Vascular and Parenchymal Alterations of the Liver and Liver Surveillance in Patients Who Received Inotuzumab Ozogamicin As the Standard of Care for Relapse/Refractory Acute Lymphoblastic Leukemia

Rationale: Inotuzumab ozagomicin (IO) has been linked to an increased incidence of veno-occlusive disease (VOD) and liver alterations. Most VOD events occurred during hematopoietic stem cell (HSCT) transplantation after IO therapy. We have previously described that the measurement of liver stiffness can anticipate the diagnosis of VOD in the context of HSCT. The mechanisms underlying the increased risk of VOD and liver damage in patients receiving IO are not well understood; in the pathogenesis endothelial damage, ozagomicin release and on-target off-tumor effects may be involved. Here, we aimed to assess the effects of IO on the changes of liver, vascular and biochemistry parameters. Methods: Intensive monitoring of the liver was incorporated into the standard of care of patients who received IO for relapsed or refractory (R / R) acute lymphoblastic leukemia (ALL). Upper abdomen ultrasound with Doppler was performed at baseline and at the end of therapy; liver stiffness measurement (LSM) by Fibroscan® (Echosens, Paris, France) at every IO course or at every IO infusion. With the exception of ursodeoxycholic acid, the patients did not receive prophylaxis for VOD. Data was collected after anonymous aggregation, in accordance with GCP and Helsinki declaration. Results are reported as median with interquartile ranges (IQR). Results: At data cut-off, 1st Apr 2019, 16 patient received baseline assessment and at least a post-IO assessment in our monitoring program. In our patent set, median age was 44.5 (IQR 30.7 - 64.0); 12/16 (75 %) patients relapsed after the last treatment and 4/16 (25 %) patients were refractory to the last treatment; patients received a median of 3 (IQR 2 - 3.7) lines before IO; 6/16 (37.5 %) patients undergone HSCT before IO, of which a patient had 1st and 2nd HSCT before IO; 5/16 (31.25 %) undergone HSCT after IO therapy (no patients had second HSCT after IO). Patients received a median of 2 (IQR 2.0 - 3.7) IO administration according to the schedule of the phase 3 trial. The median duration of the therapy was 61.5 days (IQR 43.2 - 114.0) and median progression-free survival in our population was 278.0 days (95% C.I. 264.0 - 292.0). In our patient set, we performed 113 biochemistry determination, 30 liver ultrasounds with Doppler and 116 LSM examination. One patient received a liver biopsy. Among the biochemical exams (AST, ALT, GGT and alkaline phosphatase) only the AST values significantly increased after 1st course of IO (from the median value of 21 U/L to 53 U/L after course 3). Liver ultrasound with Doppler revealed portal hypertension signs in half of the patients during IO monitoring program. Among these patients 7/16 (44%), 3/16 (17%), 5/16 (33.3%) and 3/16 (17%) showed splenomegaly, recanalization of the paraumbilical vein, dilatation of portal vein and ascites, respectively. Median LSM significantly increased from a baseline value of 6 kPa to 7.8 kPa after last post-IO assessment (p-value<0.01). The median increase of LSM values on the baseline after course 1 of IO was 3.3% (0%- 4.9%), after course 2 was 38.3% (26.4% - 45.2%) after course 3 was 43.3% (35.4% - 48.6%) and after course 4 was 56.7 (45.8% - 60.1%), see figure. Eight of the 16 patients (50%) showed an increase in LSM with values comparable to fibrosis higher than 2 (> 7.1 kPa). With a median follow up of 387.5 days (IQR 182.8-524.5) we observed one VOD event (7%); the VOD was graded severe and occurred after HSCT post-IO. Conclusions: Our clinical experience represents the first step to better understand the IO-related liver alterations, as we described the frequency and relevance of quantitative markers. Most of the patients in our set developed ultrasound and/or elastography alteration during IO therapy. Furthermore, these alterations do not seem to correlate with biochemistry. Even if most of the patients had sub-clinical vascular and parenchymal alterations of the liver portal-hypertension related, VOD incidence in our set is comparable with literature. Long-term follow-up results are expected to test whether alterations return or evolve over time. Stratifying the tailored risk liver complications with prospective non-invasive and marker-driven strategies in term of IO dosing and HSCT timing could be a great benefit for patients. * FR and GM contributed to this manuscript equally # AC and CP contributed to this manuscript equally Figure Disclosures Martinelli: Roche: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau. Papayannidis:Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Shire: Honoraria.

