Development of Anti-IL-1R3 Monoclonal Antibodies for Treating Cancer and IL-1 Family-Mediated Inflammation

Abstract IL-1R3 is the co-receptor required for signaling of IL-1β, IL-1α, IL-33 and IL-36α, β and γ. The naturally occurring IL-1 receptor antagonist (anakinra), is used to block IL-1β, and IL-1α and clinical trials have demonstrated a reduction in progression to multiple myeloma as well as increased overall survival in stage IV pancreatic cancer using anakinra. In addition, a monoclonal antibody that targets IL-1α increases overall survival in metastatic colorectal cancer. However, blocking IL-1R3 would reduce not only IL-1β and IL-1α but also IL-33 as well as IL-36α, β and γ. The data described below reveal the broad efficacy of anti-IL-1R3. In the present studies, monoclonal humanized anti-IL-1R3 antibodies were studied in the mixed leukocyte reaction (MLR), in peripheral mononuclear cells (PBMC) stimulated with LPS, heat-killed Candida albicans or anti-CD3/antiCD28 as well as in THP-1 cells, a cell line derived from a patient with acute myeloid leukemia (AML). In the MLR, anti-IL-1R3 at 5 µg/mL reduced IFNγ by 81% and IL-6 by 48% compared to 36% by anakinra. In LPS-stimulated PBMCs, IL-6 was reduced by 40% and 58% with anakinra and anti-IL-1R3 respectively. Using heat-killed Candida, the suppression of IL-6 production by anti-IL-1R3 was up to 70%, comparable to anakinra. Immuno-stimulation using anti-CD3/CD28 resulted in a similar inhibition capacity for anakinra (42%) and anti-IL-1R3 (45%) on IL-6 production also. Since neutralizing anti-IL-1α antibodies have increased overall survival in metastatic colorectal cancer, we also measured the effect of anti-IL-1R3 on intracellular levels of IL-1α. In PBMCs stimulated with LPS, the levels of IL-1α were reduced by 35% in cells cultured with anakinra at 10 µg/mL and by 66% in cells exposed to anti-IL-1R3 at same concentration. Activating PBMCs with anti-CD3/anti-CD28 led to a reduction in IL-1α by anakinra of 17%, whereas anti-IL-1R3 suppressed by 29%. We next examined the effect on THP-1 cells as a model for blocking IL-1 family members in AML. THP-1 were differentiated with phorbol myristate acetate (PMA) for 3 hours, washed and subsequently rested for 3 days. The cells were then stimulated with LPS for 3 hours and anti-IL-1R3 was added for 1 hour followed by inflammasome activation with ATP. The reduction in secretion of IL-1β was here 30% at 5 µg/mL of anti-IL-1R3. Collectively, these studies indicate that antibody blockade of IL-1R3 is effective in reducing cytokines from primary cells using in-vitro models of organ rejection, infection and immunostimulation. In THP-1 cells, the reduction in inflammasome-dependent IL-1β suggests that anti-IL-1R3 can be used to treat acute myeloid leukemia, or progression to multiple myeloma. Since anti-IL-1R3 inhibits the signaling through IL-1R1, both IL-1α and IL-1β are targeted by this antibody. Suggesting a future role for this antibody in not only AML, but also other cancer types dominated by IL-1 mediated inflammation, such as metastatic colorectal and pancreatic cancer. Disclosures Fischer: MAB Discovery GmbH: Employment. Pollyea:Ariad: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Glycomimetics: Other: DSMB member; Alexion: Other: advisory board; Celgene: Other: advisory board, Research Funding.

Download Full-text

Acute Myeloid Leukemia in Western Kenya: A Snapshot

Blood ◽

10.1182/blood-2021-153626 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1223-1223

Author(s):

Christopher Mwaniki Wanjiku ◽

Beatrice Melly ◽

Carole Kilach ◽

Teresa Cherop Lotodo ◽

Kristin Binz ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Supportive Care ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Resource Limited Settings ◽

