Upfront Hematopoietic Stem Cell Transplantation Research Articles

Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome.

Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).

Effect of upfront HSCT on patients with T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma at high risk of relapse: Single center retrospective observational study on minority rich population.

e19014 Background: T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/TLBL) is an aggressive neoplasm of lymphoid tissue. It comprises 15-25% of all cases of ALL. Given the rarity of the disease, data regarding its optimal management remains limited. Hematopoietic stem cell transplant (HSCT) is usually recommended for patients with T-ALL in second or later complete remission (CR). The data on upfront use of HSCT in ethnic minority rich population is rare. Methods: We conducted a single-center retrospective observational study in patients diagnosed with T-ALL who were followed at our center from 2004-2022. We collected and analyzed data on demographics, race, treatment regimens including HSCT, and survival outcomes. Overall survival (OS) was compared using the Kaplan-Meier curve and log-rank test. P-values < 0.05 were considered as statistically significant. Cox proportional hazards regression model was used for the statistical analysis of prognostic factors and analyses were performed using R software. Results: We identified 59 unique records with this diagnosis (78% males, 22% females). The median age at diagnosis was 20 years (range 1-48 years). Sixty one percent were ethnic minority (32% African American, 29% Hispanic), 17% were white, and 14% were of other ethnicities. Patients were treated at diagnosis with conventional chemotherapy regimens. Our transplant cohort had 10 patients, eight of whom received an allogeneic graft (2 matched related donor, 4 matched unrelated, 1 haploidentical, and 1 cord blood transplant) and 2 an autologous graft. Eight out of 10 patients received HSCT in CR1, 1/10 patient in CR2 (remission data-not available 1/10 patient). The OS of patients transplanted in CR1 did not differ significantly from the patients not receiving HSCT in CR1 (p = 0.5) with OS rates at 12, 24, and 36 months of 87.5% vs 83%, 75% vs 77%, 60%vs 77% respectively. However in the patients who eventually relapsed (n = 13), OS was significantly higher in patients receiving upfront HSCT in CR1 (n = 8) vs patients receiving chemotherapy only (p = 0.013). Furthermore, the OS from the transplant date compared between patients of age (at the time of transplant) < / = 20 years vs > 20 years didn’t differ significantly with p values of 0.29. Conclusions: Our study in T-ALL patients from a mainly minority urban population in NYC showed OS was not significantly different when transplant patients were compared to patients receiving only chemotherapy. For patients who eventually relapsed, the OS for patients receiving upfront HSCT was significantly higher than patients receiving chemotherapy only. Hence, patients at high risk of relapse might benefit from upfront HSCT. However, due to small sample size, evaluation of the effects of confounders was limited in our study.

Progress of Hematopoietic Stem Cell Transplantation and Radiotherapy in the Treatment of Extranodal NK/T Cell Lymphoma.

Extranodal Natural Killer/T-cell lymphoma (ENKTL) is an extremely rare type of lymphoma which is highly lethal. It mainly affects the midline area unfolding as a necrotic granulomatous and extremely disfiguring lesion. There are two subtypes of (NKTL); the most common one is nasal which appears in the nasal cavity including the nasopharynx, oropharynx, parts of the aero digestive tract and Waldeyer’s ring. While the other rarer subtype, appears in sites like the skin, testis, gastrointestinal tract, salivary glands and muscle. ENKTL is popular for the expression of multidrug resistance-associated P-glycoprotein, which not only plays the main role at exporting many antitumor agents outside tumor cells, but also makes the disease hard to treat. It is commonly associated with Epstein-Barr virus (EBV) infection and commonly occurs in Asian populations. However, there is no single unified consensus yet as to what is the standardized treatment for ENKTL. Radiotherapy alone treatment, has been considered as a first-line therapy for localized ENKTL, which later on was found to be insufficient for improving survival rates. Thus, the combination of chemotherapy and radiotherapy has been recommended as a therapeutic modality for localized ENKTL. Several combination modalities of radiotherapy and chemotherapy have been advised in clinical practice including concurrent, sequential and sandwich chemo radiotherapy. For the best treatment outcome, only patients with localized nasal ENKTL and low risk of treatment failure are eligible for radiotherapy. Both radiotherapy and hematopoietic stem cell transplantation (HSCT) have been used as treatment modalities in ENKTL patients. Upfront HSCT was performed for ENKTL, but it was associated with a very poor prognosis even for the limited-stage disease. The evidence supporting the use of HSCT to treat ENKTL was derived from the results of a series of phase 1 and 2 trials along with retrospective studies. The end result was a unified consensus that consolidative HSCT is not necessary in patients with newly diagnosed localized ENKTL who achieved complete response after treatment with any of the modern chemo radiotherapy regimens. Hence, HSCT is solely advised for advanced and relapsed NKTL. The main debate remains over which HSCT is the most suitable for patients with newly diagnosed advanced NKTL and relapsed NKTL.

