Ponatinib induces a sustained deep molecular response in a chronic myeloid leukaemia patient with an early relapse with a T315I mutation following allogeneic hematopoietic stem cell transplantation: a case report.

BACKGROUND: Atypical BCR-ABL1 transcripts are detected in less than 5% of patients diagnosed with chronic myeloid leukaemia (CML), of which e19a2 is the most frequently observed, with breakpoints in the micro breakpoint cluster region (µ-BCR) and coding for the p230 BCR-ABL1 protein. p230 CML is associated with various clinical presentations and courses with variable responses to first-line imatinib. CASE PRESENTATION: Here we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single-agent ponatinib. Using CastPCR, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after allogeneic hematopoietic stem cell transplantation (HSCT). CONCLUSION: This case illustrates the major interest of ponatinib as a valid treatment option for e19a2 CML patients who present a T315I mutation following relapse after HSCT.

Cytomegalovirus infection in patients who underwent allogeneic hematopoietic stem cell transplantation in Portugal: a five-year retrospective review.

Cytomegalovirus (CMV) infection is 1 of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT), mainly within the first 100 days after transplantation. We aimed to characterize CMV infection in a cohort of 305 patients with different malignancies undergoing aHSCT at the Portuguese Institute of Oncology of Porto between January 2008 and December 2012. In total, 184 patients (60.3%) developed CMV infection, mainly viral reactivations rather than primary infections (96.2% versus 3.8%, respectively). The majority of patients (166 of 184) developed CMV infection ≤100 days after transplantation, with median time to infection of 29 days (range, 0 to 1285) and median duration of infection of 10 days (range, 2 to 372). Multivariate analysis revealed that CMV infection was increased in donor (D)-/recipient (R)+ and D+/R+ (odds ratio [OR], 10.5; 95% confidence interval [CI], 4.35 to 25.4; P < .001) and in patients with mismatched or unrelated donors (OR, 2.54; 95% CI, 1.34 to 4.80; P = .004). Cox regression model showed that the risk of death was significantly increased in patients >38 years old (OR, 1.89; 95% CI, 1.14 to 3.12; P = .0137), who underwent transplantation with peripheral blood (OR, 3.02; 95% CI, 1.33 to 6.86; P = .008), with mismatched or unrelated donor (OR, 2.16; 95% CI, 1.48 to 3.13; P < .001), and who developed CMV infection (OR, 1.76; 95% CI, 1.07 to 2.90; P = .025). Moreover, patients who developed CMV infection had a significantly reduced median post-transplantation survival (16 versus 36 months; P = .002).

Acute kidney injury after allogeneic hematopoietic stem cell transplantation - Predictors and survival impact: A single center retrospective study.

INTRODUCTION AND OBJECTIVES: Acute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. PATIENTS AND METHODS: We performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. RESULTS: AKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. CONCLUSION: Patients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit.

Genetic Variation in PFKFB3 Impairs Antifungal Immunometabolic Responses and Predisposes to Invasive Pulmonary Aspergillosis.

Activation of immune cells in response to fungal infection involves the reprogramming of their cellular metabolism to support antimicrobial effector functions. Although metabolic pathways such as glycolysis are known to represent critical regulatory nodes in antifungal immunity, it remains undetermined whether these are differentially regulated at the interindividual level. In this study, we identify a key role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the immunometabolic responses to Aspergillus fumigatus. A genetic association study performed in 439 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and corresponding donors revealed that the donor, but not recipient, rs646564 variant in the PFKFB3 gene increased the risk of invasive pulmonary aspergillosis (IPA) after transplantation. The risk genotype impaired the expression of PFKFB3 by human macrophages in response to fungal infection, which was correlated with a defective activation of glycolysis and the ensuing antifungal effector functions. In patients with IPA, the risk genotype was associated with lower concentrations of cytokines in the bronchoalveolar lavage fluid samples. Collectively, these findings demonstrate the important contribution of genetic variation in PFKFB3 to the risk of IPA in patients undergoing HSCT and support its inclusion in prognostic tools to predict the risk of fungal infection in this clinical setting. IMPORTANCE The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. Activation of glycolysis is essential for innate immune cells to mount effective antifungal responses. In this study, we report the contribution of genetic variation in the key glycolytic activator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) to the risk of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation. The PFKFB3 genotype associated with increased risk of infection was correlated with an impairment of the antifungal effector functions of macrophages in vitro and in patients with IPA. This work highlights the clinical relevance of genetic variation in PFKFB3 to the risk of IPA and supports its integration in risk stratification and preemptive measures for patients at high risk of IPA.

Association of Epstein­Barr virus infection with allogeneic hematopoietic stem cell transplantation in patients in Portugal.