Western Kenya ◽

Resource Limited ◽

Acute Myeloid

Abstract Introduction: Steady advances in the treatment of acute myeloid leukemia (AML) have improved outcomes in high-resource settings, with a 5-year overall survival rate of 29% and rising in the United States. In contrast, a diagnosis of AML in many resource-limited settings automatically confers a less than 10% one-year survival rate. To better understand this significant disparity, as well as how to narrow it, it is important to gather data illustrating the current landscape of AML management in resource limited-settings, including patient characteristics, disease-related and treatment-related factors. Here we examine the population of patients with AML at a single large academic medical center in Western Kenya that serves a catchment area of more than 20 million people. Objectives: To describe characteristics of patients presenting with AML at Moi Teaching and Referral Hospital (MTRH) hematology and oncology clinic between 2014 and 2020, to help identify areas of need to inform future interventions. Methodology: Retrospective, cross-sectional chart review study of all newly diagnosed patients (age 15 years and older) with AML presenting to the MTRH adult hematology and oncology clinic from January 2014 to December 2020. Results: We reviewed the charts of 113 patients with AML. The median age at diagnosis was 40 years (range 15-86 years), with an average age of 42 years. Forty-nine percent (n=55) were female. Thirty-five patients did not have French American British (FAB) subtypes documented (this method remains the main form of AML disease classification in this resource-limited setting). M2 subtype was the most common (n= 24). Seven patients had acute promyelocytic leukemia (APML), of which 4 died due to bleeding complications and lack of access to ATRA. Three APML patients who had access to ATRA were alive more than 1 year after diagnosis. White blood count (WBC) at diagnosis ranged between 600/cm3 and 336,000/cm3 with neutrophil predominance. Mean hemoglobin at presentation was 7g/dl (range 2.6g/dl-16g/dl). Most patients had been transfused with red blood cells prior to presentation and continue to require more transfusion. Platelet counts ranged between 4,000/cm3 to 782,000/cm3 with 36% of patients (n=41) having a count of less than 50,000/cm3. Fifty patients with AML received low dose subcutaneous cytarabine (20mg subcutaneous twice a day for 10 days every 4 to 6 weeks) and 3 patients had etoposide added to their treatment (50mg/m2 intravenous once a day for 7 days). No patient was treated with standard intensive induction chemotherapy, (7+3), due to lack of adequate supportive care. Only 5 of 63 (7.9%) non-APML patients whose outcomes were established survived for more than 12 months. The median overall survival at after diagnosis was 45 days. Thirteen percent of patients were lost to follow up (n= 15) and 1 patient was referred to another facility for possible induction with 7+3. Conclusion: AML remains a disparately lethal disease in resource-limited settings, where it impacts a relatively healthy, young patient population. In well-resourced settings, many of these patients would have a reasonable chance at long term survival and potential cure, but in Western Kenya most patients die within a few months of diagnosis. Due to the lack of adequate supportive care resources, even the younger patients mostly did not receive standard-of-care intensive induction therapy. The outdated FAB classification system is still in use. Lack of access to improved diagnostics, appropriate supportive care (antimicrobials and transfusion products) and limited availability of newer, effective, and less toxic treatment regimens are the main impedance to care. More efforts are needed to improve the management of acute leukemia in under-resourced countries. Disclosures LeBlanc: Pfizer: Consultancy, Other: Advisory Board; Otsuka: Consultancy, Honoraria, Other; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Flatiron: Consultancy, Other: Advisory board; Helsinn: Consultancy, Research Funding; Duke University: Research Funding; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Amgen: Consultancy, Other: travel; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Other: Advisory board; American Cancer Society: Research Funding; Heron: Consultancy, Honoraria, Other: advisory board; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; Seattle Genetics: Consultancy, Other: Advisory board, Research Funding; CareVive: Consultancy, Other, Research Funding; NINR/NIH: Research Funding; UpToDate: Patents & Royalties.

Download Full-text

Targeted Intravenous Busulfan and Fludarabine Allogeneic Transplantation Conditioning in Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.2290.2290 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2290-2290

Author(s):

Joseph A. Pidala ◽

Jongphil Kim ◽

Claudio Anasetti ◽

Melissa Alsina ◽

Ernesto Ayala ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Large Series ◽

Myelogenous Leukemia ◽

Secondary Aml ◽

Relapsed Disease ◽

Acute Myeloid

Abstract Abstract 2290 Poster Board II-267 Reduced and intermediate intensity conditioning with allogeneic hematopoietic cell transplantation (HCT) offers promise to effectively control hematologic malignancies, while limiting treatment related toxicity and mortality (TRM). We aimed to examine the efficacy of IV targeted Busulfan and Fludarabine (IV-Bu/Flu) in a large series of adults with exclusively acute myelogenous leukemia (AML). One hundred adults (median age 48) with AML (CR1 49, CR2 25, REL1 8, REL2 1, PIF 16, untreated 1) were treated with Busulfan 130-145 mg/m2/day for four days with pharmacokinetic targeting on the final two days to achieve an area under the curve (AUC) of 5300 (+/-10%) μmol*min/L/day and Fludarabine 40mg/m2/day for 4 days, followed by transplantation of G-CSF mobilized peripheral blood stem cells (PBSC) (N=98) or unstimulated bone marrow (BM) (N=2) from allogeneic donors (MRD 38, MUD 38, MMUD 24). Acute GVHD prophylaxis consisted of tacrolimus/methotrexate (N = 77), tacrolimus/mycophenolate mofetil (N = 22), or tacrolimus/sirolimus (N = 1). Median time to neutrophil and platelet engraftment was 16 and 12 days, respectively. Non-relapse mortality was 3% at 100 days, and 15% by 1 year. The cumulative incidence of relapse was 41%. Overall survival (OS) was 59% (95% CI: 48.1 – 67.5) at 1 year, and 42% (95% CI: 30.8-53.3) at 4 years. OS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 52.9%, 40.1%, 41.2%, and 57.5% respectively; none with relapsed disease survived to 4 years (log-rank p = 0.0014). Progression-free survival (PFS) was 53% (95% CI: 42.8 – 62.2) at 1 year, and 32.3% (95% CI: 21.8 – 43.2) at 4 years. PFS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 44.1%, 33.4%, 33.9%, and 33.1%, respectively, while none with relapsed disease at transplant reached this endpoint (p = 0.0264). On multivariable modeling, remission status at HCT (relapsed disease HR 14.85 (95% CI: 2.12 - 104.2), p = 0.007), moderate/severe cGVHD (HR 0.281, 95% CI: 0.10 - 0.76; p = 0.013), and day 90 bone marrow (BM) chimerism ≥ 90% (HR 0.245, 95% CI: 0.08 - 0.79; p = 0.018) predicted overall survival, and day 90 BM chimerism ≥ 90% (HR of 0.18 (95% CI: 0.08 - 0.45), p = 0.0002) predicted PFS. The following were not significantly related with OS or PFS: age, cytogenetics, donor relation, number of induction cycles, aGVHD prophylaxis regimen, maximum aGVHD grade, WBC at diagnosis, time in first CR, or % BM blasts prior to transplant. Day 90 BM chimerism and cGVHD were significantly related with relapse. Maximum grade of aGVHD predicted non-relapse mortality. These data support the low TRM and efficacy of IV-Bu/Flu in a large series of exclusively AML patients, and demonstrate the impact of day 90 bone marrow chimerism as an important prognostic factor. Further efforts to mitigate relapse risk after HCT are warranted, particularly in those with advanced disease at time of transplant. Disclosures: Off Label Use: IV busulfan and fludarabine for the treatment of acute myeloid leukemia. Alsina:Ortho Biotech: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau. Field:PDL BioPharma: Research Funding. Fernandez:Otsuka: Honoraria.

