible. Succesful resolution involves accurate diagnosis, bleeding control with hemostatic and immunotherapy, and eradication of the autoantibodies to improve overall survival. Current treatment guidelines are based on the literature in the form of cases and observational studies due to a lack of randomized controlled trials. AH can be triggered by many pathologies, presenting as a paraneoplastic syndrome in case of malignancies or as surgical associated acquired hemophilia (SAHA). We have reviewed the literature from 2015 to 2021 regarding the new case reports to further assess if there is an improvement in the clinical approach.

Ibrutinib Monotherapy as Bridge-to-Transplant for Relapsed/Refractory Primary Oculo-Cerebral Lymphoma.

INTRODUCTION: Primary central nervous system lymphoma is an uncommon form of extranodal non-Hodgkin's lymphoma, with increasing incidence, a relatively aggressive course and a poor 5-year survival. Because of its localization, the therapeutic compounds used in this disease must be able to pass through the blood-brain barrier. Chemotherapy regimens based on high-dose methotrexate are currently the standard of care for all patients who can tolerate such drugs. Autologous stem cell transplantation is indicated for malignant lymphomas in the relapsed/refractory setting. METHODS: Three patients, with a median age of 60 years, range 53-64, were diagnosed with primary CNS lymphoma, and treated with ibrutinib monotherapy in the Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania, between September 2018 and November 2020 All the patients were relapsed-refractory following high-dose methotrexate chemotherapy. We present our experience using ibrutinib monotherapy-based treatment as a bridge-to-transplant option on a single-center case series and a review of the literature in this field. RESULTS: Two of the patients were given ibrutinib as a second line therapy, both achieving complete remission and being eligible for an autologous stem cell transplantation. The third patient achieved a short remission using six cycles of systemic chemotherapy, but was started on ibrutinib monotherapy, with limited results. CONCLUSION: Our data is limited, and these results should be confirmed by multicentric clinical trials and should be regarded as a single-center case series, with all its limitations. Still, it brings forward a new therapeutic option for this rare subtype of malignant lymphomas, which if left untreated has a dismal prognosis.

The Predictive Role of Modified Early Warning Score in 174 Hematological Patients at the Point of Transfer to the Intensive Care Unit.

INTRODUCTION: The examination of vital signs and their changes during illness can alert physicians to possible impending deterioration and organ dysfunction. The Modified Early Warning Score (MEWS) is used worldwide as a track and trigger system that can help to identify patients at risk of critical illness. Thus, the current study aimed to assess the ability of MEWS to predict the mortality of hematologic patients at the point of transfer from the ward to the intensive care unit (ICU). MATERIALS AND METHODS: The present study was retrospective, longitudinal, and observational, conducted at an oncology hospital in the city of Cluj-Napoca, Romania. We included 174 patients with hematological disorders transferred from the ward to the ICU between the 1st of January 2018 and the 1st of May 2020. We assessed the MEWS at the moment of admission in these patients in the ICU. The accuracy of MEWS in predicting mortality was assessed via the area under the receiver operating characteristic curves (AUC), and sensitivity, specificity, and hazard ratio (HR) were calculated for different MEWS cutoffs. MEWS values considering the status at discharge and frequency of death by MEWS were also analyzed. RESULTS: We calculated MEWS values considering the status at discharge (p < 0.0001), and we assessed the frequency of death by MEWS. We also calculated the hazard ratio (HR) of death depending on the selected MEWS cutoff. The best cutoff point was found to be ≥6, with an accuracy of 0.667, sensitivity of 0.675, specificity of 0.646, and AUC of 0.731. Patients with higher MEWS had a higher probability of mortality. CONCLUSION: The MEWS and cutoff points were determined on a sample of hematologic patients at the moment of admission to the ICU. The final aim is to encourage physicians to use these scores to improve awareness of organ failure to admit patients to the ICU sooner and limit overall morbidity and mortality. The presence of an ICU physician on ward rounds might help in reducing the timeframe of access to a high-dependency unit (HDU) or ICU. An extension of these scores outside hematologic patients or considering hematologic patients outside ICU must be further studied.

Mobile Health Technology for the Personalized Therapy of Hemophilia.

The management of patients with hemophilia has evolved significantly since the first treatment attempts were made in the late 1930s. Since then, each new step in the treatment of patients with hemophilia has brought important advancements, as well as its unique set of challenges. Today, a patient-centered, individualized comprehensive approach is the new paradigm, moving away from the traditional "one size-fits-all" approach, to provide the best possible care for each patient with a bleeding disorder. As part of this complex task, mobile health applications might have the capacity to play an important role in reaching that goal. However, the use of new electronic technologies as part of a comprehensive treatment approach for patients with hemophilia simultaneously presents a new set of challenges that needs consideration. In the first section, currently available treatment of hemophilia patients will be revised, while in the second part the role of IT software in the treatment monitoring of hemophilia patients will be discussed.

Current therapeutic approaches in the management of hemophilia-a consensus view by the Romanian Society of Hematology.

Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed.

Azacytidine plus olaparib for relapsed acute myeloid leukaemia, ineligible for intensive chemotherapy, diagnosed with a synchronous malignancy.

Patients with relapsed/refractory acute myeloid leukaemia (AML), ineligible for intensive chemotherapy and allogeneic stem cell transplantation, have a dismal prognosis. For such cases, hypomethylating agents are a viable alternative, but with limited success. Combination chemotherapy using a hypomethylating agent plus another drug would potentially bring forward new alternatives. In the present manuscript, we present the cell and molecular background for a clinical scenario of a 44-year-old patient, diagnosed with high-grade serous ovarian carcinoma, diagnosed, and treated with a synchronous AML. Once the ovarian carcinoma relapsed, maintenance treatment with olaparib was initiated. Concomitantly, the bone marrow aspirate showed 30% myeloid blasts, consistent with a relapse of the underlying haematological disease. Azacytidine 75 mg/m2 treatment was started for seven days. The patient was administered two regimens of azacytidine monotherapy, additional to the olaparib-based maintenance therapy. After the second treatment, the patient presented with leucocytosis and 94% myeloid blasts on the bone marrow smear. Later, the patient unfortunately died. Following this clinical scenario, we reproduced in vitro the combination chemotherapy of azacytidine plus olaparib, to accurately assess the basic mechanisms of leukaemia progression, and resistance to treatment. Combination chemotherapy with drugs that theoretically target both malignancies might potentially be of use. Still, further research, both pre-clinical and clinical, is needed to accurately assess such cases.

Clinical Remission in a 72-Year-Old Patient with a Massive Primary Cutaneous Peripheral T-Cell Lymphoma-NOS of the Eyelid, Following Combination Chemotherapy with Etoposide Plus COP.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is the rarest subtype of primary cutaneous lymphoma, accounting for approximately 2% of cutaneous lymphomas. The rarity of primary cutaneous PTCL-NOS means that there is a paucity of data regarding clinical and histopathological features and its clinical course. This malignancy is an aggressive and life-threatening hematological malignancy that often presents mimicking other less severe plaque-like skin conditions. Due to the nonspecific nature of these lesions, CD4-positive cutaneous T-cell lymphoma (CTCL) is often misdiagnosed as either mycosis fungoides or Sezary syndrome. We describe a patient who presented with a large tumoral mass in the right frontal area, with involvement of the right upper eyelid and the ocular globe, causing loss of vision greatly impacting the quality of life. Biopsy revealed primary cutaneous PTCL-NOS, treated successfully with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide combination chemotherapy. As elderly patients are indicated to receive attenuated doses of chemotherapy, CHOP-based regimens represent viable options.