Second Relapse of Pediatric Patients with Acute Myeloid Leukemia: A Report on Current Treatment Strategies and Outcome of the AML-BFM Study Group

BACKGROUND: Children with acute myeloid leukemia (AML) still experience high rates of relapse. Facing increasing survival after first relapse, it appears critically important to examine the consequences of a second relapse in more detail. However, there is no population-based data available in pediatric AML and no reliable statement about general survival, patients' characteristics or treatment approaches can be made. Herein, we report current survival results following second relapse from the BFM study group, which represents to our knowledge the largest available dataset for this subgroup of patients. PATIENTS AND METHODS: Between 2004 and 2017, 1222 pediatric patients (age less than 18 years at initial AML diagnosis) with AML (no secondary leukemia, no Down syndrome, no acute promyelocytic leukemia) were registered in the population-based AML-BFM registry and trials in Germany, Austria, Czech Republic and Switzerland providing a longitudinal data collection with treatment, response rates, survival and disease characteristics. Central review of source documentation confirmed accuracy and consistency of all reported data. Only patients with a documented date of first and second complete remission (CR1 and CR2) and a diagnosed second relapse until the age of 21 are included. Statistical analyses were performed with SAS version 9.4 (SAS Institute). All living patients were censored at the time of last follow-up, but no patient later than 03/27/2020. The median follow-up after diagnosis of second relapse was 6,5 years. RESULTS: In all registered patients, 7% (83 out of 1222) met the strict criteria for a second relapse. For further analyses patients with a date of second relapse diagnosis after 12/31/2017 (n=6), two patients with isolated CNS relapse, who did not receive systemic chemotherapy, one patient with an underlying syndrome and one patient with insufficient data have been excluded. The median age at second relapse was 9,2 years. Sixty percent (n=44) of the patients, who experienced a second relapse, did so within a year after first relapse diagnosis. Eighty percent (n=58) and 7% (n=5) had one or two previous HSCTs, respectively. Eighty-nine percent (n=65) received an anthracycline-containing re-induction (DNX-FLA) followed by FLA or another intensive treatment regimen before at first relapse. In contrast to the standardized treatment approaches in first relapse, patients with second relapse received a wide range of therapy. Forty-six patients (63%) have been treated with an intensive cytotoxic treatment (Table 1). Seventeen patients (23%) got palliation only. Among the 25 patients (35%) who proceeded to HSCT, 21 patients (88%) had a prior HSCT. Survival after second relapse was very poor with a 5-year pOS of 15±4% (see Figure 1A) and a considerable cumulative incidence of early deaths (until day 56 after diagnosis: CI ED 19±5%). Prognosis did not improve over time with consistent overall survival rates until 2017 (see Figure 1B). Causes of death include disease progression (n= 51, 70% of all patients), a combined SCT-related and disease-related cause (n=3, 5%) and SCT-related complications (n=4, 4%) or treatment-associated toxicity (n=5, 7%). The 5-year pOS was 2±2% for patients with an early second relapse vs. 33±9% for those experiencing a second relapse more than a year after the first. (p<0.0001; Figure 1C). The timing of a first relapse and age did not show any influence on overall survival. The best response achieved in the respective bone marrow sample after up to two cycles with cytotoxic treatment have been categorized. Out of 45 patients with conclusive data 31.1% (n=14) achieved a third CR with a pOS of 36±13%, while 62.2% of the patients showed a nonresponse to the treatment (n=28, pOS 7±5%) or no evidence of leukemia, but also no peripheral regeneration (6.7%, n=3, pOS 0±0%). CONCLUSION: These data provide new insights into treatment strategies, prognostic factors and outcome of children with second relapse in pediatric AML. As expected, survival is poor, but nonetheless possible in this increasingly relevant subgroup of patients. These data may serve as foundation for urgently needed international clinical trials for relapsed and refractory AML in children. Disclosures Bourquin: Servier: Other: Travel Support. Reinhardt:CLS Behring: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees.

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Failures and Successes in Pediatric Patients with Acute Myeloid Leukemia with First Relapse: A Large International Report on Current Treatment Strategies and Outcome

Blood ◽

10.1182/blood-2020-141774 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Mareike Rasche ◽

Martin Zimmermann ◽

Emma Steidel ◽

Todd A. Alonzo ◽

Richard Aplenc ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Pediatric Patients ◽

