Undergoing Bone Marrow Transplantation Research Articles

Characteristics and Outcomes of Adolescent and Young Adult (AYA) Patients with Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML): A Single-Center Retrospective Analysis

Characteristics and Outcomes of Adolescent and Young Adult (AYA) Patients with Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML): A Single-Center Retrospective Analysis

The role of palliative care in lung transplantation.

Lung transplantation confers meaningful benefit for patients by extending life and improving quality of life. Palliative care is a medical specialty that likewise aims to improve the quality of life of patients enduring serious illness and their caregivers. Yet, while transplant candidates and recipients face serious illness they rarely receive palliative care, even at end of life. While limited palliative care utilization is likely multifactorial, one key reason is a limited understanding of the specialty of palliative care and evidence for palliative interventions. In this review, we address this key barrier by discussing in depth what the specialty of palliative care is and provides to patients and their caregivers. We then discuss the growing evidence for palliative care interventions to improve quality of life and reduce symptom burdens in patients with malignancy including those undergoing bone marrow transplantation and patients with chronic organ failure. We then consider what palliative care needs exist across pre and post transplantation based on studies of palliative care needs of patients with end stage lung disease, studies of quality of life after lung transplantation, and limited studies of palliative care utilization pre and post lung transplantation. Finally, we consider different models of palliative care and discuss how palliative care might optimally be incorporated in lung transplantation using a longitudinal, integrated approach to palliative care.

Effect of Sacubitril/Valsartan on left ventricular longitudinal strain in patients with hematologic malignancies after bone marrow transplantation

Abstract Background and aims Chemotherapy is known for its potential adverse effects on myocardium. Optimal medical treatment for heart failure may reverse myocardial dysfunction in the early stages of toxicity development. We hypothesized that early initiation of treatment with sacubitril valsartan could prevent cardiotoxicity. Patients and methods 40 patients (mean age 45,3±13,1 years old, 23 male) with preserved ejection fraction, who suffered from hematologic malignancies (lymphoma, leukemia) and underwent bone marrow transplantation and were randomized to receive sacubitril/valsartan 24/26 mg bid daily or placebo. We measured at baseline, before transplantation, and after three months: i) Global Longitudinal Strain of left ventricle (LV) (GLS), ii) Left Ventricular Epicardial Strain (GLSepi), iii) Left Ventricular Endocardial Strain GLSendo), by speckle tracking imagind iv) Left Ventricular End Diastolic Volume, Left Ventricular End Systolic Volume and Left Ventricular Ejection Fraction (LVEF-Simpson's Method). Results The two treatment groups had similar age, sex atherosclerotic risk factors and cardiotoxic medication before and after bone marrow transplantation. Compared to baseline, patients treated with sacubitril/valsartan did not show a deterioration of LV GLS and GLSepi [(GLS = −20,2±3,1% vs −19,8±3,1%, p=0,551), (GLSepi = −17,9±2,8% vs −17,8±3,1%, p=0,855), (GLSendo = −23,02±3,6% vs −22,6±3,5%, p=0,572)], Conversely, patients treated with placebo group, presented a significant impairment of LV GLS and GLSepi [(GLS = −20,5±1,9% vs 18,5±2,3%, p=0,006, GLSepi = −18,1±1,5% vs −16,1±2,1%, p=0,003), (GLSendo = −23,4±2,2% vs −21,4±2,6%, p=0,008)] six months after bone marrow transplantation. No significant changes were found in LVEF after treatment with sacubitril/valsartan (57,9±5,6% vs 57,6±6,1%, p=0,733) or the placebo (60,1±5,6% vs 57,8±6,6%, p=0,166). However, in the sacubitril valsartan group, we noticed a significant reduction of left ventricular end diastolic and end-systolic volume [(103,1±27,01 ml vs 89,2±21,1 ml, p=0,012), (44,65±15,83 ml vs 36.4±8.3 ml, p=0,003), respectively]. Conclusions Treatment with sacubitril/valsartan prevented deterioration of myocardial deformation three months after bone marrow transplantation in patients with hematologic malignancies and preserved ejection fraction. Funding Acknowledgement Type of funding sources: None.

Hemoglobinuria in the Early Poststem-Cell-Transplant Period: Risk Factors and Association with Outcomes.

