Treatment-related Myelodysplastic Syndrome Research Articles

LGG-10. TREATMENT-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING CHEMOTHERAPY FOR PEDIATRIC LOW-GRADE GLIOMA

Abstract Treatment-related myeloid neoplasms are rare though well-defined secondary malignancies associated with prior cytotoxic treatment, (particularly alkylating agents and topoisomerase inhibitors). They are rarely associated with primary central nervous system tumours and have historically carried a very poor prognosis. Pediatric low-grade gliomas (pLGG) are the most common CNS tumours of childhood, and up to 50% of patients will require adjuvant therapy. This has traditionally consisted of low-dose metronomic chemotherapy, although the advent of genomic profiling and identification of molecular drivers of pLGG means novel targeted therapies are changing this paradigm. There has only been a single reported case of treatment-related myeloid leukaemia secondary to pLGG treatment. We present a novel case of a 17-year-old girl with treatment-related myelodysplastic syndrome following chemotherapeutic treatment for pLGG. The patient was initially diagnosed at age 4 with a metastatic pilomyxoid astrocytoma (primary suprasellar lesion with spinal metastases) and received first-line treatment with a vincristine and carboplatin regimen. She had disease progression at age 7 and received second-line treatment with thioguanine, procarbazine, lomustine and vincristine. Following further progression at age 16, a biopsy of the suprasellar mass showed a pilocytic astrocytoma with a KIAA1549-BRAF fusion. Prior to commencing a targeted treatment as third-line therapy, she was noted to have a macrocytic anaemia, which subsequently evolved to a bicytopenia. Bone marrow analysis showed a hypocellular marrow with an abnormal myeloid clone with a chromosomal 1q gain, consistent with a diagnosis of treatment-related myelodysplastic syndrome. Germline analysis was negative for bone marrow failure predisposition gene abnormalities. She is currently undergoing workup for bone marrow transplant. Given the poor prognosis of treatment-related myeloid neoplasms, this case represents an important note of caution when choosing appropriate therapy for pLGG, especially given the evolving role for targeted treatments in this disease with otherwise very favourable long-term survival.

A Pediatric Case of Treatment-related Myelodysplastic Syndrome While on Therapy for Pre-B Acute Lymphoblastic Leukemia.

Treatment-related myelodysplastic syndrome (t-MDS) is a rare late effect of cancer therapy. After alkylating agents, this typically occurs years after completion of therapy. Treatment of t-MDS in pediatrics is an allogeneic stem cell transplant, however, the prognosis remains poor. This case demonstrates t-MDS developing in a patient receiving treatment for pre-B acute lymphoblastic leukemia. This patient was treated with a combination of hematopoietic stem cell transplant and hypomethylating agents. These agents should be considered for use in patients with t-MDS, before transplant to limit additional chemotherapy and as maintenance therapy post-transplant to reduce the risk of relapse.

Outcomes of Allogeneic Haematopoietic Stem Cell Transplantation for Therapy-Related Myeloid Neoplasms Following Treatment for Myeloma

Introduction As the outcomes for patients with multiple myeloma continue to improve, therapy-related myeloid neoplasms (t-MN) are increasingly recognised as a treatment complication. The prognosis of tMDS is poor with life expectancy typically less than a year1. There is limited data on the management of t-MN secondary to myeloma therapies. We performed a registry study on the outcomes of patients who underwent an allogeneic haematopoietic stem cell transplant (allo-HCT) for both therapy related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) following treatment for myeloma. Methods The European Society for Blood and Marrow Transplantation (EBMT) registry was used to identify 157 patients with t-MN across 96 centres between 2006-2018. The median age of patients was 62.1 years (57.6-66.7), with 63.7% male and 36.5% female. 100 patients were transplanted for t-AML and 57 for t-MDS with a median time from myeloma diagnosis to time of allo-HCT of 72.6 (46.1-102.9) months. The median time from t-MN diagnosis to allo-HCT was 6.4 (3.9-9.4) months. We examined overall survival (OS), progression free survival (PFS) relapse and non-relapse mortality (NRM) and myeloma recurrence. The median follow-up time was 64.9 months. Results The median survival time for all patients was 14.3 months. OS at 12- and 60 months was 55% and 27% respectively and PFS at 12- and 60 months was 45% and 24% respectively. The incidence of relapse of tMN at 12- and 60 months was 35% and 45% respectively, with NRM 20% and 31% respectively. The commonest cause of death was infection (36.3% n=37) followed by disease relapse/progression (34.3% n=35). With respect to t-MN disease status 59% of patients with t-MN were in a complete remission at time of transplant. Cytogenetic results were available for all patients with 67.6% abnormal, 26.7% normal and failed/not done in 5.7% cases. IPPS-R was available in 58% of cases; Good 17(29.3%), intermediate 13(22.4%), poor 13(22.4%) and very poor 15(25.9%). Data on status of myeloma at time of allo-HCT was available in only 50 patients (CR 38%, VGPR 22%, PR 10%, stable disease 11% and progressive disease 8%). The majority of patients underwent matched unrelated transplant 79%(124) versus sibling allo 21% (n33). The majority had reduced intensity conditioning (RIC 70.3%, standard 29.7%, missing 1.3%). 130 patients had undergone prior autologous transplant (auto) for myeloma with 55.4% having one auto, 21% two autos, 5.1% three autos and 1.3% four autos. With respect to the number of lines of myeloma therapy prior to transplant; 1 line (29.4%), 2 (30.9%), 3 (16.9%), 4 (8.8%) and >4 (14%). 120 patients received chemotherapy for myeloma prior to their t-MN diagnosis, however data was missing in the remainder of patients in this study. Data on myeloma recurrence was available in 31.2% (49 patients), at 12- and 60 months myeloma recurrence was 4% and 12% respectively with myeloma NRM at 12- and 60 months 33% and 57%. Univariate analysis failed to show any statistically significant difference in outcomes with respect to t-MDS vs t-AML, t-MN disease status, Karnofsky performance status, conditioning or donor source. Multivariate analysis was not possible due to the small numbers within this study. Further analysis of this data will be undertaken. Conclusion This study indicates that allo-HCT for t-MN following treatment for myeloma is a viable treatment option. The myeloma recurrence in this study was low and further strategies to reduce t-MN relapse and NRM are needed. References; Bhatia R, Deeg HJ. Treatment-Related Myelodysplastic Syndrome - Molecular Characteristics and Therapy. Curr Opin Hematol.2011;18(2):77-82.

