Clinical Impact of JAK2V617F Allele Burden in Philadelphia-Negative Myeloproliferative Neoplasms

Objective: The impact of JAK2V617F allele burden on clinical course in Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs) is not clear. We analyzed the clinical impact of JAK2V617F allele burden in a relatively large series of patients with Ph-negative MPNs and long-term follow-up. Materials and Methods: A total of 228 patients with Ph-negative MPNs, including 118 with essential thrombocythemia (ET), 84 with primary myelofibrosis (PMF), and 26 with polycythemia vera (PV), were analyzed. The JAK2 MutaScreen assay was used to quantify JAK2V617F allele burden in genomic DNA. Results: In PV cases, high JAK2V617F allele burden was associated with a trend towards inferior overall survival. In ET, high JAK2V617F allele burden was associated with lower hemoglobin and hematocrit levels, higher lactate dehydrogenase (LDH) levels, larger spleen size, and increased bleeding and mortality rates. In PMF, high JAK2V617F allele burden was associated with higher leukocyte counts and larger spleen size. In the entire cohort, high allele burden was associated with higher leukocyte and lower platelet counts, higher LDH levels, larger spleen size, higher percentage of bleeding events, higher death rate, and inferior overall survival. Conclusion: Our results suggest that high JAK2V617F allele burdens are associated with more severe disease in PV and ET. In PMF, high JAK2V617F allele burdens were associated with more pronounced myeloproliferative phenotypes. In Ph-negative MPNs, high allele burdens were associated with more aggressive phenotypes. Our data with a long follow-up period support the possibility of JAK2V617F allele burden being used as a marker for predicting clinical phenotype in cases of Ph-negative MPNs.

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry.

Introduction: COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. Methods: This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic. Results: The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022. Discussion: Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.

Comparison of Response to Rituximab Therapy in Adults with Refractory Symptomatic Immune Thrombocytopenia According to the Presence of Accessory Spleen.

No data exist for the association between the presence of accessory spleen after splenectomy and response to rituximab in immune thrombocytopenia (ITP). We investigated the relationship between accessory spleen presence and rituximab response in splenectomized ITP patients. Fifteen chronic refractory ITP patients were included. Four weekly doses of rituximab 375 mg/m2 were administered. All patients had undergone splenectomy before rituximab administration. Accessory spleen was detected in 5 of 15 patients (33.3%). Median age at diagnosis was significantly higher in patients with accessory spleen than those without accessory spleen (40 (range 25-68 years) and 26 (range 7-40 years), respectively; p = 0.049). There was a trend for older age at time of rituximab initiation in patients with accessory spleen compared to the other group (median 51 (range 43-75 years) and 42.5 (range 30-60 years), respectively; p = 0.066). Median follow-up duration was 96 months (range 40-98). We demonstrated a significant correlation between accessory spleen presence and older age. Accessory spleen presence correlated with higher platelet and WBC counts. We showed good inverse correlation between presence of accessory spleen and time to early response (ER) to rituximab while the rate of early response (ER), late response (LR), sustained response (SR) and overall response (OR) did not differ with respect to the presence of acessory spleen.

Biosimilar Rituximab (Redditux) Added to CHOP Chemotherapy for De Novo Diffuse Large B-Cell Lymphoma Patients: Real-Life Single-Center Experience

Objective: Redditux® (RED), as a biosimilar rituximab, was approved in Turkey for all indications of the original Mabthera® (MAB) in March 2018. The aim of our study was to evaluate the efficacy and safety of RED in de novo diffuse large B-cell lymphoma. Materials and Methods: Fifty-one patients received RED combined with the CHOP regimen. The median follow-up was 31 months. The historical control group included 219 patients treated with the MAB-CHOP regimen and the median follow-up time was 38 months. We compared the response rates and survival outcomes of these RED-CHOP and MAB-CHOP cohorts. Results: In the RED cohort, the overall response rate (ORR) at the end of the treatment protocol was 86%, with 37 (72.5%) cases of complete response (CR) and 7 (13.5%) cases of partial response (PR). In the historical MAB cohort, the ORR was 84%, with CR and PR rates of 82% and 2%, respectively. The 24-month progression-free survival (PFS) rates were 73.76% (95% confidence interval [CI]: 0.59-0.84) and 85.2% (95% CI: 0.79-0.90) for the RED and MAB cohorts, respectively (p=0.0106). The 24-month overall survival rates were 78.4% (95% CI: 0.64-0.87) and 81.4% (95% CI: 0.75-0.86) for the RED and MAB cohorts, respectively (p=0.7461). For patients with high revised International Prognostic Index scores, 24-month PFS was 45.5% (95% CI: 0.17-0.71) and 63% (95% CI: 0.37-0.80) for the RED and MAB cohorts, respectively (p=0.0711). In the RED cohort, central nervous system (CNS) relapse was significantly increased compared to the MAB cohort (10% vs. 1.83%, p=0.004). Among the RED cohort, bone involvement at the time of diagnosis was a risk factor for CNS relapse (p=0.028). Thirteen patients died in follow-up. There were no serious adverse events causing the cessation of the drugs. Conclusion: RED has an ORR similar to that of MAB. However, PFS rates were worse in the RED cohort. Additionally, CNS relapse ratio was a major concern for our RED cohort. Large prospective controlled studies and real-life data with longer follow-up are needed to document the non-inferiority of RED compared to MAB.

