The Diagnostic Value of Abnormal Bone Marrow Signal Changes on Magnetic Resonance Imaging: Is Bone Marrow Biopsy Essential?

BACKGROUND: It is essential to determine whether bone marrow signal changes on magnetic resonance imaging (MRI) represent a physiological response or pathology; at present, the clinical significance of these signal changes is unclear. It is unknown whether a bone marrow biopsy is required when bone marrow signal changes are detected incidentally in individuals without suspected malignancy. OBJECTIVE: The primary purpose of this study was to determine whether incidentally detected bone marrow signal changes on MRI performed for various reasons (at the time of admission or during follow-up) are clinically significant. METHODS: We retrospectively evaluated the bone marrow biopsy clinical and laboratory findings of 42 patients with incidental bone marrow signal changes on MRI between September 2016 and January 2020. We also determined whether the patients were diagnosed with malignancy during admission or follow-up. RESULTS: Of the 42 patients, three (7%) were diagnosed with hematological malignancies during admission, while two were diagnosed with multiple myeloma and one with B-cell acute lymphoblastic leukemia. Of the 42 patients, 35 had a mean follow-up of 40.6 ± 5.3 months. One patient was diagnosed with monoclonal gammopathy of undetermined significance four months after their first admission. CONCLUSIONS: In addition to MRI, detailed clinical and laboratory evaluations should be performed to inform the decision for bone marrow biopsy and exclude hematological malignancy. If there is any doubt, a bone marrow biopsy should be performed. Moreover, since bone marrow signal changes may be a preliminary finding, follow-up of these patients is essential.

Impact of autologous stem cell transplantation on survival outcomes in patients with peripheral T cell lymphoma.

Data about the timing of autologous stem cell transplantation (ASCT) in peripheral T cell lymphoma (PTCL) are conflicting. We aimed to investigate the impact of the sequence of ASCT on the survival outcomes in patients with PTCL. Analyzes were performed retrospectively in a total of 81 patients, 16 of whom underwent upfront ASCT and 12 received salvage ASCT. In univariate analysis, upfront ASCT reduced the risk of progression and death by 77% (Hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.09-0.60) (p = 0.003) and by 84% (HR: 0.16, 95% CI: 0.5-0.55) (p = 0.003), respectively. However, in multivariate analysis, only salvage ASCT predicted a more favorable progression-free and overall survival (HR: 0.17, 95% CI: 0.06-0.48, p = 0.001 and HR: 0.20, %95 GA: 0.06-0.62, p = 0.005, respectively). In conclusion, regardless of first-line therapy, patients have more favorable outcomes if they receive salvage ASCT. Upfront ASCT does not add clinically significant benefit to survival outcomes.

Splenectomy in Immune Thrombocytopenia: A Retrospective Analysis of 25-Year Follow-up Data from a Tertiary Health Clinic.

Immune thrombocytopenia (ITP) is a rare autoimmune disorder presenting with isolated thrombocytopenia. Splenectomy is still one of the treatment alternatives for these patients. Here we aim to analyze long term follow-up data of splenectomy in immune thrombocytopenia. This retrospectively designed study was conducted in a tertiary health clinic. Patients with ITP who were splenectomized between 1990 and 2015 were included. Response to treatment was interpreted as 'complete response', 'response' or 'no response'. The incidence of response loss was evaluated. Perioperative and long term complications and overall survival rates were determined. Out of 51 patients, who underwent splenectomy after 12 months of diagnosis, 47 achieved a response (92.2%). Of 47 patients who had a platelet count at least 30.000/µL, 41 (87.2%) had CR. Incidence of loss of response was 10.5% (95% confidence interval (CI): 4%-26.1%) at 30 months. Two patients died, and overall survival rate was 97.4% (95% CI: 82.8%-99.6%) at 30 months of follow up. Considering the complications: two patients had venous thromboembolism, 11 had minor bleeding episodes and 15 suffered from perioperative infections. Our study suggests that splenectomy promises a high level of response with acceptable complication rates. Although less preferred recently, splenectomy should still be taken into consideration when remission is not achieved especially after 12 months of disease.

Real-life ruxolitinib experience in intermediate-risk myelofibrosis.