Advisory Committees ◽

First Relapse ◽

Pediatric Aml ◽

Acute Myeloid

BACKGROUND: Children with high risk acute myeloid leukemia (AML) still experience consistently high rates of relapse. Survival after first relapse increased from 21% between 1987 and 1997 up to 39% in recent studies. However, since 2009, there have been no publications on subsequent large pediatric AML relapse trials. As the indications for HSCT during first-line treatment have been extended since then, the current survival of these patients at relapse remains unclear. Herein, we report outcome results from the BFM and COG study group, which represents the largest available dataset analyzed for post-relapse survival. PATIENTS AND METHODS: Pediatric patients with first relapse of AML (no Down syndrome, secondary leukemia or FAB M3) have been analyzed from two large study groups with patients from the United States, Canada, Australia, New Zealand, Germany, Austria, Czech Republic and Switzerland. Out of 1222 patients in the BFM cohort (AML-BFM study 2004, registry 2012 and study 2012), 350 experienced at least one relapse and 197 of those had a first relapse after closure of the last I-BFM relapse trial (04/2009 through 2017). Within the Children's Oncology Group (COG) Phase 3 trials (AAML0531 and AAML1031, n=2119) 852 pediatric patients suffered a relapse. Five-year probability of overall survival (pOS) and event-free survival (pEFS) were calculated according to Kaplan-Meier. EFS was calculated for the BFM cohort as time from relapse to the next event (second relapse, death, failure to achieve a second remission or secondary malignancy) or until last follow-up, while OS reflects the time from relapse until death or last follow-up. The Cox proportional hazards model was used for multivariate analysis of outcomes. Living patients were censored at last follow-up with a median follow-up after relapse of 4·2 years (BFM) and 4·8 years (COG). Data have been frozen at 03/27/2020 (BFM) and 03/31/2020 (COG). RESULTS: In the 197 patients with relapse after closure of the last BFM relapse trial (04/2009 through 2017) the pOS at 5 years was 42±4% (BFM). The 5-year pOS in patients relapsing after COG trials 2006-2018 was 35±2% (n=852). Patients experiencing a relapse between 2014 to 2017 had a pOS of 49±6% (BFM, n=78) and 40±3% (COG, n=333). Risk classification at initial diagnosis and a short time from diagnosis to relapse predicted a diminished survival probability in both cohorts (see Table 1). However, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival: Within the BFM dataset, a subgroup analysis in all patients receiving DNX-FLA (n=156) have been performed. Initial characteristics are comparable to the total cohort. Among these patients 147 were evaluable for response (7 excluded due to early death before evaluation, 2 for insufficient data). Eighty-nine (57%) achieved a CR (n=69) or CRp (n=20) and 52 (33%) no response. Overall survival was superior for patients with a CR/CRp (54±6% (CR/CRp) vs. 32±7% (No CR/CRp); p=0·0064), but long-term survival was still possible even with a poor re-induction response. Patients with a CRp had a comparable survival to those with a CR after a second re-induction (pOS 60±11% (CRp) vs. pOS 52±7% (CR); p=0·57). Patients with >5% leukemic blasts (n=32) had the lowest survival (pOS 27±9%). The 5-year pEFS for this cohort was 29±4% (pEFS 50±6% (CR) vs. pEFS 50±11% (CRp)). The analysis of post-relapse treatment showed that the vast majority of patients who survive had a HSCT following relapse. By landmark analysis, survival was significantly higher in patients with subsequent HSCT compared to that of non-transplanted patients (BFM: pOS 53±4%, n=154 vs. pOS 5±5%, n=21; p(Mantel-Byar)=0·0002). CONCLUSION: This is the largest report to date on post relapse survival in children with AML. Our analysis confirmed previously described risk factors for poor survival while also highlighting new findings contrary to established standards. Strikingly, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival at first relapse, thereby questioning the current value of the established International Working Group Criteria published by Cheson et al for response-evaluation in pediatric AML. As the international pediatric AML community embarks on collaborative efforts to evaluate new therapies in children with relapsed AML, a comprehensive review of post relapse survival is critical. Disclosures Bourquin: Servier: Other: Travel Support. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia (AML): Princess Margaret Cancer Centre Experience

Blood ◽

10.1182/blood-2019-125449 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2609-2609

Author(s):

Muhned Alhumaid ◽

Georgina S Daher-Reyes ◽

Wilson Lam ◽

Arjun Law ◽

Tracy Murphy ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Treatment Strategies ◽

Patient Characteristics ◽

Cancer Center ◽

Advisory Committees ◽

Disease Behavior

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Teva Canada Innovation: 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; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Venetoclax and Azacitidine for Older Newly Diagnosed Patients with Acute Myeloid Leukemia: A Single-Institution Pilot Study Using Measurable Residual Disease to Guide Therapy

Blood ◽

10.1182/blood-2019-122120 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2638-2638 ◽

Cited By ~ 1

Author(s):

