Integrating Geriatric Assessment and Genetic Profiling to Personalize Therapy Selection in Older Adults with Acute Myeloid Leukemia (AML)

Introduction: Geriatric assessment can predict the risk of toxicities of chemotherapy in older adults. Genetic risk categories correlate with survival following intensive chemotherapy in AML. Integrating geriatric assessment for patient profiling and genetic profiling of leukemic cells represents an innovative precision medicine approach to personalize therapy selection in older adults with AML. We report results of a pre-planned interim analysis of a pragmatic phase II trial using such strategy that has an overarching goal to reduce early mortality (NCT03226418). Methods: Patients ≥60 years with a new diagnosis of AML underwent geriatric assessment prior to initiation of treatment. Geriatric assessment of physical function, cognitive function and comorbidity burden were used to determine fitness for intensive chemotherapy (Table 1). Additional assessment included Karnofsky Performance Scale (KPS), Patient Health Questionnaire-9 (PHQ-9), and Mini Nutritional Assessment-Short Form (MNA). Genetic profiling for therapy selection relied on karyotyping and followed the 2017 European LeukemiaNet criteria. While available mutation test results were incorporated to risk stratify, the study did not require to wait for the results prior to therapy initiation given an anticipated turnaround time of 1-2 weeks for mutation test results. Therapy selection followed the algorithm demonstrated in Figure 1. Patients with good or intermediate-risk AML received intensive chemotherapy such as 7+3 +/- gemtuzumab or midostaurin if determined to be fit. Patients with high-risk AML received low-intensity chemotherapy such as a hypomethylating agent with or without novel drugs, or CPX 351 if they were fit and met the FDA-approved indications. Patients with organ dysfunction (e.g. creatinine ≥2 mg/dl) and those requiring chemotherapy for other malignancy received low-intensity chemotherapy. Chemotherapy at diagnosis or follow up could be administered in community oncology settings. Patients were followed for assessment of quality of life, functional and oncologic outcomes. Results: Between July 2017-June 2019, a total of 31 patients (including 1 MDS patient considered screen failure) were enrolled. The pre-planned interim analysis results are based on the first 27 AML patients. Baseline characteristics included a median age of 70 years (range 60-84 years), 56% female, 96% white, and a median KPS of 80% (range 60-100%). As presented in Table 1, over half of the patients had ≥3 comorbidities, impairment in objective physical function (short physical performance battery) and Montreal Cognitive Assessment. Additionally, 67% had poor nutritional status (MNA score of ≤11) and 26% had abnormal depression screen (PHQ-9 score of ≥10). Risk categories included adverse (64%), intermediate (16%), and good-risk AML (20%). Patients had one or more of the following mutations: FLT3 ITD (11%), NPM1 (22%), biallelic CEBPA (4%), IDH1 (15%), IDH2 (8%), RUNX1 (15%), ASXL1 (22%), and TP53 (19%). Three patients received intensive chemotherapy; CPX 351 (n=2) or 7+3+ gemtuzumab (n=1). Other patients received decitabine or azacitidine alone (n=16), azacitidine and venetoclax (n=5) or decitabine and midostaurin (n=3). The median time from diagnosis to therapy initiation was 7 days (0-20 days) whereas the median time from enrollment to therapy initiation was 2 days (range 0-9). Mortality at 30 days from diagnosis was 3.7% (95% confidence interval, CI 0.7-18.3%) and at 90 days was 29.6% (95% CI 15.9-48.5%). Mortality compared favorably to an unmatched historical cohort of patients ≥60 years treated at our center between 2011-2016, where 30-day mortality was 30% (95% CI 22-40%) and 90-day was 41% (95% CI 32-52%) (Future Oncol. 2019;15:1989-95). Conclusions: Our model to personalize AML therapy selection represents an innovative approach to precision medicine that incorporates both geriatric assessment for patient profiling and genetic profiling of leukemia cells. Geriatric assessment demonstrated high frequency of impairment in objective physical and cognitive function. Patients were able to start therapy within a median of 2 days following enrollment. Pragmatic aspects of the trial included broad eligibility criteria and co-management of patients with community oncologists. Our pre-planned interim analysis data appear promising with lower rates of early mortality compared to unmatched historical controls. Disclosures Bhatt: Pfizer: Consultancy; CSL Behring: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Partner therapeutics: Consultancy; Incyte: Consultancy, Research Funding; Tolero Pharmaceuticals: Research Funding; National Marrow Donor Program: Consultancy. Al-Kadhimi:Celldex Biotech: Other: Stocks; Seattle Genetics: Other: Stocks. Armitage:Oncology Analytics: Consultancy; Partner Therapeutics: Consultancy; Samus Therapeutics: Consultancy; Ascentage: Consultancy; Tesaro bio: Membership on an entity's Board of Directors or advisory committees; Union Pacific: Consultancy. Holstein:GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Gundabolu:Samus Therapeutics: Research Funding; Jazz pharmaceuticals: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. OffLabel Disclosure: Single agent azacitidine and decitabine as well as decitabine in combination with midostaurin are not approved by the US FDA for acute myeloid leukemia.

