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Simple Summary: The initial treatment for patients with advanced-stage follicular lymphoma is usually a combo of immunochemotherapy called R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-bendamustine (R-B, for short). After six cycles of R-CHOP, continuing with rituximab for two years (maintenance therapy) has demonstrated a reduction in relapses. However, determining if this approach works well after R-B has yet to be confirmed. Here, we collected data from 476 FL patients from 17 GELTAMO centers and evaluated the efficacy of both regimens followed by rituximab maintenance therapy in untreated follicular lymphoma patients. We found a better response with R-B and relapses were more frequent with R-CHOP. During the initial treatment, low blood counts were more frequent with R-CHOP but, during maintenance therapy, they were more frequent with R-B and so were infectious complications. After six years, 79% and 67% of R-B- and R-CHOP-treated patients, respectively, did not have evidence of the disease but the number of deaths was the same in both groups. In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated follicular lymphoma showed better responses and fewer relapses, without any extra side effects in an elderly population. During maintenance, patients had more issues when using R-B but deaths were the same in both groups. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77–86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72–86) for R-bendamustine vs. 67% (95% CI: 61–73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86–96) for R-B vs. 91% (95% CI: 87–94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality. [ABSTRACT FROM AUTHOR]

Although next-generation sequencing (NGS) data on lymphomas require further validation before being implemented in daily practice, the clinical application of NGS can be considered right around the corner. The aim of our study was to validate an NGS lymphoid panel for tissue and liquid biopsy with the most common types of non-Hodgkin's lymphoma [follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL)]. In this series, 372 somatic alterations were detected in 93.6% (44/47) of the patients through tissue biopsy. In FL, we identified 93 somatic alterations, with a median of 7.4 mutations per sample. In DLBCL, we detected 279 somatic variants with a median of 8.6 mutations (range 0–35). In 92% (24/26) of the cases, we were able to detect some variant in the circulating tumor DNA. We detected a total of 386 variants; 63.7% were detected in both types of samples, 13.2% were detected only in the circulating tumor DNA, and 23% were detected only in the tissue biopsy. We found a correlation between the number of circulating tumor DNA mutations, advanced stage, and bulky disease. The genetic alterations detected in this panel were consistent with those previously described at diagnosis. The liquid biopsy sample is therefore a complementary tool that can provide new genetic information, even in cases where a solid biopsy cannot be performed or an insufficient sample was obtained. In summary, we describe and analyze in this study the findings and difficulties encountered when incorporating liquid biopsy into clinical practice in non-Hodgkin's lymphoma at diagnosis. [ABSTRACT FROM AUTHOR]

Background: The incorporation of genetic variables into risk scores for predicting venous thromboembolic events (VTE) could improve their capacity to identify those patients for whom thromboprophylaxis would be most beneficial. Proof‐of‐concept of this is provided by the TiC‐ONCO score for predicting the risk of VTE in patients with solid tumours. Our aim was to develop a similarly improved tool—the TiC‐LYMPHO score—for predicting VTE in patients with lymphoma. Methods: In a retrospective observational study of 208 patients with lymphoma, 31 (14.9%) were found to have experienced an episode of VTE either at the time of diagnosis or over the next 6 months. Clinical variables associated with VTE, determined via logistic regression analysis, plus the same genetic variables included in the TiC‐ONCO score, were used to build the TiC‐LYMPHO score algorithm. The sensitivity, specificity, predictive values and AUC of the TiC‐LYMPHO, the Khorana and ThroLy scores were compared in the same population. Results: The TiC‐LYMPHO score showed a significantly higher AUC, sensitivity and NPV (0.783, 95.35% and 97.98% respectively) than the other scores. The ThroLy score showed a significantly higher specificity (96.43% vs. 54.49%; p < 0.0001) and PPV (37.50% vs. 26.36%; p = 0.0147) than the TiC‐LYMPHO score, whereas its AUC, sensitivity and NPV were significantly lower (0.579, 19.35% and 86.48%, respectively). Conclusion: These results show that by incorporating genetic and clinical data into VTE risk assessment, the TiC‐LYMPHO score can categorize patients with lymphoma better in terms of their risk of VTE and allow individualized thromboprophylaxis to be prescribed. [ABSTRACT FROM AUTHOR]