BACKGROUND: In this retrospective cohort of patients with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis, 57 patients with MF who received ruxolitinib for MF-related symptoms or symptomatic splenomegaly were evaluated. METHODS: The median age of the patients in this cohort was approximately 58 years. Of these, there were 33 patients (57.9%) in INT-1, 23 patients (40.4%) in INT-2, and 1 patient (1.8%) at high risk. Overall, spleen size reduction of at least 35% (spleen response) was achieved in 56.6% and 63.3% of all cohort and INT-1 risk at any time, respectively. RESULTS: Symptom response and clinical improvement were observed in 21.7% and 60.7% of patients, respectively. Anemia and thrombocytopenia were prevalent, but manageable. About 73.7% of patients continued treatment during a median follow-up of 22 months. Two-year OS probability was approximately 84.5% (95% CI, 63.1‒94.0%) and 62.3% (95% CI, 37.5‒79.6%) for the intermediate-1 and -2 risk groups, respectively. CONCLUSION: Real-life experience in a community-based hospital confirms the efficacy and safety profile of ruxolitinib in intermediate-risk myelofibrosis. Treatment discontinuation rates were lower than those in clinical trials.

Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic.

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

Treosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis.

Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36-42 g/m2) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related (n = 2), unrelated (n = 23), or mismatched unrelated (n = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II-IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.

Incidence and Outcome of Late Relapse after Allogeneic Stem Cell Transplantation for Myelofibrosis.

In this cross-sectional study, we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation (SCT). A total of 94 patients who were alive and in remission at 5 years were identified with follow-up of at least 5 years (median, 9.15 years) after SCT. Thirteen patients (14%) experienced late molecular (n = 6) or hematologic (n = 7) relapse at a median of 7.1 years while 81 patients did not experience relapse. Relapse patients received either donor lymphocyte infusion (DLI) (n = 7) and/or second transplantation (n = 4). Of those, 72.7% achieved again full donor cell chimerism and molecular remission, and after a median follow-up of 45 months, the 3-year overall survival rates for patients with or without relapse were 90.9% (95% confidence interval [CI], 77% to 100%) and 98.8% (95% CI, 96% to 100%), respectively (P = .13). We conclude that late relapse occurs in about 14% of the patients and the majority can be successfully salvaged with DLI and/or second allograft. All patients with molecular relapse are alive and support the long-time molecular monitoring in myelofibrosis patients after allogeneic SCT.

Quality of Life and Symptom Burden With First- and Second-generation Tyrosine Kinase Inhibitors in Patients With Chronic-phase Chronic Myeloid Leukemia.

BACKGROUND: With the advent of tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia (CML) have a life expectancy similar to those of age- and gender-matched healthy populations. Nevertheless, patients receiving TKIs report chronic adverse events such as fatigue, edema, and muscle cramps, which lead to a decrease in their quality of life (QoL). Therefore, the aim of this study was to assess the QoL and symptom burden in patients receiving original imatinib, generic imatinib, dasatinib, and nilotinib. PATIENTS AND METHODS: A total of 121 patients with CML who received TKIs for at least 3 months were enrolled in the study. The QoL was assessed with the Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire-Chronic Myeloid Leukemia (QLQ-CML24) modules. The symptom burden was assessed with MD Anderson Symptom Inventory for Chronic Myeloid Leukemia (MDASI-CML) and EORTC QLQ-CML24. RESULTS: The median age of the study population was 53 years (range, 28-90 years), and 83 (81.4%) patients had a low-to-medium Sokal risk score. The Eastern Cooperative Oncology Group performance status of most patients were good (< 2; 96%), and comorbidity scores were low (HCT-CI < 3; 90.8%). There was no significant difference between the general health status of patients in terms of EORTC QLQ-C30 and QLQ-CML24. According to the results of the MDASI-CML and QLQ-CML24 modules, the most common symptom was fatigue (58.7%) in all groups, and there were no significant differences between the groups in terms of the effects on the daily life activities of the patients. CONCLUSION: Patients with CML receiving first- and second-generation TKIs were seen to have a similar QoL and symptom burden.

Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment.

COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.

A case of conjunctival MALT lymphoma: successfully treated with solely extended rituximab therapy.

