Unmet clinical needs and challenges in the management of acute leukemia in Turkey: a modified Delphi study.

Aim: To determine the unmet needs and challenges in management, diagnosis, treatment, follow-up and patient-physician communication in acute leukemia (AL). Materials & methods: The study was based on a modified Delphi approach. A questionnaire including the major potential obstacles was circulated twice among 13 hematologists. Results: The obstacles in AL management were limited access to the novel treatments and genetic tests, limited bed capacity, insufficient level of knowledge among allied health personnel, limited availability of psycho-oncological support and low levels of awareness in the population about the importance of stem cell donation. Conclusion: The challenges in the management of AL are critical to guide the efforts to improve the quality of healthcare delivery and the evidence-based decision making at treatment of AL patients.

A survey evaluating hematology physicians' perspectives on central nervous system prophylaxis.

Background: Central nervous system (CNS) prophylactic options for diffuse large B-cell lymphoma (DLBCL) are administered differently in most centers. Unfortunately, there is still not a consensus on which patients, which regimen, for how many cycles, and when prophylaxis should be administered. Thus, this remains an unmet clinical need. Methods: We administered a survey study under the Lymphoma Scientific Subcommittee of the Turkish Society of Haematology. The questions were directed to hematologists through the monkey survey system. Results: The CNS International Prognostic Index score is a factor that clinicians frequently use when deciding on prophylaxis and is considered reliable. Although the perspective on anatomical risk factors is similar to that reported in the literature, breast involvement is still considered a critical risk factor in Turkey. Participants considered double or triple hit and double/triple expressor lymphoma as significant risk factors. Various methods have been used to demonstrate CNS relapses. Intrathecal prophylaxis is the preferred method. Conclusion: There are diverse methodological and technical ideas. The controversial results reported in the literature on the effectiveness of CNS prophylaxis may explain this finding. Although CNS prophylactic methods for patients with DLBCL are still controversial, the effect of secondary CNS involvement on survival is inevitable. Standard practices followed by national guidelines may be effective in reducing the variety of application methods and creating homogeneous results for efficacy and survival follow-up studies.

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.

Generic Lenalidomide Rivelime Versus Brand-name Revlimid® in the Treatment of Relapsed/Refractory Multiple Myeloma: A Retrospective Single-center Experience on Efficacy, Safety and Survival Outcome.

BACKGROUND: This study aimed to compare use of original brand-name lenalidomide (Revlimid®) vs. generic equivalent (Rivelime®) in terms of efficacy, safety and survival outcome in patients with relapsed/refractory multiple myeloma (RRMM) PATIENTS AND METHODS: A total of 184 patients RRMM (median age: 62 years, 60.9% were males) who received singlet, doublet or triplet lenalidomide-containing regimens including either Revlimid® (n=74) or Rivelime® (n=110) were included in this study. Treatment response was based on evaluation of objective response to treatment (ORR) including the sum of patients who achieved partial response (PR), very good partial responses (VGPR) or complete response (CR) to therapy. Progression-free survival (PFS), overall survival (OS) and safety data were also recorded. RESULTS: Revlimid® and Rivelime® groups were similar in terms of ORR (54.1 vs. 60.0%), CR (22.5 vs. 28.8%), VGPR (55.0 vs. 50.0%) and PR (22.5 vs. 21.2%) rates. Median (SE) PFS time were similar between Rivelime® vs. Revlimid® treated patients who were in the 2nd line (30.3(3.8) vs. 22.7(7.0) months, p=0.827) or 3rd line of therapy (38.1(12.1) vs. 20.1(0.9) months, p=0.147) at lenalidomide initiation. Two groups also had similar OS rate (83.8 vs. 73.6%) and OS time (mean 122.3 vs. 123.5 months). Side effects were manageable in both groups. CONCLUSION: In conclusion, replacing Revlimid® with its generic version Rivelime® in singlet, doublet or triplet lenalidomide containing RRMM regimens seems not to compromise the efficacy of treatment, and to yield a similarly improved response rates and survival outcome and no additional toxic effects, enabling a long-term therapy.