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Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-124727 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3816-3816 ◽

Cited By ~ 2

Author(s):

Ryan J. Daley ◽

Sridevi Rajeeve ◽

Charlene C. Kabel ◽

Jeremy J. Pappacena ◽

Sarah E. Stump ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Hypersensitivity Reactions ◽

Newly Diagnosed ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: 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; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

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Pediatric-Inspired Chemotherapy Incorporating Pegaspargase Is Safe and Results in High Rates of MRD Negativity in Adults Ages 18-60 with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Blood ◽

10.1182/blood-2018-99-115486 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4013-4013 ◽

Cited By ~ 2

Author(s):

Mark Blaine Geyer ◽

Ellen K. Ritchie ◽

Arati V. Rao ◽

M. Isabella Cazacu ◽

Shreya Vemuri ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Advisory Board ◽

Lymphoblastic Lymphoma ◽

Advisory Committees ◽

Grade 3

Abstract Introduction: Among adolescents and young adults with (w/) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), treatment using a pediatric (vs. adult) regimen appears to achieve superior event-free (EFS) and overall survival (OS); this observation has driven increased interest in adapting pediatric regimens for middle-aged adults w/ ALL/LBL. However, greater risk of toxicities associated w/ asparaginase complicates administration of pediatric-inspired regimens in adults. We therefore designed a pediatric-inspired chemotherapy regimen w/ doses of pegaspargase (PEG) rationally synchronized to limit overlapping toxicities w/ other chemotherapeutic agents. Methods: We conducted a phase II multi-center trial in adults ages 18-60 w/ newly-diagnosed Philadelphia chromosome-negative (Ph-) ALL/LBL (NCT01920737). Pts w/ Ph+ ALL or Burkitt-type ALL were ineligible. The treatment regimen consisted of 2-phase induction (I-1, I-2), followed by consolidation w/ 2 courses of alternating high-dose methotrexate-based intensification and reinduction, followed by 3 years of maintenance (Figure 1). PEG 2000 IU/m2 was administered in each of the 6 intensive courses of induction/consolidation at intervals of ≥4 weeks. Minimal residual disease (MRD) was assessed in bone marrow (BM) by multiparameter flow cytometry (FACS) on day (d) 15 of I1 and following I-1 and I-2. Any detectable MRD (even <0.01% of BM WBCs) was considered positive. Toxicities were assessed by CTCAE v4.0. Results: 39 pts were enrolled (30M, 9F), w/ B-ALL (n=28), T-ALL (n=7), B-LBL (n=3), and T-LBL (n=5). Median age at start of treatment was 38.3 years (range 20.2-60.4), w/ 18 pts age 40-60. Grade 3-4 toxicities associated w/ PEG are summarized in Table 1. Grade 3-4 hyperbilirubinemia was observed post-PEG in I-1 in 9 pts, but only recurred thereafter in 1/8 pts resuming PEG. Pts completing consolidation on protocol (n=16) received median of 6 doses of PEG (range, 2-6). Four pts developed hypersensitivity to PEG and subsequently received Erwinia asparaginase. PEG was discontinued in 4 additional pts due to hepatotoxicity (n=2), pancreatitis (n=1), and physician preference (n=1). Of pts w/ available response assessments, 35/36 (97%) achieved morphologic complete response (CR) or CR w/ incomplete hematologic recovery (CRi) following I-1 (n=34) or I-2 (n=1). Both pts not achieving CR/CRi after I-I had early T-precursor ALL; one of these pts was withdrawn from study, and the other (w/ M2 marrow after I-1) achieved CR after I-2. Of the pts w/ ALL (excluding LBL) w/ available BM MRD assessments, 11/28 (39%) achieved undetectable MRD by FACS following I-1; 18/22 (82%) achieved undetectable MRD by FACS following I-2. Of the pts w/ LBL w/ available BM MRD assessments, 7/7 (100%) achieved or maintained undetectable MRD by FACS following I-1 and I-2. Ten pts underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1. Seven pts experienced relapse at median 15.2 months from start of treatment (range, 5.4-30.4), of whom 6 subsequently underwent 1st (n=5) or 2nd (n=1) alloHCT. Of the 11 pts w/ ALL w/ undetectable MRD following I-1, only one has relapsed. Five patients have died, including 2 pts in CR1 (from sepsis and multi-organ system failure), and 3 pts in relapse. At median follow-up of 22.3 months among surviving pts (range, 1.0-48.1), median EFS and OS (Figure 2A&B) have not been reached (EFS not censored at alloHCT). 3-year EFS was 62.1% (95% CI: 38.4-78.9%) and 3-year OS was 80.0% (95% CI: 57.5-91.4%). Conclusions: PEG can be incorporated into pediatric-inspired chemotherapy regimens w/ manageable toxicity for appropriately selected adults up to age 60 w/ Ph- ALL/LBL. While PEG-related AEs are common, few pts require permanent discontinuation of asparaginase. Grade 3-4 hyperbilirubinemia was common, particularly post-I-1, but recurred infrequently when PEG was continued. Two induction courses resulted in a high rate of MRD negativity post-I-2 and translated to a low rate of relapse. Though further follow-up is required, 3-year EFS is encouraging. Data regarding asparaginase enzyme activity and silent inactivation w/ neutralizing anti-PEG antibody will be presented. Ongoing and future studies will additionally investigate whether incorporating novel therapies (e.g. blinatumomab, nelarabine) into frontline consolidation therapy may reduce risk of relapse among adults receiving PEG-containing regimens. Disclosures Geyer: Dava Oncology: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Rao:Kite, a Gilead Company: Employment. Tallman:Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding. Douer:Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Pfizer: Honoraria; Spectrum: Consultancy. Park:Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy.

