Therapy-related Myelodysplastic Syndrome Research Articles

Inhibition of Canonical WNT Signaling in the Bone Marrow Niche Prevents the Development of Disease in a Mouse MDS Model with Apc Haploinsufficiency

The myelodysplastic syndromes (MDS) include a spectrum of clonal hematopoietic stem cell (HSC) disorders that are characterized by ineffective hematopoiesis, peripheral cytopenia(s), morphologic dysplasia, and a variable propensity to transform to acute myeloid leukemia (AML). A del(5q) is the most common recurring cytogenetic abnormality in MDS, and is observed in 10-20% of primary MDS, and 40% of therapy-related MDS and AML. Our lab has had a long-standing interest in understanding how loss of function of tumor suppressor genes on 5q, such as APC, contributes to the pathogenesis of MDS and AML.Apc is a key negative regulator of the canonical β-catenin (Ctnnb1)/WNT signaling pathway.WNT signaling has been implicated in self-renewal of HSCs and the regulation of hematopoiesis, and the deregulation of WNT signaling is associated with the development of hematological malignancies. Recent data suggests that WNT activation in the bone marrow (BM) microenvironment or niche may also contribute to the development of AML. Kode et al. (Nature 506:240, 2014) showed that expression of activated β-catenin in osteoblast cells in the BM microenvironment leads to AML in mice. Thus, aberrant WNT signaling in HSCs and/or the microenvironment that supports them may contribute to malignant transformation. We previously used a conditional mouse model (Mx1-Cre+, Apc fl/+, referred to as Apcdel/+) and showed that haploinsufficiency of Apc leads to ineffective hematopoiesis (Blood 115:3481, 2010). Interestingly, haploinsufficient loss of Apc in the niche stromal cells, but not the hematopoietic progenitors, led to the development of MDS, characterized by a severe macrocytic anemia, dyserythropoiesis, megakaryocytic proliferation, and mild granulocytic dysplasia (Blood 123:228, 2014). In this study, we sought to determine whether haploinsufficient loss of Apc, mediates this disease through modulating WNT signaling, versus other Apc functions, and whether inhibition of WNT signaling could prevent the development of MDS in Apcdel/+mice.Here, we demonstrate thatsignaling through the canonical WNT pathway mediates the development of MDS in Apc haploinsufficient mice. Specifically, loss of one copy of Ctnnb1 is sufficient to prevent the development of MDS in Apcdel/+ mice. Compared to the median survival of Apc del/+ mice, which was 255 days, all Apc del/+, Ctnnb1del/+ mice survived until the end of the study (~400 days) (P<0.001). In addition, we showed that altered canonical WNT signaling in the BM microenvironment is responsible for the disease. Using bone marrow transplantation of wild type BM cells, we showed that Apc del/+ recipients develop MDS and die of a fatal anemia by ~4 months of age. In contrast, Apc del/+, Ctnnb1 del/+ recipients survived on average 8-10 months longer (median survival 115 vs 413 days, P <0.0001). To determine if we could prevent the development of MDS, we treated mice with the FDA-approved antihelminth drug, Pyrvinium, an inhibitor of the WNT pathway via activation of casein kinase 1 alpha and β-catenin degradation. Apc del/+mice in the control DMSO-treated group developed disease with a median survival of 227 days; however, during this time period, none of the Pyrvinium-treated mice became moribund. The mice succumbed to MDS about 100 days after Pyrvinium treatment was suspended, indicating that the drug prevented the development of disease, and must be continuously administered. We also showed that Pyrvinium treatment does not have to be administered before anemia develops; however, the drug is more effective when it is started in animals that display mild-to-moderate anemia rather than severe anemia.These studies have important implications for the treatment of certain forms of MDS. Kode et al. (Nature 506:240, 2014) showed nuclear accumulation of β-catenin in osteoblasts from ~40% of MDS/AML patients, supporting the idea that activated WNT signaling in the BM microenvironment may contribute to the development of disease. Targeting the tumor microenvironment is now recognized as a promising approach to complement current therapies, and our data highlight a potential new strategy of targeting the WNT signaling pathway for treating some forms of MDS. DisclosuresNo relevant conflicts of interest to declare.