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To Treat or Not to Treat? Understanding Treatment Patterns in Patients with Lower-Risk Myelofibrosis at the Time of Enrollment in the MOST Study

Blood ◽

10.1182/blood-2020-134958 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-51

Author(s):

Rami S. Komrokji ◽

Brady L. Stein ◽

Robyn M. Scherber ◽

Patricia Kalafut ◽

Haobo Ren ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Symptom Burden ◽

Risk Groups ◽

Treatment Patterns ◽

Low Risk ◽

Publicly Traded ◽

Advisory Committees ◽

Therapy Initiation

Background: Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) characterized by extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms, and diminished quality of life. Treatment decisions may involve a variety of factors including prognosis and symptomatology. Data regarding real-world disease and demographic factors that contribute to therapy initiation and choice in pts with lower risk MF are limited. This analysis of data from the ongoing Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) assessed whether these factors differ for lower risk pts who were treated vs untreated at enrollment. Methods: MOST is a longitudinal, noninterventional, prospective, observational study in pts with MF or essential thrombocythemia enrolled at clinical practices within the US. Pts included in the analysis (≥18 y), had low risk MF by the Dynamic International Prognostic Scoring System (DIPSS; Blood. 2010;115:1703), or intermediate-1 (INT-1) risk by age >65 y alone. Pt data were entered into an electronic case report form during usual-care visits over a planned 36-month observation period. Pt-reported symptom burden was assessed using the MPN-Symptom Assessment Form (MPN-SAF); Total Symptom Score (TSS) was calculated (0 [absent] to 100 [worst imaginable]; J Clin Oncol. 2012;30:4098). Data were analyzed with basic descriptive and inferential statistics. Results: Of 233 pts with MF enrolled at 124 sites between 11/29/2016 and 03/29/2019, 205 were included in this analysis; 28 were excluded for being INT-1 risk for reasons other than age. Of the 205 pts, 85 (41.5%) were low- and 120 (58.5%) were INT-1 risk; 56.5% (48/85) and 59.2% (71/120), respectively, were being treated at enrollment. Pt characteristics are listed in Table 1A. Fewer low- vs INT-1 risk pts were JAK2 V617F or MPL positive, and more were CALR positive. The proportion of pts with palpable splenomegaly was similar for treated low- and INT-1 risk pts. In low risk pts, the proportion of pts with palpable splenomegaly was higher in untreated vs treated pts; whereas, in INT-1 risk pts, the opposite was observed (ie, lower proportion in untreated vs treated pts). Blood counts were generally similar across cohorts, except median leukocytes were lower for low risk treated pts and platelet counts were elevated in low- vs INT-1 risk pts. The proportion of pts with comorbidities was similar across cohorts, except for fewer cardiovascular comorbidities in low- vs INT-1 risk pts. Mean TSS was lower in low- vs INT-1 risk pts, but the proportion of pts with TSS ≥20 was greater in treated vs untreated pts in both low- and INT-1 risk groups. Fatigue was the most severe pt-reported symptom in all cohorts. Differences in mean TSS and individual symptom scores between risk groups were not significant (P > 0.05), except itching was worse among INT-1 risk pts (P=0.03). Physician-reported signs and symptoms were generally more frequent for untreated vs treated pts, irrespective of risk (all P > 0.05). Most low risk (69.4%) and INT-1 risk pts (61.2%) who were currently untreated at enrollment had not received any prior MF-directed treatment (Table 1B); the most common prior treatment among currently untreated pts was hydroxyurea (HU) in both risk groups. Of currently treated pts, HU was the most common MF-directed monotherapy at enrollment in low-risk pts, and ruxolitinib was most common in INT-1 risk pts. No low risk pts and few INT-1 risk pts were currently receiving >1 MF-directed therapy at enrollment. Conclusion: These real-world data from pts with MF enrolled in MOST show that a substantial proportion of both low- and INT-1 risk pts who had received treatment before enrollment were not being treated at the time of enrollment. Although watch-and-wait is a therapeutic option, the finding that many of these lower risk pts had in fact received prior therapies suggests an unmet need for effective and tolerable second-line treatment options. Treated pts had greater pt-reported symptom burden vs untreated pts, which suggests that high symptom burden may contribute to the decision for treatment. Prospective studies are needed to evaluate symptom burden change with therapy initiation. In this regard, future analyses of data from MOST are planned to assess the longitudinal evolution of the clinical characteristics, treatment patterns, and management of pts with MF. Disclosures Komrokji: Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria. Stein:Incyte: Research Funding; Kartos: Other: educational content presented; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmaessentia: Membership on an entity's Board of Directors or advisory committees. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kalafut:Incyte: Current Employment, Current equity holder in publicly-traded company. Ren:Incyte: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding.

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The Characteristics, Treatment Patterns, and Outcomes of Older Adults with Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-118660 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4463-4463

Author(s):

Mark A. Fiala ◽

Tanya M. Wildes ◽

Mark A. Schroeder ◽

Armin Ghobadi ◽

Keith E. Stockerl-Goldstein ◽

...