Download Full-text

Lack of Association of Mutations in IDH1, IDH2, DNMT3A with Outcome in Older Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents (± Histone Deacetylase Inhibitors).

Blood ◽

10.1182/blood.v120.21.2483.2483 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2483-2483

Author(s):

Farhad Ravandi ◽

Keyur P. Patel ◽

Rajyalakshmi Luthra ◽

Sherry A. Pierce ◽

Gautam Borthakur ◽

...

Keyword(s):

Valproic Acid ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Histone Deacetylase ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Hypomethylating Agents ◽

Idh Mutations ◽

Acute Myeloid

Abstract Abstract 2483 Background: Mutations of several genes believed to be important in the methylation apparatus of the cell have been recently described in patients with acute myeloid leukemia (AML) but their presence has not been correlated with a worse or better outcome using hypomethylating agents. Methods: We evaluated the association of mutations in IDH1, IDH2, DNMT3A, and EZH2 with the outcome [complete response (CR) rate, event free survival (EFS) and overall survival (OS)] among patients older than 60 with AML (≥ 20% blasts) treated with hypomethylating agents as their first line of treatment. TET2 mutations were not evaluated due to lack of available material. Results: Among the 68 patients (median age 72 years; range, 60 – 83) with available data, 11 patients (16%) had IDH1 or IDH2 mutations (mutually exclusive) and 10 patients (15%) had DNMT3A mutations with 5 patients (7%) having both IDH and DNMT3A mutations. Cytogenetics was diploid in 19 (28%), abnormal chromosome 5/7 and/or complex in 27 (40%), trisomy 8 in 5 (7%), miscellaneous in 14 (21%), and insufficient in 3 (4%). Presence of IDH mutations was associated with a diploid karyotype and the presence of NPM1 mutations (p=.03 and p=.02, respectively) but not with FLT3- ITD or RAS mutations (present in 7 and 4 patients, respectively). DNMT3A mutations were not associated with any specific karyotype or with the presence of NPM1, FLT3-ITD, or RAS mutations. None of the 68 patients had EZH2 mutations. All patients were treated with hypomethylating agents [decitabine in 39 (57%) and 5-azacytidine in 29 (43%)] with 42 patients (62%) receiving concomitant histone deacetylase inhibitor therapy (SAHA or valproic acid). Overall, 17 patients (25%) achieved CR; the presence of IDH or DNMT3A mutations or both was not associated with achievement of CR. With a median duration of follow-up of 60 months, the median EFS is 3.3 months (range, 0.25 – 3.75 months) and the median overall survival is 6 months (range, 0.25 – 90.5 months). Presence of IDH mutations was not associated with an impact on EFS (p=.29) or OS (p=.14). Similarly, DNMT3A mutations were not associated with an effect on EFS (p=.21) or OS (p=.58). The presence of both IDH and DNMT3A mutations was also not associated with a better or worse response, EFS, or OS as compared with patients with neither mutation. Conclusion: We were not able to detect an association between presence of IDH1/2 and DNMT3A mutations and outcome in this elderly population of patients with AML treated with epigenetic modulators. Disclosures: Ravandi: Johnson and Johnson: Honoraria; Celgene: Research Funding. Off Label Use: Use of decitabine, 5-azacytidine, SAHA, and valproic acid in the treatment of older patients with AML. Garcia-Manero:Celgene: Research Funding. Cortes:Celgene: Research Funding; Eisai: Research Funding.