Information on risk factors of hemoglobinuria after hematopoietic stem-cell transplant (HSCT) and its association with AKI, mortality, and engraftment is limited. We conducted a retrospective cohort study on all consecutive adults that underwent HSCT from January 6, 1999, to November 6, 2017. The study included 6039 patients that underwent bone marrow transplantation (BMT), umbilical cord blood, and peripheral blood stem-cell transplantation (PBSCT). Early post-HSCT, AKI occurred in 393 (7%) patients, and 52 (0.9%) patients had post-HSCT hemoglobinuria. Post-HSCT hemoglobinuria was associated with graft type (BMT+Cord), underlying disease (lymphoma, acute leukemia), and fludarabine-based conditioning regimen. Post-HSCT hemoglobinuria was associated with early (48-72 hours) post-HSCT AKI. Graft type (BMT+Cord) was associated with AKI among patients with hemoglobinuria. AKI in patients with hemoglobinuria was associated with delayed platelet engraftment and delayed WBC engraftment but not 100-day mortality. Close monitoring is recommended in this patient group to facilitate a good engraftment outcome.

Preventing 30-day readmissions for patients with cancer: A root-cause analysis.

226 Background: The high rate of unplanned 30-day readmissions for patients with cancer is a significant driver of costs and a marker of poor quality. In this study, we analyzed 30-day readmissions at our cancer center to determine causality and propose key drivers to prevent them. Methods: Patients with known cancer who were readmitted to our academic medical center within 30 days of a previous hospitalization were identified in our electronic health record by a third-party algorithm. Among patients with hematologic malignancies, only those undergoing bone marrow transplant care were included. Surveys querying causality and preventability of the readmissions were sent to the patients’ attending oncologists. Electronic chart documentation of readmissions were reviewed by two investigators to assess causality and preventability of each readmission. Results were discussed in focus groups to determine key drivers to prevent 30-day readmissions. Results: 437 readmissions were identified between 9/1/19 and 8/31/20, and 182 readmissions with corresponding surveys completed by their oncologists were identified (Table). Based on survey responses, 30 (16%) of the 182 readmissions were preventable, whereas based on our review, 56 (31%) were preventable. The top three causes of the 56 preventable readmissions were: underutilized ambulatory care (43%), premature discharge (23%), and goals of care discordance (16%). For underutilized ambulatory care, the primary treatments provided during those readmissions were: procedures such as thoracentesis and paracentesis (42%), medication administration for pain or nausea (33%), and infusions or transfusions (25%). Notably, most of these patients either did not attempt to seek outpatient care (42%) or were not able to secure an ambulatory appointment (29%) prior to their readmission. Through focus group discussions, we found that the key drivers to reduce preventable 30-day readmissions at our institution are (1) timely access to outpatient pleural effusion and ascites management, (2) timely access to ambulatory management of cancer-related symptoms (e.g., pain, nausea, weakness), (3) increased systems-wide awareness and utility of avenues of urgent care, and (4) increased palliative care efforts in patients with readmissions. Conclusions: Systematic review of 30-day readmissions revealed a greater than anticipated portion of preventable readmissions. Root-cause analysis yielded key drivers to reduce 30-day readmissions at our cancer center.[Table: see text]

Characterization of Bone Marrow Progenitor Cell Uterine Engraftment and Transdifferentiation

Regeneration of uterine tissue is an important physiological process that allows for maintenance of fertility after menstruation or pregnancy. Stem cells, especially bone marrow-derived progenitors, play a crucial role in this regeneration. Here, we describe the conversion of DsRed-labeled bone marrow-derived stem cells (BMDSCs) into specific uterine cell types with both differentiated and stem cell properties in a murine model. Irradiated recipient mice underwent bone marrow transplant with DsRed-expressing BMDSCs and were analyzed for engraftment and differentiation of BMDSCs in the uterus after 2, 6, and 16weeks. Microarray and qRT-PCR analysis of bone marrow-derived cells obtained from the uterus identified upregulation of markers indicating a contribution to the population of stromal, epithelial, endothelial, and muscle cells, followed by a late expansion of epithelial cells. Other engrafted BMDSCs in the uterus were characterized by the continued expression of specific stem cell markers such as Sca1, CD44, CD146, and CD133, indicating the some BMDSCs remain as progenitor cells. BMDSCs established in recipient mice by the 16th week were sorted by flow cytometry using DsRed and progenitor cell surface markers. In vitro cell culture studies showed that single sorted cells had clonogenic properties. These results suggest that engrafted BMDSCs in the uterus had both a stem cell component and were able to differentiate into several differentiated cell types. The pool of progenitor cells likely continues to supply differentiated uterine cells in the process of uterine repair and remodeling.

