Are Racial Disparities in Acute Myeloid Leukemia (AML) Clinical Trial Enrollment Associated with Comorbidities and/or Organ Dysfunction?

Background: Minority patient (pt) populations are underrepresented in clinical trials and the proportion of such pts accrued to cancer studies has decreased, specifically among African Americans (AA) (Kwiatkowski et al. Cancer 2013). If minority pt populations have higher rates of comorbidities, restrictive eligibility criteria may contribute to systematic exclusion from studies. To explore the validity of this potential bias within AML pts, we characterized the comorbidity profile and compared outcomes between AA and white pts with AML. Methods: Adult (≥18 years) AML pts who received chemotherapy at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic/renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Organ dysfunction was defined as ≥ grade 1 per the Common Terminology for Adverse Events. Fisher's exact and Welch's t-tests were performed to compare baseline characteristics. Multivariable logistic and Cox regression analyses were used to identify prognostic factors for response status per International Working Group criteria, and overall survival (OS). Kaplan-Meier method and log-rank test were used to estimate and evaluate OS, respectively. Results: Of 1,040 AML pts included, 939 (90.3%) identified as white and 101 (9.7%) as AA. Age, AML etiology, and AML risk were balanced between the two groups. Insurance coverage was different by race: AAs were more likely than whites to have Medicaid (11.9% vs. 5.1%), and less likely to have private insurance (16.8% vs. 34.6%), P<.001. Pts were treated with the following: 868 (83.5%) with intensive, cytarabine-based, and 172 (16.5%) with non-intensive (low-dose cytarabine or hypomethylating agents) regimens. AA pts were just as likely as whites to receive intensive therapy (P=.68) (Table 1). AA pts presented with similar frequencies of both overall and specific comorbidities. Liver function laboratory values (AST/ALT/bilirubin) and cardiac test results (QTc/LVEF) at baseline were also similar; however, a greater proportion of AAs presented with renal dysfunction when compared to whites, as measured by creatinine (48.5% vs. 36.5%, P=.01) or creatinine clearance by Cockcroft-Gault (CrCl; 55.4% vs. 47.3%, P=.01; Table 2). With a median follow-up of 12.73 months (IQR: 4.59-43.05), the OS for the cohort was 14.75 months (range: 0.03-189.25). Median OS did not differ by race (AA vs. whites: 13.7 vs. 14.9 months, P=.89). Overall, the complete response (CR) rate was 44.2%, which also did not differ by race: (AA vs. whites: 37.6% vs. 44.9%, P=.19). When adjusting for other known predictors, in a multivariable analysis, there was no difference in OS between AAs and whites (HR=1.20, P=.16); additionally, there was no association between comorbidities/organ dysfunction and OS, with the exception of liver comorbidities (HR=2.03, P=.002) and bilirubin (>1.5 x ULN vs. normal: HR= 1.69, P=.01). Clinically insignificant creatinine (>ULN - 1.5 x ULN vs. normal: HR= 0.99, P=.97) and CrCl (84-60 ml/min vs. normal: HR=0.96, P=.69) abnormalities were not independently associated with OS. Subgroup analyses by race revealed similar results for AAs, although, there were no differences in OS based upon bilirubin. With the exception of liver comorbidities (OR= 0.17, P=.01), our analysis failed to identify significant evidence of association between response and comorbidities/organ dysfunction (similar results within the AA subgroup). Although AA were less likely to achieve a CR (AA vs. whites: OR=0.56, P=.05), there was no association between response and creatinine/CrCl abnormalities, regardless of severity. Conclusions: Within this cohort, renal function eligibility criteria may be an important barrier to enrollment, specifically within the AA population. Since there is no association between clinically insignificant renal laboratory values and OS or response, the liberalization of such criterion may be justified. Future trials that broaden the renal function eligibility criterion have the potential to accrue more diverse pt populations, which may reduce recruitment racial disparities and improve the generalizability of the trials' results. Disclosures Hobbs: Amgen: Research Funding; SimulStat Inc.: Consultancy. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Gerds:CTI Biopharma: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Imago Biosciences: Research Funding. Nazha:Daiichi Sankyo: Consultancy; Incyte: Speakers Bureau; Jazz Pharmacutical: Research Funding; Abbvie: Consultancy; Tolero, Karyopharma: Honoraria; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.

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Determinants of "Fitness" for Intensive Therapy Among Acute Myeloid Leukemia (AML) Patients

Blood ◽

10.1182/blood-2019-128853 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3836-3836

Author(s):

Abby Statler ◽

Brian P. Hobbs ◽

Tomas Radivoyevitch ◽

Caitlin Siebenaller ◽

Sudipto Mukherjee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

De Novo ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Advisory Committees ◽