Amanda Winters ◽

Jonathan A Gutman ◽

Enkhtsetseg Purev ◽

Brett M. Stevens ◽

Shanshan Pei ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Ras Pathway ◽

Measurable Residual Disease ◽

Count Recovery

Background: Venetoclax (ven) was approved for older untreated acute myeloid leukemia (AML) patients due to high response rates and durable remissions. As a participating site in the dose escalation study, we observed deeper/more durable responses in some who received >400mg ven. We also noted 16/33 discontinued azacitidine (aza) after achieving a response; 9 relapsed and 7 remained in long term remission on ven only. Based on these observations, we designed a study that hypothesized: A)Higher initial doses of ven would allow deeper/more durable responses, and B)Multi modality high sensitivity measurable residual disease (MRD) testing could identify patients able to discontinue aza and remain on maintenance ven. Methods: This is an ongoing phase 2 study (NCT03466294) of 42 untreated AML patients ≥60 who decline/are ineligible for induction. Patients have adequate organ function and white blood cell counts <25x109/L (hydrea permitted). In cycle 1, patients receive aza 75mg/m2 on days (d) 1-7 and ven, escalated from 100 to 200 to 400 to 600mg on d 1-4. Ven continues at 600mg d 5-28 and bone marrow biopsies (BMBXs) are performed on d 8 and 28. Patients who achieve morphologic remission without count recovery have up to 14 days off therapy before subsequent cycles, with growth factor support; "upgraded" responses are recorded if count recovery occurs. Non responders discontinue or receive up to two additional cycles of aza and ven 600mg. Responders who remain MRD+ by multiparameter flow cytometry (MPFC, Hematologics) and/or digital droplet PCR (ddPCR) for as many identifiable diagnostic genes as possible also receive up to 2 additional cycles of aza and ven 600mg. MRD+ responders after 3 cycles continue aza and ven 400mg until toxicity/progression. Patients who experience MRD- responses at any time stop aza and continue ven 400mg daily (Fig 1). Results: 30 patients enrolled between May 2018 and July 2019; median age is 71 (60-88), 10% evolved from MDS and 10% and 73% had intermediate and unfavorable risk disease by ELN, respectively (Table 1). 732 adverse events (AEs) occurred; 46 (6%) were serious, the most common were neutropenic fever (37%) and pneumonia (13%). The most common >grade 2 related AEs were leukopenia (53%), thrombocytopenia (44%) and neutropenia (35%); there were no related grade 5 AEs. The overall response rate was 70% (21/30; CR=19, MLFS=2). Median number of cycles to achieve best response was 1. Significant blast reductions were seen on day 8; of the 28 with interpretable day 8 BMBXs, 10 achieved MLFS on day 8. 4 completed ≥1 cycle and were refractory. An additional 4 did not complete cycle 1: 1 died of disease and 3 elected to come off therapy (all subsequently died of disease). Four (19%) responders relapsed, after a median 180 days (27-279). With median follow up of 214 days, median response duration has not been reached. 10 patients died, after a median 65 days (29-256); 1/30 died within 30 days. Median overall survival has not been reached. Of the 26 who completed ≥1 cycle, 19 were MRD- by MPFC, including 18/19 who achieved CR. Of these 26, 3 were not monitored by ddPCR: for 2 patients this was due to the absence of detectable baseline mutations and for 1 patient it was due to refractory disease. The remaining 23 had ddPCR monitoring; 3 became MRD- by this modality (Fig 2). All 3 were also MRD- by MPFC and per protocol discontinued aza and initiated ven maintenance (Fig 1). MRD negativity by both parameters occurred after cycles 1, 2 and 3, respectively. One MRD- patient relapsed after 216 days; two remain in remission after 301 and 124 days. An additional 4 who achieved MRD+ responses discontinued aza at their insistence (and in violation of the protocol); 1 relapsed after 279 days, and 3 remain in ongoing remission. Univariate predictors of refractory disease were FAB M0/M1 (OR 0.070, p=0.02) and RAS pathway mutations (OR 14.25, p=0.02). Conclusions: Higher initial doses of ven are tolerated in this population. Blast reduction occurs quickly in many patients (day 8), for this low intensity regimen. Response rates are consistent with lower doses of ven. Very deep responses, as measured by highly sensitive MRD methods (MPFC and ddPCR are capable of sensitivity up to 0.02%), are attainable. Longer follow up time will determine if higher ven doses and MRD-driven decisions related to continuation of aza result in more durable responses. Increased maturation of blasts and RAS pathway mutations are predictors for refractory disease. Disclosures Lyle: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pollyea:Agios: 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; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Transition of Chronic Myeloid Leukemia to Chronic Myelomonocytic Leukemia As a Tool to Observe Development of Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v126.23.5223.5223 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5223-5223

Author(s):

Jamshid S Khorashad ◽

Srinivas K Tantravahi ◽

Dongqing Yan ◽

Anna M. Eiring ◽

Hannah M. Redwine ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Clonal Evolution ◽