Lung transplant after long-term veno-venous extracorporeal membrane oxygenation: a case report

BackgroundAlthough the number of patients who undergo extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation is increasing worldwide, there are few reports on lung transplantation after long-term ECMO (more than 1 month). We report a rare case of successful bilateral lung transplantation in a Japanese patient after 5 months of veno-venous (VV)-ECMO support.Case presentationA 27-year-old man who underwent bone marrow transplantation (BMTx) with fully matched human leukocyte antigen typing was diagnosed with bronchiolitis obliterans caused by chronic graft-versus-host disease 3 years after the BMTx. One year later, his respiratory condition had exacerbated, with carbon dioxide retention that required conventional mechanical ventilation. He was then deemed a suitable candidate for lung transplantation by a multidisciplinary transplantation selection committee. While waiting for donor lungs, his hypercapnia and acidosis became barely manageable under care with mechanical ventilation and ultimately he was switched to VV-ECMO. He remained on VV-ECMO for the next 5 months, during which period the circuit was switched nine times. In addition, sophisticated intensive care was required to manage multiple episodes of sepsis and coagulopathy. A suitable donor was identified 5 months later, and bilateral lung transplantation was initiated with continuous VV-ECMO. The procedure itself was extremely challenging owing to severe adhesions resulting from previous thoracotomy, inflammation, infection, and intrapulmonary hemorrhage. The operative time for the transplantation was about 19 h. Currently, at 2 years 8 months postoperatively, the patient is alive and well.ConclusionTransplant surgery in this patient was extremely challenging because of the presence of severe pleural adhesions and stiff native lungs secondary to hemorrhagic complications due to the prolonged ECMO support. Surgeons must recognize that lung transplantation after long-term ECMO bridging can be technically more complicated and challenging than shorter-term ECMO.

Blue Lunula Due to a Combination Chemotherapy Not Reported Before.

A dermatology consultation was sought for a 32-year-old lady admitted to the medical oncology ward. She was a known case of acute myeloid leukemia (AML) on chemotherapy. The cutaneous examination revealed blue pigmentation of the lunulae of all her fingernails, bilateral great toenails, and two adjacent toenails [Figures 1 and 2]. The oral cavity and other mucosae were within normal limits. The present nail changes occurred around 20 days ago, 10 days after she underwent bone marrow transplantation. These nail changes had been appearing 10 to 15 days after each chemotherapy cycle and would resolve partially until the next chemotherapy cycle [Figure 3a and 3b]. She had received five such cycles, comprising fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin (FLAG IDA) regimen) and azacytidine plus sorafenib.Figure 1: Blue pigmentation of the lunula of all fingernailsFigure 2: Blue pigmentation of the lunula of bilateral great toenails and two adjacent toenailsFigure 3: After 6 weeks, (a) near-complete resolution of the blue pigmentation of fingernails. (b) partial resolution of the pigmentation of toenailsBlue lunula can be caused by multiple chemotherapeutic drugs including hydroxyurea,[12] docetaxel, and combination chemotherapy (cyclophosphamide, vincristine, doxorubicin; 5-fluorouracil, doxorubicin, cyclophosphamide; vinblastine, dactinomycin, bleomycin).[3] The drugs implicated in our case have not been reported before. It is, however, difficult to ascribe it to a particular drug(s) in our patient. The mechanism by which this pigmentation occurs is not very clear; it is, however, postulated to be due to the toxic effect on the distal nail matrix basal cells or the pigment deposition in the nail matrix, or due to focal stimulation of melanocytes to produce melanin.[24] Apart from chemotherapeutic drugs, blue lunula can also be caused by zidovudine, phenolphthalein, and silver. It can also occur in Wilson’s disease, and as a normal finding in black races.[13] This case adds another chemotherapy combination as a cause of blue lunula. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

An innovation in stem cell harvesting: Heparin use

Background and ObjectivesStem cell transplantation is a growing treatment strategy for most malignant and non- malignant hematological diseases. Plerixafor and granulocyte colony stimulating factor (G-CSF) are usually used in mobilization regimens to increase the CD34+ cell count in the harvest. Heparin is a sulphated glycosaminoglycated polymer with 12−15 kDa mass. Heparin inhibits the CXCR4/SDF1 axis, as does plerixafor. In this study, our aim was to investigate the effect of using heparin on stem cell mobilization and harvesting. Materials and MethodsWe administered 5000 units of unfractioned heparin intravenously in 150 mL (mL) of isotonic sodium chloride solution, 15 min before the stem cell harvesting procedure to 141 patients who underwent bone marrow transplantation between the years of 2018 and 2019 at our Stem Cell Transplantation Unit. Thirty patients were included as a control group, and they were not given heparin. The study population included patients with multiple myeloma and lymphoma equally in each group. ResultsIn all patients hematopoeitic stem cells were successfully harvested in a single cycle of apheresis. In multiple myeloma patients who received heparin, the mean collected CD34+ cell number was 8 × 106/kg, and the mean CD34+ cell number yield was 12,555/μl. In the control group, the mean collected CD34+ cell number was 4,2 × 106/kg, and mean CD34+ cell number in yield was 492/μl. In lymphoma patients who received heparin, the mean collected CD34+ cell number was 6,8 × 106/kg, and the mean CD34+ cell number was 1421/μl. In the control group the mean collected CD34+ cell number was 4,3 × 106/kg, and the mean CD34+ cell number was 358/μl. The effect of heparin on the collected stem cell number in both myeloma and lymphoma patients was statistically significant (p < 0.01). ConclusionsOur results have shown that heparin increases harvested stem cell numbers significantly. Heparin may be a promising agent for stem cell harvesting.