The Role of Upfront Hematopoietic Stem Cell Transplantation (HSCT) in Peripheral T-Cell Lymphoma (PTCL) Patients in Complete Remission (CR) with a Special Focus on Nodal PTCL: Report from the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE), a Prospective Multicenter Cohort Study

The Role of Upfront Hematopoietic Stem Cell Transplantation (HSCT) in Peripheral T-Cell Lymphoma (PTCL) Patients in Complete Remission (CR) with a Special Focus on Nodal PTCL: Report from the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE), a Prospective Multicenter Cohort Study

Optimizing conditioning regimen with low-dose irradiation or busulfan enables the outcome of transplantation from a 6–7/8 HLA-matched donor comparable to that from an 8/8 HLA-matched unrelated donor in severe aplastic anemia patients under 40 years

With the dramatic improvements in outcomes following alternative donor hematopoietic stem cell transplantation (HSCT), interest in the use of alternative donors in severe aplastic anemia (SAA) is increasing. We conducted a multicenter prospective study to explore the efficiency and safety of upfront HSCT from a 6-8/8 HLA-matched unrelated donor (MUD) or 6-7/8 HLA-matched related donor (MRD) in acquired SAA patients under 40 years. Between August 2014 and July 2017, 115 patients were enrolled, including 48 (41.7%) patients receiving grafts from an 8/8 MUD, 25 (21.7%) from a 6-7/8 MRD, and 42 (36.5%) from a 6-7/8 MUD. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was higher in the 6-7/8 MUD group than in the 8/8 MUD group (42.9% vs. 12.8%, P=0.001). The corresponding incidence in the 6-7/8 MRD group was comparable to that in the 8/8 MUD group (21.7% vs. 12.8%, P=0.332). There was no significant difference in the incidence of chronic GVHD (24.3%, 13.6%, and 17.9%, P=0.676), graft failure (2.4%, 8.0%, and 6.3%, P=0.551), overall survival (85.7%, 96.0%, and 87.5%, P=0.424), and failure-free survival (83.3%, 88.0%, and 83.3%, P=0.885) among the three groups (6-7/8 MUD, 6-7/8 MRD, and 8/8 MUD). In multivariate analysis, conditioning regimen without low-dose irradiation or busulfan was associated with an inferior failure-free survival (HR=2.973, P=0.042). In conclusion, after an intensified conditioning regimen with additional low-dose irradiation or busulfan, the outcome of HSCT from a 6-7/8 MRD or 6-7/8 MUD is comparable to that from an 8/8 MUD.

Allogenic Stem Cell Transplantation Abrogates Negative Impact on Outcome of AML Patients with KMT2A Partial Tandem Duplication.

Simple SummaryAcute myeloid leukemia refers to a large group of diseases that can be further defined by their genetic modifications. A specific alteration called KMT2A-PTD has been previously found in 5% of newly diagnosed acute myeloid leukemia cases. This work aimed to provide specific insight into outcomes of this specific disease and identify factors that may influence survival. Integrating KMT2A-PTD in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In conclusion, our results emphasize that KMT2A-PTD should be considered as a potential adverse prognostic factor.Recently, a new subset of acute myeloid leukemia (AML) presenting a direct partial tandem duplication (PTD) of the KMT2A gene was described. The consequences of this alteration in terms of outcome and response to treatment remain unclear. We analyzed retrospectively a cohort of KMT2A-PTD-mutated patients with newly diagnosed AML. With a median follow-up of 3.6 years, the median overall survival was 12.1 months. KMT2A-PTD-mutated patients were highly enriched in mutations affecting epigenetic actors and the RTK/RAS signaling pathway. Integrating KMT2A-PTD in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In the multivariate analysis, only HSCT at any time in complete remission (HR = 2.35; p = 0.034) and FLT3-ITD status (HR = 0.29; p = 0.014) were independent variables associated with overall survival, whereas age was not. In conclusion, our results emphasize that KMT2A-PTD should be considered as a potential adverse prognostic factor. However, as KMT2A-PTD-mutated patients are usually considered an intermediate risk group, upfront HSCT should be considered in first CR due to the high relapse rate observed in this subset of patients.