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Patient Characteristics ◽

Treatment Patterns ◽

Advisory Committees ◽

Improved Outcomes ◽

Immunomodulatory Drug

Abstract Background: Advances in the treatment for multiple myeloma (MM) have dramatically improved outcomes for younger patients. Older adults, particularly those 80 years of age or older at diagnosis, have seen more modest gains. MM incidence increases with age, and as more of the population is living later into life, the segment of the MM population over 80 will continue to grow. In this study, we sought to better understand the characteristics, treatment, and outcomes of older patients with MM. Methods: We identified all patients diagnosed with MM at age 80 or older in the Surveillance, Epidemiology, and End Results Program (SEER) database from 2007-2013 to determine incidence and outcomes. Subset analysis was then performed on patients included in the SEER-Medicare linked database who were enrolled in Medicare Parts A, B, and D to further explore patient characteristics and treatment patterns. Results: The incidence of MM increases over age, peaking after age 80. The annual incidence for those aged 65-69, 70-74, 75-79, 80-84 and 85+ was 24.4, 32.7, 39.5, 42.8 and 36.4 per 100,000, respectively. Based on 2010 US population estimates, approximately 4,500 new cases of MM were diagnosed annually 2007-2013 in patients age 80 or older. In that period, 8,093 cases, approximately 1,150 per year, were reported to SEER. The estimated median overall survival (OS) of these patients was 14 months (95% CI 13.2-14.8). The estimated relative 12 month survival was 58.9% (95% CI 57.4-60.4) compared to their peers without cancer. Of the 8,093 cases of MM reported to SEER during the study period, 2,385 were present in the SEER-Medicare linked dataset. Of these, 225 were identified as smoldering MM using a previously established algorithm (Fiala, et al, JCOCCI, 2018) and excluded leaving 2,160 for the analyses. The median age was 84 (range 80-100) and 55% were female. 81% were white, 13% black or African-American, and 6% another race. At disease presentation, 22% had claims indicating hypercalcemia, 61% renal failure or chronic kidney disease, 59% anemia, and 34% MM bone involvement. The estimated median OS was 13.4 months (95% CI 12.2-15.1). Only 52% of patients had claims indicating they received systemic MM treatment within 6 months post-diagnosis. Nearly all that did received novel agents; 38% received bortezomib-based treatment, 41% immunomodulatory drug (IMID)-based, and 14% both. The others received antineoplastic chemotherapies such as melphalan or cyclophosphamide. Interestingly, bortezomib utilization increased incrementally from 25% of patients treated in 2007 to 62% in 2013 while IMID utilization declined from 67% to 49%. The median OS of those receiving treatment was 21 months (95% CI 18.5-23.1) compared to 6.3 months (95% CI 5.3-7.3) for those who did not (p <0.0001). MM treatment was associated with a 26% decrease in hazard for death (aHR 0.74; 95% CI 0.67-0.82; p < 0.0001) independent of age, race, gender, poverty, comorbidities, and proxy measures of performance status. Outcomes improved for patients in more recent years; the hazard for death decreased by 3% (HR 0.97; 95% CI 0.94-0.99; p = 0.0096) each year 2007-2013. This can be attributed to increasing treatment rates. In 2007, only 41% of patients received treatment compared to 61% in 2013. After controlling for MM treatment, the year of diagnosis was no longer a significant predictor of survival. Conclusions: The outcomes of patients with MM over 80 years old are still relatively poor; nearly half of the patients do not receive systemic treatment and for those who do the median OS is just 21 months. The population over 80, when MM incidence peaks, is projected to triple over the next few decades. It is imperative that we improve our understanding of the needs of this vulnerable subgroup of patients of MM. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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.

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Identification of Initiating Trunk Mutations and Distinct Molecular Subtypes: An Interim Analysis of the Mmrf Commpass Study

Blood ◽

10.1182/blood.v126.23.722.722 ◽

2015 ◽

Vol 126 (23) ◽

pp. 722-722 ◽

Cited By ~ 1

Author(s):

Jonathan J Keats ◽

Gil Speyer ◽

Legendre Christophe ◽

Christofferson Austin ◽

Kristi Stephenson ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Copy Number ◽

Interim Analysis ◽

Research Funding ◽

Molecular Subtypes ◽

Bayesian Clustering ◽

Clustering Method ◽

Advisory Committees

Abstract The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal study of 1000 patients with newly-diagnosed multiple myeloma from clinical sites in the United States, Canada, Spain, and Italy. Each patient receives a treatment regimen containing a proteasome inhibitor, immunumodulatory agent, or both. Clinical parameters are collected at study enrollment and every three months through the five-year observation period. To identify molecular determinants of clinical outcome each baseline and progression tumor specimen is characterized using Whole Genome Sequencing, Exome Sequencing, and RNA sequencing. This will be the first public presentation of the interim analysis seven cohort with 760 enrolled patients of whom 565 are molecularly characterized. This cohort of patients includes 14 patients with baseline and secondary samples along with 7 patients with characterized tumor samples from the bone marrow and peripheral blood. Although the median follow-up time for the cohort is only 260 days the patients on proteasome and IMiD based combinations are currently showing a PFS and OS benefit compared to those receiving combinations with each agent alone. From the raw mutational analysis we identified 24 significant genes that are recurrently mutated and the mutated allele is detectably expressed in all but one, DNAH5. Suggesting these mutations are likely contributing to myelomagenesis through an unconventional mechanism. Interestingly, DIS3 mutations are independent of KRAS, NRAS, and BRAF indicating a potential mechanistic link while PRKD2 mutations are associated with t(4;14). To identify events driving the initiation of myeloma we performed a detailed clonality analysis using a bayesian clustering method that corrects for copy number abnormalities and tumor purity to assign mutations into distinct clonal branches versus the initiating trunk mutations. On average 63.8% of mutations are trunk mutations and in 86.7% of patients at least one trunk mutation is associated with somatic hypermutation of an immunoglobulin gene as expected in a late stage B-cell malignancy. This identified many expressed trunk mutations that did not come out in the classic significance analysis like ATM, EGR1, and CCND1. To identify molecular subtypes we performed unsupervised clustering using a consensus clustering approach on independent discovery and validation cohorts, which identified 12 distinct subtypes, using a combination of silhouette score and cumulative distribution of consensus scores. This analysis identified two distinct groups associated with t(4;14) with mutations in FGFR3 and DIS3 being exclusive to one subgroup. In addition, this analysis separates patients with cyclin D translocations into three different groups, with one group having the second lowest PFS proportion. Three patients without CCND1 or CCND3 translocations were found to have IgH translocations targeting CCND2. The MAF subgroup was associated with the lowest OS and PFS proportion, and the three MAF/MAFB translocation negative patients in the subgroup all had MAFA translocations. The remaining 6 subgroups are associated with hyperdiploid copy number profiles and harbor the majority of the IgH-MYC translocation events. Two of the hyperdiploid groups are associated with a low level of NFKB activation compared to the remaining four, one of these is defined by the highest proliferation index but paradoxically the other has the second worst OS proportion. Another group is enriched with FAM46C and NRAS mutations. The genomic profiles of the paired tumors isolated from the peripheral blood and bone marrow are highly similar indicating these are not genetically distinct tumor compartments, at least in this subset of seven patients. Applying our bayesian clustering method to the serial samples resolved additional clonal clusters as mutations with similar cancer cell fractions at diagnosis clearly diverged at later timepoints. These analyses have identified tumor initiating mutations and new subtypes of myeloma, which are associated with distinct molecular events and clinical outcomes. Disclosures Jagannath: Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Merck: Honoraria; Janssen: Honoraria. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Zimmerman:Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Consultancy, Speakers Bureau. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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The Impact of Myeloproliferative Neoplasms (MPNs) on Patients' Quality of Life and Productivity: Results from the International MPN Landmark Survey

Blood ◽

10.1182/blood.v128.22.4267.4267 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4267-4267

Author(s):

Claire N. Harrison ◽

Steffen Koschmieder ◽

Lynda Foltz ◽

Paola Guglielmelli ◽

Tina Flindt ◽

...