Lymphomas are a large, heterogeneous group of neoplasms with well-defined characteristics, and this heterogeneity highlights the importance of epidemiological data. Knowledge of local epidemiology is essential to optimise resources, design clinical trials, and identify minority entities. Given there are few published epidemiological data on lymphoma in Spain, the Spanish Lymphoma and Autologous Bone Marrow Transplant Group created the RELINF project. The aim of this project is to determine the frequencies and distribution of lymphoid neoplasms in Spain and to analyse survival. We developed an online platform for the prospective collection of data on newly diagnosed cases of lymphoma in Spain between January 2014 and July 2018; 11,400 patients were registered. Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) were the most frequent lymphomas in our series. Marginal B cell lymphoma frequency was higher than that reported in other studies, representing more than 11% of mature B cell lymphomas. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) was the most common subtype of T cell lymphoma, and NK/T cell lymphomas were more frequent than expected (5.4% of total). Hodgkin's lymphoma accounted for 12% of lymphoproliferative syndromes. Overall survival was greater than 90% at 2 years for indolent B cell lymphomas, and approximately 60% for DLBCL, somewhat lower than that previously reported. Survival was poor for PTCL-NOS and angioimmunoblastic T cell lymphoma, as expected; however, it was somewhat better than that in other studies for anaplastic large cell anaplastic lymphoma kinase lymphomas. This is the first prospective registry to report the frequencies, distribution, and survival of lymphomas in Spain. The frequencies and survival data we report here are globally consistent with that reported in other Western countries. These updated frequencies and survival statistics are necessary for developing appropriate management strategies for neoplasias in the Spanish population. [ABSTRACT FROM AUTHOR]