Outcome after hematopoietic stem cell transplantation in patients with extranodal natural killer/T-Cell lymphoma, nasal type: A French study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing hematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L-asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs. 26%, p=.12 and OS: 52% vs. 53%, p=.74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p=.031 and PFS: HR: 5.231 [1.625; 16.838], p=.006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design.

Indication and benefit of upfront hematopoietic stem cell transplantation for T-cell lymphoblastic lymphoma in the era of ALL-type induction therapies

Since the introduction of leukemia-type induction therapies for T-cell lymphoblastic lymphoma (T-LBL), improvements in the long-term outcomes of T-LBL have been reported. However, indications for and the appropriate timing of hematopoietic stem cell transplantation (HSCT) have not yet been established. Therefore, we performed a multicenter retrospective cohort study of patients with T-LBL treated using leukemia-type initial therapies to compare the outcomes after HSCT at different disease stages. We enrolled 21 patients with T-LBL from a total of 11 centers, and all patients received hyper-CVAD as a leukemia-type initial regimen. HSCT was performed during the CR1/PR1 (standard disease) stage in 11 patients, while it was completed at a later or non-remission (advanced disease) stage in 10 patients. Following HSCT, the overall survival rate was significantly greater in standard disease than in advanced-disease patients (79.5% vs. 30.0% at 5 years; hazard ratio (HR) 5.97; p = 0.03), with trend to the lower incidence of relapse in the former group (27.3% vs. 60.0% at 5 years; HR 2.29; p = 0.19). A prognostic difference was not detected between cases treated with allogeneic and autologous HSCTs. Our study suggests that frontline HSCT may be a feasible treatment option for T-LBL, even in the era of leukemia-type initial therapy.

Up-front Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia Patients Aged 65-75

Up-front Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia Patients Aged 65-75

Treosulfan Conditioning for Allogeneic Transplantation in Multiple Myeloma Improved Overall Survival in Upfront Hematopoietic Stem Cell Transplantation — a Large Retrospective Study By the Chronic Malignancies Working Party of the EBMT