A Retrospective Validation Study Comparing the IPSS-M and IPSS-R Risk Stratification Scores in Primary and Secondary Myelodysplastic Syndrome (MDS)

Introduction: Myelodysplastic syndrome (MDS) is a stem cell disorder characterized by bone marrow stem cell dysfunction, cytopenia(s), and increased risk of acute myeloid leukemia (AML) transformation. Treatment of MDS varies based on a patient's estimated risk of transformation to AML and the presence of molecular and cytogenetic changes known to confer poor clinical outcomes. Significant effort over the last few decades has been undertaken to develop prognostic models to risk stratify patients, resulting in the international prognostic scoring system (IPSS), revised version (IPSS-R), and WHO classification-based prognostic scoring system (WPSS). Recently, the molecular international prognostic scoring system (IPSS-M) was proposed to consider clinical indices, laboratory and pathology parameters, cytogenetics, and mutational data in the progression of MDS. Currently, this model has only been validated within a Japanese database, wherein 42% of patients were re-stratified by IPSS-M in comparison to IPSS-R. To date, these results have yet to be validated in a cohort of patients in the U.S. Methods: We conducted a single-center retrospective validation cohort study of adults with a known diagnosis of MDS referred to Oregon Health & Science University from 2019 through 2021. The study was approved by the Institutional Review Board prior to initiation (OHSU IRB number- STUDY00023980). Patients were identified using relevant diagnostic codes for MDS and those who were <18 years of age, did not have a biopsy-confirmed diagnosis of MDS, did not have next-generation sequencing performed on diagnostic tissue, or were lost to follow-up shortly after diagnosis were excluded. Patients with treatment-related MDS were included. The primary outcomes, measured from MDS diagnosis and determined through May 2022, were overall survival (OS) and leukemia-free survival (LFS). Predictors of interest were IPSS-R, age-adjusted IPSS-R, WPSS, and IPSS-M, each with categories of "very low", "low", "intermediate" (called "moderate" for IPSS-M), "high", and "very high" risk. OS and LFS in specific prognostic risk categories/groups were estimated by the Kaplan-Meier method and compared using the log-rank test. Median follow-up was estimated by the reverse Kaplan-Meier method. Cox regression models of OS and LFS were fit to estimate the relative risk of AML transformation or death with hazard ratios (HRs) and the prognostic accuracy with concordance indices (C-index). Results: One hundred and forty-nine patients, diagnosed between 2011 and 2021, met inclusion criteria and were analyzed: 136 diagnosed with primary MDS and 13 with secondary/treatment-related MDS (Table 1). After IPSS-M re-stratification, 32% of patients were up-staged (with 24 moving into the "very high" group) and 12% down-staged (with 3 patients exiting the "very high" group) from their IPSS-R risk category. Median follow-up time was 2.8 years and 54 patients died (36%) during the study period. Among the 32 patients (21%) whose disease transformed to AML, median time from MDS diagnosis to transformation was 7 months. When considering death as a competing risk, estimated cumulative incidence of AML transformation was 14% at 1 year and 19% at 3 years post-diagnosis. IPSS-R groups were significantly segregated by LFS (log-rank p=6.3e-05; "very high" vs. "low" HR=4.08, p=3.3e-04; Figure 1, Table 1) and by OS (log-rank p=4.9e-06; "very high" vs. "low" HR=5.38, p=1.0e-04; Fig 1, Table 1). IPSS-M was also highly significantly associated with LFS (log-rank p=1.2e-07; "very high" vs. "low" HR=5.64, p=4.4e-06; Fig 1, Table 1) and OS (log-rank p=4.6e-08; "very high" vs. "low" HR=7.30, p=6.1e-06; Fig 1, Table 1). IPSS-M had better discrimination than IPSS-R for LFS (C-index 0.72 [95% CI: 0.67 - 0.78] vs. 0.68 [95% CI: 0.62 - 0.75]) and for OS (C-index 0.74 [95% CI: 0.68 - 0.81] vs. 0.70 [95% CI: 0.63 - 0.78]). This discrimination advantage was also observed for LFS (0.73 vs. 0.70) and OS (0.76 vs. 0.73) when taking into account a patient's transfusion dependence at MDS diagnosis. Discussion & Conclusion: This single-center study is the first U.S. cohort validation of the IPSS-M, finding that this mutation-incorporating prognostic index has greater discriminative potential than IPSS-R in predicting AML transformation and any-cause mortality. Further multicenter prospective studies are needed to confirm the utility of the IPSS-M model. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Shanghai fever, a fatal enteric illness, in an adult patient with neutropenia caused by treatment-related myelodysplastic syndrome: a case report