Therapy-related myelodysplastic syndrome following primary breast cancer

BackgroundTherapy-related myelodysplastic syndrome (t-MDS) is a serious clinical disease occurring after breast cancer treatment. MethodsA cohort of 11,684 invasive breast cancer (BC) patients from 1990–2014 were followed for incidence of t-MDS through institutional and the Surveillance, Epidemiology and End Results (SEER) Program registries. t-MDS cases were identified using ICD-O SEER registry codes, pathology and chart reports. Treatment, cytogenetics, and time from BC diagnosis to t-MDS and t-MDS diagnosis to last follow up or death were obtained. Incidence rate ratios were calculated using SEER national incidence rates for comparison. Results27 cases of t-MDS post BC treatment were confirmed. 96% of cases were breast cancer stage I–II at diagnosis. All patients had received radiation treatment and 59% received adjuvant chemotherapy. Two patients were alive with no evidence of disease after treatment with stem cell transplantation (age 33 and 46). t-MDS incidence was 30 times the expected population rate among patients <55 years (RR 31.8, 95% CI 15.0, 60.8) with shorter time from t-MDS diagnosis to death (median survival time: <55: 8 months, 55–74: 26 months, 75+: 23 months). ConclusionWe found elevated t-MDS risk especially among younger BC patients with stem cell transplantation the only observed curative treatment.

Association of treatment for late-onset tMDS with glioblastoma recurrence in a patient displaying long-term disease response and survival.

e13506Background: Gene therapy with autologous, mutant methylguanine methyltransferase (MGMT) modified blood cells prevents myelosuppression from O6-benzylguanine and temozolomide (O6BG/TMZ) chemot...

Causes of death in 2877 patients with myelodysplastic syndromes.

Patients with myelodysplastic syndromes face a poor prognosis. The exact causes of death have not been described properly in the past. We performed a retrospective analysis of causes of death using data of 3792 patients in the Düsseldorf registry who have been followed up for a median time of 21months. Medical files as well as death certificates were screened and primary care physicians were contacted. Death after AML evolution, infection, and bleeding was considered to be clearly disease-related. Further categories of causes of death were heart failure, other possibly disease-related reasons, such as hemochromatosis, disease-independent reasons as well as cases with unclear causes of death. Median age at the time of diagnosis was 71years. At the time of analysis, 2877 patients (75.9%) had deceased. In 1212 cases (42.1%), the exact cause of death could not be ascertained. From 1665 patients with a clearly documented cause of death, 1388 patients (83.4%) succumbed directly disease-related (AML (46.6%), infection (27.0%), bleeding (9.8%)), whereas 277 patients (16.6%) died for reasons not directly related with myelodysplastic syndromes (MDS), including 132 patients with cardiac failure, 77 non-disease-related reasons, 23 patients with solid tumors, and 45 patients with possibly disease-related causes like hemochromatosis. Correlation with IPSS, IPSS-R, and WPSS categories showed a proportional increase of disease-related causes of death with increasing IPSS/IPSS-R/WPSS risk category. Likewise, therapy-related MDS were associated with a higher percentage of disease-related causes of death than primary MDS. This reflects the increasing influence of the underlying disease on the cause of death with increasing aggressiveness of the disease.

Patients With a History of Chemotherapy and Isolated del(20q) With Minimal Myelodysplasia Have an Indolent Course

Isolated deletion (20q) is relatively common in myeloid neoplasms and has been rarely reported in cases of therapy-related myelodysplastic syndrome (MDS). Our aim was to characterize cases of isolated del(20q) in bone marrow biopsy specimens from patients with a history of chemotherapy with morphologic findings insufficient for a diagnosis of MDS. In this retrospective study from one institution, we identified 22 patients with isolated del(20q) and no or minimal dysplasia and evaluated clinical and pathologic characteristics. Eleven of the patients had a history of chemotherapy for mostly lymphoproliferative disorders. There were no statistically significant differences in peripheral blood or bone marrow features between patients with a history of chemotherapy and those without. Three patients with a history of chemotherapy had died at last follow-up; cause of death was recurrent nonmyeloid neoplasm. None of the patients with a history of chemotherapy subsequently developed a high-grade myeloid neoplasm, whereas one of the patients who had not received prior chemotherapy developed refractory anemia with excess blasts 2. The presence of del(20q) as an isolated bone marrow cytogenetic abnormality in the absence of morphologic findings sufficient for a diagnosis of acute myeloid leukemia, myeloproliferative neoplasm, or MDS portends an indolent clinical course, regardless of previous exposure to chemotherapy.