Chronic Myelomonocytic Leukemia ◽

Imatinib Treatment ◽

Advisory Committees ◽

Clonal Architecture ◽

Myelomonocytic Leukemia

Abstract Introduction. Development of abnormal Philadelphia (Ph) negative clones following treatment of chronic myeloid leukemia (CML) patients with imatinib has been observed in 3 to 9% of patients. Here we report on a 77 year old male diagnosed with CML that responded to imatinib treatment and subsequently developed chronic myelomonocytic leukemia (CMML). He achieved major cytogenetic response within 3 months but this response coincided with the emergence of monocytosis diagnosed as CMML. Five months after starting imatinib treatment the patient succumbed to CMML. We analyzed five sequential samples to determine whether a chronological order of mutations defined the emergence of CMML and to characterize the clonal evolution of the CMML population. Materials and Method. Five samples (diagnostic and four follow up samples) were available for analysis. CMML mutations were identified by whole exome sequencing (WES) in CD14+ cells following the onset of CMML, using CD3+ cells as constitutional control. Mutations were validated by Sequenom MassARRAY and Sanger sequencing and quantified by pyrosequencing. Deep WES was performed on the diagnostic sample to determine whether the mutations were present at CML diagnosis. To determine the clonal architecture of the emerging CMML, colony formation assays were performed on the diagnostic and the next two follow-up samples (Samples 1-3). More than 100 colonies per sample were plucked for DNA and RNA isolation. The DNA from these colonies were tested for the presence of the confirmed CMML mutations and the RNA was used for detection of BCR-ABL1 transcript using a Taqman real time assay. Results. Four mutations were identified by Sequenom and WES throughout the patient's time course [KRASG12R, MSLNP462H, NTRK3V443I and EZH2I669M ]. Sequenom did not identify these at diagnosis while deep WES did. Clones derived from colony formation assay revealed three distinct clones present in all samples analysed. Clone 1 had only KRASG12R, clone 2 had KRASG12R, MSLNP462H, and NTRK3V443I, and clone 3 had all four mutations. All clones containing any of these four mutations were BCR/ABL1 negative. Analysis of clonal architecture indicated that KRASG12R was acquired first and EZH2I669M last, while MSLNP462H and NTRK3V443I were acquired in between. These CMML clones increased proportionately as clinical CML metamorphosed into clinical CMML after initiation of imatinib therapy. Consistent with the colony data, pyrosequencing revealed that the ratio between the mutants remained largely stable throughout the follow up period. Conclusion. This case illustrates how targeted therapy impacts clonal competition in a heterogeneous MPN. While the CML clone was dominant in the absence of imatinib, it was quickly outcompeted by the CMML clones upon initiation of imatinib therapy. The clonal architecture analysis, in combination with in vivo kinetics data, suggest that the KRASG12R mutation alone was able to produce a CMML phenotype as clones with just KRASG12R remained at a relatively stable ratio during follow up. Unexpectedly, acquisition of additional mutations, including EZH2I669M as the last mutational event identified in this patient, did not increase clonal competitiveness, at least in the peripheral blood. These data show that clonal evolution may not invariably increase clonal fitness, suggesting that factors other than Darwinian pressures contribute to clonal diversity in myeloproliferative neoplasms. Disclosures Deininger: Gilead: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130379 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3895-3895

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Newly Diagnosed ◽

Advisory Committees ◽

Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

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Outcome of Patients with Myelofibrosis after Ruxolitinib Failure: Role of Disease Status and Treatment Strategies in 214 Patients

Blood ◽

10.1182/blood-2018-99-116289 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4277-4277 ◽

Cited By ~ 5

Author(s):