The identification of patients at higher risk of developing Epstein­Barr virus (EBV) infection in hematopoietic stem cell transplants (HSCT) is useful for the prevention of EBV­associated diseases A prospective observational study was developed that included 40 patients (27 male and 13 females, with mean age of 32.2±1.5 years old) undergoing allogeneic­HSCT between January and December 2015. EBV was examined in whole blood samples collected during routine procedures at day (D)+30, D +60, +90, D+120, D+150 and D+180 post­transplant. EBV was detected, at least once during the follow­up period in 70.0% of our patients. Results indicated that patients with unrelated donors had increased risk of developing EBV infection at D+60 and D+150 (OR=3.9, P=0.058; OR=8.0, P=0.043; respectively). Moreover, myeloablative conditioning (OR=4.3, P=0.052), anti­thymocyte globulin use (OR=12.0, P=0.030) and graft­vs.­host disease (OR=6.7, P=0.032) were associated with EBV infection at D+60, D+150 and D+90, respectively. In our series, none of these patients developed post­transplant lymphoproliferative disease. To the best of our knowledge, the present study is the first study to report EBV infection in patients undergoing aHSCT from Portugal. The study revealed that EBV infection is associated with different factors. These findings provide evidence towards the identification of high­risk patients for EBV­infection and associated disease.

Post­transplant lymphoproliferative disorder in hematopoietic stem cell transplant patients: A single center retrospective study between 2005 and 2012.

Post­transplant lymphoproliferative disorder (PTLD), despite its rarity, is an important mortality/morbidity event in transplant patients. The purpose of the present study was to retrospectively examine the clinical and pathologic characteristics, and outcomes of PTLD at the Portuguese Oncology Institute of Porto. A retrospective review of patient information was performed for patients that developed PTLD following allogeneic hematopoietic stem cell transplant (aHSCT) and were diagnosed between 2005 and 2012. The present study included a total of 15 patients, 8 females (53.3%) and 7 males (46.7%), with different clinicopathological characteristics. The most frequent clinical condition inducing aHSCT was acute lymphocytic leukemia (40.0%). Conditioning regimens consisted primarily in busulfan and cyclophosphamide, with anti­thymocyte globulin, and myeloablation was the preferential treatment. Epstein­Barr virus (EBV) was present in all patients with a median time of diagnosis following transplant of 75 days (range, 25­485 days) and a median viral load of 4.75 log10 copies/ml (range, 3.30­6.26 log10 copies/ml). PTLD diagnosis was mainly assessed by clinical findings, and histological confirmation was available for 5 patients: 3 monomorphic, 1 polymorphic and 1 with early lesions of PTLD. To the best of our knowledge, this is the first study to describe PTLD cases in HSCT patients in Portugal. The data reinforces the importance of performing EBV monitoring in high­risk patients, particularly those receiving a transplant from mismatch/unrelated donors, and those with myeloablative conditioning regimen including antithymocyte globulin. The results also suggested that EBV viral load may be significant for the prediction of PTLD development.

Genotypic resistance of cytomegalovirus to antivirals in hematopoietic stem cell transplant recipients from Portugal: A retrospective study.

The aim of this study was to characterize Human Cytomegalovirus (HCMV) drug resistance mutations in UL97 and UL54 genes in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients in Portugal. We have performed a retrospective study with 22 patients from a cohort of patients with different haematological malignancies submitted to allo-HSCT between 2010 and 2014. Patients were selected according to clinical and laboratory data of HCMV infection and management. HCMV resistance mutations were characterized by sequencing of UL97 and UL54 genes. Sequence data were compared with: 1) HCMV genome reference strain AD169; and also 2) UL97 from Merlin strain (GenBank: AY446894.2), and UL54 from TB40/E strain (GenBank: ABV71585.1). Resistance mutations were identified in seven patients (32%): five harboured resistance mutations in UL97: A594V (n = 2), C592G (n = 1), L595W (n = 1), and C603W (n = 1); and two harboured resistance mutations in UL54: P522S and L957F, one in each patient. Several natural polymorphisms and unknown mutations were found in both UL97 and UL54, with the majority of the patients harbouring more than one unknown mutation in UL97 but only one in UL54. No simultaneous mutations were found. This is the first study in Portugal to characterize HCMV UL97 and UL54 sequences and to identify HCMV drug-resistance mutations in allo-HSCT patients. The UL97 resistance mutations found were amongst the most frequent resistant mutations, while UL54 L957F mutation was here reported for the first time in a clinical specimen. This information provides important information regarding HCMV strains and antiviral resistance in our population.

Outcomes of allogeneic stem cell transplantation among patients with acute myeloid leukemia presenting active disease: Experience of a single European Comprehensive Cancer Center.

INTRODUCTION:: Allogeneic hematopoietic stem cell transplantation (ASCT) representes a potentially curative approach for patients with relapsed or refractory acute myeloid leukemia (AML). We report the outcome of relapsed/refractory AML patients treated with ASCT. METHOD:: A retrospective cohort from 1994 to 2013 that included 61 patients with diagnosis of relapsed/refractory AML. Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), relapse incidence, progression-free survival (PFS) and overall survival (OS). Statistical significance was set at p<0.05. RESULTS:: The median age was 61 years (range 1 to 65). The cumulative incidence of 90 days, 1 year, and 3 years TRM were 60%, 26.7%, and 13.3%, respectively (p<0.001). The incidence of relapse was 21.7% at 1 year, 13% at 3 years, and 8.7% at 5 years. Median OS was estimated to be 8 months (95CI 3.266-12.734) and median PFS, 3 months (95CI 1.835-4.165). CONCLUSION:: In our cohort, TRM in first years after ASCT remains considerable, but ASCT in this setting seems to be a good choice for AML patients with active disease. However, novel approaches are needed to reduce TRM and relapse in this set of patients.