Retroviral insertional mutagenesis identifies the del(5q) genes, CXXC5, TIFAB and ETF1, as well as the Wnt pathway, as potential targets in del(5q) myeloid neoplasms

An interstitial deletion of the long arm of chromosome 5, del(5q), is a recurring abnormality in myeloid disorders, including myelodysplastic syndromes (MDS), de novo acute myeloid leukemia (AML), and therapy-related myeloid neoplasms (t-MN) comprising therapy-related MDS and AML (t-MDS/t-AML).[1][1

Work up for the clopidogrel hypersensitivity that led to recognising the undiagnosed myelodysplastic syndrome.

Work up for the clopidogrel hypersensitivity that led to recognising the undiagnosed myelodysplastic syndrome.

Outcomes of Allogeneic Stem Cell Transplantation (alloSCT) for Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome

Outcomes of Allogeneic Stem Cell Transplantation (alloSCT) for Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome

A Case of Coexistence of Bone Marrow-involved Refractory Marginal Zone B-Cell Lymphoma and Therapy-related Myelodysplastic Syndrome

eISSN 2093-6338 indolent non-Hodgkin lymphoma (NHL), t-MNs have also been recognized as a fatal complication of chemotherapy, with significantly increased incidence [2]. Despite the prolonged survival of patients with indolent lymphomas due to the incorporation of immunochemotherapeutic drugs such as rituximab [3], repeated chemotherapies for persistent or refractory NHL have increased the incidence of t-MNs [4]. Thus, t-MNs have become an important cause of morbidity and mortality in patients with indolent lymphomas [2]. With the prolonged survival of patients with indolent lymphomas, the co-emergence of t-MNs could be more frequent. Here, we describe a patient with coexistence of bone marrow (BM)-involved refractory marginal zone B-cell lymphoma (MZL) and tMDS, who was treated with allogeneic hematopoietic stem cell transplantation (HSCT).

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.

Outcomes of Autologous Transplantation for Treatment-Related AML and MDS in Previously Treated Multiple Myeloma Patients (pts)

Introduction:Therapy related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) are significant long-term complications of MM treatment. We have treated pts on standard therapy protocols including TT2, TT3, TT4 and TT5. These protocols include an induction, tandem melphalan-based ASCT and consolidation, followed by three years of maintenance. As a part of the protocols, multiple bone marrow examinations including metaphase cytogenetics are performed at regular intervals, giving us the unique opportunity to examine the development of t-MDS/t-AML and understand the efficacy of subsequent treatment. Here we investigate the outcome of t-AML and t-MDS treated with autologous stem cell transplantation (ASCT) in MM patients.Materials and Methods, Results:During the period between 1998 to 2015, a total of 1558 pts were treated for MM with standard therapy protocols. We identified 68 pts out of 1558 who developed t-AML + t-MDS. Thirty-one had a confirmed diagnosis of t-AML, and thirty-seven had a diagnosis of t-MDS. The median age at diagnosis was 60 years (range 45-76). The median time from diagnosis MM of t-AML and t-MDS was 66 months (range, 9.6-155.4) and 63 months (range, 8-130), respectively. Baseline cytogenetics were as follows: complex cytogenetics in 34 pts out of 68, del(7) in 24 pts, del(5) in 17 pts, and del(17p) in 5 pts.Eighteen out of thirty-one t-AML pts were treated with ASCT. The remaining 13 pts did not receive ASCT. The treatment related mortality (TRM) at day100 (D100) in the ASCT group was 33% (6/18 pts). Neutrophil and platelet engraftment was achieved in all 18 pts by D21. Complete remission was achieved in 50% (9 out of 18) of pts. When we compared pts who received ASCT to those who were treated with chemotherapy only, the median overall survival (OS) was 11.28 months after ASCT vs 1.32 months without ASCT (p < 0.05). Nineteen out of thirty seven t-MDS pts were treated with ASCT. When we compared pts who received ASCT to chemotherapy only for t-MDS, there was no difference in survival between the groups. A mortality rate of 47% (9/19) was recorded at D200 after transplantation due to severe infections and lack of engraftment.Conclusion:t-AML and t-MDS treatment is a significant therapeutic challenge for the elderly, who often have poor risk cytogenetic markers, significant comorbidities and a compromised performance status. In our case series of post MM therapy t-AML, ASCT prolonged survival. In contrast, there was no change in survival of t-MDS pts, most likely due to high rate of infectious complications seen in this group. To our knowledge, this is the first analysis suggesting a survival benefit from ASCT in treating t-AML. Although the numbers in our study are small, we recommend that ASCT can be safely considered for t-AML patients who are physically fit, have autologous stem cells in storage and are overseen by a good supportive care team. These results need to be validated in large prospective studies. DisclosuresAtrash:University of Arkansas for Medical Sciences: Employment. Barlogie:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; International Workshop on Waldenström's Macroglobulinemia: Other: Travel Stipend; Dana Farber Cancer Institute: Other: Travel Stipend; Multiple Myeloma Research Foundation: Other: Travel Stipend; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC. Zangari:Onyx: Research Funding; Novartis: Research Funding; Millennium: Research Funding; University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Bailey:University of Arkansas for Medical Sciences: Employment. Petty:University of Arkansas for Medical Sciences: Employment. Heuck:Celgene: Consultancy; Janssen: Other: Advisory Board; Millenium: Other: Advisory Board; Foundation Medicine: Honoraria; University of Arkansas for Medical Sciences: Employment. Morgan:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; Weismann Institute: Honoraria; CancerNet: Honoraria; University of Arkansas for Medical Sciences: Employment; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jethava:University of Arkansas for Medical Sciences: Employment.