Francesca Palandri ◽

Elena Maria Elli ◽

Nicola Polverelli ◽

Massimiliano Bonifacio ◽

Giulia Benevolo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Strategies ◽

Chronic Phase ◽

Disease Status ◽

Advisory Board ◽

Advisory Committees ◽

Transfusion Dependency ◽

Investigational Agents

Abstract Introduction . Ruxolitinib (RUX) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms. Significant clinical responses may be achieved in around 50% of patients (pts). However, half of responding pts lose the response over time. Aims . To report the outcome of a large cohort of MF pts after RUX failure, in terms of disease status, treatment strategies and survival. Methods . A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Updated information at the date of July 15th 2018 was available in 442 pts who were included in the present analysis. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. RUX-related toxicity and infections were graded according to the WHO scale. Overall (OS) was estimated from the date of RUX discontinuation to the date of death or last contact, using the Kaplan-Meyer method (log-rank test). Results . After a median follow-up of 30.5 months (1.7-84.3), 214 out of 442 evaluable (48.4%) pts had discontinued RUX. 43 (20.1%) died while on therapy because of: MF progression (34.9%), infections (25.6%), heart disease (16.3%), second neoplasia (7%), hemorrhages (7%), other (9.2%). The median follow-up after RUX discontinuation for the remaining 171 pts was 11.3 months (0.5-66.7). Causes of RUX discontinuation were: drug-related toxicity (28.6%), loss/lack of response (23.4%), MF progression (12.3%), acute leukemia (AL) (13.4%), allogeneic stem cell transplantation (ASCT) (11.1%), second solid neoplasia (4.1%), other unrelated causes (i.e. pts decision; 7.1%). After stopping RUX, 68 pts received 1 line of therapy, 21 received 2 lines and 9 received >2 treatments; 73 pts did not receive any therapy. Treatments received after RUX discontinuation, alone or in combination, included hydroxyurea (HU) (n. 61, 62.2%), ASCT (n. 20, 20.4%), second-generation JAK2 inhibitors (momelotinib/fedratinib/pacritinib) (n. 11, 11.2%), splenectomy (n. 7, 7.1%), azacytidine/decitabine (n. 5, 5.1%), chemotherapy (n. 4, 4.1%), investigational agents (imetelstat/PRM151: n. 4), danazole (n. 4), erythropoietin-stimulating agents (ESA) (n. 4). A total of 95 pts (55.6%) died after RUX discontinuation, because of: MF progression (30.5%), AL (25.4%), infections (14.7%), second neoplasia (9.5%), hemorrhages (4.2%), heart disease (4.2%), ASCT (4.2%), thrombosis (2.1%), other (5.2). Median survival time from RUX stop of the 171 evaluable pts was 22.6 mos (95% CI, 13.2-30.7). Among baseline features, survival after discontinuation was significantly influenced by the dynamic international prognostic score (DIPSS) category (p<0.001), transfusion dependency (p<0.001) and driver mutation status (with triple-negative pts having the worst survival compared to JAK2V617F and CALR-mutated pts, p=0.01). During therapy, 45 out of 153 (29.4%) and 123 out of 161 (76.4%) evaluable pts achieved a SR and a SyR at any time. Survival was not affected by the previous response to RUX at any time-point. Conversely, survival significantly differed according to the reason for stopping RUX, with pts discontinuing because of AL evolution/second solid neoplasia having the worst outcome (Figure 1a, p<0.001). In pts who discontinued RUX in chronic phase, the use of second generation TKIs and other investigational agents tended to prolong survival compared to the administration of conventional medical treatments (i.e. HU, danazole, ESA) (Figure 1b, p=0.07) Discussion . After RUX failure, very limited therapeutic options are available and the prognosis of MF pts is dismal, particularly for those pts starting RUX with advanced stage disease (i.e. high DIPSS category and transfusion dependency). Also, disease evolution into AL and occurrence of a second solid neoplasia significantly reduced life expectancy. In chronic phase pts, survival probability may be improved by the use of medical therapies that are still in the experimental phase. Novel investigational agents are needed. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo:Novartis: 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.

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Safety and Efficacy of Midostaurin in Combination with High-Dose Daunorubicin in 7+3 Induction for Acute Myeloid Leukemia with FLT3 Mutation

Blood ◽

10.1182/blood-2019-129331 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3896-3896

Author(s):

Yehuda E. Deutsch ◽

Robert Wilkinson ◽

Amanda Brahim ◽

Stephanie Boisclair ◽

Jose Sandoval-Sus ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Cancer Center ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Safety And Efficacy ◽

Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with varied outcomes dependent on patient cytogenetic and mutational status. Thirty percent of adults with newly diagnosed AML have a mutation in the fms-related tyrosine kinase 3 (FLT3) gene. Midostaurin is a small molecule inhibitor that acts on multiple receptor tyrosine kinases, including FLT3. The RATIFY trial showed improved overall survival (OS) and event-free survival in patients treated with daunorubicin and cytarabine (7+3) plus midostaurin (Stone et al, NEJM 2017). In this trial, a dose of daunorubicin 60 mg/m2 was administered. High dose (HD) 90 mg/m2 daunorubicin significantly improved the rate of complete remission and overall survival, including in patients with FLT3-ITD (Luskin et al, Blood 2016). HD daunorubicin has also been shown to be more effective than idarubicin in patients with FLT3-ITD AML (Lee et al, J Clin Oncol 2017). This data raises the question of whether the combination of midostaurin and HD daunorubicin would further improve outcomes of FLT3 mutated AML patients, while maintaining a tolerable safety profile. The objective of this study is to describe the safety and efficacy endpoints of FLT3 mutated AML patients treated with HD daunorubicin plus midostaurin as part of induction therapy. Methods: We retrospectively reviewed clinical and molecular data of patients at Memorial Healthcare System, Moffitt Cancer Center, and Sylvester Cancer Center with newly diagnosed FLT3 mutated AML treated from May 1st, 2017 to July 1st, 2019. Clinical data was abstracted in accordance with institutional review board approved protocol. All patients were induced with HD daunorubicin 90 mg/m2 on days 1-3, cytarabine 100 mg/m2 on days 1-7, and midostaurin 50 mg PO twice daily on days 8-21. Growth factor and antimicrobial support were used per institutional guidelines. Demographics were analyzed using descriptive statistics. OS was analyzed using Kaplan Meier method. Other efficacy outcomes were CR, CRi (assessed according to the European Leukemia Network Criteria for AML), proportion of patients needing re-induction, and proportion of patients who underwent hematopoietic stem cell transplant (HSCT). Safety outcomes were adverse events (AEs) and early (30- and 60-day) mortality. Results: Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients. Seventy-seven percent of patients achieved a CR/CRi after one induction cycle, and 96.2% attained CR after two induction cycles. Median time to ANC and platelet recovery was 28 and 26 days, respectively. One patient died during the first 60 days, due to Enterococcus sepsis. The most common non-hematological AEs were nausea (77%), diarrhea (62%), mucositis (58%), rash (54%), and increased ALT (54%). Cumulative incidence of relapse in the cohort was 28% (n=7). Four patients relapsed pre-transplant and achieved CR2 with additional therapy. All 7 of these patients had co-occurring mutations of various types. Of the 20 patients who were considered transplant eligible, 13 (65%) underwent HSCT and 4 (20%) are pending transplant. Of the 13 transplanted patients, 3 experienced relapse post-transplant. After a median follow up of 14.5 months, median OS has not been reached. Conclusion: In our multi-center experience, induction with HD daunorubicin, cytarabine, and midostaurin is clinically effective and seems to be well tolerated. Short term mortality was low and AEs were manageable, with no unexpected safety signals. Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML. Future analyses with larger patient samples and longer follow up are warranted to further evaluate long-term safety and efficacy for this regimen. Figure Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Bradley:AbbVie: Other: Advisory Board. Talati:Agios: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding.