Download Full-text

High Expression of Myocyte Enhancer Factor 2C (MEF2C) Is Associated with Adverse Risk Features and Poor Outcome in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽

10.1182/blood.v126.23.2570.2570 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2570-2570

Author(s):

George S. Laszlo ◽

Todd A. Alonzo ◽

Chelsea J. Gudgeon ◽

Kimberly H. Harrington ◽

Alex Kentsis ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Event Free Survival ◽

Free Survival ◽

Expression Levels ◽

Acute Myeloid ◽

Enhancer Factor

Abstract Background: Myocyte enhancer factor 2C (MEF2C) was initially identified as essential transcription factor for cardiac muscle development. However, subsequent studies have indicated that MEF2C plays a much broader biological role, including in the normal hematopoietic system. Recent studies have now identified MEF2C as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML. These findings raised the possibility that MEF2C could serve as marker of poor-risk disease and, therefore, have prognostic significance in AML. To test this hypothesis, we retrospectively quantified MEF2C expression in participants of the AAML0531 trial and correlated expression levels with disease characteristics and clinical outcome. Patients and Methods: AAML0531 (NCT00372593) was a multicenter phase 3 study that determined the addition of gemtuzumab ozogamicin to intensive chemotherapy among 1,022 eligible patients aged <30 yearswith newly diagnosed de novo non-APL AML, excluding those with bone marrow failure syndromes, juvenile myelomonocytic leukemia, or Down syndrome (if ≤3 years of age) between 2006 and 2010. Cryopreserved pretreatment ("diagnostic") specimens from patients enrolled on AAML0531 who consented to the biology studies and had bone marrow samples were available were included in this study. Total RNA from unsorted specimens was extracted, quantified, and subjected to quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) using TaqMan primers to determine expression of MEF2C and, for normalization, the housekeeping gene, β-glucuronidase (GUSB). Patient samples were run in duplicate, and the ΔΔCT method quantified as 2(-ΔΔCT) was used to determine the expression levels of MEF2C relative to GUSB. Results: In all 751 available patient specimens, MEF2C mRNA was detectable and varied >3,000-fold relative to GUSB (0.0091-29.1272 [median: 0.7978]). Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67% vs. 78%, P=0.005). They also had an inferior overall survival (P=0.014; at 5 years: 55±8% vs. 67±4%), inferior event-free survival (P<0.001; at 5 years: 38±7% vs. 54±4%), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P<0.001; at 5 years: 53±9% vs. 35±5%). Of note, exploratory multiple cutpoint analyses for overall and event-free survival indicated that the most statistically significant results were centered around the Q4 cutpoint region, supporting our approach of comparing patients with the highest quartile of relative MEF2C expression with those having lower relative MEF2C expression. Importantly, MEF2C expression was strongly associated with cytogenetic and molecular abnormalities. Specifically, patients with high MEF2C expression less likely had CBF translocations (inv(16): P=0.007, and t(8;21): P<0.001) or normal karyotype AML (P<0.001); conversely, they were more likely to have leukemia with monosomy 7 (P<0.001) and abnormalities involving 11q23 (P<0.001). Furthermore, patients with high MEF2C less likely had a FLT3/ITD (P =0.018) or a mutation in either NPM1 (P=0.010) or CEBPA (P =0.002). Consistently, patients with high MEF2C expression less likely had low-risk disease (16% vs. 46%, P<0.001) and more likely had standard-risk disease (68% vs. 42%, P <0.001) than those with lower MEF2C expression. Indeed, after adjustment for disease risk, age, FAB category, and treatment arm, high MEF2C expression was no longer statistically significantly associated with inferior overall survival (hazard ratio [HR]=0.99 [95% confidence interval: 0.72-1.36], P=0.929), inferior event-free survival (HR: 1.14 [0.86-1.49], P=0.365), or higher relapse risk (HR: 1.32 [0.91-1.92], P=0.137), suggesting that MEF2C cooperates with additional pathogenic abnormalities. Conclusion: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. These findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML. Disclosures Walter: AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Pfizer, Inc.: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

Download Full-text

Outcomes By Best Response with Hypomethylating Agent Plus Venetoclax in Adults with Previously Untreated Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-149782 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2292-2292

Author(s):

Virginia Olivia Volpe ◽

Akriti G Jain ◽

Onyee Chan ◽

Eric Padron ◽

David A. Sallman ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Free State ◽