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Blinatumomab in Children with Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R-ALL): Final Results of 110 Patients Treated in an Expanded Access Study (RIALTO)

Blood ◽

10.1182/blood-2020-141336 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Franco Locatelli ◽

Gerhard Zugmaier ◽

Noemi Mergen ◽

Peter Bader ◽

Sima Jeha ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Final Analysis ◽

Publicly Traded ◽

Primary Analysis ◽

Advisory Committees ◽

Grade 3

Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and <18 years of age with R/R CD19+ BCP-ALL (defined as ≥2 relapses, relapse after allogeneic hematopoietic stem cell transplant [alloHSCT], or refractory to prior treatments) and ≥5% blasts or <5% blasts but with minimal residual disease (MRD) level ≥10−3. Blinatumomab was given as continuous infusion in a 6-week cycle (4 weeks on and 2 weeks off) for up to 5 cycles and safety follow-up visit 30 days post-treatment. Patients with <25% blasts were dosed at 15 µg/m2/day, whereas those with ≥25% blasts were dosed at 5 µg/m2/day (days 1-7 of cycle 1) followed by dose increase to 15 µg/m2/day. Primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included complete response (CR; <5% blasts) and MRD response (<10−4 blasts by PCR or flow-cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and alloHSCT rate after blinatumomab treatment. Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had <50% blasts at baseline, and 11% had <5% blasts (n=12; with MRD ≥10−3) remain unchanged compared with the primary analysis (Table 1). For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with <5% blasts but with MRD ≥10−3 at baseline, 92% (n=11) achieved CR and MRD response; 75% (n=9) proceeded to HSCT (Table 2). Of the 5 patients who had received prior blinatumomab , 4 achieved CR. Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.

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Dose-Adjusted Intensive Chemotherapy Is Safe and Tolerable in Older Patients with Ph-Negative Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2018-99-115634 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5158-5158

Author(s):

Anne S. Renteria ◽

Sangeetha Venugopal ◽

Bridget Marcellino ◽

Alla Keyzner ◽

Marina Kremyanskaya ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Chemotherapy Regimen ◽