Alloreactivity triggered by interaction between killer cell immunoglobulin-like receptors ( KIRs) and natural killer ( NK) cells plays a role in the graft-versus-tumor effect after hematopoietic stem cell transplantation ( SCT). Our aim in this study was to evaluate this role in the setting of T-cell-repleted haploidentical SCT with postinfusion high-dose cyclophosphamide ( PT-Cy). We included 33 patients. Among patient-donor pairs with at least 1 inhibitory KIR ( iKIR) gene mismatch, event-free survival ( EFS) and cumulative incidence of relapse 1 year after transplant were significantly better (85% vs. 37% [ P = 0.008] and 18% vs. 46% [ P = 0.041], respectively). A subanalysis in 12 patients with Hodgkin's lymphoma ( HL) showed an improvement in EFS 1 year after transplant in those patients with KIR ligand mismatch (100% vs. 25%, P = 0.012), although overall survival ( OS) was not affected (85% vs. 80%, P = 0.2). Eight of 12 patient-donors pairs presented iKIR mismatches. Of note, this outcome was better in the small subgroup, both for EFS (100% vs. 25%, P = 0.012) and for OS (100% vs. 37%, P = 0.004). Our data suggest that in the setting of T-cell-repleted haploidentical SCT with PT-Cy, iKIR mismatch is associated with improved survival, with particularly good results for both iKIR and KIR ligand mismatches in patients with HL. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation (allo- SCT) has become the treatment of choice in patients with intermediate-risk and high-risk acute myeloid leukemia ( AML). The quality of response to treatment, assessed in terms of detection of minimal residual disease ( MRD), has been consistently associated with prognosis and clinical outcome in patients with AML. The aim of the present study was to evaluate the prognostic impact of analyzing MRD in bone marrow using 4-color multiparametric flow cytometry ( MFC) in 29 patients with AML before and after allo- SCT. Eighteen patients who were shown to be MRD-negative [≤0.1% leukemia-associated immunophenotypes ( LAIPs)] by MFC at transplantation and underwent allo- SCT had lower rates of relapse (15% vs. 66%, P = 0.045), better overall 1-yr survival (83% vs. 52%, P = 0.021) and a lower cumulative incidence of relapse ( P = 0.032) than patients who were MRD-positive (>0.1%). All post-transplant MRD-positive patients underwent a therapeutic intervention after transplant (tapering of immunosuppression, donor lymphocyte infusion, or re-transplant) with the intention of preventing relapse. Disease was controlled and MRD disappeared in five of these patients. Disease recurred in the other seven patients. We can conclude that follow-up with MFC for the detection of MRD in AML before and after SCT is useful for predicting relapse. In the post-transplant setting, monitoring of MRD by MFC could be a key preemptive intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: As the optimal strategy for early surveillance after first complete response is unclear in Hodgkin lymphoma (HL), with the aim to identify the best one, we analyzed surveillance strategies after first-line treatment in a group of 640 Hodgkin lymphoma patients from 15 different GELTAMO centers in Spain. In this study, we have demonstrated that surveillance approaches with imaging in HL do not provide benefits for patient survival, nor do they anticipate relapse. Our results are of great importance, because they could contribute to improve the follow up after first complete response of this group of patients. The optimal strategy for early surveillance after first complete response is unclear in Hodgkin lymphoma. Thus, we compared the various follow-up strategies in a multicenter study. All the included patients had a negative positron emission tomography/computed tomography at the end of induction therapy. From January 2007 to January 2018, we recruited 640 patients from 15 centers in Spain. Comparing the groups in which serial imaging were performed, the clinical/analytical follow-up group was exposed to significantly fewer imaging tests and less radiation. With a median follow-up of 127 months, progression-free survival at 60 months of the entire series was 88% and the overall survival was 97%. No significant differences in survival or progression-free survival were found among the various surveillance strategies. This study suggests that follow-up approaches with imaging in Hodgkin lymphoma provide no benefits for patient survival, and we believe that clinical/analytical surveillance for this group of patients could be the best course of action. [ABSTRACT FROM AUTHOR]

Summary: The aims of our study were to analyse compliance with the 2014 GELTAMO SMZL Guidelines, in patients with splenic marginal zone lymphoma (SMZL), and to evaluate the outcome according to the HPLLs/ABC‐adapted therapeutic strategy. Observational prospective multicenter study of 181 SMZL patients diagnosed between 2014 and 2020. Lymphoma‐specific survival (LSS), composite event‐free survival (CEFS) and response rates were assessed. 57% of the 168 patients included in the analysis followed the Guidelines. The overall response rate was higher in the rituximab chemotherapy and in the rituximab arms compared with the splenectomy arm (p < 0.001). The 5‐year overall survival was 77% and the 5‐year LSS of 93%. There were no differences in the 5‐year LSS according to the treatment received (p = 0.68). The 5‐year CEFS in the overall series was 45%, and there were significant differences between scores A and B (p = 0.036). There were no significant differences when comparing LSS and progression‐free survival in patients treated with rituximab or rituximab chemotherapy at diagnosis or after observation. Our data support HPLLs/ABC score as a practical tool for the management of SMZL, observation as the best approach for patients in group A and rituximab as the best treatment for group B. [ABSTRACT FROM AUTHOR]