Keyword(s):

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Well Being ◽

Ability To Work ◽

Advisory Committees ◽

The Past ◽

Night Sweats ◽

The Impact

Abstract Background Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) whose associated disease burden includes a range of debilitating symptoms, thrombosis, hemorrhage, and shortened survival. To enhance patient care, it is important to understand the impact of MPNs in patients' lives; however, little is known regarding how these conditions affect patients' quality of life (QOL), activities of daily living, productivity, and emotional well-being. The US LANDMARK survey (Mesa et al. BMC Cancer 2016) captured data for US patients. Here, we present an interim analysis of results of another MPN LANDMARK survey conducted in the rest of the world. Methodology MPN LANDMARK survey is a cross-sectional survey of MPN patients across 6 countries (Australia, Canada, Germany, Japan, Italy, and UK). Patients completed an online questionnaire to measure MPN related symptoms experienced over the past 12 months and the impact of their condition on their QOL and ability to work. Additional questions related to employment productivity and activity impairment (including absenteeism and loss of productivity over the past 7 days). Patients included in this interim analysis had completed the survey by July 18, 2016, with enrollment continuing in all countries. Results Patients: Overall, 437 patients had completed the survey (98 MF, 121 PV, 218 ET). For MF and PV, the male to female gender split was relatively even (54% male for each), whereas an expected greater proportion of ET patients was female (70%). Patients with MF were significantly older than PV and ET patients (mean ages, 62, 59, and 55 years, respectively) and more had been diagnosed within 2 years of experiencing their symptoms (83% MF, 67% PV, 71% ET). MPN Symptoms (Table): Most patients (94%) experienced MPN-related symptoms in the past 12 months. The most commonly reported symptom among all subtypes was fatigue (69% MF, 62% PV, 73% ET), incidence of other common symptoms varied depending on disease subtype (MF: shortness of breath [38%], bruising [36%], night sweats [35%], early satiety [33%]; PV: night sweats [36%], trouble concentrating [36%], trouble sleeping [34%], dizziness [34%]; ET: trouble sleeping [37%], dizziness [37%], bruising [35%], night sweats [35%]). When asked which symptom patients would most like to have resolved, most patients preferred to have feeling of fatigue/tiredness improved across all disease subtypes (31% MF, 30% PV, 33% ET). Patients experienced an average of 6.4 symptoms at diagnosis but this progressed to an average of 7.6 symptoms since diagnosis after a median time of 6 years. QOL: A majority of patients indicated that they experienced a reduction in QOL due to MPN symptoms (87% MF, 71% PV, 73% ET) with 33% and 26% of MF and ET patients expressing that their condition has caused emotional hardship, and one-third of patients with PV reporting that they have felt worried or anxious about their disease (39%). MPN Impact on Activity/Employment: Patients reported a high impact on their ability to work, 12% reported voluntarily leaving their job, 10% had taken early retirement, 10% had moved onto disability living allowance, 8% moved to a lower paid job, and 2% experienced involuntary loss of work (Table). Of the patients who were in full-time or part-time employment at the time of the survey (MF [n=17]), PV [n=41], ET [n=98]), approximately, 40% had been absent from work within the past 7 days; this was the highest in MF patients (41% MF, 38% PV, 33% ET). On an average, over the past 7 days, MF patients had missed 3.1 hours from work, PV patients 2.3 hours and ET patients 2 hours. Across all subgroups, a substantial proportion of patients reported impairment in work (mean: 34% MF, 33% PV, 31% ET) and overall activity (mean: 46% MF, 42% PV, 39% ET). Conclusions This interim analysis from the MPN LANDMARK survey indicates that MPN patients experience a high burden of disease, including a high prevalence of symptoms, an increase in the number of symptoms from diagnosis and reduction of their emotional well-being, QOL, and ability to work. These results are consistent with those from the previous US LANDMARK survey with the addition of novel data on how MPNs impact work. When treating MPN patients, care should be taken in trying to manage a patient's disease burden, so as to minimize the impact on a patient's daily life. Further results from additional survey responses will be presented at the congress. Disclosures Harrison: Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Koehler:Novartis Inc. (Germany): Consultancy, Other: Training. Komatsu:Shire: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boothroyd:Novartis: Employment, Equity Ownership. Spierer:Novartis: Employment. Ronco:Novartis: Employment. Taylor-Stokes:Adelphi Real World: Employment. Waller:Adelphi Real World: Employment. Mesa:Celgene: Research Funding; Galena: Consultancy; Novartis: Consultancy; CTI: Research Funding; Ariad: Consultancy; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding.