Advisory Committees ◽

Best Response ◽

Baseline Characteristics ◽

Acute Myeloid

Abstract Background: Venetoclax plus hypomethylating agents (HMA) (HMA+VEN) is a standard of care treatment for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. In the phase 3 VIALE-A trial, azacididine (aza)+VEN compared to aza alone demonstrated an improved overall survival of 14.7 months versus 9.6 months, respectively. A common toxicity with HMA+VEN is myelosuppression. The prognostic implications of incomplete count recovery despite leukemia free state after HMA+VEN treatment in AML is unclear. We aimed to compare the outcomes of those who achieved complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) in AML patients treated frontline with HMA+VEN. Methods: Patients seen at Moffitt Cancer Center between 2019 and 2021 diagnosed with AML and treated with frontline HMA+VEN were retrospectively evaluated and included for analysis. Patients were stratified by best response; either CR, CRi, or MLFS. Baseline characteristics were compared by chi square (categorical variables) and t- test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Results: Of the 102 patients treated with HMA+VEN in the frontline setting, 48% (n=49) had blast clearance with a best response of CR in 27/102 (26.4%), CRi in 16/102 (15.7%), or MLFS in 6/102 (5.9%). The remainder had residual disease. Baseline characteristics were similar among the three response groups (Table 1) as was mutational distribution (Table 2). There was no difference between AML WHO classification subtype (p= .148). Decitabine or aza was used at the discretion of the treating physician did not significantly impact responses (p= .225). In those who achieved CR, 14% had prior therapy related AML compared to 37.5% in CRi and 33.3% in MLFS (p= .314). Antecedent MDS or MPN with transformation to AML was seen in 22.2%, 18.8%, and 66.7% of CR, CRi, and MLFS respectively (p= .029). Of those, 3.7% in CR group had HMA use for prior MDS/MPN compared to 0% in CRi and 50% in MLFS (p= .000). The median relapse free survival was not reached for CR, CRi, and MLFS (Figure 1), it is important to note that 3 of the 6 MLFS patients died without relapse . At median follow up of 23 months, median overall survival (OS) in the CR group was significantly longer, 31 months, compared to 18 months in the CRi group and 8.5 months in the MLFS group (p=0.0415) (Figure 2). Transplant was achieved in 26% of CR and 6.3% of CRi and 0% of MLFS and was not significant among the groups (p = .124). Conclusion: Patients who received frontline HMA+VEN for AML directed therapy and achieved CR/CRi had better survival compared to those who achieved MLFS. Our data suggest that incomplete recovery of blood counts plays a significant role in overall survival regardless of leukemia free state. Further, the data demonstrate significantly higher secondary AML with antecedent MDS or MPN in the MLFS group compared to CR and CRi groups. Of those, prior HMA therapy was also identified as significantly higher in the MLFS group compared to CR and CRi groups which may contribute to the prolonged cytopenias and worse OS. While the limitation to this study is overall small number of patients, it suggests that a goal of CR over CRi or MLFS is desirable for superior OS. In the future, it would be of interest to incorporate the rates of responses and variables that may have an impact such as therapy dose adjustment, time to response, and delays in therapy due to cytopenia. Additional studies identifying dose adjustments or other ways to improve hematologic recovery would be valuable to potentially improve outcomes in this difficult to treat population. Figure 1 Figure 1. Disclosures Padron: Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Kura: Research Funding. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Updated Results of a Randomized Phase II Trial of Idarubicin and Cytarabine with Clofarabine or Fludarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.1067.1067 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1067-1067

Author(s):

Nicholas J. Short ◽

Farhad Ravandi ◽

Xuelin Huang ◽

Jorge E. Cortes ◽

Naveen Pemmaraju ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Cell Transplant ◽

Newly Diagnosed ◽

Historical Cohort ◽

To Receive ◽

Acute Myeloid

Abstract Background: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in acute myeloid leukemia (AML). We sought to evaluate the relative safety and efficacy of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FAI) in adult patients (pts) with newly diagnosed AML. Methods: Adult pts ≤60 years of age with newly diagnosed non-APL AML were randomized using a Bayesian adaptive design to receive either CIA or FAI. All pts received induction with idarubicin 10 mg/m2 IV daily on days 1-3 and cytarabine 1000 mg/m2 IV daily for on days 1-5. Pts in the CIA arm also received clofarabine 15 mg/m2 IV daily on days 1-5; pts in the FAI arm received fludarabine 30 mg/m2 IV daily on days 1-5. Responding pts could receive up to 6 cycles of consolidation with attenuated doses of the same drug combination. The primary endpoint was to compare the event-free survival (EFS) of CIA and FAI. Secondary endpoints included the CR/CRp rates, overall survival (OS) and the safety of the regimens. Results: Between 8/2011 and 6/2016, 182 pts have been randomized to receive either CIA (n=106) or FAI (n=76). Baseline characteristics of the 2 arms were well-balanced and are summarized in Table 1. Response rates are summarized in Table 2. Of the 180 pts evaluable for response, the CR/CRp rate was similar in the CIA and FAI arms (80% and 81%, respectively). However, the rate of MRD negativity by multiparameter flow cytometry at the time of CR/CRp was significantly higher in pts who received CIA than in those who received FAI (80% vs. 64%, respectively, P<0.05). Rates of stem cell transplant (SCT) in first remission were similar in the two arms (35% vs. 38%, respectively). The median duration of follow-up was 27 months. The median EFS and OS for the entire cohort were 12 months and 39 months, respectively. The median EFS was similar in the CIA and FAI arms (13 months and 12 months, respectively, P=0.91). The imbalance in sample size between these two arms was caused by better performance of the CIA arm during the initial period of the trial, although the difference largely disappeared after further follow-up. There was also no difference in OS between the two regimens; the 2-year OS rates were 51% and 57%, respectively (P=0.24). No difference in survival was observed if pts were censored at the time of SCT. Overall, treatment was safe with 8-week mortality rates of 4% in the CIA arm and 1% in the FAI arm. When compared to a historical cohort of pts treated with idarubicin and cytarabine (IA) alone, the triplet regimen (pooled population of CIA + FAI) resulted in improved EFS and OS among a subgroup of patients <40 years of age. In this group of younger patients, the median EFS for CIA/FAI (n=38) and IA (n=16) were 25 months and 9 months, with a 2-year EFS rate of 52% and 33% respectively (P=0.27). There was also a strong trend towards superior OS in the CIA/FAI compared to the IA groups (median OS: not reached vs. 20 months; 2-year OS rate 68% vs. 47%; P=0.08). Conclusions: In adult pts with newly diagnosed AML, CIA and FAI resulted in similar rates of CR/CRp and had similar EFS and OS. Compared to a historical cohort of pts treated with IA alone, the addition of a nucleoside analogue appears to result in superior EFS and OS in younger pts. Disclosures Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Daver:Ariad: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Jain:Novimmune: Consultancy, Honoraria; Infinity: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding. DiNardo:Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Download Full-text