BackgroundShanghai fever is a rare community-acquired enteric illness with sepsis caused by Pseudomonas aeruginosa. Cases of Shanghai fever in pediatric patients have been reported; however, to the best of our knowledge, there are no reports of adult cases.Case presentationA 65-year-old man visited the emergency department with sudden onset of abdominal pain. He was diagnosed as treatment-related myelodysplastic syndrome after treatment of follicular lymphoma. Moderate tenderness in the middle right abdominal quadrants was noted. Computed tomography showed abdominal free air with a small amount of effusion to the surrounding edematous small intestine, and we performed emergency exploration. During operation, we found multiple bowel perforations with patchy necrotic lesions. The patient was admitted to an intensive care unit postoperatively. Blood culture showed Pseudomonas aeruginosa. His condition improved; however, on the 8th postoperative day, the abdominal drain tube showed turbid drainage. We performed re-operation and found anastomotic leakage with two new bowel perforations. After the re-operation, the patient showed signs of septic shock and his general condition got worse, and the patient died due to multiple organ failure on the 12th postoperative day.ConclusionShanghai fever may occur in an adult patient with neutropenia.

TCL-224: Not All Pancreatic Masses Are Pancreatic Adenocarcinomas

Introduction T-cell acute lymphoblastic leukemias (T-ALL) and T-cell lymphoblastic lymphomas (T-LBL) are both lymphoblastic neoplasms involving the blood and bone marrow, respectively. T-LBL typically present with lymphadenopathy and/or a mediastinal mass. We describe a case of T-LBL, which presented as a pancreatic malignancy. Case Report A 42-year-old man with no significant past medical history presented with jaundice of 10 days duration. Physical examination was unremarkable, while CT of the abdomen showed a pancreatic head mass 3.2 x 2.9 cm engulfing the superior mesenteric vein with retroperitoneal lymph node enlargement. Significant labs included total bilirubin 16.3 mg/dL, direct bilirubin 9.5 mg/dL, CA19-9 10 U/mL, LDH 161 units/L, and no cytopenia. He underwent an endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA), along with ERCP with distal common bile duct stent placement. Initial pathology was indeterminate. Chest CT revealed a 7.8 x 5.1 cm lobulated heterogeneous anterior mediastinal mass involving the anterior and lateral pericardial surface, thus precluding biopsy due to high risk of vascular injury. Repeat EUS-guided FNA of the pancreatic mass revealed T-LBL. Cerebrospinal fluid (CSF) analysis showed clonal T lymphocytes positive for CD3, CD4, and CD5, and T-cell rearrangement, while bone marrow biopsy revealed no lymphomatous involvement. After the diagnosis of stage IVA extramedullary T-LBL with CNS involvement, he received six cycles of Hyper-CVAD chemotherapy and intrathecal methotrexate. After achieving complete remission, he next underwent autologous stem cell transplant (ASCT) with a conditioning regimen of total body irradiation and etoposide. At five years follow-up, the patient remained in remission but developed worsening cytopenia and a bone marrow biopsy revealed treatment-related myelodysplastic syndrome (T-MDS) with monosomy 7. Subsequently, he underwent a haploidentical allogeneic stem cell transplant, with a follow-up bone marrow biopsy showing no evidence of MDS. Discussion The differential diagnoses of pancreatic masses include pancreatic adenocarcinoma, chronic pancreatitis, neuroendocrine tumor, or lymphoma. To our knowledge, this is possibly the first case of extramedullary T-LBL presenting as a pancreatic mass. Risk-adaptive treatment strategy incorporating hyper-CVAD chemotherapy and early ASCT was effective in achieving long-term remission and is potentially an effective treatment strategy in T-LBL.

Favorable Outcome After Adjuvant Involved-Field Radiotherapy After Autologous Hematopoietic Stem-Cell Transplantation in Patients With High-Risk Relapsed/Refractory Lymphoma: A Single-Center Experience

BackgroundPatients with refractory or relapsed lymphoma diagnosed with bulky disease at relapse or with residual disease after salvage treatment are considered to have a dismal outcome, even after autologous hematopoietic stem-cell transplantation, as a result of disease recurrence. To minimize the risk of relapse after receipt of a transplant, involved-field radiotherapy (IFRT) to sites of either bulky or localized residual disease has been utilized; however, the ideal timing for irradiation remains controversial. The aim of this study was to assess the safety and efficacy of IFRT in the early period after transplantation. Patients and MethodsWe retrospectively evaluated the outcome of 24 autografted patients with relapsed/refractory lymphoma who presented with bulky disease at relapse or who had a persistent localized residual mass after salvage treatment and consolidated with IFRT within 4 months after autografting. ResultsNo significant toxicity was noticed during the early postradiotherapy period, while graft function was not impaired. After a median follow-up of 3 years for survivors, 21 patients were alive, 19 of whom were event free, while 2 patients died of disease recurrence and 1 died of treatment-related myelodysplastic syndrome. The 3-year overall, lymphoma relapse-free, and event-free survival rates were 86%, 86%, and 82%, respectively. ConclusionTaking into consideration the poor-risk features of the study cohort, IFRT provided early after autologous hematopoietic stem-cell transplantation showed a safe and well-tolerated toxicity profile and demonstrated long-term effective tumor control, as reflected in the promising survival rates.