Role of large unstained cells in predicting successful stem cell collection in autologous stem cell transplantation.

INTRODUCTION: Sufficient stem cell collection is mandatory for Autologous stem cell transplantation (ASCT). Peripheral CD34+ stem CD34 + stem cell counting by flow cytometry is the gold standard method in both the predicting and timing of successful stem cell collection. Large unstained cells (LUC) are large peroxidase-negative cells that are displayed on certain automatic cell counters and present large lymphocytes, virocytes, blasts, abnormal cells and hematopoietic stem cells. In this study, we evaluated the role of LUC parameters in the timing and prediction of successful stem cell collection. METHODS: Patients with a diagnosis of multiple myeloma, lymphoma and testis tumor who proceed to ASCT were included in this study. Preapheresis LUC parameters were analyzed with Siemens ADVIA® 2120i system., Kruskal Wallis, Mann-Whitney U, Spearman Rho and receiver-operator curve (ROC) tests were used for analyses. RESULTS: Ninety patients were evaluated. Peripheral CD34 + cell count was positively correlated with both LUC count (p = 0014) and LUC percentage (p = 0,01). LUC percentage in peripheral blood was positively correlated with mobilized stem cell count in the yield (p = 0.003). We found a LUC count of > 0.485 × 109/L as a cut-off value for detecting > 20 × 106/L CD34 +cells in the peripheral blood with a sensitivity of 64.6% and specificity of 75%. We defined > 2.15% as a cut-off value for LUC percentage to collect > 5 × 106/kg of stem cells with a sensitivity of 64% and specificity of 63%. Additionally, total nucleated cell (TNC) count was negatively correlated with LUC percentage (p = 0.014) and positively correlated with LUC count (p = 0.001). CONCLUSION: LUC parameters are readily available, simple and cheap tools that can be useful in both timing of CD34 count by flow cytometry in peripheral blood and in the prediction of successful mobilization. LUCs can also be an indicator of graft composition.

Alpha-1-Antitrypsin Experience for Steroid-Resistant Acute Graft-Versus-Host Disease.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) treatment has a low response rate and a high risk of infection in allogeneic hematopoietic stem cell transplantation. The standard approach to be applied in this situation is uncertain. This study aims to evaluate the effectiveness and safety of alpha-1-antitrypsin (AAT). In the study, the results of five SR-aGVHD patients received AAT evaluated. Complete response was seen 2 of four patients with gastrointestinal (GI) aGVHD, partial response in one GI and one liver aGVHD. The overall response rate was 80%. AAT is an effective and safe treatment option in SR-aGVHD.

Pretransplant Consolidation Therapies Improve the Outcome of Myeloablative Allogeneic Transplantation in Adults with Ph-negative Acute Lymphoblastic Leukemia.

BACKROUND AND AIM: The benefit of pre-transplant consolidation in patients with acute lymphoblastic leukemia (ALL) who achieved first complete remission (CR1) has not yet been clearly demonstrated. Here, we aimed to investigate the relationship between the treatments received before transplantation and transplant outcome in Ph-ALL patients who underwent myeloablative allo-HSCT in CR1. PATIENTS AND METHODS: A total of 55, 32 (58.2%) men and 23 (41.8%) women, who underwent allo-HSCT with the diagnosis of Ph-ALL were evaluated retrospectively. All patients underwent to allo-HSCT with myeloablative conditioning regimen in the 1st CR from the available donor. RESULTS: In patients who received >2 consolidation, the 2-year and 3-year OS was 69% and 65%, respectively, while the 2-year and 3-year OS was 39% and 26%, respectively, in those who received < 2 consolidation (P =.03). RFS was similar in both groups (P = .8). One year- NRM was found 28% in patients who received ≥ 2 consolidations, and 37% in patients who received <2 consolidation (P =.06). L-asparaginase, high dose methotrexate, and cranial treatments given before transplantation had no effect on transplant outcomes (P > .05). CONCLUSION: Contrary to the belief that pre-transplant consolidation is not beneficial in ALL patients who proceed with allo-HCST in CR1, our results showed that consolidation treatments reduce NRM and improve the survival.