Impact of Hypomethylating Agent Therapy in Myelodysplastic Syndromes with Chromosome 3 Abnormalities

Background In myelodysplastic syndromes (MDS), abnormalities of chromosome 3 (i.e. inversion 3 (inv(3)), translocation 3q (t(3q)), or deletion 3q (del(3q)) represent a poor-risk karyotype in the Revised International Prognostic Scoring System (IPSS-R). In acute myeloid leukemia (AML) patients with 3q abnormalities, patients with inv(3)/t3;3 represented the most unfavorable group with a median overall survival (OS) of 10.3 months (Lugthart et al., 2010). We previously presented a single institution experience regarding outcomes of MDS patients with chromosome 3 abnormalities. Here, we sought to further define outcomes of chromosome 3 abnormalities in MDS and address the impact of hypomethylating agents (HMA) on outcome in multiple institutions.Patients and Methods Patients were identified through the MDS Clinical Research Consortium and were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality involving chromosome 3. Data analyzed included baseline demographics, disease characteristics, IPSS/IPSS-R scores, treatment and outcome. Responses to HMA therapy were evaluated using International Working Group (IWG) 2006 criteria. Kaplan-Meier estimates were used for overall survival.Results A total of 413 patients were identified with a median age at diagnosis of 67 years. WHO classification was as follows: 9% RA/RARS, 12% RCMD, 26% RAEB-1, 31% RAEB-2, 2% MDS/MPN, 7% MDS Unclassified, 13% AML; 34% had t-MDS. Overall, 97% of patients were higher risk by IPSS-R (i.e., intermediate to very high risk) with a median blast % in bone marrow of 8%. Distribution of cytogenetic abnormalities were inv(3) (10%), del(3q) (12%), t(3q) (18%), monosomy 3 (22%), 3p abnormalities (22%), and other chromosome 3 changes (17%). Median OS for the cohort was 12.0 months (95% C.I. 10.8 to 13.9 months) and 31% of patients without AML transformed to AML. IPSS-R was predictive of median OS across subgroups (P < 0.00001). The specific cytogenetic abnormality was predictive for survival (P < 0.00001) with median OS for t(3q) 19 months, inv(3) 13 months, del(3q) 13 months, 3p 10 months, monosomy 3 9 months, and other 3 abnormalities 11 months. There was no survival difference between patients with translocations of 3q21 versus 3q26 (median OS 18 months versus 18.6 months, P = 0.96). Patients with an isolated chromosome 3 abnormality had significantly improved OS (25.1 months versus 10.9 months (P < 0.00001). Complex karyotype (>/= 3 abnormalities) was observed in 74% of patients and was associated with decreased OS (11 months versus 21 months, P < 0.00001). Of patients who received HMA therapy (48%), the overall response rate was 46% (17% hematological improvement (HI), 7% PR, 20% CR, 2% marrow CR (CRm) with stable disease in 23%). Median OS with and without HMA was 15.5 months versus 8.4 months (p=0.038). In int-2/high risk patients by IPSS, HMA treated patient had a median OS of 14.0 months versus 7.6 months for patients not treated with HMAs (P = 0.005) with no benefit for HMAs in lower-risk patients (median OS 24.5 months with HMA versus 38.7 months without; P =0.41). Cox regression modeling with HMA therapy, IPSS and clinical site confirmed the HMA OS benefit in higher-risk patients (HR 0.69; 95% CI 0.53-0.89; P = 0.005), but showed decreased OS in lower-risk patients (HR 2.0; 95% CI 1.03-3.92; P = 0.04). Allogeneic transplantation was performed in 18% (n=75) of patients, with median OS of 18 months versus 10 months in non-transplanted patients (P < 0.00001).Conclusion In this large cohort of patients with MDS and oligoblastic AML associated with chromosome 3 abnormalities, survival was heterogeneous but overall poor, with isolated chromosome 3 abnormality and t(3q) patients having a more favorable OS than patients with other chromosome 3 anomalies. MDS patients with 3p changes have poor outcomes. Although some patients with chromosome 3 respond to HMA therapy, the overall survival remains poor and novel approaches are needed. DisclosuresSekeres:Amgen: Membership on an entity's Board of Directors or advisory committees; 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. Steensma:Amgen: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Lancet:Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau.