The impact of JAK2V617F mutation on Philadelphia-negative myeloproliferative neoplasms.

BACKGROUND: JAK2V617F mutation is expressed in almost all polycthemia vera (PV), 55% of essential thrombocythemia (ET), and 65% of primary myelofibrosis (PMF) patients. Studies investigating phenotypic effects of JAK2V617F mutation on Philadelphianegative myeloproliferative neoplasms (Ph-negative MPNs) have reported controversial results. This study aims to determine the impact of JAK2V617F mutation on clinical phenotype and outcome in Ph-negative MPNs. METHODS: Clinical correlates and long-term prognostic relevance of the JAK2V617F mutation were analyzed in 410 Phnegative MPNs-170 ET, 135 PV, 105 PMF- from two institutions and followed for a mean of 76.7 months (SD 62.1) (mean 87 months (SD 67.8), 70.4 months (SD 56.4), 68 months (SD 57.4), respectively for ET, PV, and PMF). Two hundred and twenty-eight patients were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction (PCR), and 182 patients were genotyped using melting curve analysis. RESULTS: In PV patients, JAK2V617F mutation was associated with higher rate in females, lower hemoglobin (Hgb) level, higher leukocyte and platelet count and higher prevalence of thrombosis (p = 0.008, p = 0.018, p = 0.001, p = 0.001, and p = 0.035, respectively). In ET patients, JAK2V617F mutation was associated with higher Hgb and hematocrit (Hct) levels and lower platelet count (p = 0.001, p = 0.001, and p = 0.001, respectively). JAK2V617F-negative ET patients showed a trend towards higher rate of leukemic transformation (p = 0.061). JAK2V617F mutation-positive PMF patients had higher leukocyte count, greater spleen size and showed a trend towards higher Hgb level (p = 0.019, p = 0.042, and p = 0.056, respectively). Among PMF patients with JAK2V617F mutation, the rate of female patients was lower (p = 0.001). Overall survival (OS) in Dynamic International Prognostic Scoring System (DIPSS) - plus high risk PMF patients was shorter compared to the other risk groups (p = 0.001). Leukemia-free survival (LFS) was shorter in DIPSS - plus high risk PMF patients than the other risk groups (p = 0.005). In the entire cohort of Ph-negative MPN patients, JAK2V617F mutation was associated with higher leukocyte count, higher Hgb and Hct levels and lower platelet count, higher frequency of phlebotomies, a trend towards older age, a trend towards greater spleen size, a trend towards a higher prevalence of risk factors for cardiovascular diseases and thrombosis (p = 0.001, p = 0.005, p = 0.001, p = 0.003, p = 0.004, p =0.052, p = 0.056, p = 0.052, and p = 0.059, respectively).

Brentuximab vedotin and bendamustine: an effective salvage therapy for relapsed or refractory Hodgkin lymphoma patients.

The prognosis is poor for relapsed or refractory (R/R) classical Hodgkin Lymphoma (cHL) patients. The brentuximab vedotin (Bv) and bendamustine (B) combination has been used as a preferable salvage regimen in R/R cHL patient trials. We retrospectively evaluated response rates, toxicities, and the survival in R/R cHL patients treated with the BvB combination. In a multi-centre real-life study, 61 R/R HL patients received intravenous doses of 1.8 mg/kg Bv on the first day plus 90 mg/m2 B on the first and second days of a 21-day cycle as a second-line or beyond-salvage regimen. Patients' median age at BvB initiation was 33 (range: 18-76 years). BvB was given as median third-line treatment for a median of four cycles (range: 2-11). The overall and complete response rates were 82% and 68.9%, respectively. After BvB initiation, the median follow-up was 14 months, and one- and two-year overall survival rates were 85% and 72%, respectively. Grade 3/4 toxicities included neutropenia (24.6%), lymphopenia (40%), thrombocytopenia (13%), anaemia (13%), infusion reactions (8.2%), neuropathy (6.5%), and others. The BvB combination could be given as salvage regimen aiming a bridge to autologous stem cell transplant (ASCT), in patients relapse after ASCT or to transplant-ineligible patients with manageable toxicity profiles.