BackgroundAllogeneic hematopoietic stem cell transplantation (AlloSCT) for treatment of multiple myeloma (MM) is controversial mainly due to high non-relapse mortality (NRM) with myeloablative conditioning. However, AlloSCT is probably the only treatment that result in cure of a small fraction of patients. Treosulfan is a prodrug of a bifunctional alkylating agent which has both myelotoxic and immunosuppressive properties. Conditioning regimes with treosulfan have been tried in various hematologic neoplasia such as AML and MDS indicating low NRM and increased progression free survival (PFS). Previous studies on use of treosulfan condition in AlloSCT for MM indicated feasibility, stable engraftment and low NRM. In the present study we have analysed the results of low and high dose treosulfan respectively on OS, RFS, relapse incidence and NRM as well as results of Treosulfan conditioning compared to non-Treosulfan reduced intensity conditioning (RIC) and non-Treosulfan myeloablative conditioning (MAC).Patients and MethodsWe conducted a retrospective analysis of 4544 patients with MM undergoing AlloSCT 2008-2016 reported to the EBMT data registry. Out of 537 patients receiving Treosulfan based conditioning the impact of dose could be analysed in 441. Three hundred and twenty-seven patients received a total dose of >36g/m2 and 114 <=36g/m2.These patients were compared to 2830 patients receiving RIC, and 1177 receiving MAC. 1103 patients were transplanted upfront and 3441 patients in later lines following relapse/progression. Patient characteristics shown in table 1.ResultsThe 5-year OS in upfront Treosulfan conditioned patients was 62%, which was significantly superior to both non-Treo RIC and MAC patients respectively, apparently due to a tendency for lower NRM (10%) albeit a higher relapse rate (Table 2). Patients in later lines of conditioning had either low NRM (3rd line) or no significant difference (2nd line) (Table 2). Heterogeneity in the material makes it difficult to interpret results in the patients transplanted late in the course of the disease.A higher total treosulfan dose, >36g/m2, showed a tendency for improved OS and RFS compared to the lower dose treosulfan as well as RIC and MAC (table 2) respectively.In multivariate analysis of upfront transplanted patients, with a model adjusted for ISS score at diagnosis, age, Karnofsky score, response at AlloSCT, interval between diagnosis and transplant, donor type and donor - patient sex match, treosulfan and RIC retained significance for OS, HR 0.57 (P=0.006) and RFS, HR 0.65 (P=<0.005). For 2nd line Treosulfan RFS was significantly worse, HR 1.46 (P=<0.005) while there was no significant difference for OS between conditioning regimes in 2nd or for OS and RFS in 3rd line (table 2). The factors associated with most inferior OS in upfront line of conditioning was Karnofsky <90 and ISS score III at diagnosis. ISS score III at diagnosis was also associated with inferior OS also in 2nd and 3rd line (Table 2) A less then partial response at AlloSCT was consistently a factor associated with inferior RFS regardless of line of treatment with HR 1.67 (P=<0.005) in upfront, HR 1,63 (P=<0.005) in 2nd line and HR 1,66 (P=<0.005) for 3rd line or later (Table 2)In multivariate analysis of treosulfan based conditioning regimes, upfront line of conditioning was superior for OS, PFS and relapse as expected (Table 3). Notably was an increased hazard ratio for donor-patient sex match other than female to male in OS, PFS as well as relapse, HR 1.64 (P=0.02), HR 1.66 (P=0.004) and HR 1.83 (P=0.003) respectively (Table 3).ConclusionsConditioning upfront with Treosulfan containing regimens for AlloSCT in multiple myeloma, is associated with a superior overall survival and a low NRM, however with a slightly higher relapse rate compared to other regimens. A higher dose > 36g/m2 tends to further improve OS, RFS and relapse rate without increasing NRM. The better results of Treo conditioning in female to male transplants as compared to other sex combinations and in contrast to MAC transplants may be due to the overall lower NRM with treosulfan, thus utilizing the GVM more effectively as indicated by the trend for lower relapse rate. In conclusion, Treosulfan containing regimens appear to be of value in upfront AlloSCT. Prospective studies on Treosulfan conditioning are warranted to further define the best dosing in MM AlloSCT. [Display omitted] DisclosuresNiederwieser:Miltenyi: Speakers Bureau; Novartis: Research Funding. Beelen:Medac: Consultancy, Other: Travel Support. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Garderet:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Kroeger:Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding.

Updated Guidelines for the Treatment of Acquired Aplastic Anemia in Children.

This review aimed to provide updated guidelines for the management of children with acquired aplastic anemia (AA), particularly focusing on hematopoietic stem cell transplantation (HSCT). Failure-free survival for children with aplastic anemia has been shown to be better after bone marrow transplantation (BMT) from matched or one-locus mismatched related donors (MRD/1MMRD) than after immunosuppressive therapy (IST). A combination of the absence of minor paroxysmal nocturnal hemoglobinuria clones and short telomere length was identified as a strong predictor of a poor response to IST. Upfront HSCT from matched unrelated donors (MUD) and MRD was recently demonstrated to have comparable outcomes. Moreover, unrelated cord blood transplantation (UCBT) and haploidentical HSCT have shown promising outcomes, and the fludarabine/melphalan-based regimen has resulted in excellent survival without poor graft function. BMT from MRD/1MMRD is the treatment of choice. When a MRD/1MMRD is not available, upfront BMT from a MUD should be considered for patients with only a slim chance of responding to IST. UCBT and haploidentical HSCT are promising options. This updated treatment algorithm should improve overall outcomes for children with AA.

Redefining the role of etoposide in first-line treatment of peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) have an aggressive biological course and poor clinical outcomes. Despite producing somewhat less-than-satisfactory results, the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remains the de facto standard in PTCL treatment. Addition of etoposide to CHOP backbone to overcome such unsatisfactory results has yielded contradictory information. We aimed to thoroughly analyze the impact of incorporating etoposide into first-line treatment. Using merged data from the Korean National Health Insurance Service and National Cancer Registry, a total of 1933 patients (median age, 58 years) were evaluated for clinical characteristics and treatment outcomes. Thirty-eight percent (n = 748) of the 1933 patients received CHOP or CHOP-like regimen, 35.1% (n = 678) received CHOP-like regimen plus etoposide, 5.9% (n = 113) received other backbone chemotherapy plus etoposide, and 20.3% (394) received other treatments in the first-line setting. When we divided the patients into 3 groups according to regimen (group 1, CHOP or CHOP-like regimen; group 2, CHOP or CHOP-like regimen plus etoposide; group 3, all others), group 1 was associated with longest progression-free survival (PFS; P < .001) and overall survival (OS; P < .001). This lack of benefit with etoposide addition was observed across different PTCL subtypes and age groups. Adding etoposide led to longer hospitalizations and cytopenias requiring more transfusion. Upfront hematopoietic stem-cell transplantation led to better OS. Addition of etoposide to CHOP-like regimens does not result in better PFS or OS for patients with PTCL. Overall, Asian patients with PTCL do not benefit from chemotherapy intensification of first-line treatment. We hereby provide crucial information on establishing standardized PTCL treatment.