Cart Analysis ◽

Cardiac Abnormalities ◽

Oncology Research ◽

Baseline Characteristics

Background: Determining which AML patients (pts) are "fit" for intensive chemotherapy (IC), both in real-world scenarios and for clinical trial eligibility (particularly as it relates to regulatory indications) is challenging. While age, AML etiology, and cardiac function have been invoked, these oversimplify the clinical assessment and recommendation for IC vs. Non-IC (NIC). We compared baseline characteristics among pts receiving IC and NIC, and evaluated associations between treatment receipt and pt characteristics. Adjusting for treatment received, pts' attributes were further evaluated for association with overall survival (OS). Methods: Adult (≥18 years) AML pts who received IC or NIC at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic and renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Fisher's exact and Welch's t-tests were performed to compare baseline characteristics. Multivariate logistic and Cox regression were used to identify significant prognostic factors for treatment receipt and OS, respectively. The Kaplan-Meier method estimated distributions of OS, which were compared among pt cohorts using the log-rank test. Classification and regression tree (CART) analysis was performed to characterize the best decision process used to select pts for NIC. Results: Of 1,082 AML pts analyzed, 901 (83.2%) were treated with intensive, cytarabine-based chemotherapy, and 181 (16.8%) with non-intensive (low-dose cytarabine or hypomethylating agents) regimens. As expected, baseline characteristics were significantly imbalanced between groups; pts receiving NIC were more likely to be older (P<.001), have ≥3 comorbidities (P<.001), another cancer (P=.02), myocardial (P<.001), renal (P=.006) conditions, abnormal renal (creatinine (P=.004), creatinine clearance by Cockcroft-Gault (CrCl, P<.001)), and abnormal liver function (bilirubin (P=.03)). And less likely to have de novo disease (P<.001), favorable ELN risk (P=.008), private insurance (P<.001), and mild cardiac abnormalities (QTc 450-480ms (P<.001), LVEF 50-40% (P<.001)) (Tables 1 & 2). Multivariable stepwise regression revealed independent associations with the following attributes (favoring NIC over IC): older age (OR=1.10, P<.001), etiology (prior MDS vs. de novo; OR=2.52 , P<.001), liver (bilirubin >1.5xULN vs. normal; OR=3.04, P=.02), renal (CrCl <60 ml/min vs. normal; OR=3.17, P=.002), myocardial conditions (atrial fibrillation/congestive heart failure/coronary artery disease vs. normal); OR=2.33, P=.001) and mild cardiac abnormalities (QTc 450-480ms vs. normal: OR=0.46, P=.01; LVEF 50-40% vs. normal: OR=0.33, P=.03). Clinically, in making decisions about NIC, the first step is age, followed by comorbidity. CART analyses revealed that when a comorbidity is identified, age is then re-assessed; depending upon the type of comorbidity present, various age thresholds determined NIC vs. IC. With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). OS was significantly different between groups (median OS, NIC vs. IC: 4.9 vs. 20.4 months, P<.001). In multivariate analyses controlling for treatment (IC vs. NIC), age, sex, insurance, number of comorbidities, AML etiology, and ELN risk, having another cancer (HR= 0.97, P=.78), renal (HR=1.10, P=.56) or myocardial comorbidity (HR= 0.94, P=.60) were not significantly associated with OS. Liver (bilirubin >1.5xULN: HR=1.70, P=.01), renal (creatinine >1.5xULN: HR=1.55, P=.001; CrCl<60ml/min: HR=1.37, P=.01), and cardiac dysfunction (QTc >480-500ms: HR=1.36, P=.04; LVEF 50-40%: HR=1.38, P=.04) were, however, associated with worse survival. Conclusions: Age, comorbidities, and organ dysfunction are associated with AML treatment determination. Pts who presented with cancer/renal/myocardial comorbidities and renal/liver dysfunction were more likely to receive NIC, despite the comorbid conditions not having an impact on OS. Further research needs to elucidate the extent to which NIC is the optimal treatment decision for pts exhibiting varying severities of cancer/renal/myocardial comorbidities. Disclosures Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:McGraw Hill Hematology Oncology Board Review: Other: Editor; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Celgene Corporation: 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; Projects in Knowledge: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Advani:Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Gerds:Sierra Oncology: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding. Nazha:Daiichi Sankyo: Consultancy; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Abbvie: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees.

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Initial Liver Iron Predicts Cardiac Chelation Efficacy of Deferasirox (Exjade®) Monotherapy in Chronically Transfused β-Thalassemia (β-Thal) Patients: 18- and 24-Month Data.

Blood ◽

10.1182/blood.v114.22.4069.4069 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4069-4069

Author(s):

John C. Wood ◽

Alexis A. Thompson ◽

Carole Paley ◽

Tara Glynos ◽

Barinder Kang ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Employment Equity ◽

Advisory Committees ◽

Liver Iron ◽

Cardiac Iron ◽

Equity Ownership

Abstract Abstract 4069 Poster Board III-1004 Introduction Transfused patients with β-thal major are known to experience clinical consequences of cardiac iron overload despite the widespread use of iron chelation therapy. Approximately 71% of patients will suffer cardiomyopathy, congestive heart failure (CHF) and death. Previous trials have confirmed the efficacy of deferasirox (Exjade®) in removing cardiac iron in patients with β-thal major. This ongoing study evaluates the effects of deferasirox on cardiac iron and left ventricular ejection fraction (LVEF) in patients with β-thal major in a prospective, single-arm, multi-center trial using cardiac MRI T2*. All patients have completed 18 months of therapy and we also report preliminary results from 24 months. Methods 28 patients were enrolled at four US centers. Entry criteria included MRI evidence of cardiac iron (T2* <20 ms) and normal LVEF (≥56%). Deferasirox was administered at 30–40 mg/kg/day for 18 months. Following core study completion (18 months), patients could continue treatment for an additional 6 months if their 18-month cardiac T2* was <20 ms and they demonstrated ≥25% improvement in cardiac T2* or LIC from baseline. Serum ferritin (SF) was assessed monthly. Liver iron concentration (LIC), cardiac T2* and LVEF were assessed by MRI every 6 months. Serum creatinine (SCr), biochemical and hematological status were also monitored. All results are reported as mean ± SE (range) unless otherwise stated. Baseline: All 26 evaluable patients (7 M/19 F; aged 10–44 years) received ≥150 lifetime transfusions. SF was 4307 ± 613 ng/mL (312–12,655), cardiac T2* was 9.5 ± 0.8 ms (1.8–16.1), LIC was 20.6 ± 3.15 mg Fe/g dry weight (dw; 3.6–62.3) and LVEF was 61.8 ± 0.8%. Results At the time of analysis, 22 and 9 patients had 18- and 24-month evaluations, respectively. Six patients discontinued the core trial due to patient decision (n=2), adverse events (AEs; n=2) or abnormal lab tests (n=2). Two of these patients died after discontinuing; the first enrolled with markedly elevated baseline cardiac iron (T2* = 1.8 ms) and died secondary to CHF. The second patient withdrew due to an AE and died 2 months later due to sepsis and multi-organ failure. 18-month results: At 18 months, 10/22 patients were on 40 mg/kg/day. The mean improvement in cardiac T2* from baseline in all patients was 2.2 ms (22%; P=0.016), with 13 patients improving, four remaining stable (T2* change <10%) and five worsening. Baseline LIC was a powerful predictor of response (Figure); cardiac T2* in 14 patients with LIC <18.5 mg Fe/g dw improved 2.2% per month, with 13/14 patients showing large improvements and one patient remaining stable. In contrast, in eight patients with LIC >18.5 mg Fe/g dw, mean T2* worsened 1.4% per month (P<0.0001); three patients remained stable and five worsened significantly. Improvements in cardiac iron were correlated with changes in LIC (r2 = 0.27, P=0.013). In general, initial T2* did not predict therapeutic response, although all three patients with T2* <6 ms increased their cardiac iron. LIC decreased 4.1 mg Fe/g dw over the study interval (P=0.003). LVEF remained stable. 24-month results: At 24 months, 7/9 patients were on 40 mg/kg/day. Relative to the 18-month time-point, 8/9 patients (89%) increased their cardiac T2*, with a mean improvement of 2.7% per month. Mean LIC, SF and LVEF were unchanged over the extension. Safety parameters from patients treated with 30–40 mg/kg/day deferasirox (n=25) were in line with previous studies at 20–30 mg/kg/day. Conclusions Deferasirox monotherapy resulted in statistically significant improvements in cardiac and hepatic iron after 18 months. Baseline LIC <18.5 mg Fe/g dw was a strong predictor of favorable response. LVEF remained stable during the study. Patients in the extension (18–24 months) improved their cardiac T2* without further improvements in LIC or SF. Deferasirox monotherapy at 30–40 mg/kg/day provides good cardiac chelation in patients with moderate cardiac and liver iron burdens. More aggressive therapy is warranted for more severe iron overload. Disclosures: Wood: Novartis: Research Funding. Thompson:Novartis: Research Funding. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Glynos:Novartis Pharmaceuticals: Employment. Kang:Novartis Pharmaceuticals: Employment, Equity Ownership. Giardina:Novartis: Research Funding, Speakers Bureau. Harmatz:Ferrokin: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Coates:Hope Pharma: Consultancy, Research Funding; Sangart Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Non-Pegylated Liposomal Encapsulated Doxorubicin Reduces Cardiotoxicity in 1st Line Treatment of Diffuse Large B-Cell Lymphoma (DLBCL). Final Results of a Randomized Trial