IFNG-AS1 and MAF4 long non-coding RNAs are upregulated in acute leukemia patients who underwent bone marrow transplantation

Purpose of the studyAcute graft versus host disease (aGVHD) is an immune-mediated reaction that results in impaired immune and body function after allogeneic hematopoietic stem cell transplantation (allo-HSCT). lncRNAs have been discovered as particular T cell regulators, and alloreactive T cells have been known as a critical factor in aGVHD. As a result, we investigated the importance of lnc-MAF4 and IFNG-AS1 expression levels in aGVHD patients versus non-aGVHD patients. Material and MethodsThis research included 38 patients with hematological disorders who were undergoing primary allo-HSCT. Human identical siblings or unrelated donors were used to collect stem cell. Samples were taken within days 0, 7, 14, 28, and 52±8 after transplantation. The expression of lncRNA levels was measured using the QRT-PCR technique. And the data were analyzed using GraphPad Prism 6 ResultsOur data revealed that LncRNA MAF4 and INFG-AS1 expression levels in aGVHD were not significantly different compared to the non-GVHD group immediately after transplantation, nor at day 7 or 14. However, the aGVHD group showed an overt up-regulation of the two lncRNAs on samples taken at day 28 and 52±8 compared to non-GVHD patients. DiscussionSince the intracellular pathway of these lncRNAs shows a direct relationship with the IFNγ cytokine production resulting in differentiation to TH1 cells and inhibition of differentiation to TH2 cells, they can be, therefore, considered as suitable molecular candidates for the prediction of aGVHD in patients receiving HSCT.

Efficacy of Oral Cryotherapy in the Prevention of Oral Mucositis Associated with Cancer Chemotherapy: Systematic Review with Meta-Analysis and Trial Sequential Analysis.

Background: This review aimed to evaluate the efficacy of oral cryotherapy in the prevention of chemotherapy-induced oral mucositis using meta-analysis and trial sequential analysis, as well as to assess the quality of the results by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Methods: A comprehensive search of three databases including Medline, Embase and Central was performed to identify randomized controlled trials that used oral cryotherapy for the prevention of chemotherapy-induced oral mucositis. The primary outcome was the incidence of oral mucositis for trials employing oral cryotherapy as the intervention for the prevention of oral mucositis. The meta-analysis was performed using the random-effects model and random errors of the meta-analyses were detected by trial sequential analysis. Results: A total of 14 RCTs with 1577 participants were included in the present meta-analysis. Patients treated with oral cryotherapy were associated with a significantly lower risk of developing oral mucositis of any grade (risk ratio (RR), 0.67 (95% CI: 0.56–0.81, p < 0.05)). Findings from the subgroup analyses showed that oral cryotherapy significantly reduced the risk of oral mucositis in patients undergoing bone marrow transplantation (RR 0.69, CI: 0.54–0.89, p < 0.05) as well as chemotherapy (RR 0.66, CI: 0.58–0.75, p < 0.05). Findings from the trial sequential analysis suggested that the evidence on oral cryotherapy as a preventive intervention for oral mucositis in patients with solid malignancies receiving conventional chemotherapy was conclusive. Conclusion: Oral cryotherapy is effective in preventing oral mucositis in patients undergoing chemotherapy for the management of solid malignancies. The use of oral cryotherapy in preventing oral mucositis in bone marrow transplantation settings showed promising efficacy, but the evidence is not conclusive and requires more high-quality randomized controlled trials.

Validity and reliability of the Turkish version of the functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) quality of life questionnaire in patients undergoing bone marrow transplantation.

The Functional Assessment of Cancer Therapy-Bone Marrow Transplant Version 4 (FACT-BMT) is a widely used instrument to assess quality of life in individuals treated with bone marrow transplantation (BMT). Our aim was to determine the reliability and validity of the Turkish version of the FACT-BMT in patients undergoing BMT. Patients between the age of 20 and 65 years and who had undergone BMT at least 3 months before the study were included. Validity was determined using exploratory and confirmatory factor analysis. To determine convergent validity, the European Cancer Research and Treatment Organization Quality of Life Questionnaire-Cancer30 (EORTC QLQ-C30), the Brief Fatigue Inventory (BFI), and the Eastern Cooperative Oncology Group (ECOG) performance score were used. Cronbach's alpha, intra-class correlation coefficient (ICC), and item-total correlation (ITC) values were calculated to assess the reliability of the FACT-BMT. Totally, 114 patients (F/M: 47/67) treated with BMT (mean age: 49.50 ± 12.50 years) were included. Confirmatory and exploratory factor analysis revealed that the FACT-BMT and the Bone Marrow Transplantation Subscale (BMTS) had sufficient fit. The FACT-BMT was moderately to strongly correlated with the EORTC QLQ-C30, the BFI, and the ECOG performance score (p < 0.001). Cronbach's alpha and ICC values of the FACT-BMT were acceptable (0.925 and 0.956, respectively). The ITC values of each item of the FACT-BMT were also acceptable (ranged from 0.296 to 0.737). Patients undergoing autologous BMT had a significantly higher BMTS score than those undergoing allogeneic BMT (p < 0.05). The Turkish version of the FACT-BMT is valid, reliable, and sensitive to changes in quality of life in patients undergoing BMT.