Lymphoblastic Leukemia ◽

Intensive Chemotherapy ◽

Advisory Committees

Abstract Background The outcomes of older adults with acute lymphoblastic leukemia (ALL) remain poor when compared to younger ALL patients [PMID 19897583, 28419558, 22409379, 10653870]. Asparaginase (Asp) induces death of human lymphoblasts, and effective asparagine depletion is associated with improved outcomes in ALL. PEG-Asparaginase (PEG-Asp), which has a longer half-life than Asp, is a key component of the intensive chemotherapeutic regimens utilized for treatment of pediatric and younger adult ALL [PMID 29450465]. Frequently, older patients with Ph-negative ALL are not offered PEG-Asp containing pediatric chemotherapy regimen because of concerns related to tolerability and safety in this population [PMID 28355969]. Methods The Adult Leukemia Program at Mount Sinai Hospital developed an age-based, dose-adjusted, CALGB 10403 based intensive chemotherapy regimen for adults (≥40 years) with a diagnosis of Ph-negative ALL. For patients up to 60 years, prednisone (PRD) dose was reduced from 60 to 40 mg/m2/day from D1 to D28, and PEG-Asp reduced from 2500 to 1000 units/m2 (D4). For patients aged 61 years and above, PRD was further reduced to 25 mg/m2/day, and PEG-Asp to 1000 units/m2 on D4. In CD20+ ALL, rituximab x 8 doses were added to the regimen. CNS-prophylaxis consisted of intrathecal methotrexate at D1, D8 and D29 during induction, and during subsequent courses of chemotherapy based on the CALGB 10403 protocol. A PEG-Asp oriented supportive care plan was developed to prevent and treat Asp-related adverse effects. After the administration of PEG-Asp, Antithrombin III (ATIII) and fibrinogen levels were monitored on the same day, twice a week, for at least two weeks. If ATIII levels were < 70% and/or fibrinogen levels < 120 mg/dL, levels were corrected with the administration of ATIII concentrate and/or cryoprecipitate, respectively. Results Twelve patients with a median age of 58 years (45 - 76) were evaluable, and three patients were ≥ 70 years. Nine patients had B-cell ALL and three T-cell ALL. Three patients had a white blood cell count > 30 x103/µL at diagnosis. An ECOG status ≤ 2 at diagnosis was described in all patients, and all of them had multiple complex cytogenetic and molecular abnormalities. Ten patients had significant co-morbidities at diagnosis, including diabetes, hypertension, previous history of cancer, coronary artery disease, obesity, alcohol related chronic pancreatitis, and chronic diarrhea. Nine out of the twelve patients (75%) attained a bone marrow morphological complete remission (CR) at the end of induction (EOI), three of them with detectable minimal residual disease (MRD) that became undetectable after completing course II. Of the three patients who had ≥5% bone marrow blasts at EOI, one attained a CR with undetectable MRD at the end of course IA and another when switched to blinatumomab, and the third one died of progressive disease. No patient experienced early death. Five patients underwent allogeneic hematopoietic stem cell transplantation (HCT) while in CR (age range 46 to 60 years) and four remain in CR at last follow up (median 489 days, range 181 - 841), and one died of relapsed disease 67 days post-HCT. The other six patients who are receiving chemotherapy are alive and in remission at last follow up (median 272 days, range 52 - 639). The common adverse effects associated with PEG-Asp administration in this older group of patients were asymptomatic hypofibrinogenemia and depleted ATIII levels requiring supplementation (n=8), severe hyperbilirubinemia (n=1), and non-life-threatening venous thrombosis (n=1). Severe allergic reaction, clinical pancreatitis and cognitive impairment were not observed. Conclusion This age-based dose-adjusted PEG-Asp containing regimen was associated with an encouraging CR rate and a tolerable and manageable adverse event profile in this older patient population with significant co-morbidities. Treatment related mortality was 0%. Ten of 12 patients are currently in sustained remission, either with chemotherapy alone or following allogeneic HCT (median follow up 422 days, range 52 to 841 days). Treatment optimization for older patients with ALL utilizing an intensified, age-adjusted PEG-Asp containing induction and consolidation therapy regimen is associated with favorable outcomes and provides an effective bridge to potentially curative therapies such as HCT. Further prospective evaluation is under way. Table. Table. Disclosures Kremyanskaya: Incyte: Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.

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Allogeneic Hematopoietic Stem Cell Transplantation for Primary Refractory Acute Lymphoblastic Leukemia - a Report from the Acute Leukemia Working Party of the EBMT

Blood ◽

10.1182/blood.v128.22.4668.4668 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4668-4668

Author(s):

Jiří Pavlů ◽

Myriam Labopin ◽

Johanna Tischer ◽

Ioanna Sakellari ◽

Matthias Stelljes ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Acute Lymphoblastic Leukemia ◽

Prognostic Factor ◽

Board Of Directors ◽

Acute Gvhd ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Factors Associated