Blood ◽

10.1182/blood.v118.21.2676.2676 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2676-2676 ◽

Cited By ~ 5

Author(s):

Michael A. Fridrik ◽

Andreas L Petzer ◽

Felix Keil ◽

Wolfgang Willenbacher ◽

Ulrich Jaeger ◽

...

Keyword(s):

Heart Failure ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Line Treatment ◽

Advisory Committees ◽

End Of Treatment ◽

Clinical Heart Failure

Abstract Abstract 2676 Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) has improved the treatment results in DLBCL substantially. With more patients being cured from the lymphoma long term toxicity becomes an even more important issue. By replacing doxorubicin with non-pegylated liposomal encapsulated doxorubicin in the R-CHOP regimen (R-COMP) we tried to reduce the cardiotoxicity of R-CHOP in the 1st line treatment of DLBCL. We randomized 88 patients with untreated DLBCL to one of two treatment arms. R-CHOP consisted of rituximab 375 mg/sqm, cyclophosphamide 750 mg/sqm, doxorubicin 50 mg/sqm, vincristine 2 mg, each iv. day 1 and prednisolone daily po for 5 consecutive days. Six cycles of chemotherapy and 8 cycles of rituximab were planned. In the R-COMP arm doxorubicin was replaced with non-pegylated liposomal encapsulated doxorubicin 50 mg/sqm iv day 1. Forty and 39 patients were eligible in the R-COMP and R-CHOP arm, respectively. The two arms were well balanced with respect to age, smoking status, heart function, hypertension, and international prognostic index. The primary endpoint of the study was the left ventricular ejection fraction (LVEF) measured by the Simpson method at randomization, after each cycle and 8 weeks after the end of treatment. Mean and standard error were compared by the two-sample t test. Mean LVEF was significantly lower in the R-CHOP arm (62.29%) than in the R-COMP arm (63.56%) (P=.0333). Out of all LVEF measurements 10 (4.6%) vs. 31 (15.8%) were <55% in the R-COMP arm and R-CHOP arm, respectively (P<.001). The N-terminal proB-type of the natriuretic peptide (NT-proBNP) is a strong marker for heart failure. Levels of NT-proBNP began to rise in the R-CHOP arm after the 5th cycle and were significantly different after the end of treatment (median 73 pg/ml vs. 188.2 pg/ml) in the R-COMP arm and R-CHOP arm, respectively. Three (7.5%) and 12 (33.3%) patients had a NT-proBNP >450 pg/ml in the R-COMP arm and R-CHOP arm, respectively (P=.005). Side effects were lower in the R-COMP arm. We observed 26 and 40 severe adverse events in the R-COMP and R-CHOP arm, respectively (P=.029). Most of those were due to infection. The rate of grade 3 and 4 neutropenias was comparable in both arms giving evidence, that non-pegylated liposomal encapsulated doxorubicin was not under-dosed. Although the study was not powered to show differences in efficacy, we had no signal of lower efficacy. The remission rate was 97.5% (CR+CRu 75.0%) and 82.0% (CR+CRu 69.2%) with R-COMP and R-CHOP, respectively. The 3 cases progressing during treatment were in the R-CHOP arm. Clinical heart failure usually appears after several years of treatment. The difference in LVEF may translate in a lower rate of clinical heart failure with longer follow-up. Disclosures: Fridrik: Cephalon: Research Funding. Off Label Use: Non-pegylated liposomal encapsulated doxorubicin in the treatment of lymphoma. Willenbacher:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AESCA: Honoraria, Research Funding. Jaeger:Cephalon: Membership on an entity's Board of Directors or advisory committees. Greil:Cephalon: Research Funding.

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The Impact of Comorbidities and Organ Dysfunction Commonly Used for Clinical Trial Eligibility Criteria on Outcome in Acute Myeloid Leukemia (AML) Patients Receiving Induction Chemotherapy

Blood ◽

10.1182/blood-2019-130319 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 16-16

Author(s):

Abby Statler ◽

Brian P. Hobbs ◽

Tomas Radivoyevitch ◽

Caitlin Siebenaller ◽

Sudipto Mukherjee ◽

...