Systematic review of gastrostomy complications and outcomes in pediatric cancer and bone marrow transplant

Nutrition support is essential in children with cancer, including those undergoing bone marrow transplant (BMT), to reduce the risk of malnutrition and associated deleterious outcomes. Enteral nutrition is more commonly provided via nasogastric than gastrostomy tubes because of safety concerns with the latter in immunocompromised children. This systematic review investigated the incidence and type of complications and outcomes in pediatric cancer patients fed by gastrostomy. Databases were searched for randomized and observational studies investigating the use of any gastrostomy device in children aged <18 years with any cancer diagnosis, including those undergoing BMT. Five cohort and 11 case series studies were included. Owing to clinical heterogeneity, meta-analyses were not performed. Quality of evidence varied, with five studies judged at serious risk of bias and poor quality; however, the remaining 11 were considered to range from moderate to good quality. Across studies, 54.6% of children developed one or more complications, of which 76.6% were classified as minor, 23.4% major. The most frequent complications included inflammation (52% of episodes), infection (42.1%), leakage (22.3%), and granuloma (21%). Evidence regarding infection rates in cancer/BMT patients compared with other disease states was inconclusive. Gastrostomy feeding was associated with improvement or stabilization of nutrition status in 77%-92.7% of children. Gastrostomy feeding in this population is relatively safe and effective in stabilizing or improving nutrition status throughout treatment. Complications are frequent but mostly minor. Placement requires careful consideration of the complications, benefits, nutrition risk and status at diagnosis, and quality of life.

Dose individualization of intravenous busulfan in pediatric patients undergoing bone marrow transplantation: impact and in vitro evaluation of infusion lag-time.

To apply therapeutic drug monitoring and dose-individualization of intravenous Busulfan to paediatric patients and evaluate the impact of syringe-pump induced Busulfan infusion lag-time after in vitro estimation. 76 children and adolescents were administered 2 h intravenous Busulfan infusion every 6 h (16 doses). Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying Non-Compartmental Analysis. In vivo infusion lag-time was simulated in vitro and used to evaluate its impact on AUC estimation. Mean (%CV) Busulfan AUC, Cmax, clearance and t1/2 for pediatric population were found 962.3 μm × min (33.1), 0.95 mg/L (41.4), 0.27 L/h/kg (33.3), 2.2 h (27.8), respectively. TDM applied to 76 children revealed 6 (7.9%) being above and 25 (32.9%) below therapeutic-range (AUC: 900-1350 μm × min). After dose correction, all patients were measured below toxic levels (AUC < 1500 μm × min), no patient below 900 μm × min. Incorporation of infusion lag-time revealed lower AUCs with 17.1% more patients and 23.1% more younger patients, with body weight <16 kg, being below the therapeutic-range. TDM, applied successfully to 76 children, confirmed the need for Busulfan dose-individualization in paediatric patients. Infusion lag-time was proved clinically significant for younger, low body-weight patients and those close to the lower therapeutic-range limit.

The importance of tears stability in SARS-CoV-2 transmission: COVID-19 prevalance in dry eye patients

ObjectiveTo investigate whether dry eye disease (DED) is a risk factor for COVID-19.MethodIn this retrospective cohort study, patients who were diagnosed with DED by an ophthalmologist and whose Schirmer test was less than 5 mm were identified. Patients who missed follow-up examinations, patients with malignancy, Human Immunodeficiency Virus patients and patients having undergone bone marrow transplantation were excluded. Among the DED patients, patients with positive SARS-CoV-2 PCR tests were identified on October 11, 2020. Subsequently, patients were divided into four age groups (25–49; 50–64; 65–79; and 80+). The COVID-19 prevalence per 100,000 people was determined for each age group, and risk analysis was performed by comparing this with the general population in Turkey.ResultsIn total, 10,023 DED patients were identified and included in the study. Among these, the PCR test was positive in 359 patients. The COVID-19 prevalence per 100,000 population in DED patients was calculated as 3581.7, while according to the Ministry of Health data, it was 524.7 in the general Turkish population. The odds ratio of DED patients versus the general population was 6.62 (P < 0.001) (7.66 in the 25–49 group; 6.59 in the 50–64 group; 6.23 in the 65–79 group; and 7.24 in the 80+ age group).ConclusionsThe present study showed a high COVID-19 prevalence in DED patients compared to the general population. These findings support the concept that the ocular surface may be a gateway for SARS-CoV-2 and that the tear film is important part of the immune system.