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Overview of Primary and Secondary Myelofibrosis in Young Adults: Genomic Characteristics, Treatment Strategies and Outcomes

Blood ◽

10.1182/blood-2019-123536 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4177-4177

Author(s):

Andrew T Kuykendall ◽

Chetasi Talati ◽

Kendra L. Sweet ◽

Eric Padron ◽

David A Sallman ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Treatment Strategies ◽

Cell Transplant ◽

Advisory Committees ◽

Treatment History ◽

Secondary Myelofibrosis

Introduction: Primary and secondary myelofibrosis (MF) [i.e. occurring after a prior diagnosis of polycythemia vera [PV] or essential thrombocythemia (ET)] are myeloid malignancies often diagnosed in the 6th and 7th decade of life. In the rare occurrence that younger patients receive this diagnosis, prognostic recommendations are poorly extrapolated and optimal treatment strategies are unclear. Prior studies assessing young MF patients have suggested a more indolent course for this cohort. Here we aim to analyze our experience with young MF patients in terms of genetic makeup, treatment history, and outcomes. Methods: We assessed a database of primary and secondary MF patients who presented to our center between 1/2000 and 6/2019. We identified patients who were 50 years or younger at the time of MF diagnosis. Clinical and genetic features along with treatment history and outcomes were analyzed. Kaplan-Meier method was used for survival analysis. Patients surviving at 240 months after diagnosis were censored at that time. Results: Among 599 MF patients, 63 (11%) were ≤50 at the time of diagnosis. Median age at diagnosis was 43.6 years (yr). Median time from diagnosis to first presentation to our institution was 4.2 months (mo) (range 0-35 yr). Thirty-eight (60%) and 44 (70%) were seen within 1 and 5 years of diagnosis, respectively. Females accounted for 62% (n = 39) of patients. Forty-five (71%) patients had primary MF, 4 (6%) had post-PV MF and 13 (21%) post-ET MF. Median follow-up for the cohort was 94.9 mo. Among 62 patients in whom IPSS at diagnosis could be calculated, 20 (32%) were low, 27 (44%) intermediate-1, 12 (19%) intermediate-2, and 3 (5%) high-risk. JAK2 mutation was detected in 22/60 (37%), CALR in 21/44 (48%), MPL in 0/49 (0%). One patient was triple-negative. Extended targeted gene sequencing was performed in 42/63 patients during their clinical course. Sequencing occurred at a median time of 2.6 yr after diagnosis (range 0-35 yr). Genes most commonly mutated were ASXL1 (12%), TET2 (12%), EZH2 (10%), and DNMT3A (10%). No mutations involving SRSF2, U2AF1, ZRSR2, or SF3B1 were seen. Thirteen patients did not receive active treatment during follow-up. Among those receiving treatment, median time to first treatment was 9.4 mo (range 0-331 mo). The most common initial treatments were erythropoiesis-stimulating agents (ESAs) (14%), hydroxyurea (28%), and ruxolitinib (22%). In total, 29 (46%) received ruxolitinib with median time to ruxolitinib treatment of 27.2 mo. Median duration of ruxolitinib treatment was 44.5 mo. Fourteen patients underwent allogeneic hematopoietic stem cell transplant (AHCT) at a median of 57.4 mo after diagnosis (range 6-123 mo). Transformation to acute myeloid leukemia (AML) occurred in 5 patients at a median time of 99 mo (range 51-178 mo) after diagnosis. Median overall survival (OS) was not reached. Five and 10-year OS estimated at 93% and 77%, respectively. No difference was seen in OS for patients with primary and secondary MF (p = 0.40). Conclusions: Primary and secondary MF are rarely diagnosed in patients ≤ 50 years old. In this cohort, patients are often CALR mutant, have lower-risk disease, and lack splicing mutations. Initial treatment strategies are varied, but favor cytoreductive approaches. The prognosis in these patients is favorable, but high-risk mutations can occur and progression to AML occurs in a minority of patients. AHCT remains a curative option; however, optimal timing for transplant is not clear. Figure Disclosures Kuykendall: Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria; Incyte: Honoraria, Speakers Bureau. Talati:Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Agios: Honoraria; Pfizer: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. Komrokji:JAZZ: Consultancy; Agios: Consultancy; celgene: Consultancy; pfizer: Consultancy; Incyte: Consultancy; Novartis: Speakers Bureau; DSI: Consultancy; JAZZ: Speakers Bureau.