The AETHERA trial demonstrated that brentuximab vedotin (BV) consolidation after autologous stem cell transplantation (ASCT) in patients with Hodgkin lymphoma (HL) at high risk of relapse/progression increases progression-free survival (PFS). Patients previously exposed to BV were excluded from that trial. However, BV alone or in combination with chemotherapy is frequently used as front-line treatment and/or pre-ASCT salvage therapy. We analyzed data from 156 patients with high-risk HL who underwent ASCT with (BV-CON, n = 62) or without (non-BV, n = 94) BV consolidation. Fifty-seven patients received BV-based salvage regimens before ASCT. The 3-year overall survival and PFS for all patients were 91.6% and 70.0%, respectively. Multivariate analysis showed that BV-CON was associated with better PFS (HR 0.39, p = 0.01), whereas positive PET at transplant leaded to worse PFS (HR 2.71, p = 0.001). BV-CON improved PFS in PET-positive patients (72.2% vs. 43.0%, p = 0.05), with a beneficial trend observed in PET negative (88.8% vs. 75.2%, p = 0.09). BV-CON patients with or without BV exposure pre-ASCT had a significantly better PFS than non-BV with or without BV pretransplant treatment (HR 0.36, p = 0.004). The efficacy of real-life BV consolidation therapy was similar to that in the AETHERA trial. This therapeutic strategy improves survival independently of BV exposure prior to ASCT. [ABSTRACT FROM AUTHOR]

Summary: Although follicular lymphoma (FL) patients relapsing within 24 months after first‐line treatment (POD24) have a poor prognosis, some cases show notable survival after first relapse (SF1R). We aimed to characterize the POD24 FL population and to identify the main prognostic factors at progression. We selected 162 POD24 patients (80F; median age at first relapse 59 years) from a cohort of 1067 grades 1‐3a FL‐treated patients. The remaining 905 patients treated with first‐line immunochemotherapy and diagnosed during the same period were used to compare outcomes in terms of survival. After a median follow‐up of 11.0 years, 96 patients died (10y‐SF1R of 40%). Age over 60 years (p < 0.001), high lactate dehydrogenase (LDH) (p < 0.001), haemoglobin (Hb) less than 120 g/L (p < 0.001), advanced stage (p < 0.001), high‐risk Follicular Lymphoma International Prognostic Index (FLIPI) (p < 0.001), histological transformation (HT) (p < 0.001) and reaching less than complete response (CR) after salvage therapy (p < 0.001), predicted poor SF1R at relapse. In multivariate analysis only high‐risk FLIPI and HT maintained prognostic significance for SF1R. POD24 patients not transformed and with low/intermediate FLIPI at relapse behaved better than the remaining cases. POD24 patients showed an excess mortality of 38% compared to the general population. Although outcome of POD24 FL patients is poor, a considerable group of them (low/intermediate FLIPI and not transformed at first relapse) behave better. [ABSTRACT FROM AUTHOR]

Simple Summary: Inherited predisposition to hematological malignancies is more common than previously perceived. The main objective of our study was to analyze the whole-exome sequencing data for the genomic characterization of sixteen patients with a strong family or personal onco-hematological history. When a duo analysis was performed, we detected pathogenic or likely pathogenic (P/LP) germline variants in four out of the six families studied. In the remaining four individuals, we detected three P/LP germline variants in genes with a potential role in cancer development. Next-generation sequencing strategies lead to the identification of novel candidate genes (NFATC2 and TC2N) potentially involved in the development of these germline syndromes. The recognition of predisposing variants is crucial for disease management and follow-up of affected patients and their relatives. The familial occurrence of hematological malignancies has been underappreciated. Recent studies suggest that up to 15% of adults with myeloid neoplasms carry germline pathogenic variants in cancer-predisposing genes. This study aimed to identify the underlying germline predisposition variant in patients with a strong family or personal onco-hematological history using whole exome sequencing on sixteen uncharacterized individuals. It was carried out in two groups of patients, one with samples available from two affected relatives (Cohort A) and one with available samples from the index case (Cohort B). In Cohort A, six families were characterized. Two families shared variants in genes associated with DNA damage response and involved in cancer development (CHEK2 and RAD54L). Pathogenic or likely pathogenic germline variants were also found in novel candidate genes (NFATC2 and TC2N). In two families, any relevant pathogenic or likely pathogenic genomic variants were identified. In Cohort B, four additional index cases were analyzed. Three of them harbor clinically relevant variants in genes with a probable role in the development of inherited forms of hematological malignancies (GATA1, MSH4 and PRF1). Overall, whole exome sequencing is a useful approach to achieve a further characterization of these patients and their mutational spectra. Moreover, further investigations may help improve optimization for disease management of affected patients and their families. [ABSTRACT FROM AUTHOR]