Increased p53 Expression in Patients with Therapy-Related MDS/AML Is Common and May be Associated with a Poor Prognosis

Therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) occur as a late complication of cytotoxic chemotherapy and/or radiation for neoplastic and non-neoplastic disorders and are a major cause of non-relapse mortality. The prognosis of t-MDS/AML is poor because of an increased incidence of adverse cytogenetic features and relative resistance/intolerance to conventional therapies. TP53 is a tumour suppressor and cell cycle regulatory protein. Mutations in the TP53 gene are known to be associated with adverse outcomes in a variety of cancers including haematological malignancies.We examined p53 expression using immunohistochemical staining, as a surrogate marker for TP53 mutation, in marrow biopsies of 39 patients with t-MDS/AML from a single institution and correlated p53 expression with survival. Formalin fixed, paraffin embedded marrow trephine samples at diagnosis of t-MDS/AML were stained with DO-7 mouse p53 monoclonal antibody. Positive expression was defined as per Modified Quick Score. Of 39 patients, 35 had t-MDS and 4 had t-AML. 51% of patients had marrows at diagnosis that showed p53 positivity and 49% were negative. In a control group of 47 MDS patients in our centre, 22% were p53 positive and 78% were p53 negative. Of the t-MDS/AML group, age at diagnosis and gender distribution was similar in p53 positive and negative patients. Median latency (time from diagnosis of primary malignancy to diagnosis of t-MDS/AML) was similar between p53 positive and negative patients (66 vs. 52 months, p=0.51). A similar distribution was noted for the type of primary tumours (haematological vs. solid tumour) among the two groups, but all patients with more than one prior malignancy were noted to be p53 positive (N=4) whereas all patients who developed t-MDS after cytotoxic therapy for non-neoplastic disorders were p53 negative(N=3). There was no difference in p53 expression based on the type of primary therapy received (chemotherapy and/or radiotherapy) but a greater proportion (71%) of patients who received combined chemotherapy and radiation was p53 positive. A higher proportion of p53 negative patients had lower risk cytogenetics and normal karyotype whereas in p53 positive group there was lower incidence of good risk and a higher proportion to intermediate risk cytogenetics. However, equal numbers of patients with higher risk cytogenetics were found between p53 positive and negative groups. These findings were again reflected by IPSS-R risk groups (Table 1). Median overall survival was 10.5 months in p53 positive group compared to 22.5 months in p53 negative patients, p= 0.208. (Figure 1)In conclusion, our study demonstrated that a higher proportion of patients with t-MDS/AML were positive for p53 than in de novo MDS which may be related to poor outcomes in this group. p53 positive t-MDS/AML patients tend to have lower incidence of favourable karyotypes and showed poor survival compared to their counterparts who were p53 negative. Analysis of p53 expression by immunohistochemistry is a readily accessible, cost-effective method of assessment without the need for expensive gene sequencing and is a clinically useful prognostic tool. It may be particularly useful in patients with t-MDS/AML.Table 1p53 expression in Therapy-related Myeloid Neoplasmsp53 Positive (N=20, 51%)p53 Negative (N=19, 49%)Primary TumourHaematological (22) Solid Tumour (10) Autoimmune disease (3) More than one disorder (4)45% 60% 0 100%55% 40% 100% 0Primary TherapyChemotherapy alone (27) Radiotherapy alone (5) Combined therapy (7)44% 60% 71%56% 40% 29%Cytogenetic RisksLow (very good, good) (14) Intermediate (8) High (poor, very poor) (12)29% 75% 50%71% 25% 50%IPSS-RLower (very low, low)(12) Intermediate (4) Higher (high, very high) (16)33% 75% 50%67% 25% 50% [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low-Dose Hypomethylating Agents (HMAs) Are Effective in Patients (Pts) with Low- or Intermediate-1-Risk Myelodysplastic Syndrome (MDS): A Report on Behalf of the MDS Clinical Research Consortium