Predisposition to transformation from myelodysplastic syndrome into acute myeloid leukemia – case presentation

Predisposition to transformation from myelodysplastic syndrome into acute myeloid leukemia – case presentation

De Novo and Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome: Similarities and Differences in SNP-Array Detected Chromosomal Aberrations in Pre-Transplant Blood Samples

De Novo and Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome: Similarities and Differences in SNP-Array Detected Chromosomal Aberrations in Pre-Transplant Blood Samples

Treatment-related myelodysplastic syndrome after treatment for soft tissue sarcoma: a case report

Treatment-related myelodysplastic syndrome after treatment for soft tissue sarcoma: a case report

A Case of Secondary Myelodysplastic Syndrome Spontaneously Resolved by Discontinuance of Trimetazidine Dihydrochloride

Treatment-related Myelodysplastic Syndrome (t-MDS) is well known and serious complication of cancer treatment. However, MDS cases caused by therapy of common nonmalignant diseases are unusual and represent diagnosic and therapeutic challenge. We experienced a case of secondary MDS, possibly induced by trimetazidine dihydrochloride, which was spontaneously resolved by discontinuance of the drug. The main purpose of this report is to point at the importance of continuous and careful monitoring of pharmacovigilance data of different medications and their possible “relation” with some diseases or pathological conditions which are, in fact, adverse drug event.

Long-Term Follow up of Patients with HIV-Associated Non-Hodgkin Lymphoma (NHL) after Autologous Stem Cell Transplantation (ASCT)

Background:The Blood and Marrow Transplant Clinical Trials Network 0803 study confirmed the safety and efficacy of ASCT in HIV-infected patients with lymphoma. Short term toxicity and transplant related mortality was low (5.2%) and engraftment, treatment-related mortality and survival outcomes were not statistically significantly different from that of age and diagnosis matched CIBMTR controls. However, median follow up in that trial was 24 months after ASCT, and the questions of second cancer incidence and other infections in a this population remain (Alvarnas et al, ASH 2014). Herein we report the long term outcomes of ASCT in HIV-infected patients.Methods: Retrospective cohort trial of 52 HIV-infected patients who underwent ASCT for high-risk NHL at City of Hope from January 1, 1998 to December 31, 2011. Two patients were excluded from the analysis due to early post-transplant mortality: one patient died at day 22 due to multiorgan failure, and another died at day 72 due to relapsed lymphoma. Fifty patients with a minimum survival of 100-days post ASCT were evaluated for long-term outcomes. Estimation of event-free survival (EFS) and overall survival (OS) was computed using Kaplan-Meier curves and the cumulative incidence of relapse was estimated with competing risk of mortality.Results: Median follow up was 5.43 years (range 0.30-14.96 years). Median age at the time of transplantation was 45 years (range 26-64 years of age). Prior to transplant, 23 patients (46%) were in complete remission and 27 (54%) were in partial remission. Most patients had aggressive NHL, with diffuse large B-cell lymphoma (48%) and Burkitt lymphoma (24%) being most common histologies. Other subtypes included Burkitt-like (10%), plasmablastic (10%), follicular lymphoma (2%), and T-cell lymphomas (6%). Nine patients relapsed (18%), at a median time of 97 days (range 54-253 days) post ASCT. Fifteen patients (30%) died; 8 out of 15 (53%) died due to relapse. Opportunistic infections (OI) occurred in 8 patients (16%) at a median of 0.68 years (range 0.17-10.82 years). Types of OI included CMV retinitis (1), HSV/Zoster (1), HPV (1), Candida esophagitis (1) and PJP (3). One patient died from OI (PJP). Seven patients (14%) developed a second primary malignancy (SPM) at median time to SPM of 5.63 years (range 1.02-14.35 years). Type of SPM included treatment-related myelodysplastic syndrome (t-MDS) with progression to acute myelogenous leukemia (AML) (2) observed at 3.2 years and 12.6 years, respectively, after ASCT; squamous cell carcinoma of the tongue (1), and skin cancers, including melanoma (1) at 14.3 years post ASCT, basal cell carcinoma (2) at 5.5 and 5.6 years post ASCT, and squamous cell carcinoma in situ (1) at 1.0 year post ASCT. Two patients died from the t-MDS.Conclusions: Thirty-five of 50 patients (70%) were alive at the time of analysis confirming the efficacy of this procedure. EFS/OS at 1 year and 5 years post ASCT was 78% (95% CI:67.3%-90.4%)/82% (95% CI: 71.9%-93.4%) and 71.4% (95% CI:59.8%-85.3%)/73.3% (95% CI: 61.8%-86.9%), respectively. Relapse of NHL tended to occur early post-transplant. Cumulative incidence of relapse was 18% at 1 year post ASCT (95% CI: 8.8%-29.8%). Development of OI was also seen early post-ASCT. While SPM appeared as late as 14.35 years following ASCT, it was no higher than that seen in the non-HIV ASCT setting. This is the largest single institution study reporting long-term follow up of HIV-positive patients post ASCT for NHL and demonstrating that while SPM remain a long term concern neither SPM, OI or HIV infection were major factors in mortality. DisclosuresNo relevant conflicts of interest to declare.

Treatment-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (AML) in children with cancer: A single-center experience

Treatment-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (AML) is a devastating early or late complication of treatment for childhood cancer related with a significant morbidity and mortality. We retrospectively studied survivors of childhood cancer. Overall, 287 patients were recorded in the databases and we identified three (1.04%) with t-MDS. The primary cancer diagnoses were Langerhans cell histiocytosis (one patient) and acute lymphoblastic leukemia (ALL; two patients). The mean age of patients was 12.1 years. All patients had received systemic antifungal treatment for invasive pulmonary aspergillosis successfully treated with voriconazole and liposomal amphotericin B before diagnosis of t-MDS. Two patients (66%) remain alive after a median follow-up period of 3.5 years.