Simple Summary: Follicular lymphoma (FL) is the most prevalent subtype of indolent lymphoma, accounting for 70% of all cases. The estimated risk of histological transformation (tFL), such as diffuse large B cell lymphoma (DLBCL), varies from 2–3% per year to 7–8% at 10 years in different series. Treatment after transformation is not clearly established. Allogeneic hematopoietic stem cell transplantation (alloSCT) could be an option for these patients, but it has not been widely explored. We analyze the efficacy and toxicity of alloSCT in 43 patients from 14 Spanish centers. We observed long-term survival in around one third of the patients, especially those who developed chronic graft versus host disease, indicating that alloSCT continues to be a potentially curative option for patients with tFL, mainly due to the graft versus lymphoma effect. Background: Transformation of follicular lymphoma into an aggressive lymphoma (tFL) worsens the prognosis and the standard treatment is not completely defined. Allogeneic hematopoietic stem cell transplantation (alloSCT) could be a potentially curative option for these patients, but it has not been widely explored. Methods: We designed a retrospective multicenter study to analyze the efficacy and toxicity of alloSCT in tFL patients and potential prognostic factors of survival. Results: A total of 43 patients diagnosed with tFL who underwent alloSCT in 14 Spanish centers between January 2000 and January 2019 were included. Median age was 44 (31–67) years. After a median follow-up of 58 months, estimated 5-year overall survival (OS) and progression-free survival (PFS) were both 35%. Estimated 100-day and 1-year non-relapse mortality (NRM) were 20% and 34%, respectively. The type of conditioning regimen (3-year OS of 52% vs. 20%, respectively, for reduced-intensity vs. myeloablative conditioning) and development of chronic graft versus host disease (cGVHD) (3-year OS of 75% vs. 40%) were the only factors significantly associated with OS. The only variable with an independent association with OS was cGVHD (HR, 3.4; 95% CI, 1.2–9.6). Conclusions: Our results indicate that alloSCT continues to be a potentially curative option for patients with tFL. [ABSTRACT FROM AUTHOR]

Background: A variable incidence of profound cytopenia has been described in patients receiving chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL). This complication leads to severe infection in some cases, especially those who present additional risk factors including prior hematopoietic stem cell transplantation (HSCT).Study Design and Methods: We report a case of breakthrough invasive fungal infection in a patient with prolonged neutropenia after CAR-T cell therapy administered for relapsed B-cell ALL after allogeneic haploidentical HSCT.Results: After disease progression was discarded, therapy with antifungal agents, G-CSF and thrombopoietin analogue was started. However, no sign of haematological recovery or infection improvement was observed. A fresh mobilized selected CD34-stem cell boost from her haploidentical transplant donor was infused without further conditioning. Within 15 days of mobilized CD34-boost administration the patient showed complete resolution of both the aplasia and fungal infection.Discussion: This case illustrates as proof-of-concept the efficacy and safety of selected CD34-stem cell boost from prior donor as salvage treatment of prolonged cytopenias after CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3–5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n = 4; infection, n = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n = 1; infection, n = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma. [ABSTRACT FROM AUTHOR]

This study shows that the clinical and biologic characteristics of adult patients with BL and BLL were similar to those of patients from the BL-IPI cohort. Consequently, the BL-IPI was validated in our series of patients with BL and BLL. Keywords: Burkitt lymphoma; prognosis; International Prognostic Index; validation EN Burkitt lymphoma prognosis International Prognostic Index validation 1993 1996 4 08/22/22 20220801 NES 220801 Chemoimmunotherapy including rituximab and high-dose or infusional chemotherapy constitute the standard treatment for patients with Burkitt's lymphoma (BL) or Burkitt's lymphoma and leukemia (BLL) [[1], [3]]. [Extracted from the article]