Durable Remission after Salvage Chemotherapy with Combining Bortezomib and Vorinostat Followed By CD19 CAR-T Therapy in a Patient with MLL-Rearranged ALL after Early Relapse Post Allogeneic Hematopoietic Stem Cell Transplantation

Durable Remission after Salvage Chemotherapy with Combining Bortezomib and Vorinostat Followed By CD19 CAR-T Therapy in a Patient with MLL-Rearranged ALL after Early Relapse Post Allogeneic Hematopoietic Stem Cell Transplantation

Long-Term Follow-up of Patients with Chronic Granulomatous Disease Receiving Bone Marrow Transplantation Using Immunosuppressive Conditioning Regimen

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder caused by a mutation of one of 5 subunits of the nicotinamide adenine dinucleotide phosphate oxidase and resulting in the impairment of microbial activity of phagocytes. The disease is characterized by recurrent and severe infections of bacterial and fungal origin and a high rate of inflammatory bowel disease. Recently, the prognosis of CGD patients has been improved by the earlier diagnosis, management of infectious complications, and application of allogeneic hematopoietic stem cell transplantation (HSCT). However, allogeneic HSCT in patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality.In Hiroshima University Hospital, 38 patients with CGD underwent bone marrow transplantation (BMT) with immunosuppressive conditioning regimen since 2004. All patients with CGD suffered from recurrent and severe infections and/or intractable inflammatory bowel disease. The age of 38 patients at the time of BMT was 2 to 40 years. Six patients over 15 years old were died from GVHD and transplant-related complications.In this study we report our single-center results of long-term follow-up of 11 survivals with CGD who underwent BMT from 2004 to 2009. All 11 patients with CGD were 91-phox deficiency. The age of 11 patients at the time receiving BMT was 4 to 28 years. Seven patients were over 20 years of age, and 4 patients were 7 to 9 years, respectively. The conditioning regimen consisted of fludarabine, cyclophosphamide, 3 to 3.6 Gy of total body irradiation, melpharan, and/or antithymoglobulin. Bone marrow cells were obtained from 5 HLA-matched, 1 -mismatched related, 4 HLA-matched and 1 -mismatched unrelated donors, respectively. Acute GVHD of grade I - II developed in 4 of 11 patients. Three cases occurred in patients given transplants from unrelated donors, one from HLA-matched elder sister. All patients have exhibited 100% of complete myeloid donor chimerism and cleared all infectious and inflammatory complications. Ten of 11 patients have shown 100% of performance status without any medical supports. Four adolescent patients have been to junioror senior high school students with complete cure. Four adulthood patients fathered children 3 to 6 years after BMT. The wives of 3 patients naturally conceived, implying the successful preservation of patients' fertility. One has a child by the artificial fertilization using his frozen sperm before BMT. Only a patient who underwent BMT from HLA-matched elder sister has been suffering from chronic GVHD followed by cryptogenic organizing pneumonia. He has engaged in deskwork with 90% of Karnofsky performance status. These results suggest that BMT using immunosuppressive conditioning regimen is safe and effective for the successful transplantation followed by the improvement of quality of life for CGD patients. DisclosuresNo relevant conflicts of interest to declare.

Non-Transferrin-Bound Iron Serves As Iron Source for Aspergillus Fumigatus Growth