Keyword(s):

Clinical Trial ◽

Logistic Regression ◽

Board Of Directors ◽

Organ Dysfunction ◽

Induction Chemotherapy ◽

Research Funding ◽

Organ Function ◽

Eligibility Criteria ◽

Advisory Committees ◽

Dose Modifications

Background: Clinical trial recruitment is hindered by patient (pt), provider, and organizational barriers. The prohibitory impact of specific comorbidity/organ function criteria, however, has not been studied in the AML pt population. While intended to protect pts, trial eligibility criteria, when excessive, exclude pts irrespective of expected toxicities (Statler et al. Leukemia 2017). Yet, research demonstrates adverse events and outcomes are similar among eligible and ineligible AML pts (Statler et al. Blood 2018). We characterized the multi-morbidity prolife of AML pts prior to induction chemotherapy and compared outcomes among those with and without baseline comorbidities/organ dysfunction that have been used in clinical trial eligibility criteria. Methods: Adult (≥18 years) AML pts who received chemotherapy at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic/renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Univariate associations between dose modifications and pt characteristics were tested using logistic regression. Cox proportional hazards and logistic regression were used to identify significant prognostic factors for overall survival (OS) and complete remission (CR) status per International Working Group criteria. Kaplan-Meier method was used to estimate median OS. Results: Of 1,082 AML pts analyzed, the median age was 60.6 years (IQR: 50.2, 69.1), 53.1% (n=574) were male, 86.8% (n=939) were white, and 45.7% (n=494) had Medicare insurance. A majority (n=680, [62.9%]) had de novo AML, and 55.3% (n=598) had intermediate-risk disease. Pts were treated with: intensive cytarabine-based (n=901 [83.3%]), or non-intensive (low-dose cytarabine or hypomethylating agents (n=181 [16.7%]). Of those with comorbidities, the most common were vascular (n=540 [49.9%]), endocrine (n=272 [25.1%]), and neurological (n=220, [20.3%]) (Tables 1 and 2). With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). In multivariate analyses controlling for treatment, age, sex, insurance, number of comorbidities, AML etiology, and ELN risk, the only comorbidity associated with OS was liver disease (HR=1.90, P=.004). However, baseline AST (3xULN vs. normal: HR=1.02, P=.94; >3-5x ULN vs. normal: HR=1.42, P=.30.), ALT (3xULN vs. normal: HR=0.76, p=0.45, >3-5xULN vs. normal: HR=1.58, P=.23) and bilirubin (1.5xULN vs. normal: HR=1.34, P=.08) were not associated with a worse OS. Minor renal dysfunction was also not associated with OS, when measured by creatinine (1.5xULN vs. normal: HR=1.06, P=.52) or creatinine clearance by Cockcroft-Gault (CrCl 84-60 ml/min: HR=0.95, P=.62). Baseline LVEF abnormalities, though, were associated with increased mortality, and as severity increased the effect size increased in a dose-response fashion (50-40%: HR=1.38, P=.04; <40%: HR=1.66, P=.009). The pattern for baseline prolonged QTc was similar; increasing values of QTc was associated with increased mortality (>480ms: HR=1.36, P=.04; ≥501: HR=1.72, 95%, P=.001). With the exception of liver comorbidities (OR=0.26, P=.03), our analysis failed to identify significant evidence of association between response and comorbidities/organ dysfunction. Comorbidities and liver function abnormalities were also not associated with dose modifications during AML treatment, while pts with clinically significant renal (CrCl ≤ 30 ml/min) and/or cardiac (LVEF ≤50%) abnormalities at baseline did have a higher odds of a dose reduction in univariate analysis. Conclusions: The majority of AML pts within this cohort (n=953 [88.1%]) presented with at least 1 comorbidity and/or 1 clinically insignificant liver or renal abnormality that could have excluded them from clinical trials. Yet, survival, response, and dose modification outcomes did not significantly differ between pts with and without comorbid conditions or minor liver/renal abnormalities. These results suggest future AML trials may liberalize comorbidity and organ function eligibility criteria, which will likely improve recruitment rates and provide equitable access to investigational products. Disclosures Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Celgene Corporation: Consultancy, Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.

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Phase 1b Study of the Epichaperome Inhibitor PU-H71 Administered Orally with Ruxolitinib Continuation for the Treatment of Patients with Myelofibrosis

Blood ◽

10.1182/blood-2019-130310 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4178-4178 ◽

Cited By ~ 1

Author(s):

Naveen Pemmaraju ◽

Krishna Gundabolu ◽

Kristen Pettit ◽

Moshe Talpaz ◽

Nikolai A. Podoltsev ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Myeloproliferative Neoplasm ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Therapeutic Window ◽

Costal Margin ◽

Advisory Committees ◽

Phase 1B

Background: Myelofibrosis (MF) is a life-threatening disease characterized by splenomegaly, constitutional symptoms, and shortened survival. Although ruxolitinib, a JAK1/2 inhibitor, is approved for Intermediate or High-risk MF and can reduce the spleen size and improve quality of life, many patients discontinue due to loss of efficacy. In preclinical models, the activity of mutated JAK2 is tightly regulated by epichaperomes, a complex network of proteins which forms under cellular stress, such as cancer, and nucleates on heat shock protein 90 (Hsp90), which in turn assumes a specific conformation in its ATP binding domain. PU-H71 is a first-in-class inhibitor of tumor epichaperome-specific Hsp90, which potently kills cancer cells via disruption of the epichaperome and degradation of JAK2 as well as other client proteins. Prior dose-ranging studies of PU-H71 administered intravenously to patients with cancer identified a safe and tolerable dose. In this study, we assess an oral formulation of PU-H71 and evaluate the hypothesis that its cancer-specific mechanism combined with ruxolitinib may result in added clinical benefit as well as a wider therapeutic window. Methods: This is a multicenter, Phase 1b study with dose escalation and expansion cohorts designed to assess the safety, tolerability, PK, and preliminary efficacy of PU-H71 in patients with PMF, Post-PV MF, Post ET MF. Up to 24 patients who have active disease and receiving ≥3 months of ruxolitinib therapy (and on a stable dose for 8 weeks before starting therapy with PU-H71) will be enrolled. Evidence of persistent or worsening disease consisting of disease-related symptoms and splenomegaly of at least 5 cm below the costal margin as measured by physical examination are required. Additional inclusion criteria include a baseline platelet count of ≥50,000/mL and AST/ALT ≤2 x Upper Limit of Normal. Patients with a QT interval corrected using Fridericia's formula (QTcF) >480 ms (corrected) or left ventricular ejection fraction (LVEF) ≤50% are excluded. The study will employ a standard 3+3 dose escalation design beginning with 50 mg/day to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), with additional patients treated in a dose expansion cohort. Response to treatment will be assessed by the 2013 revised International Working Group-Myeloproliferative Neoplasm Research and Treatment and European Leukemia Net. Additional assessments will include symptom burden assessment using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, bone marrow histology, JAK2V617F allele burden, serum cytokine profiles, flow cytometry of peripheral blood mononuclear cells for epichaperome status, and pharmacokinetic studies. Enrollment is ongoing. Clinical trial information: NCT03935555. Disclosures Pemmaraju: abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding. Gundabolu:Samus Therapeutics: Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Jazz pharmaceuticals: Consultancy. Pettit:Samus Therapeutics: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Incyte: Research Funding; Constellation: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Podoltsev:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Kartos Therapeutics: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; AI Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding, Speakers Bureau. Eisenberg:Samus Therapeutics: Research Funding. Youssoufian:Samus Therapeutics: Consultancy. Duggan:Samus Therapeutics: Employment. Wallner:Samus Therapeutics: Employment. Verstovsek:Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Gilead: Research Funding; Protaganist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte: Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding.