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Phase II Trial of Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized with NFKB2 Rearrangement. (Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR)

Blood ◽

10.1182/blood-2018-99-119337 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2011-2011

Author(s):

Leon Bernal-Mizrachi ◽

Craig E. Cole ◽

Leonard Heffner ◽

Ajay K Nooka ◽

Ravi Vij ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Interim Analysis ◽

Proteasome Inhibitor ◽

Research Funding ◽

Treated Patient ◽

Data Monitoring Committee ◽

Caspase 8 ◽

Open Label ◽

Advisory Committees

Abstract Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation. Activation of this caspase resulted from NFKB2 interaction with FADD/caspase-8/p62 (unpublished data). Based on this findings, we design this study to examine the efficacy of NFKB2 break apart FISH to predict the response to the duplet ixazomib and dexamethasone (Id) vs ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients (1-3 lines of therapy). Methods: In this phase 2 biomarker driven open label trial, relapse patients with <4 lines of therapy were randomized to ixazomib 4 mg weekly 3 of 4 weeks and 40 mg weekly dexamethasone vs Id plus 25 mg of lenalidomide daily days 21/28, based on the status of NFKB2 rearrangement in plasma cells. Patients were screened for NFKB2 rearrangement was detected by NFKB2 break apart FISH. Patients without NFKB2 rearrangement received Id and patients with NFKB2 rearrangement were subsequently randomized in a 1:1 fashion to receive Id or IRd. The primary endpoint is to compare the response rate of Id or IRd at 4 cycles according to the rearrangement status of NFKB2 Results: At the moment of interim analysis, 26 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=16, NFKB2 FISH [+] Id, n=6 and IRd, n=4) received a median of 2 prior lines of therapy. A higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (56.3% CI:29.9%-80.3% vs. 16.7% CI:0.4%-64.1%, P=0.16), including significantly higher rates of ≥very good partial response, ≥ partial response, ≥ minimal response (12%, 37.5%, 6% vs. 0%, 0%, 16%, respectively). ORR for IRd arm is for now 25% CI:0.6%-80.6%. Patients that continue treatment after cycle 4 that achieve minimal response or better improved their depth of response in 6% in Id treated NFKB2 FISH negative patients and 25% of IRd treated NFKB2 FISH negative patients. The most common (≥10%) grade 2/4 include pneumonia 20% (Id treated NFKB2 FISH negative), thrombocytopenia 16% (Id NFKB2 FISH positive), neutropenia 60% (IRd NFKB2 FISH positive. Treatment discontinuations only occurred in 1 Id treated patient (5%). Conclusion: Interim analysis demonstrate a trend higher efficacy of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in Tourmaline 1 trial. This study was registered at www.clinicaltrials.gov as # NCT02765854. Disclosures Bernal-Mizrachi: Takeda Pharmaceutical Company: Research Funding; Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership. Cole:Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees; University of Michigan: Employment. Heffner:ADC Therapeutics: Research Funding; Kite Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kelkar:Empire Genomics: Employment. Lonial:Amgen: Research Funding. Kaufman:Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy; BMS: Consultancy; Janssen: Consultancy.

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Physical and Psychological Impairments As Practical Frailty Markers in Elderly AML Fit for Intensive Chemotherapy; Interim Data of a Prospective Cohort Study

Blood ◽

10.1182/blood-2019-123584 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3831-3831

Author(s):

GI June MIN ◽

Byung Sik Cho ◽

Sung-Soo Park ◽

Silvia Park ◽

Young-Woo Jeon ◽

...

Keyword(s):

Cohort Study ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Prospective Cohort ◽

Research Funding ◽

Handgrip Strength ◽

Intensive Chemotherapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Elderly Aml

Background The comprehensive geriatric assessment (CGA) typically refers to a multidimensional assessment designed to evaluate an older person's functional ability, physical health, cognition, psychological health, nutritional status, and social support. There is a significant heterogeneity in terms of their underlying health and resilience to the burden of disease and treatments in elderly AML (eAML). To date, a few have evaluated the predictive value of CGA among newly diagnosed eAML. The purpose of this study is to investigate the potential clinical value of CGA as a screening test for frailty in eAML. We designed a comprehensive CGA battery with measures which previously validated, standardized, and widely used. This study is a single-center prospective observational cohort study focused on discriminating between those older patients who are fit for intensive therapies and those who are vulnerable and may experience excess toxicity. Patients and method This prospective cohort study is to investigate the predictive values of each domain of CGA to discriminate vulnerable patients in eAML fit for intensive chemotherapy. Between November 2016 and July 2019, we enrolled newly diagnosed eAML patients aged ≥60 years considered fit for intensive chemotherapy, who had adequate performances and organ functions. All the enrolled patients were administered various questionnaires for an initial CGA and functional evaluation divided into 3 categories; (1) Social and Nutritional support (OARS and MNA), (2) Psychological (MMSE-KC, SGDS-K, PHQ-9, NCCN distress thermometer, MADRS, and KNU-DESC), and (3) Physical function (ECOG, KIADL, SPPB, Handgrip strength, and PTA by professional ENT evaluation). Results Seventy-seven patients were enrolled, in whom the median age of 64 years (range, 60-74), 58.4% were males, and 93.5% and 77.9% of patients had on ECOG score of 0~1 and HCT-CI score of 0~2, respectively. All enrolled patients were treated with intensive chemotherapy, and 62.3% achieved the first complete remission. Three patients experienced early death within 60 days (3.9%). During induction chemotherapy, the median recovery period for neutrophil and platelet counts was 26 (range, 24-29) and 30 (range, 27-33) days, respectively. The median hospitalization days for induction chemotherapy were 32 days (range, 21-104), and infection and GI complications (NCI-CTC-AE based any grade 79.2% and 67.5% respectively) were the most common complications primarily affecting tolerance to the initial chemotherapy. The grade III to IV infection, GI complications, hepatopathy, and acute kidney injury developed in 67.5%, 42.9%, 37.7%, and 16.9% of patients, respectively. Physical impairments were significantly associated with a higher incidence of infection (intact vs. any impairments; 46.4% vs. 79.6%, p=0.003), of which handgrip strength was most accurate tool to predict infection risk (p =0.032), and a trend of more GI complications (intact vs. any impairments; 28.6% vs. 51.0%, p=0.056), resulting in prolonged hospitalization (intact vs. any impairments; 32.2±1.7 days vs. 37.5±2.1 days, p=0.088) for the period of induction chemotherapy. Psychological impairment (intact vs. any impairments; 30.9±1.3 days vs. 38.2±2.1 days, p=0.005), particularly cognitive dysfunction measured by MMSE-KC (p=0.033), was also significantly associated with prolonged hospitalization. Conclusions This data demonstrates that a significant proportion of eAML fit for intensive chemotherapy based on performance status and comorbidity had social, nutritional, physical, psychological impairments by initial CGA assessments. These interim data focusing on early events suggest that impaired physical and/or psychological functions would be useful to identify eAML with intolerance to intensive chemotherapy. This ongoing exploratory prospective study will enroll more eAML patients (targets number=100) and further follow up currently enrolled patients, which will give us invaluable data to develop practical frailty marker and a new model for fitness for intensive chemotherapy. Disclosures Kim: Takeda: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Kim:Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding.