Clinical Characteristics and Outcomes of COVID-19 in Turkish Patients with Hematological Malignancies

Objective: Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey. Materials and Methods: In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection. Results: Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use. Conclusion: Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.

IgG4 producing POEMS syndrome: A rarely recognized subtype.

Serum IgG4 is typically measured for Immunoglobulin G4-related Disease (IgG4-RD), a fibroinflammatory condition associated with polyclonal increase in serum IgG4. Yet, increased IgG4 may still be monoclonal, and little is known about IgG4 POEMS syndrome. We present a case of 40-year-old male with a mass lesion in the left sacral ala. The mass was composed of non-neoplastic fibrous tissue and dense infiltrate of mature plasmacytes with dense eosinophilic cytoplasm and eccentrically placed nuclei that express monoclonal Lambda free light chains and show diffuse positivity for IgG and IgG4. We discuss clinical manifestations and challenges encountered in the diagnosis and treatment of this rare coexistence.

Brentuximab vedotin consolidation therapy after autologous stem-cell transplantation in patients with high-risk Hodgkin lymphoma: Multicenter retrospective study.

The AETHERA trial reported an increased progression-free survival (PFS) when brentuximab vedotin (BV) was used as maintenance therapy in high-risk Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). Thus, we aimed to determine the impact and safety of BV as maintenance after ASCT in real-world patients. Seventy-five patients with relapsed/refractory HL started on BV consolidation therapy after ASCT due to high risk of relapse, between January 2016 and July 2019, from 25 institutions, were included in the study. The median follow-up time was 26 months. The most common high-risk features were primary refractory or relapsed disease <12 months (n = 61), lack of complete response (CR) to the last salvage regimen (n = 51), and having had at least two salvage regimens (n = 29). At the time of analysis, 42 patients completed consolidation courses, and BV was discontinued in 33 patients. Fifty patients had an ongoing response (CR in 41, PR in 6, and SD in 3 patients), 25 had progressed. Ten died in the follow-up, eight with progressive disease and two due to infection while in CR. The 2-year PFS and OS rates were 67.75% (95% confidence interval [CI]: 0.55-0.77) and 87.61% (95% CI: 0.76-0.94), respectively. Seventeen patients (23%) received BV in the pre-ASCT treatment lines, and there was no survival difference between the BV-naïve and BV-exposed groups. The most common adverse events were neutropenia (27%) and peripheral neuropathy (21%). Sixteen patients (21.3%) experienced grade 3 or 4 toxicity. BV was discontinued due to adverse event in 12 patients. Consolidation with BV after ASCT can achieve a 2-year PFS of 67.75% (95% CI: 0.55-0.75) with an acceptable toxicity profile.

Case Report: Severe COVID-19 Pneumonia in a Patient With Relapsed/Refractory Hodgkin's Lymphoma.

First identified in China in December 2019, coronavirus disease 2019 (COVID-19) has rapidly evolved into a global pandemic. The presence of haematological malignancies are expected to increase the risk of adverse outcomes from this viral infection due to the immunosuppression brought about by the underlying cancer and the effects of therapy. We present a 55-year-old woman diagnosed with relapsed/refractory Hodgkin's lymphoma (HL) who had been heavily pretreated with multiagent chemotherapy, autologous hematopoietic stem cell transplantation (autoHCT), allogeneic hematopoietic stem cell transplantation (alloHCT) and was complicated with EBV associated posttransplant lymphoproliferative disease (PTLD) and chronic graft-versus-host-disease (GVHD). The patient was recently treated with brentuximab and donor lymphocyte infusion (DLI) for relapse after alloHCT. She suffered from severe COVID-19 pneumonia and eventually succumbed to acute respiratory distress syndrome (ARDS) and multiorgan failure. Of note, this is the first reported case of COVID-19 in a HL patient who was being treated with brentuximab for relapse after alloHCT.

The impact of CYP2D6*4 and GSTP1 Ile105Val polymorphisms on the susceptibility to develop BCR-ABL1 negative myeloproliferative neoplasms.