An Analysis of Prognostic Markers and the Performance of Scoring Systems in 1837 Patients with Therapy-Related Myelodysplastic Syndrome - a Study of the International Working Group (IWG-PM) for Myelodysplastic Syndromes (MDS)

Background: The International Prognostic Scoring System (IPSS) for MDS has recently been revised (IPSS-R). However both scoring systems were developed after exclusion of therapy-related cases and data on its usefulness in treatment-related MDS (tMDS) is limited.Aims and Methods: We analyzed 1837 pts from Spanish, German, Swiss, Austrian, US, Italian, and Dutch centers diagnosed 1975-2015. Complete data to calculate the IPSS/-R was available in 1511 pts. The impact of prognostic features was analyzed by uni- and multivariable models and estimated by a measure of concordance for censored data (Dxy).Results: Median age was 68 years. 1% of pts had 5q-syndrome, 13% RCUD, 4% RARS, 27% RCMD/-RS, 18% RAEB 1, 18% RAEB 2, 4% CMML 1, 2% CMML 2, 3% MDS-U, and 7% AML (RAEB-T) according to WHO-classification. Regarding cytogenetics 38% exhibited good, 14% intermediate, and 48% poor-risk according to IPSS, and 2% very good, 36% good, 17% intermediate, 15% poor, and 31% very poor according to IPSS-R. Prognostic risk groups were 12% IPSS low, 34% int 1, 36% int 2, and 18% high, while the IPSS-R was very low in 8%, low in 20%, intermediate in 17%, high in 23%, and very high in 32%.The most frequent primary diseases were NHL 28%, breast cancer 16%, myeloma 6%, prostate cancer 6%, Hodgkins disease 5%, and 4% gastrointestinal tumors. Patients received chemotherapy in 75% and radiotherapy in 47%. Regarding chemotherapeutic drugs, most pts received combination regimens containing alkylating agents in 65%, topoisomerase inhibitors in 44%, antitubulin agents in 26%, and antimetabolites in 26%.Median follow-up from MDS diagnosis was 59 months, median survival 16 months. Since a disease altering treatment is, at least in higher risk disease, which is overrepresented in tMDS, standard of care, we decided to analyze treated as well as untreated pts to avoid a selection bias. This included stem cell transplantation in 16% with a median survival of 24 months.Features with influence on survival and time to AML in univariable analysis included FAB, WHO, IPSS, IPSS-R, cytogenetics, hb, platelets, marrow and peripheral blasts, ferritin, LDH, fibrosis, ß2-microglobulin, and use of alkylating agents for the treatment of primary disease. For hemoglobin, platelets, LDH, fibrosis, and ß2-microglobulin the influence was stronger on survival. Year of diagnosis, age, gender, neutrophil count, WBC, use of chemo or radiotherapy as well as other chemotherapeutic agents had no marked influence on both outcomes.According to our results, both the IPSS (Dxy 0.29 for survival, 0.32 for AML) and IPSS-R (Dxy 0.34, 0.32 for AML) perform moderately in tMDS, but not as well as in primary MDS (pMDS). Therefore, existing prognostic models need to be adjusted to tMDS. However, this appears to be not without difficulties. The scores tested, as well as most prognostic variables themselves perform inferior compared to pMDS. It becomes even more complicated since tMDS in itself is even more heterogeneous than pMDS. Scores and variables perform differently depending on the primary disease or therapy. The IPSS/-R and its variables perform for example better in pts with solid tumors compared to hematologic diseases or in pts who have received radio- instead of chemotherapy, but also in pts after prostate compared to breast cancer.In addition to the integration of further variables, new cutoffs, or the weighting of existing variables, we are currently testing the possibility of separate score versions for different tMDS subgroups. Separate score versions for survival and time to AML would also give differing weights to most features. Hemoglobin, platelets and cytogenetics would get more weight for survival, while marrow blasts would be more important regarding AML.Conclusion: In contrast to early descriptions of tMDS, with poor risk cytogenetics in the vast majority of pts and a uniformly poor prognosis, surprisingly we find good risk karyotypes in a relatively large number of pts. Although, poor risk cytogenetics are still overrepresented, this indicates, different types of tMDS exist. Our analysis shows that many variables exhibit prognostic influence in tMDS and the IPSS or preferably IPSS-R can be applied in these pts. However, the prognostic power of both scores is inferior compared to pMDS, making an optimized tMDS score reasonable. Currently data from further IWG centers is integrated in our database and further analyses are performed to propose a tMDS specific score. [Display omitted] DisclosuresKomrokji:Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau; Incyte: Consultancy; Celgene: Consultancy, Research Funding. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Celgene: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Onconova: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Platzbecker:Boehringer: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Low BCL11A Expression in the Myeloma Microenvironment at Diagnosis Is Associated with Early Development of MDS Cytogenetic Abnormalities and Poor Overall Survival