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Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood-2019-131678 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 260-260 ◽

Cited By ~ 2

Author(s):

Jacob Appelbaum ◽

Anisha Loeb ◽

Kelda Gardner ◽

Carole M. Shaw ◽

Paul C. Hendrie ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Remission Induction ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Cox Models ◽

Kaplan Meier ◽

Hazard Ratios ◽

Additional Chemotherapy

Background: Measurable residual disease (MRD) following intensive induction chemotherapy for AML is associated with a high risk of relapse and shortened survival even after allogeneic hematopoietic stem cell transplantation (HSCT). Thus, it may be advisable to give additional chemotherapy to reduce or eradicate MRD prior to HSCT. However, this may expose patients to additional toxicity and delay HSCT. We used our institutional database to examine how often additional chemotherapy eliminated MRD and compared survival among patients with MRD according to whether they next received additional chemotherapy or allogeneic HSCT. Methods: We reviewed 1272 remission induction attempts in 917 patients at our institution from 2008-2016. We identified 217 patients in CR/CRi with MRD (<5% abnormal blasts, assessed by multiparameter flow cytometry) generally after one course of therapy. Four patients were excluded due to ambiguous reporting or the presence of an additional concurrent hematologic neoplasm. Baseline clinical variables were used to calculate the treatment related mortality score, TRM (Walter et al. JCO 2011; 29(33):4417-4424). Comparisons used chi square tests for categorical and rank sum tests for continuous variables. Survival was evaluated using the Kaplan Meier method. Univariate Cox models found that performance status (HR 1.7, 95% CI 1.4-2.2) but not presentation WBC, cytogenetic risk, sex, or secondary AML were associated with significant hazard ratios. Kaplan-Meier analysis was used to examine the effect of treatment strategy on survival. Results: The median follow-up time was 31.1 months, the median survival following 1-2 cycles of remission induction was 11 months (95%CI 9.1 - 12.42). Next therapies were HSCT in 80 patients, additional chemotherapy in 49 patients (28 intensive; 10 less intensive, e.g. azacitidine; 11 novel agents) and none in 84 patients. In the patients who received additional chemotherapy, MRD was eliminated in 10/49 patients (20.4%, 95% CI 10.2 - 34.4%, CR = 7 pts, CRp = 3 pts): 0/21 following novel agents or low intensity therapy and 10/28 following intensive therapy (36%; 19-56%). Median survival from initial chemotherapy was similar regardless of whether MRD was eliminated by chemotherapy (12.4 mo) or was not (11.0 mo). Following chemotherapy, 16 patients were subsequently transplanted: 7 of 10 in CR/CRi and 9 with residual AML (6 patients with residual AML received intensive chemotherapy). Survival from the time of initial chemotherapy was longer in the 80 patients who received HSCT as first treatment for MRD than in the 49 who received chemotherapy (top figure panel, median 13.8 mo vs 11.6 mo, p = 0.01). and was not statistically different from the survival times of the 16/49 who received HSCT after chemotherapy for MRD, despite the "guarantee time" these 16 enjoyed. From the time of transplantation, survival was shorter among the 16/49 patients who received chemotherapy followed by transplant compared to those transplanted upfront (bottom figure panel median 4.4 vs. 10.4 mo, p = 0.02). There was no difference in survival after transplantation between patients whose MRD was eliminated (n = 7 pts) or not (n = 9) by chemotherapy. Among patients treated with HSCT up front, 23 of 80 (28.8%; 95%CI 19.1-40%) survived longer than 1 year. Univariate Cox models found that performance status at presentation (HR 1.7, 95% CI 1.4-2.2) but not presentation WBC, cytogenetic risk, sex, or secondary AML were associated with significant hazard ratios. Conclusion: Intensive chemotherapy eliminated MRD in only 36% of cases, whereas less intensive or novel therapy was unsuccessful in 21 consecutive cases. Whether preceding chemotherapy eliminated residual MRD had no effect on post-HCT outcome. There was a trend toward improved long-term survival in patients who were transplanted upfront rather than after additional chemotherapy. Overall, the use of additional chemotherapy to eliminate MRD prior to HCT does not seemingly improve HCT outcomes and appears less successful than proceeding directly to HCT. Absent a clinical trial, HCT may be the best treatment of people with MRD+ AML. Our data provide a historical response rate for such trials. Figure Disclosures Gardner: Abbvie: . Percival:Nohla Therapeutics: Research Funding; Pfizer Inc.: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Halpern:Bayer Pharmaceuticals: Research Funding; Pfizer Pharmaceuticals: Research Funding. Scott:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Walter:Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership; Agios: Consultancy; Amgen: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Jensen:Juno Therapeutics, a Celgene Company: Research Funding; Bluebird Bio: Research Funding.