Visceral leishmaniasis: a differential diagnosis to remember after bone marrow transplantation.

Leishmania infection in immunocompromised hosts is reported in the literature, mostly concerning human immunodeficiency virus infected patients. It is not well characterized in the context of stem cell transplantation. We report a rare case clinical case of visceral leishmaniasis after allogeneic bone marrow transplantation. A 50-year-old Caucasian male was referred to allogeneic bone marrow transplantation with a high-risk acute lymphoblastic B leukemia in first complete remission. Allogeneic SCT was performed with peripheral blood stem cells from an unrelated Portuguese matched donor. In the following months, patient developed mild fluctuating cytopenias, mostly thrombocytopenia (between 60 and 80∗10(9)/L). The only significant complaint was intermittent tiredness. The common causes for thrombocytopenia in this setting were excluded-no evidence of graft versus host disease, no signs of viral or bacterial infection, and no signs of relapsed disease/dysplastic changes. The bone marrow smear performed 12 months after transplantation revealed an unsuspected diagnosis: a massive bone marrow infiltration with amastigotes.

Outcomes of allogeneic stem cell transplantation among patients with acute myeloid leukemia presenting active disease: Experience of a single European Comprehensive Cancer Center / Resultados do transplante alogênico de células-tronco em doentes com leucemia mieloide aguda com doença ativa: experiência de um único Centro Oncológico Europeu

Summary Introduction: Allogeneic hematopoietic stem cell transplantation (ASCT) representes a potentially curative approach for patients with relapsed or refractory acute myeloid leukemia (AML). We report the outcome of relapsed/refractory AML patients treated with ASCT. Method: A retrospective cohort from 1994 to 2013 that included 61 patients with diagnosis of relapsed/refractory AML. Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), relapse incidence, progression-free survival (PFS) and overall survival (OS). Statistical significance was set at p<0.05. Results: The median age was 61 years (range 1 to 65). The cumulative incidence of 90 days, 1 year, and 3 years TRM were 60%, 26.7%, and 13.3%, respectively (p<0.001). The incidence of relapse was 21.7% at 1 year, 13% at 3 years, and 8.7% at 5 years. Median OS was estimated to be 8 months (95CI 3.266-12.734) and median PFS, 3 months (95CI 1.835-4.165). Conclusion: In our cohort, TRM in first years after ASCT remains considerable, but ASCT in this setting seems to be a good choice for AML patients with active disease. However, novel approaches are needed to reduce TRM and relapse in this set of patients.

Resumo Introdução: o transplante alogênico de células-tronco hematopoiéticas (TCTH-alo) representa uma abordagem potencialmente curativa para pacientes com leucemia mieloide aguda (LMA) recorrente ou refratária. Nosso trabalho apresenta o resultado de pacientes com recaída ou doença refratária tratados com TCTH-alo. Método: coorte retrospectiva incluindo 61 pacientes de 1994 a 2013 com diagnóstico de recidiva/LMA refratária. Os desfechos de interesse foram mortalidade relacionada ao transplante (MRT), incidência da doença aguda e crônica do enxerto contra hospedeiro (DECH), incidência de recaídas, sobrevida livre de progressão (PFS - progression-free survival) e sobrevida global (SG). A significância estatística foi considerada para p<0,05. Resultados: a média de idade foi de 61 anos (variação de 1 a 65). A incidência cumulativa de 90 dias, 1 ano e 3 anos de MRT foram de 60%, 26,7% e 13,3%, respectivamente (p<0,001). A incidência de recaída foi de 21,7% em 1 ano, 13% em 3 anos e 8,7% em 5 anos. A SG mediana foi estimada em 8 meses (IC 95% 3,266-12,734) e a mediana de PFS, em 3 meses (IC 95% 1,835-4,165). Conclusão: em nossa coorte, MRT no primeiro ano após o transplante permanece considerável, mas TCTH-alo nesse cenário parece ser uma boa opção para pacientes com LMA ativa. No entanto, novas abordagens são necessárias para reduzir MRT e recaída nesse conjunto de pacientes.

Rhizomucor and scedosporium infection post hematopoietic stem-cell transplant.

Hematopoietic stem-cell transplant recipients are at increased risk of developing invasive fungal infections. This is a major cause of morbidity and mortality. We report a case of a 17-year-old male patient diagnosed with severe idiopathic acquired aplastic anemia who developed fungal pneumonitis due to Rhizomucor sp. and rhinoencephalitis due to Scedosporium apiospermum 6 and 8 months after undergoing allogeneic hematopoietic stem-cell transplant from an HLA-matched unrelated donor. Discussion highlights risk factors for invasive fungal infections (i.e., mucormycosis and scedosporiosis), its clinical features, and the factors that must be taken into account to successfully treat them (early diagnosis, correction of predisposing factors, aggressive surgical debridement, and antifungal and adjunctive therapies).