Outcomes and Predictors of Relapse with Use of Hypomethylating Agents in Combination with Venetoclax Prior to Allogeneic Transplant in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-150815 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2327-2327

Author(s):

Imran Nizamuddin ◽

Timothy Seijung Oh ◽

Yazan Numan ◽

Max Farber Kelsten ◽

Madelyn Burkart ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Maintenance Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Intermediate Risk ◽

Hypomethylating Agents ◽

Significant Difference ◽

Acute Myeloid

Abstract Introduction The treatment of acute myeloid leukemia (AML) has evolved tremendously. Recently, venetoclax with hypomethylating agents (HMA/ven) demonstrated durable responses in the frontline and relapsed/refractory (R/R) settings. This regimen is now standard of care for older adults or those unfit for intensive induction chemotherapy (DiNardo CD, N Engl J Med, 2020). Our institution also often uses HMA/ven to treat fit patients (pts) with high risk disease characteristics. Because HMA/ven was studied in transplant-ineligible pts, outcomes following potentially curative allogeneic hematopoietic stem cell transplantation (HSCT) remain unknown. This retrospective study aims to describe characteristics and outcomes of pts treated with HMA/ven who proceeded to HSCT. Methods Adult pts diagnosed with AML and treated with HMA/ven either in the frontline or R/R setting between 1/2010 and 2/2020 at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University were identified. Hypomethylating agents included either azacitadine or decitabine. Data were collected and analyzed based on demographics, laboratory and clinical characteristics, and disease and toxicity outcomes. Efficacy endpoints included complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with incomplete platelet recovery (CRp). Survival curves for overall survival (OS) and leukemia-free survival (LFS) were calculated using the Kaplan-Meier method. Univariate analyses were performed to determine impact of clinical variables on outcomes (significance defined as p≤0.05). Cohorts were compared using χ 2 or Fisher's exact test for categorical variables and the unpaired t-test for continuous variables. Results Clinical and demographic features at time of diagnosis are listed in Table 1. In total, 257 pts received HMA/ven. Of these, 36 pts received a HSCT, which was the population analyzed in this study. In the front-line setting 11 (31%) pts received HMA/ven and 25 (69%) pts received HMA/ven for R/R disease. 25 (69%) pts received azacitadine and 11 (31%) pts received decitabine (5 days, n=5, 14%; 10 days, n=6, 17%). Based on ELN guidelines, 23 (64%) pts had adverse risk disease at diagnosis. Response to HMA/ven in the pre-transplant setting is shown in Table 2. Of 35 evaluable pts, 34 achieved remission (CR, n=32, 91%; CRi, n=1, 3%; CRp, n=1, 3%). Table 3 shows outcomes following HSCT. 14 (39%) pts relapsed post HSCT and 13 (36%) pts received treatment for relapse. With a median follow-up of 11.6 months, median LFS from time of transplantation was 11.2 months. Median OS was not reached over follow up period but estimated to be 25.4 months. There was a significant difference in rates of relapse based on ELN classification at diagnosis (p=0.0296). In comparison, presence of complex/monosomal karyotypes (p=0.593), blast percentage at diagnosis (p=0.456), donor type (p=0.484), and number of previous lines of therapy (p=0.822) did not predict for relapse. Median LFS in adverse and favorable/intermediate risk ELN groups was 5.8 and 19.8 months, respectively. Median OS in adverse and favorable/intermediate risk ELN groups was 25.4 and 29.5 months, respectively. Following transplant, 10 (28%) pts received maintenance therapy with a median of 5 cycles (range 1-14); 8 pts (22%) received HMA/ven maintenance following HSCT. There was no significant difference in relapse rates between those who received maintenance therapy (n=6, 43%) and those who did not (n=8, 57%) (p = 0.107). Median time to relapse from HSCT was 4.42 months in those who received maintenance therapy compared to 2.98 months in those who did not receive maintenance therapy (p=0.370). Following relapse, 10 (28%) pts were retreated with HMA/ven, but less than half (n=4, 40%) had a response. To date, 22 (61%) pts are alive with the majority (n=19, 86%) in remission. 14 (39%) pts died with half in remission at the time of death. Conclusions Our study showed that HMA/ven can feasibly be used not only to bridge to transplant, but to achieve durable remissions post HSCT. For those pts that relapsed post HSCT, duration of remission was very short. ELN classification was the only factor that informed relapse risk. Prospective studies must be done to understand which cytogenetic and molecular subgroups benefit the most from HMA/ven prior to transplant. Figure 1 Figure 1. Disclosures Abaza: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Altman: Biosight: Consultancy, Other: Travel fees, Research Funding; Fujifilm: Research Funding; Kura: Research Funding; Immunogen: Research Funding; Kartos: Research Funding; Daiichi Sankyo: Consultancy; ALZ Oncology: Research Funding; Theradex: Consultancy, Other: Advisory boards; Syros: Consultancy; Amgen: Research Funding; Aprea: Research Funding; Boehringer Ingelheim: Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; GlycoMimetics: Other: Participation on an advisory board; AbbVie: Consultancy, Other: Advisory Board, Research Funding; BMS: Research Funding; Kura Oncology: Consultancy. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria.