Background: HMAs improve survival of pts with higher-risk MDS; however, the role of HMAs is less clear in pts with lower-risk MDS. These pts have a heterogeneous prognosis, and some may benefit from early HMA therapy. To test the hypothesis that low-dose HMA therapy would be safe and effective in pts with lower-risk MDS, we treated pts with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS with low-dose HMA regimens using 3 days of either 5-azacytidine (AZA) or decitabine (DAC). Methods: Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN were eligible for this study. Pts were treated with AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2 IV daily for 3 consecutive days on a 28-day cycle. The primary efficacy outcome was the overall improvement rate (OIR) defined as the composite of complete remission (CR), CR with insufficient hematologic recovery (CRi) and hematologic improvement (HI). Secondary outcomes included safety profile, duration of response, conversion to transfusion independence, event-free survival (EFS), and overall survival (OS). EFS was defined as the time to HMA failure, progressive disease, transformation to acute myelogenous leukemia (AML) or death from any cause. Chi-square test was performed to evaluate differences in response rates. EFS and OS were calculated using Kaplan-Meier estimates and compared using the log-rank test. Results: Between 11/2012 and 6/2015, 88 pts with lower-risk MDS were treated; 83 of them are currently evaluable for response assessment (65 MDS, 15 CMML and 3 MDS/MPN). Thirty pts received AZA (36%) and 53 pts (64%) received DAC. Median time from diagnosis to treatment was 5 weeks (range 1-272 weeks). Median age was 71 years (range 44-85 years). Sixteen pts (19%) had therapy-related MDS. Thirty-eight pts (46%) were transfusion-dependent for RBCs and/or platelets at baseline, and 17 pts (20%) had received prior growth factor support with erythropoietin-stimulating agents or G-CSF. By IPSS, 13 pts (16%) had low-risk and 70 pts (84%) had intermediate-1-risk disease. By the MDACC lower-risk scoring system, 38 pts (46%) had high-risk, 38 pts (46%) had intermediate-risk and 7 pts (8%) had low-risk disease. Twenty-seven pts (33%) had ≥5% bone marrow blasts. By IPSS, cytogenetics were good-risk in 55 pts (66%), intermediate-risk in 20 pts (24%) and poor-risk in 8 pts (10%). Mutation analysis was performed in 76 pts at the time of enrollment, 43 (57%) of whom had at least one molecular mutation. TET2 mutation was identified in 17 pts (22%), RUNX1 in 8 pts (11%), TP53 in 6 pts (8%), ASXL1 in 5 pts (7%), IDH1/2 in 5 pts (7%) and DNMT3A in 4 pts (5%). The median follow-up was 13 months (range 2-30 months) and median number of cycles received was 9 (range 2-29 cycles). The OIR for the entire cohort was 61%; 32 pts (39%) achieved CR, 11 (13%) achieved CRi and 8 (10%) achieved HI. Of the 38 transfusion-dependent pts at baseline, 9 (24%) became transfusion-independent. The median time to best response was 2.2 months (range 0.8 to 19.6 months). Median duration of response has not been reached with 71% of responders still on study. Low-dose HMA therapy was well-tolerated with only 6 pts (7%) requiring dose reduction and 19 pts (23%) requiring dose delay. AML developed in 4 pts (5%), and 17 pts (20%) have died. For the entire cohort, the 1-year EFS rate was 67%, and the 1-year OS rate was 86%. The median EFS and OS have not been reached. When stratified by IPSS and the MDACC lower-risk scoring systems, there was not a significant difference in OIR, EFS or OS among various risk groups (Table 1). Conclusions: Among pts with low- and intermediate-1-risk MDS, low-dose HMA therapy was well-tolerated and resulted in an OIR of 61%. Response rates, EFS and OS did not differ when pts were stratified by IPSS or the MDACC lower-risk scoring system. A randomized trial of low-dose AZA vs. DAC vs. best supportive care in lower-risk MDS is ongoing. Table 1. Response and survival rates by risk stratification Risk Stratification Risk Group N OIR (%) P (OIR) 1-year EFS rate (%) P (EFS) 1-year survival rate (%) P (OS) IPSS Low 13 54 0.540 83 0.751 86 0.295 Intermediate-1 70 63 65 85 MDACC Lower-Risk Scoring System Low 7 71 0.851 67 0.925 100 0.179 Intermediate 38 61 77 92 High 38 61 58 78 All Patients 83 61 67 86 Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Onconova: Consultancy. DiNardo:Novartis: Research Funding. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Verstovsek:Incyte Corporation: Research Funding.

Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Allografting versus Autografting for Follicular Lymphoma: An Ongoing Conundrum.

It has been more than 2 decades since the initial reports on autologous transplantation for follicular lymphoma [1,2]. These studies were paradigm changing because they provided the first evidence of a curative therapy in this chronically relapsing illness. However, autologous transplantation was effective in only a fraction of carefully selected patients with chemotherapy-sensitive disease. Relapse rates were high, possibly caused by infusion of occult lymphoma cells [3]. Therapy-related myelodysplastic syndrome/acute myeloid leukemia, mostly occurring in the first 5 years after transplant, emerged as a considerable problem, attributable to conditioning, to prior treatment, and possibly to stem cell mobilization method [4,5]. Allogeneic transplantation was soon found to have a very low incidence of disease recurrence but also a high early mortality [6]. Three prior studies have compared autologous and allogeneic transplantation with consistent conclusions: allogeneic transplantation has much higher treatment-related mortality, regardless of conditioning intensity, but lower rates of recurrence [7-9]. In this issue, Klyuchnikov et al. [10] address the same issue again, from a somewhat different angle: They include only patients with prior exposure to rituximab, only allo-transplants undergoing reduced-intensity conditioning, and limit their analysis to patients with follicular grades I and II disease. They find that allogeneic transplant recipients tend to have more advanced disease, die much more frequently from complications, and relapse less. Patients with high lactate dehydrogenase and poor

T(3;8)(q26;q24) With MYC Rearrangement in Acute Myeloid Leukemia: A Case Report

Rearrangements of 3q26 have been described in 5% of de novo or therapy-related acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and blast phase of chronic myeloid leukemia. The most common translocations involving 3q26 are t(3;12)(q26;p13), t(3;21)(q26;q22), t(3;3)(q21;q26), t(2;3)(p15∼23;q26∼27), and rarely, t(3;7)(q26;q21). However, t(3;8)(q26;q24) with or without monosomy 7 is …

An analysis of the demographic profile, clinical manifestations, investigations and outcome of paediatric myelodysplastic syndrome: A single centre, cross-sectional study

Purpose: Pediatric myelodysplastic syndrome (MDS) is a relatively rare entity, with distinct clinical features and more aggressive course than its adult counterpart. The aim of this study was to analyze the incidence of pediatric myelodysplastic syndrome at a tertiary cancer care center in southern India along with clinical manifestations, investigations and outcome. Methods: On retrospective analysis of 1094 cases of pediatric hematological malignancies over a five-year period from September 2009 to August 2014, a total of seven cases of pediatric myelodysplastic syndrome were identified. Presenting complaints, physical examination, investigations including haemogram, biochemistry, bone marrow examination and cytogenetics were reviewed. The diagnosis of MDS was made if there was dysplasia in at least 10% of cells in two or more cell lineages. All patients were risk stratified using the revised IPSS. Results: Out of 1094 cases of pediatric hematological malignancies presenting at our institute within the study period, there were only seven cases of pediatric MDS with an incidence of 0.65%. There were no genetic predispositions nor any cases of therapy related MDS. The most common presentation was with fever and all patients had significant splenomegaly. All patients had anemia (Median-6.2 gm / dL) with elevated WBC counts (Median-30,900 / uL) and thrombocytopenia (Median-50,000 / uL). The marrow cytogenetics was normal in five patients. Most patients fell into the high and very high-risk category of the revised IPSS, with only two patients of low risk. All seven patients were given only supportive care but one progressed to AML for which he was treated with remission induction. Only two patients were alive at the time of analysis and median survival was 9 months. Conclusion: Pediatric MDS is a rare disease with a short clinical history, aggressive course and generally poor outcomes as compared to the adult variant. A hematopoietic stem cell transplant may be the only viable option for survival.

Non-hematologic predictors of mortality improve the prognostic value of the international prognostic scoring system for MDS in older adults.