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Hypophosphatemia after High Dosage Iron Substitution with Ferric Carboxymaltose (FCM) and Iron Isomaltoside (IM) — the Randomised Controlled Home Afers 1 Trial

Blood ◽

10.1182/blood-2018-99-114386 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3627-3627 ◽

Cited By ~ 2

Author(s):

Insa E. Emrich ◽

Fabio Lizzi ◽

Seiler-Mußler Sarah ◽

Christian Ukena ◽

Dominic Kaddu-Mulindwa ◽

...

Keyword(s):

Iron Deficiency ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Iron Deficiency Anaemia ◽

Ferric Carboxymaltose ◽

Advisory Committees ◽

Deficiency Anaemia ◽

Iron Substitution ◽

Plasma Phosphorus

Abstract In iron deficiency anaemia patients, intravenous administration of either ferric carboxymaltose (FCM) or iron isomaltoside (IM) both allow high dosage iron substitution within a single outpatient visit. In contrast, other iron compounds require repetitive, low dosage infusions. Recently, FCM was reported to frequently induce acute, reversible hypophosphatemia. It remains enigmatic whether these hypophosphataemic effects of FCM are substance-specific, or whether they generally occur after high dosage iron substitution. A direct comparison of phosphorus regulation after high dosage iron substitution with either FCM or IM is clinically important, as hypophosphatemia after FCM has anecdotally been associated with osteomalacia and bone fractures. In the HOMe AFers 1 (HOMburg evaluations on application of Ferrum study 1) trial, we recruited normophosphatemic women with gynaecological bleeding and subsequent iron deficiency anaemia, in whom we assessed the longitudinal biochemical response over 28 days to a single intravenous injection of equivalent doses of randomly-assigned FCM and IM (1000 mg). The primary study hypothesis was that the incidence of hypophosphatemia - defined as plasma phosphorus < 2.0 mg/dl at least out of three post-infusion study time points (day 1, day 8, and week 5) - differs between FCM and IM. HOMe AFers 1 initially planned to recruit 60 women. An interim analysis was pre-specified and scheduled in July 2018, with the option to stop further patient recruitment if the incidence of hypophosphatemia differs significantly at this interim analysis. At the time point of the interim analysis, 26 patients have been recruited. One patient withdrew her acceptance to participate after day 1, leaving 25 patients for our per protocol interim analysis. Baseline plasma phosphorus did not differ significantly between FMC (3.3 ± 0.4 mg/dl) and IM (3.6 ± 0.6 mg/dl; p = 0.135). Analysis on the primary endpoint demonstrated that significantly more women developed hypophosphatemia < 2.0 mg/dl after FMC infusion (9 out of 12 patients) than after IM infusion (1 out of 13 patient) (p=0.001). Further, the minimum plasma phosphorus during any of the three post-infusion study time points was lower after FMC (1.8 ± 0.3 mg/dl) than after IM (2.7 ± 0.6 mg/dl; p < 0.001). As expected, ferritin and haemoglobin increased in both study groups after iron infusion. No severe adverse events occurred in either group. In conclusion, while both FCM and IM provide efficient iron substitution in iron deficiency anaemia, FCM induced a substantially higher incidence of hypophosphatemia. Disclosures Emrich: Pharmacosmos: Consultancy, Honoraria, Research Funding. Stilgenbauer:Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brandenburg:Pharmacosmos: Consultancy, Honoraria, Research Funding; Vifor: Consultancy, Honoraria. Heine:Pharmacosmos: Consultancy, Honoraria, Research Funding.

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Remission and Survival after Single Versus Double Induction with 7+3 for Newly Diagnosed Acute Myeloid Leukemia: Results from the Planned Interim Analysis of Randomized Controlled SAL-Daunodouble Trial

Blood ◽

10.1182/blood-2020-140246 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-3

Author(s):

Christoph Röllig ◽

Björn Steffen ◽

Nael Alakel ◽

Regina Herbst ◽

Richard Noppeney ◽

...

Keyword(s):

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Early Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Npm1 Mutation ◽

Randomized Controlled ◽

Induction Cycle ◽

Single Versus

Background Double induction using two subsequent 7+3 regimens of cytarabine plus anthracycline is commonly performed in AML patients with an adequate performance status in order to maximize dose intensity upfront. However, for patients with a good early response at day 15 of first induction, there is no prospective randomized evidence on the necessity or value of a second induction cycle. Aims In order to answer the question if good responders of the first 7+3 induction could be spared a second induction cycle, we set up randomized-controlled SAL DaunoDouble trial. The study prospectively assesses the outcome of patients with a good early response with respect to the number of induction cycles (single versus double). We assumed non-inferiority of single induction in terms of complete remission (CR/CRi) rate, based on a margin of 7.5%. Here, we present the results of the planned interim analysis. Methods Patients (pts) 18-65 years with newly diagnosed AML, normal cardiac and organ function received a first induction cycle with seven days of cytarabine plus three days of daunorubicin ("7+3"). Response assessment in bone marrow was done on day 15 after the initiation of chemotherapy and confirmed by central review. A blast count <5% was defined as good response. Pts with good response were randomized to receive a second induction cycle (arm D) or no second induction cycle (arm S). Primary endpoint was CR/CRi after completion of induction, secondary endpoints were RFS, and OS. Results Between 2014 and 2020, 624 evaluable pts were enrolled and received the first induction cycle with 7+3. A marrow blast clearance below 5% on day 15 was achieved in 298 pts (48%), providing eligibility for randomization. Of these patients, 150 were randomized into arm S and 148 into arm D, respectively. Median age was 52 years, 92% had de novo AML, NPM1 mutation was present in 53%, FLT3-ITD in 25% of pts. Favorable, intermediate and adverse risk (ELN 2017) were present in 56%, 34% and 10% of pts, respectively. CR/CRi rates at the end of induction were 86% after single induction and 85% after double induction. The CR/CRi rates in 224 pre-defined per-protocol pts were 88% versus 91%, resulting in a CR difference of 3% (95%-CI -0.047-0.111; p for non-inferiority test 0.145). After a median follow-up time of 24 months, RFS was slightly but not significantly lower after single induction with a 3-year RFS of 53% versus 64% (HR 1.4, p=0.125), whereas no differences were seen in 3-year OS, with a of rate of 74% versus 75% (HR 1.1, p=0.645) after single versus double induction. Conclusion The interim analysis results show that in good responders, the difference between CR rates after single versus double induction was even smaller than the predefined 7.5% margin, suggesting a trend for non-inferiority of single induction, although statistical significance was not reached. The trial continued recruitment. These findings suggest that in good responders, it may be safe to omit a second induction cycle if a second cycle poses a high risk. Figure. CR + CRi, RFS and OS after randomization to single versus double induction. Disclosures Alakel: Pfizer: Consultancy. Jost:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; JAZZ: Other: travel support; Celgene: Other: travel support. Novak:Roche: Consultancy; Janssen: Other: Travel expenses; Takeda: Consultancy; Amgen: Consultancy, Other: Travel expenses; Pfizer: Consultancy; Novartis: Consultancy. Krause:Takeda: Honoraria; Celgene: Other: Travel Support; MSD: Honoraria; Pfizer: Honoraria; Siemens: Research Funding; Gilead: Other: Travel Support. Held:Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy; Acrotech: Research Funding; Spectrum: Research Funding; Amgen: Research Funding. Platzbecker:AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Müller-Tidow:Daiichi Sankyo: Research Funding; Pfizer: Research Funding, Speakers Bureau; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau.