Prolonged survival of myeloma patients on Total Therapy regimens including IMIDS and novel agents has been associated with increased incidence of treatment-related myelodysplastic syndrome and acute leukemia (t-MDS/AL). MDS cytogenetic abnormalities (MDS-CAs) are often observed prior to t-MDS/AL development. Among 1,080 patients on TT2 and TT3 protocols, MDS-CA occurred in 11% and t-MDS/AML in 3%. Risk features of MDS-CA included TT3b treatment, age ³65 yr, male sex, elevated B2M, and MM relapse. Lower doses of CD34 HSCs applied with first transplants raised the probability of MDS-CAs, and lower CD34 HSCs dosing was an independent contributor to MDS-CAs and clinical t-MDS (Usmani et al., 2013). Although patients with MDS-CAs do not always develop t-MDS/AML, the phenomenon, also recognized in other tumors, requires understanding and development of preventive measures. We analyzed gene expression profiling (GEP) of bone marrow core biopsies at diagnosis from patients enrolled in our TT2 (n=88) and TT3 (n=263; training set) trials to identify genes associated with time to MDS-CA. Univariate Cox regression identified BCL11A as the only gene with expression associated with the time to development of MDS-CA (q <0.1). Incidence of MDS-CA for MM patients enrolled in TT2 and TT3 is 11% (Usmani et al., 2013); 3-year estimate of patients with low BCL11A expression is 8% vs. 3.9% for those with higher expression (Figure 1). Univariate analysis of baseline variables linked shorter time to MDS-CA with Age ≥ 65 yr, B2M > 5.5 mg/L, GEP70-defined high risk and low BCL11A expression, while female sex was linked with longer time to MDS-CA development. In multivariate analysis, females retained independent prognostic significance for time to MDS-CA (HR-0.41, p 0.006), as did B2M > 5.5 mg/L (HR-1.95, p=0.038) and BCL11A expression <10.323 (HR-3.24, p <0.001). In addition to its role in normal hematopoietic development (Yu et.al., 2012), BCL11A is a central transcription factor in normal erythropoiesis (Xu et.al. 2012), and differences in its expression may reflect abnormal erythropoiesis. Indeed, lower Hb levels before HSC mobilization was associated with MDS-CA development in MM patients (Papanikolaou et al., 2013) while BCL11A expression is lower in core biopsies from MM patients than in those from healthy donors. BCL11A expression correlated with a set of genes associated with erythropoiesis (r>0.55) (e.g., GYPA, TFRC, RHAG, TRIM10, ANK1, SPTA1). BM cell fractions from MM patients were purified using MACS and FACS and BCL11A expression was analyzed by qRT-PCR demonstrating that BCL11A is highly expressed in CD19+ B cells and CD235a+ erythroid cells, intermediately expressed in CD34+ HSPCs, and absent in CD3+ T cells and CD15+ myeloid cells. BCL11A expression in paired biopsies and CD138-selected PCs does not correlate, further demonstrating that BCL11A expression originates in the MM microenvironment. As suppression of hematopoiesis is common to MDS and MM, we determined whether loss of BCL11A was associated with survival independent of MDS-CA status. Lower BCL11A expression in bone biopsies was associated with poor overall survival of patients on the TT2 protocol (p=0.0182) and TT3 protocol (p=0.0015). Taken together, these data demonstrate that low BCL11A expression in newly diagnosed MM is an independent predictor of early MDS-CA development, and is associated with altered hematopoiesis and poor overall survival, and may be a biomarker of t-MDS/AML risk. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Levetiracetam as a possible cause of secondary graft failure after allogenic hematopoietic stem cell transplantation

BackgroundLevetiracetam is increasingly used as antiepileptic drug (AED) of choice in children as well as in adults with complex diseases due to its lack of interactions and a large spectrum of action. Secondary graft failure, i.e. loss of donor cells after initial engraftment, is a relatively uncommon but serious and life-theatening complication after pediatric hematopoietic stem cell transplantation. Methods and resultsWe report a case of secondary graft failure after hematopoietic stem cell transplantation for treatment-related myelodysplastic syndrome during antiepileptic treatment with levetiracetam.Exclusion of all other possible etiologies left levetiracetam as the most likely cause of the imminent complete secondary graft failure after hematopoietic stem cell transplantation. Furthermore, the blood cell count improved just a few days after cessation of levetiracetam medication. ConclusionThus, we recommend that in case of secondary graft failure after hematopoietic stem cell transplantation, all possible causes should carefully be excluded, including adverse events through new generation AED agents. Switching to different AEDs with less harming effect on bone marrow function should strongly be considered.

Pre-Transplant Azacitidine and Allogeneic Hematopoietic Cell Transplant (HCT) Outcomes of One Hundred Fifty-Nine Patients up to Age Seventy-Five with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