PURPOSE: Primary ocular adnexal lymphomas are cured by radiotherapy; however, complications are frequent and relapses may occur. In this case, we aimed to report the efficacy and safety of extended systemic rituximab (anti-CD 20 monoclonal antibody) therapy of conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: In the standard regimen, rituximab is used as four consecutive weekly infusions of 375 mg/m2 in patients with low-grade lymphomas. We treated a patient who had bilateral conjunctival MALT lymphoma with rituximab 375 mg/m2 intravenously once weekly for 10 weeks as a first-line therapy. RESULTS: During the examination of the sixth week, we observed partial response of the lesions in both eyes. At the end of the tenth cure, complete remission was achieved. No local or systemic adverse effect was observed. The patient has no signs of recurrence during the 22-months follow-up period. CONCLUSION: Extended rituximab therapy may be an effective and well-tolerated first-line treatment option for bilateral conjunctival MALT lymphoma.

Molecular screening and the clinical impacts of BCR-ABL KD mutations in patients with imatinib-resistant chronic myeloid leukemia.

The present study aimed to detect the frequency of kinase domain (KD) mutations in order to evaluate their clinical significance and functional importance in 45 patients with chronic myeloid leukemia (CML) who were resistant to imatinib therapy. Sanger sequencing was used (45 patients), along with allele-specific oligonucleotide polymerase chain reaction (ASO-PCR; 3 patients), for the screening of mutations. BCR/ABL KD was amplified by nested PCR and sequencing was performed. Secondly, ASO-PCR was performed to confirm the results of the sequence analysis for E255K mutations. Mutations were detected in 11/45 patients (24.44%) via Sanger sequencing. D241G (4.4%), C369C (4.4%), K285N (2.2%), A380T (2.2%) and A366V (2.2%) mutations were detected. E255K (8.8%) was detected by ASO-PCR and Sanger sequencing. Mutations are a primary reason for suboptimal responses, loss of response and resistance to imatinib. In particular, the E255K mutation, which is characterized by resistance to imatinib and nilotinib, was detected in four patients. Analyzing the mutations and monitoring patients with CML may improve their prognosis and survival rate. ASO-PCR assays will be beneficial for the routine monitoring of mutations.

Effects of Deeper Molecular Responses on Outcomes in Chronic Myeloid Leukemia Patients in Chronic Phase Treated With Imatinib Mesylate.

BACKGROUND: The prognostic significance of complete cytogenetic response (CCyR) is well defined in patients with chronic phase chronic myeloid leukemia treated with imatinib as first-line therapy. However, the effect on outcomes of obtaining molecular response itself and the depth of it is not clear. In this study we aimed to determine the frequency of complete molecular response (CMR) during long-term follow-up and the clinical significance of CMR on patient outcomes and survival. PATIENTS AND METHODS: We retrospectively evaluated the files of 178 chronic phase chronic myeloid leukemia patients using imatinib therapy. Forty-seven patients with missing data were excluded from the study and the assessment was done in 131 patients. CMR was defined as undetectable BCR-ABL transcripts using real-time quantitative polymerase chain reaction with a sensitivity level of ≥ 104 in 2 consecutive analyses at least 3 months apart. Cytogenetic and molecular monitoring during treatment was performed according to the European LeukemiaNet recommendations criteria. Our primary objective was to analyze the association of deeper molecular response with differences in progression-free survival (PFS). RESULTS: Eighty-eight patients (67%) achieved CMR at any time in a median of 65 months of follow-up. The rate of CMR was higher in patients who achieved CCyR at 12 months and major molecular response (MMR) at 18 months. Fewer events occurred in the CMR group than the MMR group (26.1% vs. 50.0%). Overall survival was not different in both groups. CMR was associated with longer PFS with borderline significance. CONCLUSION: Prolonged imatinib therapy helps to achieve a deeper molecular response in the long-term. Achieving deeper molecular response at any time positively affects maintaining the cytogenetic and molecular responses, and decreases the transformation to accelerated and/or blastic phase. The slight prolongation in PFS did not reach statistical significance.

Azacitidine versus decitabine in patients with refractory anemia with excess blast-Results of multicenter study.