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A Study of Tbo-Filgrastim (Granix) to Disrupt the Bone Marrow Microenvironment in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-115603 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2146-2146

Author(s):

Meagan Jacoby ◽

Reetom Bera ◽

Theresa Fletcher ◽

Mark A. Fiala ◽

Kathryn Trinkaus ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Overall Response Rate ◽

Stopping Rules ◽

Early Stopping ◽

Advisory Committees ◽

Stimulating Factor

Abstract Multiple myeloma is the second most common hematologic malignancy in the US. The current standard of care for transplant eligible patients is therapy with high-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT). Although ASCT improves progression-free (PFS) and overall survival (OS), it is not curative and virtually all patients will relapse. Attempts to improve upon HDM by adding other agents to transplant protocols have largely resulted in unacceptable increases in toxicity. Preclinical studies performed by our group suggest that granulocyte-stimulating factor (G-CSF) disrupts the bone marrow microenvironment, resulting in a striking loss of plasmablasts, plasma cells, and decreased expression of chemokine/cytokines contributing to plasma cell maintenance. Tbo-filgrastim (Granix, Teva Pharmaceuticals) is a recombinant methionyl human granulocyte colony-stimulating factor. We hypothesized that tbo-filgrastim treatment may provide a potent and well-tolerated method to disrupt the 'myeloma cell niche', rendering patients more sensitive to HDM. Methods: Here, we report results from an open label, single center, phase II randomized study to test the efficacy and safety of tbo-filgrastim plus HDM (tbo-filgrastim arm) versus HDM alone (SOC arm) prior to ASCT (NCT02112045). Patients were randomized 1:1 to tbo-filgrastim on Day -7 through Day -2 (480 or 960 mcg/day, based on weight) and melphalan on Day -2 prior to ASCT (140 or 200 mg/m2, based on age) or melphalan alone. The primary objective was to compare CR rate at day 100. Secondary objectives included comparison of the toxicity, overall response rate, PFS, OS, and rate of neutrophil and platelet engraftment between the two arms. Eligible patients were ≥18 years with symptomatic multiple myeloma enrolled within 12 months of receiving at least 2 cycles of any systemic therapy, were undergoing their first ASCT, and had an adequate ASCT collection product (at least 2 million CD34+ cells/kg). Target enrollment was 176 patients, with an interim analysis of efficacy and futility planned after 88 patients reached Day 100 post-ASCT. Early stopping rules for unacceptable toxicity were in place. Responses were evaluated by IMWG criteria. Results: Ninety patients were enrolled (median age 59.5, range 33 to 77) and 89 were evaluable for response. The early stopping rules for toxicity were not met. The planned interim analysis showed that the proportion of patients in CR at Day 100 was similar between the arms and the study was halted for futility (39.5% on the tbo-filgrastim arm vs. 37.8% on SOC arm). The overall response rate (CR + VGPR + PR) between the tbo-filgrastim and the SOC arm was 95% vs 93%, respectively. At the interim analysis, with median follow-up time for the study of 21.7 months, (range 8.8 to 25.8), the median PFS and OS had not been reached for either arm. There was no difference in PFS between the tbo-filgrastim and the SOC arm (84% vs 80%, respectively, p=0.60). There was no difference in OS between the tbo-filgrastim and the SOC arm (90.9% vs 95.6%, respectively, p=0.43). All patients in the study achieved neutrophil (ANC > 0.5 K/cumm) and platelet (> 20 K/cumm) engraftment. The median time to neutrophil engraftment for the tbo-filgrastim arm was 5 days (range, 3-9) vs 4 days (range, 3-7) in the SOC arm, p<0.001. There was no difference in the median time to platelet engraftment between the arms (11 days in the tbo-filgrastim arm, range 2-23, and 10 days in the SOC arm, range 1-24, p=0.67). Adverse events for both arms were typical of those observed in the ASCT population. Conclusions: The administration of tbo-filgrastim in the setting of HDM prior to ASCT is feasible, without excess toxicity or loss of engraftment. There was no difference in Day +100 CR or ORR rates, PFS, or OS in patients treated with tbo-filgrastim plus HDM versus HDM alone with a median follow-up of 21.7 months. The lack of efficacy may be secondary to the high pre-ASCT response rates seen with modern agents. Disclosures Jacoby: Celgene: Speakers Bureau; NovoNordisk: Consultancy. Schroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: 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, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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