Simple Summary: We present the long-term results of patients receiving allogeneic stem cell transplantation (allo-SCT) for relapsed/refractory mantle cell lymphoma (R/R MCL) in the last 25 years in Spain. We conclude that allo-SCT may be a curative option in R/R MCL with a low cumulative incidence (CI) of relapse, although non-relapse mortality (NRM) is still high, which is mainly secondary to acute graft-versus-host disease (aGVHD). Results are better for fit patients, using HLA-identical (related or unrelated) or haploidentical related donors and without previous ASCT. However, the arrival of new highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, being administered far away from the optimal timing. Allo-SCT is a curative option for selected patients with relapsed/refractory (R/R) MCL, but with significant NRM. We present the long-term results of patients receiving allo-SCT in Spain from March 1995 to February 2020. The primary endpoints were EFS, OS, and cumulative incidence (CI) of NRM, relapse, and GVHD. We included 135 patients, most (85%) receiving RIC. After a median follow-up of 68 months, 5-year EFS and OS were 47 and 50%, respectively. Overall and CR rates were 86 and 80%. The CI of relapse at 1 and 3 years were 7 and 12%. NRM at day 100 and 1 year were 17 and 32%. Previous ASCT and Grade 3–4 aGVHD were associated with a higher NRM. Grade 3–4 aGVHD, donor type (mismatch non-related), and the time-period 2006–2020 were independently related to worse EFS. Patients from 1995–2005 were younger, most from HLA-identical sibling donors, and were pretreated less. Our data confirmed that allo-SCT may be a curative option in R/R MCL with low a CI of relapse, although NRM is still high, being mainly secondary to aGVHD. The arrival of new, highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, far away from the optimal timing of treatment. [ABSTRACT FROM AUTHOR]

What is Known and Objective: Rosai‐Dorfman disease (RDD) is an infrequent entity of unknown aetiology. Currently, there is no clear consensus on the treatment, and nothing has shown definitive safety and efficacy. We describe the case of a woman diagnosed with pulmonary RDD, who responded to thalidomide treatment after failure of four previous lines of systemic chemotherapy. Case Description: We present the case of a 74‐year‐old woman diagnosed with pulmonary RDD and autoimmune complications. We decided to use thalidomide as a rescue treatment after the failure of corticosteroids and several chemotherapies. Our patient achieved remission of the disease and remained stable for years. What is New and Conclusion: To the authors' knowledge, this is the first reported case in which thalidomide treatment induced remission in refractory pulmonary RDD. Thalidomide showed a rapid onset of action, with lasting responses, which could make it an exciting option for treating this life‐threatening. [ABSTRACT FROM AUTHOR]

Background: Allogeneic stem cell transplantation is the treatment of choice for acute myeloid leukemia (AML) patients. Unmanipulated haploidentical transplantation (Haplo‐HSCT) is commonly used for those AML patients who need a timely transplant and do not have a suitable matched donor, but relapse rates are still high, and improvements are needed. Adoptive immunotherapy using natural killer cells (NK cells) could be a promising tool to improved Haplo‐HSCT but, to date, no optimal infusion and manufacturing protocols have been developed. Study Design and Methods: In this study, we describe a quick and reproducible protocol for clinical‐grade production of haploidentical donor NK cells using double immunomagnetic depletion and enrichment protocol and overnight IL‐15 stimulation. Results: Thus, we have obtained 8 viable and functional NK cell products that have been safely infused to five AML patients undergoing unmanipulated Haplo‐HSCT. Discussion: Our results demonstrate the safety and feasibility of manufactured NK IL15 cells obtained from an adult allogeneic donor in the setting of haploidentical transplantation for AML patients. [ABSTRACT FROM AUTHOR]