Inter-individual variations in the genes encoding xenobiotic-metabolizing enzymes have been reported to alter susceptibility to various diseases involving hematological disorders. The purpose of this case-control study was to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing BCR-ABL1 negative myeloproliferative neoplasms (MPN). PCR-RFLP was used for genotyping single nucleotide polymorphisms (SNP) in CYP2D6 and GSTP1 in 139 patients with MPN and 126 controls. There was a significantly increased risk for developing BCR-ABL1 negative MPN for the group bearing the CYP2D6*4 variant allele (X2: 4.487; OR 1.738; 95% CI 1.040-2.904; p = 0.034). The platelet count was higher in CYP2D6*4 allele carriers (p = 0.047). There was no association between the GSTP1 Ile105Val polymorphism and the risk of developing MPNs. MPN patients bearing the GSTP1 Ile105Val variant allele had a higher prevalence of bleeding complications (X2: 7.510; OR 4.635; 95% CI 1.466-14.650; p = 0.006). Our study provides new data that the CYP2D6*4 polymorphism may be associated with an increased risk to develop MPNs while the GSTP1 Ile105Val polymorphism does not show such an association. To our knowledge, the current study is the first to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing MPNs in the Turkish population. Further studies with more patients and controls are needed to support our data.

Immune Thrombocytopenia in a Very Elderly Patient With Covid-19.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a decreased number of platelets and mucocutaneous bleeding. Many viruses have been identified as triggers of the autoimmune process, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), parvovirus, rubella, and measles. Association with the new severe acute respiratory syndrome coronavirus, SARS-CoV-2 infection (Covid-19 infection) has been rarely reported. Here, we report the oldest case of ITP patient triggered by the novel coronavirus infection. He showed inadequate response to IVIG but responded to corticosteroids with no severe adverse events. Further studies are warranted to determine the optimal therapeutic strategies for ITP with the Covid-19 infection.

A Case with Hepatic Involvement Mimicking Metastatic Disease in Multiple Myeloma.

Multiple myeloma is a type of plasma cell disorder and can be seen in different forms. According to current knowledge, it is not a curable disease. Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma. We present a 53-year-old female patient who started with SMM which turned into multiple myeloma after four years. Despite 26 cycles of lenalidomide treatment, we performed the second autologous stem transplantation. After 12 years from the diagnosis of the disease, it was transformed into plasma cell leukemia and widespread nodular lesions were seen in the liver. Different presentations could be seen due to malignant plasma cell infiltrations or primary amyloidosis. Liver involvement is one of them and is less common than other organ involvement. We report a case of myeloma presenting with extensive nodular involvement in the liver and misdiagnosed as metastatic disease. It is important because of its rarity and change of the treatment approach.

Short Tandem Repeat-Polymerase Chain Reaction (STR-PCR) with Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) Method Using for Chimerism Analysis.

BACKGROUND: Recently molecular chimerism analysis after allogeneic hematopoietic stem cell transplantation (AHSCT) has become more important. The use of quantitative chimerism methods aims to assess the kinetics of engraftment to determine graft rejection and failure or relapse of the underlying disease after AHSCT. An accurate and sensitive determination of chimerism status is mandatory after AHSCT. This study aimed to compare two chimerism methods: Multiplex Short Tandem Repeat-Polymerase Chain Reaction (STR-PCR) and quantitative Real Time-PCR (qRT-PCR). METHODS: Thirty-nine blood samples at +28 day were used to extract DNA. Most patients had been diagnosed with acute leukemia (74.3 %) and other hematological diseases. For Multiplex STR-PCR method, PCR products were separated on an ABI 3130 Genetic Analyzer (Applied Biosystem, USA) and for qRT-PCR, an ABI 7500 (Applied Biosystem, USA) Plate System Real Time Analyzer was used to determine the quantification of chimerism per-centage. RESULTS: Of the 39 analyzed samples, 82% concordant chimerism results were detected for both STR-PCR and qRT-PCR methods. Ten mixed chimerisms (MC) were found by qRT-PCR whereas of only 3 MC cases were detected by STR-PCR. In the discordant group of 7 by qRT-PCR, we observed Acute Graft versus Host Disease (aGVHD). Three MC cases that were detected by both STR- and qRT-PCR methods died because of relapse. CONCLUSIONS: The quantitative chimerism method along with multiplex STR-PCR method is important for early detection of MC. qRT-PCR methods can be valuable options in the prevention of graft failure and assisting with fast and early treatment strategies for patients undergoing AHSCT.