Allogeneic hematopoietic stem cell transplantation for heavily pretreated patients with mycosis fungoides and Sezary syndrome.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is a promising strategy for treatment of heavily pretreated mycosis fungoides/Sezary syndrome (MF/SS). Herein, we aimed to evaluate the outcomes of AHSCT for heavily pretreated patients with MF/SS retrospectively. This analysis included consecutive 19 patients with MF/SS who received 20 AHSCT between 2012-2021 in our transplant center. Eight patients have been previously reported. Fifteen patients had diagnosis of MF and referred to SS in five patients. In our cohort, all cases had advanced disease (stages IIB: n = 1, IIIA: n = 7; IIIB: n = 4, IVA: n = 4, and IVB: n = 3). Nine patients (47.4%) had developed large cell transformation. Only two patients received AHSCT in complete response, one very good partial response and two partial response while the others had progressive disease (n = 15) before transplant. Seven (35%) patients were alive at the time of analysis, with a median follow up of 10.5 months (range, 0.3-113 months) after AHSCT. Nine patients (47.4%) died without disease relapse or progression. Non-relapse mortality was 35.9% at 1 year and 26.9% at 3 years and thereafter. For all patients the probability of overall survival was 48.5% and 32.3% at 1- and 5-year post-transplant, respectively. AHSCT for MF/SS resulted in an estimated progression free survival of 45.4% at 1 year. Given the poor prognosis of patients not receiving transplants and in the absence of curative non-transplantation therapies, our results support that AHSCT is able to effectively rescue 32.3% of the population of transplant eligible, heavily pretreated patients in 5 years.

Prospective Follow-up of Panel Reactive Antibodies From Diagnosis Until Completion of Therapy Including Allogeneic Stem Cell Transplantation Among Patients With Acute Leukemia.

OBJECTIVES: Existence of panel reactive antibodies is the limiting step in both solid-organ and hematopoietic stem cell transplantation. There are hypotheses related to panel reactive antibody formation, but there is no knowledge about its formation in acute leukemia at diagnosis and during the chemotherapy period, in which there is a strong myelosuppression and immunosuppression. We aimed to determine the panel reactive antibodies positivity in acute leukemia patients at diagnosis and during the entire therapy period, including stem cell transplantation. MATERIALS AND METHODS: In this single-center prospective study, we enrolled 35 patients with acute leukemia (8 with acute lymphoblastic leukemia, 27 with acute myeloid leukemia). Serum samples were obtained before induction therapy and every 3 months thereafter until the last follow-up or death, for a median of 369 days (minimum-maximum, 9-725 days). Panel reactive antibodies were defined with single-antigen bead assays on a Luminex platform. RESULTS: A total of 10 patients (29%) were found to have panel reactive antibodies at any time point. At diagnosis, 5 patients (14.3%) had antibodies of either class I (n = 2) or II (n = 1) or both (n = 2), and in 4 patients these persisted during median follow-up of 168 days (minimum-maximum, 9-322 days). Among the remaining 30 patients, an additional 5 (17%) developed de novo antibodies. Incidence rate of development of de novo antibodies was 5.5 per 10 000 person-days. There was no effect of transfusion load on the development of panel reactive antibodies. Differences in percentages in males versus females, blood type mismatch, and graftversus-host disease were higher in patients who had de novo antibodies after transplantation. Positivity at any time had no statistically significant effect on overall survival (P = .71). CONCLUSIONS: Panel reactive antibodies do not occur frequently in the acute leukemia setting despite intensive transfusions.

Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience.

Classical Hodgkin lymphoma (cHL) is considered a curable disease; however, in approximately one-third of the responding patients, the disease relapses following completion of therapy. One of the drugs that have been approved for the treatment of relapsed/refractory cHL is nivolumab, an immune check point inhibitor that shows its effects by blocking the programmed death 1 (PD-1) receptor. In this study, we present a retrospective "real-life" analysis of the usage of nivolumab in patients with relapsed/refractory cHL that have joined the named patient program (NPP) for nivolumab, reflecting 4 years of experience in the treatment of relapsed/refractory cHL. We present a retrospective analysis of 87 patients (median age, 30) that participated in the NPP in 24 different centers, who had relapsed/refractory cHL and were consequently treated with nivolumab. The median follow-up was 29 months, and the median number of previous treatments was 5 (2-11). In this study, the best overall response rate was 70% (CR, 36%; PR, 34%). Twenty-eight of the responding patients underwent subsequent stem cell transplantation (SCT). Among 15 patients receiving allogeneic stem cell transplantation, 9 patients underwent transplantation with objective response, of which 8 of them are currently alive with ongoing response. At the time of analysis, 23 patients remained on nivolumab treatment and the rest discontinued therapy. The main reason for discontinuing nivolumab was disease progression (n = 23). The safety profile was acceptable, with only nine patients requiring cessation of nivolumab due to serious adverse events. The 24-month progression-free and overall survival rates were 58.5% (95% CI, 0.47-0.68) and 78.7% (95% CI, 0.68-0.86), respectively. Eighteen patients died during the follow-up and only one of these was regarded to be treatment-related. With its efficacy and its safety profile, PD-1 blockers became an important treatment option in the heavily pretreated cHL patients.

Severe upper eyelid mass in a patient with mycosis fungoides.

Mycosis fungoides is a cutaneous T-cell lymphoma that has been rarely reported to involve ocular structures. Ophthalmic manifestations usually appear in advanced disease. A case of a 58-year-old man presenting with progressive, full thickness, giant upper eyelid mass is presented. The patient had a long history of recurrent tumoral lesions on the trunk and limbs, previously diagnosed as mycosis fungoides. The histopathological examinations of eyelid tumor supported the diagnosis of mycosis fungoides. The mycosis fungoides was stage as IIB (T3N0M0B0) by TNMB classifications and referred to the Hematology and Radiation Oncology clinics. The importance of ophthalmic involvement is being seen in advanced or refractory cases, and there is a possible relation between mycosis fungoides and poor prognosis by being an early indicator of systemic involvement.

Is cytomegalovirus a risk factor for haemorrhagic cystitis in allogeneic haematopoietic stem cell transplantation recipients?

BACKGROUND: Haemorrhagic cystitis (HC) is usually a serious complication in allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients. In this study, our aim was to define risk factors and outcomes for patients with HC in an allo-HSCT setting. METHODS: We retrospectively evaluated 249 allo-HSCTs performed between 2011 and 2016 in our centre. RESULTS: HC was diagnosed in 98 patients (39%) at a median of 119 days (range 5-580) and 91 (93%) of the patients had late onset disease. In univariate analysis, HC was related to cytomegalovirus (CMV) reactivation (P<0.001) and BK viraemia (P<0.001); in multivariate analysis, the presence of CMV reactivation was determined to be an independent risk factor (odds ratio: 22.1; 95% CI 1.73, 282.44; P=0.017). There was no association detected between acute graft versus host disease and patients diagnosed with HC within 100 days of transplant. HC was significantly increased by the presence of myelo-ablative conditioning (odds ratio: 31.28; 95% CI 3.98, 246.87; P=0.001) and BK viraemia (odds ratio: 3.93; 95% Cl 1.10, 14.05; P=0.035) in patients with HC grade II and beyond. Forced hydration was recommended in all patients with grade I HC. Patients with HC and clots were treated with continuous bladder irrigation, and 14 of 44 patients with BK viraemia received cidofovir ± ribavirin. Eight of these patients (57%) responded to treatment. Refractory HC was detected in 17 patients (17%) and resolved by a variety of procedures. CONCLUSIONS: This study suggests that CMV reactivation is associated with increased risk of HC in multivariate analysis, however, this result is not confirmed in patients with HC grade II and beyond.