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Targeting Immune Dysregulation in Childhood Evans Syndrome

Blood ◽

10.1182/blood-2018-99-110734 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3564-3564

Author(s):

Amanda Bell Grimes ◽

Taylor Kim ◽

Susan E. Kirk ◽

Michele P. Lambert ◽

Rachael F. Grace ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Strategies ◽

Immune Dysregulation ◽

Systemic Autoimmune Disease ◽

Evans Syndrome ◽

Advisory Committees ◽

Immunomodulatory Agents ◽

Autoimmune Cytopenias

Abstract Background: Evans Syndrome (ES) describes the simultaneous or sequential occurrence of 2 or more autoimmune cytopenias - most often autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), but also autoimmune neutropenia (AIN) - which are often refractory to therapy and chronic in nature. Historically, ES has been attributed to idiopathic autoantibody production, but recent advances in our understanding of this disease have revealed associations with more well-described underlying disorders of immune regulation when properly investigated. These include autoimmune lymphoproliferative syndrome (ALPS) and more novel immune dysregulation disorders such as Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) defects, among the more historically well-known systemic autoimmune diseases (such as systemic lupus erythematosus [SLE]) and common variable immunodeficiency (CVID). Importantly, recent data shows improved outcomes among ES patients in whom underlying immune dysregulation is identified and for whom appropriately targeted immunomodulating treatments are then utilized. Despite this, the majority of underlying and potentially targetable pathologies driving ES in children remain undiagnosed; and treatment strategies are therefore empiric, resulting in sub-optimal outcomes among this population of patients. Aims: We aim to better describe the diagnostic rates, treatment strategies, and clinical outcomes among a large cohort of pediatric patients with this rare and poorly studied disease, in order to identify barriers to appropriate and timely diagnostic investigation, to highlight areas for future research, and to better inform clinical practices. Methods: We completed a retrospective chart review including pediatric ES patients followed at 3 large tertiary centers over a recent 6-year period (2012 - 2018). All patients meeting eligibility criteria (those aged 6 months - 21 years, with 2 documented autoimmune cytopenias as defined by current international expert committee standards, and not having undergone solid organ or stem cell transplantation) were reviewed in accordance with IRB-approved protocols. Chi-squared test or Fisher's exact test were utilized to compare nonparametric categorical data. Mann-Whitney U-test was used to compare nonparametric continuous data. A Kruskal-Wallis one way ANOVA test was used to compare ranks between more than two categories. Statistical analyses were performed using SPSS Statistics 24 (IBM, Armonk, NY). A Bonferroni correction was applied to correct for multiple comparisons. A p<0.05 was defined as statistically significant. Results: 48 eligible patients with ES were identified, with length of follow-up ranging from 0 to 12 years (median = 2.7 years). Underlying immune dysregulation was identified in 46% of patients - 12 with systemic autoimmune disease, 4 with ALPS, 3 with CVID, and 3 with other disorders of immune regulation (n=22). Notably, 100% of pediatric ES patients in whom a definitive immune dysregulation disorder was identified required ≥ 3 therapies (mean follow-up = 3.7 years), vs. only 58% of ES patients in whom no unifying immune diagnosis was made (mean follow-up = 3.2 years) [p=0.008]. Furthermore, second- and third-line immunomodulatory agents (including mycophenolate, hydroxychloroquine, 6-mercaptopurine, belimumab, ofatumumab, abatacept, rituximab, sirolimus, cyclosporine, azathioprine, danazol, and methotrexate) were utilized at a significantly higher rate among those with underlying immune dysregulation identified (82%) vs. those without (31%) [p=0.003]; and ≥3 immunomodulatory agents were required significantly more often in the group with underlying immune dysregulation identified (32%) vs. those without (0%) [p=0.016]. Among those in whom a unifying diagnosis was made, difference in time to diagnosis among groups was statistically significant (p=0.036), with the time to diagnosis for systemic autoimmune disease shorter than that for other immune dysregulation disorders. Overall, ES preceded identification of an underlying immune dysregulation disorder by an average of 3.7 years. Conclusion: A thorough investigative approach is necessary in pediatric ES patients, given the importance of identifying the more global immune dysregulation which would allow for targeted treatment strategies and lead to improved overall long-term outcomes among this population of patients. Figure. Figure. Disclosures Lambert: Bayer: Membership on an entity's Board of Directors or advisory committees; Summus: Consultancy; Rigel: Consultancy; Sysmex: Consultancy; Shionogi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Educational Concepts in Medicine: Consultancy; CSL: Consultancy. Grace:Agios Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy. Despotovic:Novartis: Research Funding; AmGen: Research Funding; Sanofi: Consultancy.