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Improvement in Right Ventricular Function Following 1 Year of Deferasirox Therapy in Patients with β-Thalassemia.

Blood ◽

10.1182/blood.v114.22.5106.5106 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5106-5106

Author(s):

Gillian Smith ◽

Dudley J. Pennell ◽

John B. Porter ◽

M. Domenica Cappellini ◽

Lee Lee Chan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Left Ventricular ◽

Myocardial Iron ◽

Advisory Committees ◽

Off Label ◽

Cardiac Siderosis ◽

Rv Function

Abstract Abstract 5106 Background Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients with β-thalassemia. Once-daily oral iron chelation therapy with deferasirox (Exjade®) has been shown to reduce body iron burden in patients with transfusion-dependent anemias, and the removal of myocardial iron has been demonstrated in several clinical studies including the prospective, multicenter EPIC study. Here we report for the first time an evaluation of right ventricular (RV) function assessed using magnetic resonance (MR) techniques in β-thalassemia patients with myocardial siderosis treated with deferasirox in the EPIC study. Methods The cardiac sub-study of EPIC enrolled patients with β-thalassemia aged ≥10 yrs who had MR myocardial T2* >5–<20 ms (indicating cardiac siderosis), left ventricular ejection fraction ≥56%, serum ferritin (SF) levels of >2500 ng/mL, MR (R2) liver iron concentration (LIC) of >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/day and subsequent dose adjustments of 5–10 mg/kg/day were based on changes in SF, month-6 cardiac T2* and safety parameters. The following RV parameters were assessed using MR; ejection fraction (RVEF), volumes (end-systolic [RVESV] and end-diastolic [RVEDV]) and mass (RVM). All parameters were assessed at the CMR core laboratory in London, UK after 6 and 12 months of deferasirox treatment. Results 114 patients were enrolled in the cardiac sub-study (54 male, 60 female; mean age 20.9 ± 7.3 years). Baseline myocardial T2* was <10 ms in 47 (41%), and 10–20 ms in 67 (59%) patients. Mean baseline LIC was 28.2 ± 10.0 mg Fe/g dw, median serum ferritin was 5235 ng/mL, and the mean amount of transfused blood in the previous year was 185 mL/kg. 68% of patients had received prior deferoxamine (DFO) and 32% DFO/deferiprone combination chelation therapy. Mean actual deferasirox dose over 12 months was 32.6 mg/kg/day. RVEF increased significantly from a mean ± SD baseline of 65.8 ± 6.2% to 67.6 ± 6.4% at 6 months (P=0.013) and 68.7 ± 5.7% at 12 months (P<0.0001; Figure). RVESV significantly decreased from 35.0 ± 14.5 mL at baseline, to 33.4 ± 12.8 mL (P=0.034; Figure) by 12 months and RVEDV significantly increased from 101.0 ± 31.8 mL at baseline to 105.7 ± 33.4 mL (P=0.04; Figure) by 12 months. There were no significant correlations between any of the RV function parameters assessed and T2*. There was a borderline significant reduction in RVM from 46.8 ± 14.6 g at baseline to 44.9 ± 12.4 g at 12 months (P=0.088). Reference RVEF, RVESV, RVEDV and RVM have been defined in healthy subjects as 66 ± 6 %, 50 ± 14 mL, 144 ± 23 mL and 48 ± 12 g, respectively (A M Maceira et al. Eur Heart J 2006;27:2879–88), although values were shown to vary significantly by gender, body surface area and age. Conclusions To our knowledge, this is the first study to show a change in RV volumes and improvement in RV function associated with iron chelation. The RVEF improved with increased RVEDV and decreased RVESV, which is suggestive of improved RV and left ventricular compliance respectively resulting from removal of myocardial iron. However, improvements in pulmonary vascular resistance may also play a role. Disclosures Smith: Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Lee:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Research Funding; GPO-L-ONE clinical study sponsor by Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Hmissi:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

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A Randomized Phase 2 Trial of Bortezomib–Dexamethasone Versus Bortezomib–Dexamethasone with Added Cyclophosphamide or Lenalidomide in Multiple Myeloma Patients Achieving Stable Disease After Four Cycles of Bortezomib–Dexamethasone Administered as Second-Line Treatment.

Blood ◽

10.1182/blood.v114.22.4937.4937 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4937-4937

Author(s):

Meletios A. Dimopoulos ◽

Huw Roddie ◽

Meral Beksac ◽

Lotfi Benboubker ◽

Romualdas Jurgutis ◽

...

Keyword(s):