Aplastic anemia and clonal evolution: germline and somatic genetics

Clonal progression to myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure (BMF). Recognizing risk factors for the development of MDS or AML would inform individualized treatment decisions and identify patients who may benefit from early or upfront hematopoietic stem cell transplantation. Now that next-generation DNA sequencing is available in the clinical laboratory, research has focused on the implications of germline and somatic mutations for diagnosing and monitoring patients with BMF. Most germline genetic BMF disorders are characterized by a high propensity to develop MDS or AML. Recent studies of somatic variants in marrow failure revealed a high frequency of clonal hematopoiesis with the acquisition of mutations in genes associated with MDS or AML. The evaluation and implications of germline and somatic mutations for the development of clonal disorders in patients with BMF and challenges of clinical genetic testing will be summarized in this paper based on the reports from the 58th American Society of Hematology (ASH) Annual Meeting. Key words: Bone marrow failure; Anemia, aplastic; Myelodysplastic syndrome; Leukemia, myeloid, acute; Germline genetics; Somatic genetics; Clonal progression; Next generation sequencing; American Society of Hematology Annual Meeting

Aplastic anemia and clonal evolution: germ line and somatic genetics.

Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure (BMF). Recognizing risk factors for the development of MDS or AML would inform individualized treatment decisions and identify patients who may benefit from early or upfront hematopoietic stem cell transplantation. Now that next-generation DNA sequencing is available in the clinical laboratory, research has focused on the implications of germ line and somatic mutations for diagnosing and monitoring patients with BMF. Most germ line genetic BMF disorders are characterized by a high propensity to develop MDS or AML. Many affected patients lack the physical stigmata traditionally associated with the inherited marrow failure syndromes. Although any single inherited marrow failure disorder is rare, multiplexed genetic sequencing that allows simultaneous evaluation of marrow failure genes en masse demonstrated that, as a group, these inherited disorders compose a significant subset (5% to 10%) of patients with BMF. Early diagnosis of a germ line genetic marrow failure disorder allows individualized monitoring and tailored therapy. Recent studies of somatic variants in marrow failure revealed a high frequency of clonal hematopoiesis with the acquisition of mutations in genes associated with MDS or AML. Investigation of somatic mutations in marrow failure revealed important insights into the mechanisms promoting clonal disease but also raised additional questions. This review will focus on the evaluation and implications of germ line and somatic mutations for the development of clonal disorders in patients with BMF. Challenges and limitations of clinical genetic testing will be explored.

Blastic Plasmacytoid Dendritic Cell Neoplasm. a Population-Based Analysis from the SEER and NCDB Databases

IntroductionBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare hematologic malignancy that was grouped with myeloid malignancies in the 2008 WHO classification. The current available literature is limited to small case series and single-institution experiences. This population study using the Surveillance, Epidemiology, and End Results Program (SEER) and the National Cancer Database (NCDB) is the largest to explore epidemiologic and outcome data in BPDCN. SEER collects cancer incidence and survival data from cancer registries covering approximately 26% of the US population. NCDB is a nationwide, facility-based, comprehensive, clinical-surveillance resource for oncology data coming from more than 1500 Commission of Cancer (CoC)-accredited programs.MethodsUsing data from the SEER and NCDB registries, this study respectively identified 379 (years 2000-2013) and 216 (years 2004-2012) adult patients over the age of 20 diagnosed with BPDCN (ICDO-3 coding 9727). We used the SEER registry to estimate incidence rates, ratios and trends and the NCDB registry to study clinical characteristics, survival and outcomes. The JMP statistical software and the SEER*STAT 8.3.2 were used to conduct statistical analysis. We analyzed survival using the Kaplan-Meier method and used log-rank tests to compare survival distributions. The prognostic effect of pertinent clinical variables was studied using multivariate Cox proportional hazards models. All tests of statistical significance were two-sided and P < 0.05 was considered significant.ResultsThe median age at diagnosis for BPDCN was 52 years (20-93). The incidence of BPDCN was found to be 0.45/1,000,000 age-adjusted to the 2000 US standard population with similar trends over the years. No racial disparities were identified. The male:female ratio was 2 (P<0.00001). The bone marrow was the most common primary site of involvement (42%) followed by the skin (20%) and the heart, mediastinum and pleura (13%). The median overall survival for the entire cohort was found to be 23 months (95% CI; 17-34). Survival rates at 1 year, 2 years and 5 years were found to be 66%, 49% and 38% respectively. 20 patients (10%) underwent a hematopoietic stem cell transplantation (HSCT) as part of their initial therapy and the median overall survival for these patients was not reached compared to a median survival of 19 months for patients who did not undergo upfront HSCT (95% CI; 15-30, P=0.006). A univariate and multivariate analysis was performed including age, race, sex, HSCT, insurance status, income, treatment facility (academic versus non-academic) and disease primary site. Young age and HSCT were predictors of better outcomes. 60 years and older was found to be the age cut-off associated with significantly inferior survival based on receiver operating characteristic (ROC) curve analysis.ConclusionBPDCN is a rare hematologic malignancy associated with a poor median survival of less than two years. Males are twice more likely to be affected than females. The bone marrow is the primary site of involvement in most cases. Younger age (<60 years) and HSCT were predictors of significantly better outcomes.Kaplan-Meier survival curve for the entire cohortKaplan-Meier survival curves in patients Age <60 versus > 60Kaplan-Meier survival curves in patients who underwent HSCT versus those who did not [Display omitted] [Display omitted] [Display omitted] DisclosuresAl-Kali:Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Disparities in the Upfront Use of Hematopoietic Stem Cell Transplant Among Patients with Acute Myeloid Leukemia

Background:The incidence for acute myelogenous leukemia (AML) is on the rise in the United States (US). Roughly 20,000 new AML patients are expected to occur in 2016 in the US (data from Surveillance Epidemiology and End Results Program). It is mainly a disease of older individuals with median age of 67 years. Unfortunately, most patients are not cured. Recent data suggest that early referral for hematopoietic stem cell transplant (HSCT) leads to more favorable outcomes, particularly those with non-good risk cytogenetics compared to alternate therapies. The objective of our study was to assess the use of upfront HSCT among AML patients with a focus on patients with non-good risk cytogenetics and determine disparity in its access based on sociodemographic and regional considerations.Methods:We analyzed data obtained from National Cancer Data Base (NCDB) Participant User Files for patients diagnosed with AML between 2004 and 2013 using the International Classification of Diseases for Oncology version 3 (ICD-O-3) codes 9840-9861, 9865-9874, 9891-9931. The data is collected prospectively by joint program of Commission on Cancer (CoC) and American Cancer Society. It covers nationwide oncology outcome from more than 1,500 CoC-accredited hospitals. Over 70% of all newly diagnosed cancer cases in the US are captured by NCDB. Since unique ICD-O-3 codes exist for the good-risk but not for intermediate- or poor-risk AML, we categorized the AML subtypes as good risk or non-good risk for analytic purposes. We considered patients with t(15;17), inv(16) and t(8;21) with corresponding ICD-O codes of 9871, 9896, and 9866, as good-risk patients. All others were considered non-good risk. Proportion of HSCT usage was estimated in various subgroups with 95% confidence intervals calculated using robust estimates of standard error.Results:We identified 80,087 patients who were diagnosed with AML between 2004 and 2013. Majority of these patients were Whites (85.9%), males (53.8%) and between the ages of 40 and 79 years (71.5%). The overall use of upfront HSCT increased consistently over time. This occurred predominantly among the non-good risk AML from a rate of 6.5% in 2004 to 12.5% in 2013 (Figure). Non-good risk patients who were Black, had Medicare insurance, with lower annual household income, and treated at facilities located in the East, South and Central parts of US ( AL, KY, MS, TN) had less access to HSCT (Table).Conclusion:The use of upfront HSCT in AML has almost doubled in the past decade, predominantly among those with non-good risk cytogenetics. Nevertheless, we found substantial disparity among sociodemographic and geographic subgroups. Future studies should try to understand and address how to bridge this gap. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treatment Outcomes and Prognostic Factors of Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the curative option for treatment of acute myeloid leukemia (AML). Even after HSCT, the relapse rate of AML ranged from 20% to 55%. The prognosis of relapsed AML after HSCT is very poor. But, treatment guideline for relapsed AML after HSCT has not been defined. Thus, we aimed to investigate treatment outcomes and prognostic factors of patients with relapsed AML after allogeneic HSCT.Patient and Method: Among 624 patients with AML who received HSCT in Asan Medical Center, Korea between 1995 and 2014, 219 patients who had a relapse of AML after HSCT were included in this retrospective study.Results: Seventy-two patients (32.9%) reattained complete remission (CR). Refractory AML at the time of HSCT (odds ratio [OR], 0.199, P=0.001), high BMI (> 28) (OR, 0.88, P=0.032), graft source from peripheral blood (OR, 0.299, P=0.001) and shorter relapse free interval (< 6 months) (OR, 0.199, P=0.001) were significant negative predictors for CR achievement (Table1). Of included patients, survival after relapse was median 5.2 months (95% CI, 3.96-6.44, months). Leukemia free survival of patients reattaining CR after relapse was median 10.6 months (95% CI, 8.1-13.2 months). Twenty-seven patients received second HSCT following salvage chemotherapy. Patients who had underwent upfront HSCT without chemotherapy for AML and relapse before 6months after HSCT were significantly associated with worse survival after relapse (Hazard ratio [HR], 3.106, P=0.006 and HR, 2.018, P=<0.001, respectively). Donor lymphocyte infusion following salvage chemotherapy and second HSCT had a significant impact on better survival (HR, 0.131, P=0.002 and HR, 0.423, P=0.003, respectively). Male gender (Hazard ratio [HR] 2.465, P=0.012) and extramedullary relapse (HR, 4.215, P=0.001) were negative factors affecting shorter leukemia free survival after relapse.Conclusion: Donor lymphocyte infusion following salvage chemotherapy and second HSCT can be beneficial option for relapsed AML patients after HSCT. But, novel treatment modalities need to be investigated for improving survivals of relapsed AML patients after HSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Biomarkers for predicting clinical response to immunosuppressive therapy in aplastic anemia.