Download Full-text

Combination of Sorafenib and 5-Azacytidine in Older Patients with Untreated Acute Myeloid Leukemia with FLT3-ITDmutation

Blood ◽

10.1182/blood.v128.22.1611.1611 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1611-1611 ◽

Cited By ~ 3

Author(s):

Maro Ohanian ◽

Guillermo Garcia-Manero ◽

Elias J. Jabbour ◽

Naval Daver ◽

Gautam Borthakur ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Median Overall Survival ◽

Cell Transplant ◽

Overall Response ◽

Grade 3 ◽

Acute Myeloid

Abstract Background: The combination of 5-azacytidine (AZA) and sorafenib has been reported to be a safe and effective strategy in patients with relapsed and/or refractory FLT3-ITD mutated acute myeloid leukemia (AML). We hypothesized that combining sorafenib with AZA, may be used effectively in older patients with untreated AML whose leukemic cells harbor the mutation. Methods: Patients were eligible if they had untreated AML with a FLT3-ITD clone detectable by polymerase chain reaction (at least 10% mutation burden), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. The treatment regimen included AZA 75 mg/m2daily for 7 days combined with sorafenib 400 mg twice daily for 28 days. Cycles were repeated approximately every 4 to 5 weeks. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Results: Overall, 23 patients with untreated AML with a median age of 74 yrs (range, 61-86 yrs) were enrolled. They included 14 (61%) patients with normal cytogenetics, 2 (9%) with complex karyotype, 4 (17%) with other miscellaneous abnormalities, and 3 (13%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all patients with a median allelic ratio of 0.35 (range, 0.01-0.89). The overall response rate in 22 evaluable patients was (77%) including 7 (32%) with CR, 9 (41%) CRi/CRp, and 1 (5%) PR. Patients have received a median of 3 (range, 1-35) treatment cycles with the median number of cycles to response being 2 (range, 1-5) and the median time to achieve response, 1.9 months (range, 0.7-4.3 months). The median duration of CR/CRp/CRi is 14.5 months (range, 1.2-28.7 months). Two (9%) patients have proceeded to allogeneic stem cell transplant. With a median follow-up of 4.2 months (range, 0.9-61.4), 8 patients remain alive, 7 still in remission (CR/CRP/CRi). The median overall survival for the entire group is 8.8 months, and 9.2 months in the 17 responding patients (Figure 1). Treatment-related grade 3/4 adverse events included: grade 3 diarrhea (n=2), grade 3 pneumonitis (n=3), grade 4 sepsis (n=2), grade 3 infections (n=3). When patients treated with AZA + sorafenib (n=23) were compared to a matched cohort of historical patients older than 60 years who were treated with hypomethylator-based therapy without sorafenib (n=20), overall response rates (including CR, CRp, CRi, and PR) were statistically similar (77% vs.31%, respectively; p=0.6). The median overall survival for the two groups were 8.8 months and 9.4 months (p=0.67), respectively. The remission duration for the responding patients treated with AZA+sorafenib was significantly longer (16 months) than those on other hypomethylator-based regimens without sorafenib (3.8 months)(p=0.008) (Figure 2). Conclusions: The combination of AZA and Sorafenib is effective and well tolerated in older patients with untreated FLT3-ITD mutated AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Download Full-text

Survival Outcome of Patients with Acute Myeloid Leukemia Transformed from Myeloproliferative Neoplasms

Blood ◽

10.1182/blood.v128.22.1940.1940 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1940-1940 ◽

Cited By ~ 5

Author(s):

Dai Chihara ◽

Hagop M. Kantarjian ◽

Kate J Newberry ◽

Farhad Ravandi ◽

Naval G. Daver ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Treatment Strategies ◽