Renal Function ◽

Board Of Directors ◽

Research Funding ◽

Safety Data ◽

Phase 2 ◽

Advisory Committees ◽

Ortho Biotech ◽

Function Group ◽

Grade 3 ◽

Renal Function Group

Abstract Abstract 4937 Bortezomib (Velcade®) plus dexamethasone (Vel/Dex) is known to be effective and well tolerated in patients with multiple myeloma (MM). As demonstrated in the frontline setting, the addition to Vel/Dex of cyclophosphamide (VCD) or lenalidomide (Revlimid®; VRD) may lead to improved efficacy, but may be associated with increased toxicities; however, few studies have prospectively assessed Vel/Dex as second-line therapy. This randomized, open-label, parallel-group, phase 2 study in patients who have relapsed after or are refractory to primary MM therapy is designed to evaluate the safety and efficacy of an additional 4 cycles of Vel/Dex, VCD, or VDR in patients achieving stable disease (SD) after 4 cycles of Vel/Dex. Bortezomib-naïve patients aged ≥18 years, with measurable MM, KPS ≥60, life expectancy ≥6 months, adequate hematologic and hepatic function, and without grade ≥2 peripheral neuropathy (PN) received 4 3-week cycles of Vel/Dex (Vel 1.3 mg/m2 IV on days 1, 4, 8, and 11, and Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12). Patients then received a further 4 cycles of therapy as follows: patients achieving at least a partial response (PR) received Vel/Dex; patients with SD underwent central randomization to receive Vel/Dex, VCD, or VRD; patients with progressive disease (PD) discontinued treatment. Here we report efficacy and renal function improvement in patients who had the opportunity to complete the initial 4 cycles of Vel/Dex as of April 2009, and safety data for patients who received at least 1 dose of study drug. Response was assessed by IMWG uniform response criteria based on measurement of serum and urine M-protein prior to treatment on day 1 of each cycle, at end of treatment, and monthly thereafter. Renal function as defined by calculated glomerular filtration rate (GFR; Cockcroft–Gault formula) was assessed prior to treatment on day 1 of cycles 1–5. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of 122 patients have been enrolled; by data cut-off (July 21 2009), 24 (20%) had not completed a single treatment cycle and are excluded from the safety population (N=98). Eighteen had received <4 cycles at data cut-off. Of the remaining 80 who were eligible for response, 63 had completed 4 cycles, 6 discontinued prior to completing 4 cycles (due to PD in 3 patients, death in 1, drug-related AEs in 2), 9 were not under treatment at data cut-off, and 2 had died. Their median age was 62 years (range 34–86), 55% were male, 21.3% had KPS ≤70; median time from prior therapy was 18.6 months. Response rate in the efficacy population was 41/80 (51%) after 4 cycles, including 8% CR. Median times to first and best response were 37 and 57 days, respectively. Patient renal function (by GFR) at baseline, median improvement in GFR, and responses achieved by the 10 patients in whom GFR improved by at least one renal function group are shown in the Table. Among the 98 patients who received at least one treatment dose, mean cumulative doses of bortezomib and dexamethasone were 14.6 mg/m2 (4.9, 4.5, 4.4, and 4.3 mg/m2 in cycles 1–4) and 478 mg (151.8, 145.6, 145.4, and 144.0 mg for cycles 1–4), respectively. Most patients (90%) reported AEs, including 39% with grade 3/4 AEs and 23% with serious AEs, within the first 4 cycles. The most common grade 3/4 AEs included thrombocytopenia (13%), anemia (7%), and pneumonia (6%). AEs resulting in dose reductions/treatment stop were seen in 21%/10% of patients. Incidence of sensory PN and PN was 29% (3% grade 3/4); most PN events were reversible, with 68% resolving within a median 53 days. Updated efficacy and safety data for the first 4 cycles of Vel/Dex for all patients enrolled by July 31 will be presented. Table: Improvement in renal function (as measured by GFR)* Renal function group at baseline, n† <15 mL/min 3 15–<30 mL/min 6 30–<60 mL/min 33 ≥60 mL/min 36 Median GFR (median improvement from previous cycle), mL/min At baseline 58.3 After cycle 1 64.4 (4.8) After cycle 2 68.9 (2.9) After cycle 3 68.6 (9.9) After cycle 4 73.5 (9.4) Renal improvement by at least 1 grade, n (response achieved) 10 <15 to 15–<30 mL/min 1 (1 CR) 15–<30 to 30–<60 mL/min 1 (1 PR) 30–<60 to ≥60 mL/min 8 (2 CR, 1 VGPR, 3 PR, 2 SD) * 1 patient only had a baseline GFR measurement and was not included in the renal analysis † 1 patient had no baseline GFR measurement Disclosures Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Beksac:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Langer:Celgene: Consultancy; Ortho Biotech: Consultancy. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees.

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Defibrotide (DF) in the Treatment of Hepatic Veno-Occlusive Disease (VOD) in Stem Cell Transplant (SCT) and Non-SCT Patients (Pts): Early Intervention Improves Outcome - Updated Results of a Treatment IND Expanded Access Protocol

Blood ◽

10.1182/blood.v118.21.487.487 ◽

2011 ◽

Vol 118 (21) ◽

pp. 487-487 ◽

Cited By ~ 2

Author(s):

Paul G. Richardson ◽

Angela R. Smith ◽

Stephan A Grupp ◽

Nancy A. Kernan ◽

Sally Arai ◽

...

Keyword(s):

Early Intervention ◽

Board Of Directors ◽

Research Funding ◽

Historical Control ◽

Cell Transplant ◽

Phase 3 ◽

Eligibility Criteria ◽

Advisory Committees ◽

Common Diagnosis ◽

Improved Outcome

Abstract Abstract 487FN2 Background: Given the life-threatening nature of severe VOD (sVOD) and multi-organ failure (MOF), DF was made available in the US through a prospective treatment IND protocol (T-IND) to gather additional safety and response data from SCT patients (pts) with sVOD who were not eligible for a pivotal Phase 3 trial. Following completion of this Phase 3 trial, the T-IND protocol has continued and been amended to include pts who would have met eligibility criteria for the completed phase 3 trial, as well as pts with non-severe VOD and non-SCT pts who develop VOD after chemotherapy (chemo). This is the largest prospective evaluation of DF for the treatment of sVOD/MOF post SCT and non-SCT pts to date. Methods: Pts were initially required to have a diagnosis of VOD by Baltimore criteria (total bilirubin > 2.0 mg/dL with > 2 of the following: hepatomegaly, ascites or 5% weight gain) with MOF (either renal and/or pulmonary failure) that followed SCT. Following treatment of 104 pts, an amendment expanded eligibility criteria to include pts with VOD after chemo and pts with non-severe VOD (defined as no MOF). Key exclusion criteria included clinically significant bleeding or >1 pressor to maintain BP. CR was defined as bilirubin < 2 mg/dL + resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d) with treatment duration recommended for at least 21d. Results: This interim analysis is based on 269 pts enrolled between December 2007 and March 2011 at 67 centers. Nearly all pts (n=251) had undergone SCT (with allogeneic SCT in 225, 90%); 18 developed VOD after chemo alone. Of the 269 cases of VOD, 200 were severe at study entry, with 25% (66/269) of all pts dialysis dependent and 31% (83/269) ventilator dependent. Median age was 16 years (range 0.1 – 70); 55% were male. In the SCT pts, the most common diagnosis was leukemia (29% AML; 22% ALL; CML 3%; 4% other), with conditioning of CY (71%), BU (46%) and TBI (38%) respectively; 18% had undergone multiple SCTs (>1 SCT). Median onset of VOD was 15 d post-SCT. When presenting after chemo alone (n=18), median onset of VOD was 16 d after the first dose, most frequently after CY (61%), cytarabine (44%) and vincristine (39%), and for treatment of leukemia (AML 33%, ALL 33%, other 6%). Overall mean number of days of DF administration in all pts was 22 (range 1–88).Of 269 pts, 32% (85/269) achieved a CR and 50% [ by Kaplan-Meier estimate] survived to D+100. In the subgroup of SCT pts, 31% (78/251) achieved CR and 50% survived to D+100; 134 pts met entry criteria for the original Phase 3 trial and comparison to the Phase 3 historical control showed a statistically improved outcome in CR (30% vs 9%, p=0.0006) and D+100 survival (46% vs 25%; p=0.006). Of 200 pts with sVOD, CR was 28% and D+100 survival was 44%. In the 18 chemo only pts, CR was 39% and D+100 survival was 50%. CR rate and D+100 survival for the 69 pts with non-severe VOD were 42% and 62%, respectively. Delay of >2 d (vs < 2 d) in the start of DF after VOD diagnosis resulted in reduced CR (23% vs 35%, p=0.0339) and survival (37% vs 56%, p=0.01). Children as compared to adults had higher rates in CR (35% vs 29%) and survival (55% vs 43%). Toxicity proved generally manageable: 22% of pts experienced a total of 81 related AEs, primarily consisting of hemorrhage (19%) and hypotension (4%). Hemorrhage included pulmonary bleeding (6%), GI hemorrhage (3%), epistaxis (3%) and hematuria (3%). Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic SCT pts was 8%. Conclusions: In 269 pts with mainly sVOD/MOF, DF therapy achieved significantly improved outcome compared to an untreated historical control. Importantly, CR and survival were improved in pts who were treated within 2d of VOD diagnosis (vs. later) and in pts who had not yet progressed to sVOD. As with prior studies, there was a low incidence of DF-associated toxicities. Interestingly, the incidence of GvHD in allo-SCT pts was low, consistent with the reduction of GvHD seen in the large randomized EBMT pediatric prevention study. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after SCT, as well as its use in pts who have not progressed to advanced MOF. The use of DF for VOD following intensive chemotherapy without SCT also appears promising, but more research in this patient population is needed. Enrollment to the T-IND study continues. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Symons:Otsuka Pharmaceuticals: Research Funding. Martin:Gentium: Research Funding. Massaro:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Tudone:Gentium: Employment. Hume:Gentium: Employment. Iacobelli:Gentium SpA: Employment. Soiffer:Gentium: Honoraria.