HCT is the only known curative treatment for MDS. Treatment with the DNA methyltransferase inhibitor azacitidine (aza) has been utilized prior to HCT for tumor debulking and to slow leukemic progression. To discern the impact of aza treatment, we retrospectively analyzed the post transplant outcomes of 159 patients (pts) according to pre-HCT aza exposure. Patients included those with a diagnosis of MDS or CMML at any time point in their disease course and subsequently received a HCT. Eligible patients proceeded to HCT if they had adverse disease features such as elevated IPSS risk, treatment related MDS, progression or refractory disease. Consecutive patients receiving a HCT from July 2004 and May 2011 were evaluated. All obtained a myeloablative HCT using fludarabine and IV-busulfan [targeted to an AUC of 3500, 5300, 6000 or 7500]. GVHD prophylaxis was with tacrolimus plus either methotrexate or sirolimus or mycophenolate mofetil. Those with mismatched donors also received ATG. Seventy pts, median age of 56.5 (24.8 – 71.6) years (yrs), did not receive pre-transplant aza (NO AZA group). Forty pts were older than 55 yrs (57%). At diagnosis, IPSS risk was Low (4), Int-1 (25), Int-2 (17), High (5), not evaluable (4) (NE), AML (6) and CMML (9). Twenty-one had treatment related MDS and 15 had AML at one time. Donors included 28 match related donors (MRD), 31 matched unrelated donors (MUD) and 11 mismatched unrelated donors (mMUD). Median follow-up of surviving patients was 70.0 (29.7 – 106.6) months. Eighty-nine pts, median age of 57.8 (25.6 – 73.8) yrs, received a median of 4 (1-12) cycles of aza prior to HCT (YES AZA group). Fifty-four (61 %) were older than 55 yrs. At diagnosis, IPSS risk was Low (n=4), Int-1 (n=26), Int-2 (n=32), High (n=15), NE (n=2), AML (n=2) and CMML (n=8). Twenty-three had treatment related MDS and 11 had AML at one point. Donors included MRD (n=38), MUD (n=40) and mMUD (n=11). Median follow-up of surviving patients was 48.3 (24.1 – 103.2) months. Prior to allografting the number of marrow blasts in the No-AZA vs Yes-AZA was: <5% (n=41 vs 49), 5-10% (n=12 vs 19), 11 – 20% (n=10 vs 11), >20% (n=3 vs 4) and CMML (n=4 vs 6). All patients engrafted with no difference in engraftment rates or toxicities between the groups. At 3 years, the RFS and OS suggest improvement with preHCT AZA and approached statistical significance. Tabled 1CI NRMCI RELRFSOSNo AZA 1yr18.7 (10.5 – 28.7)38.6 (27.6 – 50.2)42.9 (31.6 – 54.5)58.6 (46.9 – 69.8) 3yrs35.7 (24.7 – 47.4)41.4 (30.2 – 53.1)24.1 (14.8 – 34.8)28.3 (18.4 – 39.4)Yes AZA 1yr18.1 (10.8 – 26.8)27.0 (18.3 – 36.6)55.1 (44.7 – 65.2)67.4 (57.4 – 76.7) 3yrs24.1 (15.7 – 33.5)33.9 (24.4 – 44.0)42.5 (32.5 – 52.9)48.0 (37.7 – 58.4)P=0.05P=0.06 Open table in a new tab Utilization of pre-HCT 5-aza is a feasible strategy and doesn’t appear to have any negative impact on HCT outcomes. Given the beneficial disease control facilitated by aza it should be offered to patients with high risk MDS being considered for a HCT.

Family History Of Hematologic Malignancies and Disorders In a Population Based Study Of Myelodysplastic Syndromes (MDS)

BackgroundMDS is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis and an increased risk for developing acute myeloid leukemia (AML). The majority of MDS cases are sporadic, but rare familial cases have been described and are often ascertained through clinic-based referrals. To our knowledge, no population based study of MDS has examined the frequency of family history of hematologic malignancies and disorders in patients, nor associations with disease characteristics and outcomes. MethodsNewly diagnosed MDS cases are being identified by rapid case ascertainment by the Minnesota Cancer Surveillance System (MCSS), a population-based cancer registry in Minnesota. Eligibility criteria include all newly diagnosed cases of MDS during the period April 1, 2010-October 31, 2014, between 20-85 years, Minnesota resident, and ability to understand English or Spanish. Proxy interviews are not being conducted. Medical records and biologic samples are obtained and questionnaires are filled out by participants. Centralized pathology and cytogenetics review confirm diagnosis and classify by subtype and risk score including the Revised International Prognostic Scoring System (IPSS-R). Since 2010, information on family history has been obtained through questionnaire responses and/or medical record review on 353 MDS patients. Cases were considered to have a positive family history if they reported a first degree relative with MDS, leukemia, lymphoma or other hematologic condition (multiple myeloma [n=4], Waldenstrom's macroglobulinemia [n=1] and idiopathic thrombocytopenic purpura [n=1]). Treatment related MDS cases were excluded leaving 330 MDS patients for analysis. Unconditional logistic regression was used to calculate crude odds ratios (ORs) and 95% confidence intervals (CI) overall and by sex. ResultsA total of 61/330 (18.5%) cases reported a family history of a hematologic condition. The mean age at diagnosis was 71.3 years in those with a family history compared to 72.2 years in those without a family history (p=0.53). There was no difference in the sex distribution between the two groups. Though not statistically significant, the odds of having abnormal cytogenetics or an IPSS-R of High/Very High was lower for those having a positive family history (OR 0.57 [CI 0.25-1.33, p=0.19 and 0.67 [CI 0.24-1.84, p=0.29], respectively). The odds of survival at one year after diagnosis was significantly higher in those with a family history (OR 2.79 [CI 1.04-7.51, p=0.04]) compared to those without (Table). Further stratification by sex revealed that this association was strongest for males (OR=4.23, [CI 0.94-19.0, p=0.06] compared to females (OR=1.84 [CI=0.47-7.19, p=0.38]). DiscussionIn this population based study of adults with MDS, the prevalence of MDS cases having a positive family history was higher than previous reports. Additionally, cases reporting a family history of hematologic malignancies and disorders appear to experience lower risk disease and have significantly improved overall survival, especially males. It is possible that patients with a family history of hematologic conditions are diagnosed earlier in the course of their disease secondary to increased awareness about blood disorders and/or more active screening within the family. Our analysis is limited by relatively small numbers, but enrollment is ongoing so subsequent analyses with larger numbers of subjects may be more revealing. Additionally, a prospective study to examine these families further, including detailed medical histories and collection of biospecimens (saliva, blood, skin) for genetic analyses is underway in order to identify potential mechanisms and mutations involved in the development of MDS and progression to AML. Disclosures:No relevant conflicts of interest to declare.TableVariableNo Family History (%)Positive Family History (%)OR (CI)p-valueAge group<60 years30 (11.2)7 (12.3)1.12 (0.46, 2.68)0.81≥60 years239 (88.9)50 (87.7)RefCytogeneticsAbnormal58 (41.7)9 (29.0)0.57 (0.25, 1.33)0.19Normal81 (58.3)22 (71.0)RefIPSS-RLow/VL47 (46.1)13 (50.0)RefIntermediate17 (16.7)6 (23.1)1.28 (0.42, 3.89)0.41High/VH38 (37.3)7 (26.9)0.67 (0.24, 1.84)0.29Autoimmune conditionYes89 (33.1)21 (36.8)1.18 (0.65, 2.14)0.59No180 (66.9)36 (63.2)RefSurvival 1 yrYes134 (72.0)36 (87.8)2.79 (1.04, 7.51)0.04No52 (28.0)5 (12.2)Ref