Survival Outcome ◽

Hazard Ratio ◽

Complex Karyotype ◽

Acute Myeloid

Abstract Purpose: Progression to acute myeloid leukemia (AML) from myeloproliferative neoplasms (MPNs) is almost always fatal. To explore the best treatment strategies for this serious complication, we analyzed the survival outcome of patients with MPNs who progressed to AML based on treatment received at our institution. Patients and Methods: A total of 273 patients who were diagnosed with AML secondary to MPNs between 1989 and 2016 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were calculated. Results: The patients progressed to AML from essential thrombocythemia (ET, N=60), polycythemia vera (PV, N=49), primary myelofibrosis (PMF, N=105), post-ET/PV MF (N=37), and MPN-unclassifiable (N=22). The median age of the patients was 67 (range: 28-92). The median time to AML transformation from MPN diagnosis was 64.5 months (range: 0.9-477.7 months). Complex karyotype was seen in 99 patients at the time of transformation (38%). With a median follow up of 16.5 months (range: 2.7-115.7 months), 247 patients had died (88% from AML, 6% from treatment-related mortality, 6% with other cause including infection and GVHD). Ninety-nine patients received hypomethylating including agent (HMA), 71 a high-dose cytarabine regimen, 52 a low-dose cytarabine regimen, 28 other treatments, and 24 patients did not receive any treatment due deterioration of the patientfs condition or patientfs decision. The median PFS and OS after progression to AML were 2.6 months and 7.0 months, respectively. There was no significant improvement in PFS and OS by date of diagnosis (1989 to 2016). Also, complete response (CR) rate and survival outcome were not significantly different by type of treatment (Figure A) or prior MPN subtype. Overall, 46 patients (27 in CR, 14 not in CR, 4 unknown due to the transplant outside) proceeded to allogeneic transplant (allo-SCT), and the median overall survival after transplant was 15.3 months (6.1-29.4 months). Although it was not statistically significant, patients who achieved a CR before allo-SCT had longer OS than those who received allo-SCT without achieving a CR (35.1 vs 8.9 months; Figure B). Complex karyotype was associated with both shorter PFS (Hazard ratio: 2.2, 95%CI: 1.6-2.9) and OS (Hazard ratio: 2.0, 95%CI: 1.5-2.6). Summary: Survival outcome for AML secondary to MPN remains very poor, and there has been no improvement in survival outcome since 1989. Further studies are urgently needed to test new treatment strategies and to detect residual disease post allo-SCT. Considering dismal outcome after transformation, studies are also needed to explore strategies to prevent this fatal complication. Disclosures DiNardo: Daiichi Sankyo: Research Funding; Abbvie: Research Funding; Agios: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Download Full-text

Characteristics and Outcomes Of Patients (pts) With Multiple Myeloma (MM) Who Develop Therapy (t)-Related Myelodysplastic Syndrome (MDS), t-Chronic Myelomonocytic Leukemia (CMML), Or t-Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v122.21.1424.1424 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1424-1424

Author(s):

Naveen Pemmaraju ◽

Dhaval Shah ◽

Hagop M Kantarjian ◽

Verena Wagner ◽

Robert Z. Orlowski ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chemotherapeutic Agents ◽

Chronic Myelomonocytic Leukemia ◽

Advisory Committees ◽

Myelomonocytic Leukemia ◽

Acute Myeloid

Abstract Background There has been a significant improvement in the outcome for patients (pts) with MM over the last decade, mainly due to the availability of immunomodulatory (IMiD) drugs and proteasome inhibitors (PI). The improvement in survival has also increased the risk of second primary malignancies (SPM), such as therapy-related myelodysplastic syndrome (t-MDS), therapy-related chronic myelomonocytic leukemia (t-CMML) or therapy-related acute myeloid leukemia (t-AML). However, little is known about the characteristics and outcomes of pts with t-MDS, t-CMML or t-AML. Methods We aimed to study the characteristics and outcome of pts who developed t-MDS, t-AML and t-CMML as SPM after the treatment of MM. We reviewed our database of pts with MM who were treated at our institution between 1993 and 2011. We identified 49 pts who were diagnosed to have t-MDS, t-CMML, or t-AML. The primary objective of this study was to evaluate the time to develop t-MDS, t-AML and t-CMML, their response to treatment and overall survival. Results Median age of pts at diagnosis of MM was 61 years. Forty-seven (96%) pts had symptomatic MM, while 2 (4%) had asymptomatic myeloma. Forty-seven (95%) pts with symptomatic myeloma received systemic therapy. Eleven (22%) pts were treated with IMiD or PI: lenalidomide 3, thalidomide 6 and bortezomib 2. Thirty-eight (78%) pts were treated with various conventional chemotherapeutic agents including melphalan, cyclophosphamide, doxorubicin, vincristine, etoposide, cisplatin, idarubicin, thiotepa, busulfan, carmustine and cytarabine. Fourteen (28%) pts also received radiation therapy to the affected areas. Twenty (41%) pts underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). Fourteen pts received maintenance therapy after auto-HCT with either thalidomide, lenalidomide, dexamethasone or bortezomib. Median time from the diagnosis of MM to t-MDS, t-CMML or t-AML was 6 years [0 – 24]. Thirty-four (69 %) pts developed t-MDS, 12 (24%) t-AML, and 3 (6%) t-CMML. Median age at diagnosis of t-MDS, t- CMML, or t-AML was 65 years. Twenty-seven (79%) pts with t-MDS and all 12 pts with t-AML had complex/high risk cytogenetics. Most common cytogenetic abnormalities involved chromosome 5 and 7. Thirty four (69%) pts received at least 1 cycle of induction chemotherapy either with conventional chemotherapeutic agents or investigational drugs. Only 9 pts (26%) achieved complete remission (CR). Median duration of CR in these pts was 4 months [1 – 62]. Median overall survival (OS) of pts who received induction therapy was 6.0 months [0-30]. Five (11%) pts received an allogeneic stem cell transplant with three achieving CR. Median OS in this subgroup of pts was 18 months [9 – 23]. Median OS for all 49 pts after diagnosis of t-MDS, t-CMML or t-AML was 6.0 months [0 – 30] Conclusion Development of t-MDS, t-CMML, or t-AML in pts with MM is associated with a poor outcome. These pts in general have complex cytogenetic abnormalities, chemo-resistant disease, a short CR and OS. A better understanding of disease biology and novel therapeutic approaches are warranted. Disclosures: Orlowski: Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Qazilbash:Otsuka: Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Download Full-text