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Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of "Donors for All"

Blood ◽

10.1182/blood-2021-147329 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 423-423

Author(s):

Warren Fingrut ◽

Ioannis Politikos ◽

Eric Davis ◽

Stephanie Chinapen ◽

Kristine Naputo ◽

...

Keyword(s):

Racial Disparities ◽

Board Of Directors ◽

Research Funding ◽

African Ancestry ◽

Relative Proportion ◽

Unrelated Donor ◽

Advisory Committees ◽

Alternative Donor ◽

To Receive ◽

Over Time

Abstract Background: Understanding disparities in allograft access is a prerequisite to interpret outcomes. Moreover, while alternative donors extend access, the extent to which there are racial disparities in availability of optimal donors is not established. Methods: We evaluated access to alternative donor allografts (all other than HLA-identical sibling donors) in adults 19-65 years according to recipient ancestry over time between 1/2016-4/2021. During this period an 8/8 HLA allele-matched unrelated donor (URD) had priority followed by double unit cord blood (dCB) (usually preferred if < 60 years) or haploidentical donors with mismatched URDs being considered most recently. We examined access to any acceptable donor, as well as an optimal donor, by recipient ancestry. To determine trends over time, we compared early (1/2016-1/2018, 25 months), middle (2/2018-2/2020, 25 months), & pandemic (3/2020-4/2021, 14 months) time periods. Results: 592 adults (median 53.5 years, range 19-65) received alternative donor allografts. 374 (63%) had European & 218 (37%) non-European origins (66 African, 56 Asian, 55 White Hispanic, 41 other). Overall, 340 (56%) patients received 8/8 URD, 139 (23%) dCB, 69 (11%) haploidentical, & 44 (7%) 5-7/8 URD grafts with 14 (2%) patients having no graft. Europeans (263/374, 70%) mostly received 8/8 URD donors, whereas only one-third of non-Europeans (77/218, 35%) did (p < 0.01). Moreover, non-European patients were more likely than Europeans to receive HLA-disparate donors of all types: 36% of non-Europeans received dCB vs 16% of Europeans, 18% vs 8% for haploidentical donors, 10% vs 6% for 5-7/8 URD grafts. African ancestry patients (n = 66) were the least likely to receive 8/8 URDs (13/66, 20%) with 27/66 (41%) of them receiving dCB, 16/66 (24%) haploidentical, & 10/66 (15%) 5-7/8 URD grafts. When analyzing by period, the relative proportion of patients receiving allografts from 8/8 URDs, dCB, & haploidentical donors remained unchanged over time (Figure 1). However, while 14 patients (13 non-Europeans including 11 of African ancestry) had no graft, the utilization of 5-7/8 URDs (4% of alternative donor allografts 1/2016-1/2018, 8% 2/2018-2/2020, 14% 3/2020-4/2021) has decreased the "no graft" incidence to 1% of patients most recently (Figure 1). We then analyzed access to an "optimal donor" defined as an 8/8 URD < 35 years (Shaw et al., BBMT 2018), a dCB graft with each unit with a CD34+ dose > 1.5 x10^5/kg & > 4/8 HLA-match (Politikos et al., BBMT 2020), or a haploidentical donor < 40 years without recipient high titer donor-specific antibodies (McCurdy et al., Seminars in Hematology 2016 & others). Mismatched URDs were excluded based on lack of literature guiding an "optimal" definition. Of 8/8 URDs/ dCB/ haploidentical transplant recipients, 424/548 (77%) received an optimal donor with 269/340 (79%) URD, 94/139 (68%) dCB, & 61/69 (88%) haploidentical grafts being optimal. Transplanted non-Europeans were less likely to receive an optimal 8/8 URD / dCB / haploidentical donor than transplanted Europeans (67% vs 84%, p < 0.01) with White Hispanic & African patients having the lowest chances at 56% & 61%, respectively. Analysis of the 3 periods showed the likelihood that non-European patients received an optimal 8/8 URD / dCB / haploidentical donor is not improving: optimal allografts in 63% of non-Europeans vs 78% of Europeans 1/2016-1/2018, 68% vs 88% 2/2018-2/2020 & 68% vs 92% 3/2020-4/2021. Notably, the greatest disparity was seen at the pandemic's onset (3/2020-9/2020, Figure 2). Conclusion: Our data suggests access to 8/8 URDs for non-Europeans is not improving but utilization of all potential alternatives (dCB, haploidentical, 5-7/8 URD) is increasingly providing "donors for all". However, when incorporating the concept of an "optimal" 8/8 URD/ dCB/ haploidentical donor, there is a significant disparity in access to optimal donors for non-Europeans, with Africans & White Hispanics the least likely to receive an optimal graft. This disparity is also not improving, and worsened at the pandemic's onset. Optimization of dCB, haploidentical, & mismatched URD transplants, & recognition of optimal donor definitions for each, is critical to further improve allograft outcomes. Future studies must also investigate the extent to which futile 8/8 URD pursuits adversely impact non-European patient transplant outcomes. Figure 1 Figure 1. Disclosures Politikos: Merck: Research Funding; ExcellThera, Inc: Other: Member of DSMB - Uncompensated. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Gyurkocza: Actinium Pharmaceutical Inc.: Research Funding. Perales: Omeros: Honoraria; Novartis: Honoraria, Other; NexImmune: Honoraria; Nektar Therapeutics: Honoraria, Other; MorphoSys: Honoraria; Miltenyi Biotec: Honoraria, Other; Merck: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Cidara: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria. Ponce: Ceramedix: Consultancy, Honoraria; Takeda Pharmaceuticals: Research Funding; CareDx: Consultancy, Honoraria; Kadmon pharmaceuticals: Consultancy, Honoraria; Seres Therapeutics: Consultancy, Research Funding; Generon Pharmaceuticals: Consultancy.