The decision to select hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST) as initial therapy in acquired aplastic anemia (AA) is currently based on patient age and the availability of a human leukocyte antigen (HLA)-matched donor. Although IST is a promising treatment option, the ability to predict its long-term outcomes remains poor due to refractoriness, relapses, and the risk of clonal evolution. Several predictive biomarkers for response to IST have been posited, including age, gender, pre-treatment blood cell counts, cytokines, gene mutations, paroxysmal nocturnal hemoglobinuria (PNH), and telomere length (TL). While previous studies have provided substantial biological insights into the utility of IST, the prognostic power of the reported biomarkers is currently insufficient to contribute to clinical decision making. Recently, a large retrospective analysis proposed the combination of minor PNH clones and TL as an efficient predictor of IST response. Identification of a reliable predictor would provide a useful tool for determining the most appropriate treatment choice for AA patients, including up-front HSCT from HLA-matched unrelated donor. The present review summarizes studies evaluating the utility of biomarkers in predicting the clinical response to IST of patients with AA, and provides a baseline for prospective studies aimed at validating previously reported biomarkers.

Acquired aplastic anemia in Korean children: treatment guidelines from the Bone Marrow Failure Committee of the Korean Society of Pediatric Hematology Oncology.

The treatment of choice for aplastic anemia (AA) in children has been HLA-matched family donor (MFD) hematopoietic stem cell transplantation (HSCT). For those lacking MFD, immunosuppressive therapy (IST) consisting of horse antithymocyte globulin (ATG) and cyclosporine has been successful. The choices of second and third line treatments are more complex and debatable, especially in the situation of unavailability of horse ATG. IST with rabbit ATG seems to be less effective. Recently, improved survival of non-MFD HSCTs has been documented. The outcome of matched or mismatched unrelated donor, umbilical cord blood, or haploidentical family donor transplantations will be discussed in AA children after IST failure. Experimental approaches of upfront HSCT using non-MFDs will be briefly touched. In this review, a treatment guideline for children with AA from the Korean Society of Pediatric Hematology Oncology will be presented along with a brief review of literature on current clinical practices in Korea.