The appearance of non-transferrin-bound iron (NTBI) as a consequence of saturated transferrin (Tf) levels in patients undergoing bone marrow transplantation is multifactorial. Chemotherapy-induced tissue damage on the one hand side, causing iron release from apoptotic cells, and chemotherapy-induced bone marrow suppression leading to diminished iron consumption for erythropoiesis on the other hand side as well as chronic transfusion therapy for anemia are among the major contributing factors for iron overload. The existence of NTBI is known to be associated with therapy-related complications, including infections. Nowadays invasive aspergillosis is, in spite of antifungal prophylaxis, still a serious problem with mortality rates ranging up to 70%-90%. The possible interaction of invasive aspergillosis and iron metabolism has been reported.In this study we specifically assessed the role of NTBI on the in vitro growth of Aspergillus fumigatus (A. fumigatus ; ATCC46645) in the presence of plasma. Therefore the growth of A. fumigatus in cultures containing 10% human plasma and various NTBI levels was explored. This assay revealed that the presence of NTBI, but not high Tf-saturation without NTBI, led to a considerable growth advantage. These findings suppose that A. fumigatus growth depends on the presence of NTBI rather than total iron availability. Correspondingly, addition of sufficient amounts of human apo-Tf to eliminate NTBI prevented A. fumigatus growth. These results clearly show that NTBI only exists and promotes A. fumigatus growth if Tf is saturated and disproves the widely believed notion that that Aspergillus utilizes iron from Tf. In contrast to apo-Tf, iron chelators (e.g. deferiprone or deferoxamine) tested in our in vitro system stimulated, rather than inhibited A. fumigatus growth, despite elimination of NTBI.To better understand the underlying molecular mechanisms, different A. fumigatus mutant strains with defects in iron acquisition systems are under investigation. Preliminary data indicate that the uptake of NTBI is not solely dependent on siderophore-mediated iron uptake.In conclusion our findings clearly indicate that NTBI is relevant for fungal growth, at least in vitro in the presence of plasma. Further ongoing experiments aim to clarify whether different clinical A. fumigatus isolates differ in their ability to utilize Tf- bound iron and NTBI. In addition, plasma samples from patients, who had undergone bone marrow transplantation, with already known levels of NTBI, should help to further corroborate the relevance of NTBI for fungal growth in vivo . DisclosuresPlatzbecker:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding.

FLT3 ITD AML Outcomes Are Impacted By Exposure to One Cycle of Cytarabine Based Consolidation, Pre- and Post-Transplant TKI Therapy, and Presence of Minimal Residual Disease (MRD) Prior to Allogeneic Blood or Marrow Transplant

Background:FLT3 ITD AML is associated with high rates of relapse and short relapse free survival. Prognosis after relapse is extremely poor, making optimization of initial therapy for this group of patients important. Most data now suggest allogeneic transplant should be the standard consolidation for FLT3 ITD AML. Although peri-transplant tyrosine kinase inhibitor (TKI) use is common, there is no consensus on the best way to incorporate TKIs into the management of these patients. A comprehensive review of treatment outcomes is needed to determine which strategies reduce the risk of relapse and prolong survival.Methods:We conducted a retrospective chart review for 112 patients with FLT3 ITD mutations seen at JHH between 2005 and 2016 who underwent bone marrow transplantation to collect demographic, diagnostic, transplant and survival data. Differences in the distribution of demographic, clinical, and biological characteristics were analyzed for significance using Fisher's exact test. Consolidation was defined as any cytarabine-based regimen after remission induction therapy. MRD positivity included the presence of >0 to 5% abnormal blasts by morphology or flow cytometry and/or persistence of genetic abnormalities (cytogenetics, mutation panels) prior to transplant. Overall survival (OS) was defined as the time interval from date of transplant to date of death from any cause or to last follow up visit. Relapse free survival (RFS) was defined as the time interval from date of transplant to date of relapse or death from any cause. Survival was censored at 2 years post-transplant. Time was censored at the last follow-up visit if relapse or death were not observed. Survival estimates were calculated using Kaplan-Meier method and comparison of survival distributions were done using log-rank test. TKI included are quizartinib, sorafenib, and gilteritinib.Results:Patient characteristics are summarized in Table 1.Outcomes based on disease characteristics including NPM1 status, allelic ratio and cytogenetics are listed in Table 2. Patients with NPM1 mutations had improved RFS (HR=0.4165, p=0.0193). Patients with no detectable MRD prior to transplant have improved RFS (HR=0.4394, p=0.0023) and OS (HR=0.5526, p=0.0437).Outcomes related to treatment strategies are also summarized in Table 2. Patients with at least 1 cycle of post remission consolidation had lower rates of MRD (p=0.0046) (Table 3), and improved RFS (HR=0.5191, p=0.0228) and OS (HR=0.4728, p=0.0143) (Figure 2). Patients who received consolidation and pre-transplant TKI had the best outcomes (Figure 1). In the absence of consolidation, pre-transplant TKI usage was associated with longer RFS (median 1.819 years versus 0.8548 years, p = 0.2105) and OS (median 1.995 years versus 1.249 years, p=0.4384) compared to those with no pre-transplant TKI use. Patients who received either consolidation or pre-transplant TKI had similar outcomes. Non-myeloablative conditioning regimens trended toward favorable outcomes over myeloablative regimens despite older patients and lower rates of NPM1 mutations (HR=.6358, p=0.1346 for OS, HR=0.6471, p=0.1231 for RFS). There was no difference in OS or RFS between matched and haploidentical donors. Post-transplant TKI use improves RFS (HR=0.5503, p=0.0339) and OS for all patients (HR=0.4679, p=0.0102). For patients who had MRD prior to transplant, TKI use post-transplant was associated with median RFS of 1.499 years versus 0.7425 years for those who did not use post-transplant TKI (Figure 2). Post-transplant TKI use also improved OS (HR=0.3737, p =0.0308) for patients without MRD prior to transplant.Discussion:Remission status at time of transplant is key to outcomes. Consolidation, as well as use of TKI pre- and post-transplant are associated with favorable outcomes. Although patients who were given consolidation had more favorable outcomes, it is unclear if patient characteristics (higher NPM1 %, lower AR>50%, and younger age) confounded their outcomes. Matched and haploidentical donors confer similar outcomes. This data supports treatment of FLT3 ITD AML patients to include induction, 1 cycle of post remission consolidation, TKI use prior to transplant, and transplant with post-transplant TKI maintenance. [Display omitted] DisclosuresSmith:Celgene: Consultancy; Curis: Consultancy; Ariad/Takeda: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Swinnen:Genentech: Consultancy; Pharmacyclics: Consultancy. Levis:Astellas Pharma Us: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; FujiFilm: Research Funding; Daiichi Sankyo, Inc.: Consultancy, Honoraria.