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Phase 1 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

Blood ◽

10.1182/blood-2019-126009 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3892-3892

Author(s):

Colin D. Godwin ◽

Megan Othus ◽

Mary-Elizabeth M. Percival ◽

Bart L. Scott ◽

Pamela S. Becker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Left Ventricular Systolic Dysfunction ◽

Phase 1 ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3

Background: We recently found that CLAG-M was safe and produced higher rates of CR/CRi and higher measurable residual disease (MRD)-negative CR (measured by multiparameter flow cytometry [MFC]) than standard "7+3" therapy in fit patients with newly-diagnosed AML or other high-grade myeloid neoplasm with ≥10% blasts (HG-MN). Since addition of the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) to chemotherapy reduces relapse risk and improves survival in some AML patients, we conducted a phase 1 study (NCT03531918) to determine the maximum tolerated dose (MTD) of GO with CLAG-M in fit adults with newly-diagnosed AML (APL excluded) or HG-MN. Patients and Methods: Adults ≥18 years were eligible if they were fit (treatment-related mortality [TRM] score ≤13.1, corresponding to < 13.1% risk of TRM within 1 month) and had LVEF ≥45%, creatinine ≤2.0 mg/dL, and bilirubin ≤2.5-times upper limit of normal. Patients with concomitant illness with expected survival <1 year, with uncontrolled infection, or in myeloid blast phase of chronic myeloid leukemia were excluded. Doses were escalated in cohorts of 6 patients over 2 dose levels of GO ("GO1": 3 mg/m2 on day 1; "GO3": 3 mg/m2 on days 1, 4, and 7 [doses capped 4.5 mg]); the highest dose level achieved could then enroll an additional 6 patients (12 total) if ≤2 dose-limiting toxicities (DLTs) were observed. CLAG-M consisted of cladribine 5 mg/m2/day (days 1-5), cytarabine 2 g/m2/day (days 1-5), G-CSF 300 or 480 μg/day (for weight <76 kg vs. ≥76 kg; days 0-5), and mitoxantrone (18 mg/m2/day; days 1-3). A second course of CLAG-M (without GO) was given if MRD-negative CR/CRi was not achieved. DLT was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia/infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. The protocol was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board. Results: We enrolled 18 patients, median age 66 (range: 28-77) years, median TRM score 3.92 (range: 0.14-10.3) with newly-diagnosed AML (n=14) or HG-MN (n=4); 7 were "favorable", 4 "intermediate and 7 "adverse" by 2017 European LeukemiaNet criteria. The first 6 patients were treated at GO1, with 1 DLT (grade 3 left ventricular systolic dysfunction). Two subsequent cohorts of 6 were treated at GO3. Three DLTs occurred at this second dose level (grade 4 aminotransferase level increase, grade 3 posterior reversible encephalopathy syndrome, grade 3 intracranial hemorrhage). As prespecified in the protocol, with ≤4/12 DLTs the MTD was formally not reached and GO3 was declared the recommended phase 2 dose. Among 18 evaluable patients, 13 achieved CR and 2 CRi for a CR/CRi rate of 83% (95% confidence interval: 59-96%). 13/15 CR/CRi patients were negative for MRD by MFC and cytogenetics for an MRDneg CR/CRi rate of 72% (49-88%). The 3 patients without CR/CRi had marrow aplasia without MFC evidence of AML at time of study removal. Two underwent allogeneic hematopoietic cell transplantation in aplasia; the other achieved later neutrophil recovery prior to AML recurrence 2.5 months following induction without interval therapy. 5/18 did not have platelet recovery to 100,000/µL prior to the next therapy/removal from study. Median time to absolute neutrophil count of 1000/µL (achieved in 16/18 patients) and platelet count of 100,000/µL (achieved in 13/18 patients) was 35 (range: 24-48) days and 31 (range: 26-48) days, respectively. Besides infections and neutropenic fever, hypertension and left ventricular systolic dysfunction were the most common adverse events. One patient had severe, self-limited liver toxicity characterized by weight gain and elevated aminotransferases without hyperbilirubinemia and did not meet typical clinical criteria for sinusoidal obstructive syndrome. There were no deaths within 56 days of starting induction in this study cohort. Conclusions: CLAG-M with fractionated-dose GO is feasible in patients with newly-diagnosed AML/HG-MN and appears to have high anti-tumor efficacy. CR/CRi and MRDneg CR rates were similar to what we observed with CLAG-M alone (86% and 71%, respectively). A phase 2 study based on these findings has been initiated, using event-free survival as primary efficacy endpoint. Disclosures Othus: Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Percival:Nohla Therapeutics: Research Funding; Pfizer Inc.: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Scott:Agios: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Gardner:Abbvie: Speakers Bureau. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Walter:Agios: Consultancy; Amgen: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; 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. OffLabel Disclosure: Cladribine is not approved for AML, only Hairy Cell Leukemia, however it is widely used for AML with literature supporting it.

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