JACIE: A 20 year-old voluntary body functioning worldwide.

Hematopoietic Stem Cell Transplantation (HSCT) is a well estabished treatment modality for patients with severe disorders of the hematopoietic system. HSCT is the pioneer of not the adoptive immunotherapy but also cellular therapies. It was first performed in 1957; since then the transplantation numbers have increased every year in almost all parts of the World. However, the increase in the quality of this procedure was not as fast as the numbers. The first Standards for hematopoeietic cell collection, processing and transplantation in Europe was established in 1998 by the European Group for Bone Marrow Transplantation (EBMT) and The International Society for Hematotherapy and Graft Engineering Europe I (SHAGE Europe) and the Joint Accreditation Committee of ISCT EBMT (JACIE) was founded. JACIE is a non-profit voluntary organization that helps all the stakeholders of HSCT, the teams, goverments, regulators, payers and, mostly, the patients. In this review the aims and the twenty years history of JACIE in the World and in Turkey is explained.

Adult Stem Cells and Medicine.

Stem cells can be either totipotent, pluripotent, multipotent or unipotent. Totipotent cells have the capability to produce all cell types of the developing organism, including both embryonic and extraembryonic tissues. The Hematopoietic Stem Cells (HSC) are the first defined adult stem cells (ASC) that give rise to all blood cells and immune system. Use of HSCs for treatment of hematologic malignancies, which is also called bone marrow (BM) transplantation or peripheral blood stem cells (PBSC) transplantation is the pioneer of cellular therapy and translational research. However, stem cell research field is developing so fast that, innovative approaches using HSCs for treatment of refractory diseases are growing rapidly. Hematopoietic stem cell transplantation (HSCT) has been widely used to achieve cure in different hematological diseases. Applications include the treatment of marrow failure syndromes, leukemia, lymphoma, multiple myeloma (MM), certain inherited blood disorders, autoimmune diseases and as an enzyme replacement in metabolic disorders. Innovative approaches such as haploidentical stem cell transplantation, new monoclonal antibodies and immunotherapies as well as Chimeric Antigen Receptor T-cell (CAR-T cell) therapies are on the way as promising treatment options especially for patients with refractory hematologic malignancies and even in solid tumors. However, there are still some challenges remaining before some of these therapies are translated into clinical application. In this paper, HSCs including its properties, niches, clinical usage and its contribution to modern medicine today and in the future will be discussed.

Upper respiratory viral infections in patients with haematological malignancies after allogeneic haematopoietic stem cell transplantation: a retrospective study.

BACKGROUND: Community respiratory viruses (CRVs) are associated with upper respiratory viral infections (URI), pneumonia or life-threatening respiratory disease in patients with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Our aim is to demonstrate our URI experience related to CRVs after allo-HSCT. METHODS: From January 2013 to November 2015, 39 post allo-HSCT patients with acute URI symptoms were included in the study. We evaluated CRVs by multiplex PCR from nasopharyngeal wash and throat swabs. RESULTS: The median age of the patients was 39 (range 20-67 years). A total of 25 patients (64%) had viral panel positivity at a median 140 days post-transplant (range 3-617 days). The most common agents detected were respiratory syncytial virus (32%) and parainfluenza (32%). The patients with viral panel positivity had significantly lower lymphocyte count (1.05×109/l versus 3.09×109/l; P=0.013). During follow-up, 20 patients (80%) were diagnosed with pneumonia. Patients with concurrent bacterial or fungal infections were more likely to have pneumonia (100% versus 68%; P=0.023). 10 patients (40%) died due to pneumonia and related complications. Lower lymphocyte counts and higher C-reactive protein levels at the time of viral panel positivity were risk factors for mortality (1.5×109/l versus 0.39×109/l, P=0.007; 74.2 versus 199.7, P=0.006). CONCLUSIONS: The viral panel was positive in 64% of patients with acute URI symptoms. Lower lymphocyte count was detected in CRV-positive patients. The onset of concomitant bacterial or fungal infections increased the risk of lower respiratory infection disease. Indeed, prospective studies should be designed for risks and outcomes of CRVs in allo-HSCT recipients.