GATA2 Mutations In Nonsyndromic Pediatric Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is rare in children. Certain inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia, severe congenital neutropenia and Shwachman Diamond syndrome, markedly increase the risk of MDS during childhood. However, the genetic factor(s) underlying sporadic pediatric MDS are unknown. Germline mutations in GATA2, a hematopoietic transcription factor, explain four MDS-predisposing conditions: monocytopenia and mycobacterial infection (MonoMAC); dendritic cell, monocyte, B and NK cell lymphoid deficiency (DCML); primary lymphedema with myelodysplasia progressing to acute myeloid leukemia (Emberger syndrome); and a subset of familial MDS. Cases of pediatric MDS have been observed in some of the reported pedigrees. In addition, three individuals have been reported with large, de novo deletions encompassing GATA2 and surrounding genes and manifesting developmental delay, intellectual disability and dysmorphic features alongside their hematologic abnormalities. We identified a novel GATA2 splice site variant (c.1018-2A>C) in a teenager with MDS, WHO classification refractory cytopenia of childhood (RCC). Although he was found to have monocytopenia and B and NK cell deficiencies, he had no history of infections associated with MonoMAC or pertinent family history. We, therefore, hypothesized that mutations in GATA2 might be present in additional cases of pediatric MDS that were neither associated with an IBMFS nor relevant personal or family history.Two Baylor College of Medicine biology studies open to children with hematologic disease were queried for patients with the diagnosis of MDS. Exclusion criteria included treatment-related MDS, diagnosis of an IBMFS, prior diagnosis of severe aplastic anemia or infections suspicious for MonoMAC or DCML, and known or suspected family history of a GATA2-associated disorder. Cases lacking a pre-hematopoietic stem cell transplantation (HSCT) tissue sample available for study were also excluded. In addition to the patient described above, six children were identified who met eligibility criteria. DNA was isolated from banked peripheral blood or bone marrow cells and GATA2 sequencing performed, including upstream and intronic regulatory regions. Array comparative genomic hybridization was also performed on one sample that lacked GATA2 sequence variants, but was notable for complete absence of heterozygosity (AOH), including 6 polymorphic sites with minor allele frequencies of 0.20 or greater. Pertinent clinical and laboratory features were extracted by medical record review blinded to GATA2 status.We found heterozygous GATA2 mutations in three of the six additional patient samples. Thus, four of this seven patient, pediatric MDS cohort had mutated GATA2. Two of the newly identified mutations were splice site variants: a previously described c.1018-1G>A and a novel variant altering the exon 7 splice site acceptor (c.1114-1G>C). The third mutation was a de novo 3.1-3.3 Mb deletion encompassing the entire GATA2 locus and contiguous genes, and was established to be germline by analysis of skin fibroblasts. Notably, the patient had normal neurocognitive development and was without dysmorphic features. Their ages of presentation were 5, 9, 12 and 15 years. With the exception of the initial case, peripheral blood T and B cell phenotyping was not obtained prior to HSCT. Monocytopenia of less than 200/µL was present in five of seven patients, three of whom had a GATA2 mutation. All four GATA2 mutation cases had RCC and three of the four had monosomy 7 at diagnosis. In contrast, the three cases lacking GATA2 mutation presented with the MDS classification refractory anemia with excess blasts (RAEB-2), with either a normal karyotype, complex karyotypic changes or chromosome 13.q12q14 deletion.GATA2 mutation may explain a significant portion of sporadic, seemingly nonsyndromic pediatric MDS, particularly cases with monosomy 7. Evaluation of larger cohorts is warranted to ascertain the true prevalence. Although this cohort is small, we recommend GATA2 sequencing be performed as part of the initial evaluation of pediatric MDS as the identification of a germline mutation has critical implications for related donor selection and genetic counseling. AOH in GATA2 sequencing should prompt deletion analysis, even in cases without infections, dysmorphic features or neurocognitive impairment. Disclosures:No relevant conflicts of interest to declare.

An Update on Radioimmunotherapy for Lymphoma

SUMMARY Radioimmunotherapy is a promising treatment for B-cell lymphoma. 90Y-ibritumomab tiuxetan (Zevalin®) and 131I-tositumomab (Bexxar®) combine the potent antilymphoma effect of radiation with the specificity of antibody targeting. They have shown efficacy in follicular lymphoma in the setting of relapsed or refractory disease as consolidation regimens after first-line therapy, and in the front-line setting as single agents. Given their tolerability, they are actively being investigated as therapies or adjuncts for elderly patients with relapsed or high-risk diffuse large B-cell lymphoma. They have been added to autologous and allogeneic stem cell transplant preparatory regimens in early clinical trials with acceptable safety and efficacy. Early concerns over excess rates of treatment-related myelodysplastic syndrome and acute myelogenous leukemia have not come to fruition, but these questions remain to be fully answered. Ultimately, these are promising treatments for a variety of B-cell lymphomas. They are also models for the development of new radioimmunotherapies.