The International Prognostic Scoring System (IPSS) is commonly used to predict survival and assign treatment for the myelodysplastic syndromes (MDS). We explored whether self-reported and readily available non-hematologic predictors of survival add independent prognostic information to the IPSS. Retrospective cohort study of consecutive MDS patients ≥age 65 who presented to Dana-Farber Cancer Institute between 2006 and 2011 and completed a baseline quality of life questionnaire. Questions corresponding to functional status and symptoms and extracted clinical-pathologic data from medical records. Kaplan-Meier and Cox proportional hazards models were used to estimate survival. One hundred fourteen patients consented and were available for analysis. Median age was 73 years, and the majority of patients were White, were male, and had a Charlson comorbidity score of <2. Few patients (24%) had an IPSS score consistent with lower-risk disease and the majority received chemotherapy. In addition to IPSS score and history of prior chemotherapy or radiation, significant univariate predictors of survival included low serum albumin, Charlson score, performance status, ability to take a long walk, and interference of physical symptoms in family life. The multivariate model that best predicted mortality included low serum albumin (HR=2.3; 95% CI: 1.06-5.14), therapy-related MDS (HR=2.1; 95% CI: 1.16-4.24), IPSS score (HR=1.7; 95% CI: 1.14-2.49), and ease taking a long walk (HR=0.44; 95% CI: 0.23-0.90). In this study of older adults with MDS, we found that low serum albumin and physical function added important prognostic information to the IPSS score. Self-reported physical function was more predictive than physician-assigned performance status.

Chromosomal 3 Abnormalities in Myelodysplastic Syndromes: Implications on Prognosis and Response to Treatment

Abstract Background: Cytogenetic abnormalities are the most powerful co-variates in myelodysplastic syndromes (MDS) prognostic models. In the revised international prognostic scoring system (R-IPSS), abnormalities of chromosome 3 (i.e. inv(3), t(3q), del(3q)) represent a poor risk karyotype and this derivation alone translates to higher risk disease for risk of acute myeloid leukemia (AML) transformation and decreased overall survival (OS). In the recent World Health Organization (WHO) MDS pathology classification meeting, a proposal was entertained to classify MDS with chromosome 3 abnormalities as a separate entity. There is only minimal data to support such classification and chromosome 3 karyotype data regarding response to hypomethylating agents (HMA) or allogeneic transplantation is limited. In response to this proposal, we examined outcomes of MDS patients and chromosome 3 abnormalities. Patients and Methods: MDS patients with chromosome 3 abnormalities were identified through the Moffitt Cancer Center MDS database (n=1900). Patients were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality in chromosome 3. MDS data included baseline demographics, disease characteristics, treatment and outcome. Response was evaluated by IWG 2006 criteria. Kaplan-Meier estimates were used for overall survival Results: A total of 129 patients were identified in our cohort with a median age of 70 years. WHO classification was as follows: 8% RA/RARS, 18% RCMD, 40% RAEB-1, 29% RAEB-2, 4% MDS/MPN, 1% AML. One third of the patients had t-MDS. Overall, 92% of patients were higher risk by R-IPSS (intermediate to very high risk) with a mean blast % in bone marrow of 7.2%. Distribution of cytogenetic abnormalities were inv(3) (7%), del(3q) (18%), t(3) (18%), monosomy 3 (19%), 3p abnormalities (15%), and other chromosome 3 changes (23%). Median OS for the cohort was 17.4 months (95% C.I. 14.6 to 20.2 months) and 51% of patients transformed to AML. R-IPSS was predictive for median OS across subgroups (p=0.04). Of interest, cytogenetic abnormality was predictive for survival (p=.001) with median OS as follows: inv(3) (30 months), t(3) (26 months), 3p (22 months), del(3q) (17 months), other (17 months) and monosomy 3 (13 months). Complex karyotype (>/= 3 abnormalities) was observed in 68% of patients and correlated with decreased OS (14 months versus 30 months, p Conclusion: To our knowledge, this is the largest cohort reported to date describing MDS patients with chromosome 3 abnormalities. These patients have a poor prognosis and very high rate of leukemic transformation. However, survival was heterogeneous based on the specific cytogenetic abnormality with inv(3) having more favorable overall survival. Azacitidine therapy is effective in this population. Although the median OS is similar to patients with poor karyotype on the AZA-001 study, the ORR is less than expected. Allogeneic transplantation has significant impact on improved OS but is only an option for a subset of patients. Disclosures Lancet: Celgene: Consultancy. List: Celgene: Consultancy. Komrokji: Celgene Corporation: Consultancy, Research Funding.