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Long-Term Subgroup Analyses from Azacitidine Vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the Pethema Registry

Blood ◽

10.1182/blood-2021-150649 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1256-1256

Author(s):

Jorge Labrador ◽

Adolfo de la Fuente ◽

David Martínez-Cuadrón ◽

Rebeca Rodríguez-Veiga ◽

Josefina Serrano ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Subgroup Analysis ◽

Myeloid Leukemia ◽

Research Funding ◽

Real Life ◽

Advisory Committees ◽

Baseline Characteristics

Abstract INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs have demonstrated efficacy in monotherapy and in combination with targeted therapies. However, there is little direct comparative data on AZA and DEC in first-line treatment, and we do not know which group of patients might benefit from each drug. Results of the full analysis set (FAS) were presented previously (Labrador J, et al. ASH 2020). Here, we report long-term clinical efficacy from prespecified patient subgroup analyses. METHODS We conducted a retrospective study to compare real-life clinical outcomes between AZA and DEC in patients with AML ineligible for intensive chemotherapy included in the PETHEMA registry, and analyzed clinical variables associated with response and overall survival (OS) between AZA and DEC. RESULTS A total of 626 patients were included for the FAS between 2006 and 2019. 487 (78%) received AZA and 139 (22%) received DEC. Baseline characteristics were comparable in both groups, except for the percentage of bone marrow blasts (44% vs. 34% in the DEC group compared to AZA, p=0.010). In the FAS, there was no difference in the CR, CR/CRi or ORR (CR/RCi + PR) rate: 18%, 20.5% and 32% with AZA vs. 23%, 25% and 39.5% with DEC (p=0.20, p=0.27 and p=0.12). In the subgroup analysis, DEC was associated with higher CR/CRi rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.088 - 0.801), bone marrow blast count < 50% (95% CI: 0.293 - 0.965), secondary AML (95% CI: 0.223 - 0.918) and adverse cytogenetics (95% CI: 0.171 - 0.857) (Figure 1A). DEC was associated with higher ORR rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.116 - 0.782), leukocytes < 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts < 50% (95% CI: 0.321 - 0.920) (Figure 1B) 120 days-mortality was 25.4% after AZA and 27.1% after DEC, p=0.70. Patients who did not achieve at least a PR had significantly higher 120-day mortality with both HMAs (OR 8.85 and 8.22 for AZA and DEC, respectively). In the subgroup analysis, patients with leukocytes ≥ 10 x10 9/L (95% CI: 1.069 - 4.157) and those with estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m 2 (95% CI: 1.249 - 4.664) had higher 120-day mortality with DEC than with AZA (Figure 1C) With a median follow-up of 12 months, median OS was 10.4 months (95% CI: 9.2 - 11.7) for AZA vs. 8.8 months (95% CI: 6.7 - 11.0) for DEC (p = 0.455). The subgroup analysis revealed that patients ≥ 80 years (95%: CI 1.005 - 2.341), with leukocytes ≥ 10 x10 9/L (95% CI 1.039 - 2.062), platelet count <20 x10 9/L (95% CI: 1.150 - 3.422) and those with eGFR ≥ 45 mL/min/1.73m 2 (95% CI: 1.040 - 2.059) did benefit for treatment with AZA compared to DEC (Figure 1D). CONCLUSIONS Our study provides real-life data on the outcomes of AML patients treated with AZA compared to DEC in a large retrospective cohort with long-term follow-up. In addition, we identify for the first time some baseline characteristics that could benefit from AZA or DEC in terms of responses, 120-day mortality and OS. These findings could help us to choose the most appropriate HMA in monotherapy or for the development of new combinations. Figure 1 Figure 1. Disclosures de la Fuente: Novartis: Research Funding; Abbie: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Tolero Pharmaceutical: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

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