Objectives: Diffuse large B‐cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%‐40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high‐risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor‐related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. Methods: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R‐CHOP (n = 1327). Results: Five‐years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R‐TS), identifying four different risk groups, with 5‐years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. Conclusions: (a) All variables of the original TS retain an independent prognostic role, and R‐TS remains predictive in the rituximab era; (b) R‐TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets. [ABSTRACT FROM AUTHOR]

Objective: Challenging differential diagnosis. Background: Intraventricular administration of methotrexate (MTX) using an Ommaya reservoir is a useful therapeutic maneuver for malignant CNS involvement in patients with hematological malignancies. MTX-induced subacute neurotoxicity is a rare complication that typically progresses with involvement of the basal ganglia. Local toxicity due to misplaced catheters has been described, although the impact of normally positioned catheters on toxicity is not clear. Case Report: We report the case of a 21-year-old man diagnosed with stage IV diffuse large B-cell lymphoma who experienced a central nervous system relapse. While receiving intraventricular MTX using an Ommaya reservoir and systemic MTX, he experienced sudden left-side hemiparesis. All diagnostic tests were negative except for altered MRI findings with FLAIR hyperintensity in the basal ganglia and restricted diffusion in the same location that followed the track of the Ommaya catheter. The syndrome resolved after administration of high-dose steroids, and the patient received subsequent MTX courses without recurrence. Conclusions: MTX-induced neurotoxicity is a rare adverse event related to systemic and intrathecal administration of the drug. Many cases of Ommaya-related CNS symptoms have been described, although most were related to misplaced or malfunctioning catheters. Here we present a case of subacute MTX toxicity affecting the area around a correctly positioned catheter, suggesting that the catheter track could be more susceptible to MTX-induced toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Background: High‐risk acute leukemia (AL) and myelodysplastic syndrome (MDS) remain a therapeutic challenge. Unmanipulated haploidentical‐related donor transplantation based on a myeloablative conditioning regimen (HAPLO‐MAC) and post‐transplant cyclophosphamide (PT‐Cy) as prophylaxis against graft vs host disease (GvHD) is now a promising rescue strategy that could become universally available. Objective: To evaluate the results of HAPLO‐MAC with PT‐Cy in patients with AL and MDS reported to the Haploidentical Transplantation Subcommittee of the Spanish Group for Hematopoietic Transplantation (GETH). Patients and methods: We report our multicenter experience using an IV busulfan‐based HAPLO‐MAC regimen and PT‐Cy for treatment of 65 adults with high‐risk AL and MDS. Results: Engraftment was recorded in 64 patients (98.5%), with a median time to neutrophil and platelet recovery of 16 and 27 days, respectively. The cumulative incidence of grade II‐IV acute GvHD and chronic GvHD was 28.6% and 27.5%, respectively. After a median follow‐up of 31 months for survivors, the cumulative incidence of non‐relapse mortality and relapse at 2 years was 18.8% and 25%, respectively. Estimated 30‐month event‐free survival and overall survival were 56% and 54.5%, respectively. Conclusion: HAPLO‐MAC comprising an IV busulfan‐based conditioning regimen enabled long‐term disease control with acceptable toxicity in high‐risk AL and MDS. [ABSTRACT FROM AUTHOR]