The present study aimed to compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndrome (MDS). A total of 88 patients diagnosed with refractory anemia with excess blast (RAEB) treated with azacitidine (n=57) or decitabine (n=31) were evaluated. Comparisons between azacitidine and decitabine groups were performed in the whole cohort, and in a 1:1 propensity score-matched cohort in order to reduce the simple selection bias. Patients who received azacitidine or decitabine had comparable overall response rates in both the unmatched (49.1% vs. 64.5%, p=0.166) and the propensity-matched cohorts (52% vs. 68%, p=0.248). The cumulative incidence of AML transformation at one year was comparable between azacitidine and decitabine in the unmatched (24.0% vs. 31.3%, p=0.26) and in the propensity-matched cohorts (18.7% vs. 31.5%, p=0.11). There was no difference in terms of transfusion requirement, febrile neutropenia episodes or the need for antifungal use during the treatment cycles in the propensity-matched cohort. The median overall survival was 20.4 months for azacitidine and 16.8 months for decitabine (p=0.59). Finally, we found that at least a four-cycle treatment with any HMA was a favorable factor. In conclusion, both azacitidine and decitabine have similar efficacy and toxicity profiles in the treatment of MDS-RAEB.

Efficacy and safety of eltrombopag in treatment-refractory primary immune thrombocytopenia: a retrospective study.

Eltrombopag was used in patients with chronic primary immune thrombocytopenia (ITP) who did not tolerate or were refractory to two or more previous treatments. The primary aims of the study were to determine the efficacy and safety of long-term eltrombopag treatment. Data were extracted from medical chart records retrospectively. Platelet count of at least 50 000/µl at any time point during the treatment was defined as the 'response'. Median duration of eltrombopag treatment was 29 weeks (11-74). The number of patients who had a platelet count of at least 50 000/µl at any time point was 26 (83.9%). The response was achieved by the second week in most of the patients. Concomitant ITP medications were withdrawn in nine out of the 11 patients. Eltrombopag was discontinued in one patient due to sustained response despite discontinuation of the treatment. Age, sex, concomitant ITP treatments, and previous ITP treatment failures had no impact on the treatment response. The treatment was discontinued due to thrombosis in only four patients. Four patients experienced a minor bleeding event. Hepatotoxicity and all other adverse events were mild and manageable. Eltrombopag is effective, safe, and well tolerated in the long-term treatment of chronic ITP patients.

Miliary Tuberculosis Induced Acute Liver Failure.

Hepatobiliary tuberculosis is uncommon even in endemic countries. It is associated with a high mortality and is even diagnosed early in the disease course. Acute liver failure (ALF) caused by tuberculosis bacilli has been reported in only a few reports. All previous cases have been diagnosed by postmortem examination. Time to antituberculosis treatment is very critical. In case of suggestive findings on clinical and radiologic examination, antituberculosis treatment should be initiated immediately. Drug use can be a challenge in patients with ALF. However, as long as the other possible causes of ALF can be excluded and hepatotoxic drugs were avoided during the early course of treatment, such a highly fatal presentation of tuberculosis can be treated safely. Here, we report a case of acute liver failure as a presentation of miliary tuberculosis. He was treated successfully with antituberculosis treatment.

Pulmonary Endarterectomy in a Patient with Immune Thrombocytopenic Purpura.

Immune thrombocytopenic purpura (ITP) patients are at high risk for bleeding complications regarding surgeries involving cardiopulmonary bypass. We report an ITP patient with chronic thromboembolic pulmonary hypertension who underwent uncomplicated pulmonary endarterectomy with receiving postoperative intravenous immunoglobulin (IVIG) therapy. The positive outcome of this case may suggest that pulmonary endarterectomy surgery is performed safely for ITP patients.

Myelodysplastic syndrome with t(9;22)(p24;q11.2), a BCR-JAK2 fusion: case report and review of the literature.

The human JAK2 gene is mainly targeted by two types of genetic lesions that play roles in the pathogenesis of hematologic malignancies: intragenic mutations and chromosomal translocations. Chromosomal translocations of JAK2 are typically associated with myeloid or lymphoid malignancies with an aggressive course and poor outcome. Here we report a t(9;22)(p24;q11.2) translocation, in a MDS patient and review results associated with BCR-JAK2 fusion reported in the literature.