Treatment with methotrexate, rituximab, and cytosine arabinoside followed by autologous stem cell transplantation in primary central nervous system lymphoma: A single-center experience.

OBJECTIVE/BACKGROUND: Primary central nervous system lymphoma (PCNSL) is associated with worst prognosis compared with other aggressive non-Hodgkin's lymphomas. However, recent trials have demonstrated that long-term progression-free survival can be achieved by immunochemotherapy. Our goal is to present our experience in aggressive PCNSL in this study. METHODS: We retrospectively evaluated the clinical features and management of 13 PCNSL patients who were diagnosed and treated between 2006 and 2015. RESULTS: Nine patients received rituximab (R) 375mg/m2/day on Day 1, methotrexate (MTX) 3.5g/m2/day and cytosine arabinoside (ARA-C) 4.4g/m2/day on Day 2, as well as ARA-C 4.4g/m2/day on Day 3 every 28days, and underwent autologous stem cell transplantation. Two patients received procarbazine instead of ARA-C. One patient relapsed, and allogeneic hematopoietic stem cell transplantation was performed. All nine patients are followed in complete remission. Two of 13 patients received one course of MTX and 36-45Gy radiotherapy and died. One patient with renal transplantation had progressive disease and died. Grade 3-4 hematological toxicity was detected in 11 (85%), Grade 3-4 mucositis in 11 (85%), and febrile neutropenia in 12 (92%) patients. The median overall survival in the R-MTX-ARA-C/procarbazine group was 28±16months. CONCLUSION: R-MTX-ARA-C followed by autologous stem cell transplantation seems a promising strategy with high response rates in PCNSL.

Allogeneic hematopoietic stem cell transplantation for refractory mycosis fungoides (MF) and Sezary syndrome (SS).

Cutaneous T cell lymphoma is a heterogeneous group of lymphoproliferative disorders with different clinical behavior and prognosis in which malignant T cells accumulate in the skin. In the relapsed/refractory stage, treatment strategy varies depending on clinical perspective. We retrospectively evaluated advanced stage relapse or refractory mycosis fungoides and Sezary syndrome patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our hospital. The overall response rate was 25%, while the disease progressed and relapsed after transplant in 38% of patients. Allo-HSCT may be a reasonable treatment option in the relapsed/refractory stage.

A rare complication after allogeneic stem cell transplantation: post-transplant erythrocytosis.

Post-transplant erythrocytosis is an infrequent complication and has been reported after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in aplastic anemia, acute myeloid leukemia, and chronic myeloid leukemia. The pre-disposing factors and treatment are not clearly defined. We present 11 post-transplant erythrocytosis cases. More studies should be conducted to distinguish the pathogenesis and follow-up for this rare complication.

Aspergillus Thyroiditis after Allogeneic Hematopoietic Stem Cell Transplantation.

Aspergillus thyroiditis is a rare disorder detected in immunocompromised patients during disseminated infections. Early management is essential to prevent high mortality. A 61-year-old allogeneic stem cell male recipient presented with painful thyroid nodular enlargement. He had low TSH and low free T4 levels. The thyroid ultrasound showed a hypoechoic nodule; biopsy indicated suppurative Aspergillus thyroiditis. He was successfully treated by amphotericin B.