Isolated Myeloperoxidase Expression in Pediatric B/Myeloid Mixed Phenotype Acute Leukemia Is Associated with Improved Survival Using ALL-Only Regimens

Background: Mixed phenotype acute leukemia (MPAL) represents a heterogeneous group of leukemias accounting for 2-5% of all newly diagnosed acute leukemias. Diagnostic criteria for mixed phenotype MPAL have evolved over time, with the World Health Organization (WHO) 2016 criteria now being recognized as the more definitive standard. According to WHO classification, isolated expression of myeloperoxidase (MPO) allows for myeloid lineage assignment in patients with an otherwise typical B-acute lymphoblastic leukemia (B-ALL) phenotype, thus meeting criteria for MPAL B/myeloid. Our goal was to determine if there were differences in treatment and survival between this group of patients, classified as MPAL B/myeloid isoMPO, and other MPAL patients.Methods: Data was obtained through a retrospective chart review of pediatric MPAL patients treated between 2001 and 2016 at Children's Healthcare of Atlanta. Cases were identified through our institutional tumor registry and pathology department flow cytometry database. Cases were eligible if the patients were between ages of 1 and 21 years at diagnosis and the leukemia met the WHO 2016 MPAL criteria. We excluded therapy related cases, non-myeloid cases (rare B/T subtype), and cases with a t(9;22) translocation. Data were extracted from clinical records for patient, disease and treatment related variables. All flow cytometry reports were reviewed by study hematopathologists. Cases were divided into two groups - MPAL B/Myeloid isoMPO and other MPAL cases. MPAL B/myeloid cases were classified as MPAL B/Myeloid isoMPO if there was a single B-lineage blast population expressing MPO as the only WHO MPAL myeloid marker. An event was defined as treatment failure requiring therapy change prior to end of induction (EOI), induction failure, induction death, remission death, or relapse. Event-free survival (EFS) and overall survival (OS) were calculated using Kaplan-Meier survival curves. Groups were compared using the log rank test. Chi-squared test was used for sampling distribution analyses.Results: Of the 35 MPAL cases included in our study, 21 (60%) met criteria for MPAL B/myeloid isoMPO. 20 of these patients were treated with ALL chemotherapy alone. One patient underwent bone marrow transplantation (BMT) due to a low DNA index. None of these patients were switched to myeloid therapy during their treatment course. The other 14 MPAL cases consisted of 5 MPAL B/myeloid (non-isolated MPO), 7 MPAL T/myeloid and 2 MPAL patients with t(v;11q23); MLL rearranged. Of these 14 cases, 10 were treated at least in part with myeloid chemotherapy and 7 proceeded to BMT. 6 of 10 patients in this group who started with ALL induction were switched over to AML therapy, with 3 being changed prior to EOI due to treatment failure. Despite these treatment differences, those with MPAL B/myeloid isoMPO had better outcomes. 3-year EFS was significantly higher at 84% for the MPAL B/myeloid isoMPO group compared to 57% in the other MPAL group (p=0.027 log rank test, Fig 1A). 3-year overall survival was 100% and 68%, respectively (p=0.083 log rank test, Fig 1B).Conclusion: There continues to be no consensus as to how to treat MPAL and the changing definition of MPAL has contributed to the difficulty in treating this rare and heterogeneous disease. While the WHO 2016 criteria have simplified the definition of MPAL, it has created a group of patients as shown here, that may be falsely categorized as MPAL. Our results suggest that MPAL B/myeloid isoMPO patients behave clinically like typical B-ALL patients, and should be treated as such. Consideration should be given to redefining the current MPAL WHO criteria to explicitly exclude these cases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.