Simple Summary: Conventional cytogenetic approaches are the gold standard for the identification of chromosomal alterations in myeloid neoplasms. Next-generation sequencing panels are a new approach for the detection of copy number variations (CNV) or translocations. Here we report on a commercial panel utility including frequent mutations, CNVs and translocations in myeloid neoplasms. A total of 135 patients with myeloid neoplasms and three with acute lymphoblastic leukemia were analyzed by NGS. When comparing with gold standard techniques, 48 frequent alterations were detected by both methodologies, ten of them observed only by conventional methods and another eight only by NGS. Additionally, 38 secondary CNVs were detected in any of the genes included in the panel for mutational analysis. With those results we determine that NGS represents a reliable complementary source of information for the analysis of CNVs and translocations. Conventional cytogenetics are the gold standard for the identification of chromosomal alterations recurrent in myeloid neoplasms. Some next-generation sequencing (NGS) panels are designed for the detection of copy number variations (CNV) or translocations; however, their use is far from being widespread. Here we report on the results of a commercial panel including frequent mutations, CNVs and translocations in myeloid neoplasms. Frequent chromosomal alterations were analyzed by NGS in 135 patients with myeloid neoplasms and three with acute lymphoblastic leukemia. NGS analysis was performed using the enrichment-capture Myeloid Neoplasm-GeneSGKit (Sistemas Genómicos, Spain) gene panel including 35 genes for mutational analysis and frequent CNVs and translocations. NGS results were validated with cytogenetics and/or MLPA when possible. A total of 66 frequent alterations included in NGS panel were detected, 48 of them detected by NGS and cytogenetics. Ten of them were observed only by cytogenetics (mainly trisomy 8), and another eight only by NGS (mainly deletion of 12p). Aside from this, 38 secondary CNVs were detected in any of the genes included mainly for mutational analysis. NGS represents a reliable complementary source of information for the analysis of CNVs and translocations. Moreover, NGS could be a useful tool for the detection of alterations not observed by conventional cytogenetics. [ABSTRACT FROM AUTHOR]

Molecular diagnosis of myeloid neoplasms (MN) is based on the detection of multiple genetic alterations using various techniques. Next-generation sequencing (NGS) has been proved as a useful method for analyzing many genes simultaneously. In this context, we analyzed diagnostic samples from 121 patients affected by MN and ten relapse samples from a subset of acute myeloid leukemia patients using two enrichment-capture NGS gene panels. Pathogenicity classification of variants was enhanced by the development and application of a custom onco-hematology score. A total of 278 pathogenic variants were detected in 84% of patients. For structural alterations, 82% of those identified by cytogenetics were detected by NGS, 25 of 31 copy number variants and three out of three translocations. The detection of variants using NGS changed the diagnosis of seven patients and the prognosis of 15 patients and enabled us to identify 44 suitable candidates for clinical trials. Regarding AML, six of the ten relapsed patients lost or gained variants, comparing with diagnostic samples. In conclusion, the use of NGS panels in MN improves genetic characterization of the disease compared with conventional methods, thus demonstrating its potential clinical utility in routine clinical testing. This approach leads to better-adjusted treatments for each patient. [ABSTRACT FROM AUTHOR]

Background: Telomeres are nucleoprotein structures present at the terminal region of the chromosomes. Mutations in genes coding for proteins involved in telomere maintenance are causative of a number of disorders known as telomeropathies. The genetic origin of these diseases is heterogeneous and has not been determined for a significant proportion of patients.Methods: This article describes the genetic characterization of a cohort of patients. Telomere length was determined by Southern blot and quantitative PCR. Nucleotide variants were analyzed either by high-resolution melting analysis and Sanger sequencing of selected exons or by massive sequencing of a panel of genes.Results: Forty-seven patients with telomere length below the 10% of normal population, affected with three telomeropathies: dyskeratosis congenita (4), aplastic anemia (22) or pulmonary fibrosis (21) were analyzed. Eighteen of these patients presented known pathogenic or novel possibly pathogenic variants in the telomere-related genes TERT, TERC, RTEL1, CTC1 and ACD. In addition, the analyses of a panel of 188 genes related to haematological disorders indicated that a relevant proportion of the patients (up to 35%) presented rare variants in genes related to DNA repair or in genes coding for proteins involved in the resolution of complex DNA structures, that participate in telomere replication. Mutations in some of these genes are causative of several syndromes previously associated to telomere shortening.Conclusion: Novel variants in telomere, DNA repair and replication genes are described that might indicate the contribution of variants in these genes to the development of telomeropathies. Patients carrying variants in telomere-related genes presented worse evolution after diagnosis than the rest of patients analyzed. [ABSTRACT FROM AUTHOR]