Abstract Patients with acute lymphoblastic leukemia (ALL) who are refractory to initial and re-induction chemotherapy have a dismal prognosis unless they undergo allogeneic hematopoietic cell transplantation (HCT). Due to a lack of studies investigating primary refractory (PREF) ALL there are no known factors potentially influencing transplantation outcomes in these patients. We believe it is important to identify these factors and clarify outcomes of HCT in PREF ALL in this era of novel therapies for chemo-refractory ALL. The outcomes of 86 adult patients who underwent their first HCT for PREF ALL between 2000 and 2012 were reported to the European Society for Blood and Marrow Transplantation (EBMT) Registry. PREF disease was defined as failure to achieve complete remission (CR, <5% of blasts in the bone marrow) after two or more courses of induction chemotherapy. A total of 70 patients were transplanted using a myeloablative conditioning regimen, of whom 52 received a total body irradiation (TBI)-based regimen (median dose 12 Gy; range: 8-14). Sixteen patients were transplanted using a reduced-intensity conditioning (RIC) regimen, as defined by the EBMT criteria. In 6 patients, the RIC regimen incorporated TBI at a dose of 6 Gy or less. In vivo T-cell depletion was used in 28 (33%) patients (anti-thymocyte globulin was used in all but 6 who received alemtuzumab). The median duration of follow-up in live patients was 106 months (range 9-181 months). Study main endpoints were survival, CR rate, leukemia free survival (LFS), and non-relapse mortality (NRM). A total of 76 (89%) patients demonstrated neutrophil engraftment at a median of 18 days (9-87) and 9 (11%) patients experienced primary graft failure. Grade II or higher acute GVHD was documented in 28 (34%) patients, while 14 (17%) patients experienced grade III/IV acute GVHD. Chronic GVHD of any severity developed in 27 (32%) patients of those surviving more than 100 days. With a median follow-up of 106 months, 20 patients were alive and free of leukemia. The probability of survival (Figure A) for the whole group was 36% (95% confidence interval (CI) 25 - 46) at 2 years and 23% (95% CI 13 - 32) at 5 years. The probabilities of LFS and NRM at 2 and 5 years were 28% (95% CI 18 - 38) and 17% (95% CI 8 - 25) and 20% (95% CI 12 - 29) and 29% (95% CI 19 - 39), respectively. In all, 66 (76%) patients achieved CR after transplant at a median time of 31 days (28 - 147 days). For patients achieving CR, the survival was 36% (95% CI 25 - 46) and 29% (95% CI 18 - 41) and relapse incidence was 51% (95% CI 38 - 63) and 54% (95% CI 41 - 66) at 2 and 5 years, respectively. The following factors associated with improved survival and LFS with P <0.10 in univariate analysis entered multivariate analysis: the use of TBI, absence of extramedullary disease, no more than 2 induction courses, male sex, and infusion of female cells into male recipient. In multivariate analysis, use of TBI was associated with improved survival (Hazard Ratio (HR) 0.53; 95% CI 0.29-0.973; P=0.04), (Figure B). Similarly, factors associated with improved LFS were: use of TBI (HR 0.44; 95% CI 0.24-0.82; P=0.01) and infusion of female hematopoietic cells into male recipient (HR 0.45; 95% CI 0.23-0.90; P=0.01). Presence of extramedullary disease was associated with increased NRM (HR 4.92; 95% CI 1.85-13.02; P=0.001). We developed a score using the summation of the number of prognostic factors found to be significant for LFS by multivariate analysis: use of TBI and infusion of female hematopoietic cells into male recipient. This allows delineation of three prognostic groups as follows: score 0 (both prognostic factors present): (N=14), 5 year survival: 57% (95% CI 31 - 83) and 5 year LFS: 50% (95% CI 24 - 76); score 1 (only 1 prognostic factor): (N=45), 5 year survival: 22% (95% CI 9 - 34); and 5 year LFS 12% (95% CI 2 - 22); score 2 (no prognostic factor): (N=24), 5 year survival and LFS: 8 (95% CI 0 - 19) (Figure C). In conclusion, our data support the use of allogeneic HCT in selected patients with PREF ALL who cannot reach CR. Conditioning regimens should contain TBI and male patients may benefit from a female donor. Clearly there is a need for introduction of modern therapies capable of improving anti-leukemic control prior to and after transplantation. Figure 1 Figure 1. Disclosures Stelljes: Pfizer: Consultancy. Fanin:Novartis: Speakers Bureau. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Phase 2 Results of Clofarabine In Combination with Etoposide and Cyclophosphamide In Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v116.21.866.866 ◽

2010 ◽

Vol 116 (21) ◽

pp. 866-866

Author(s):

Nobuko Hijiya ◽

Jo-Anne Paul ◽

Michael J. Borowitz ◽

Blythe Thomson ◽

Michael Isakoff ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Lymphoblastic Leukemia ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Abstract 866 Background: Dramatic improvements have been made in treating children with newly diagnosed acute lymphoblastic leukemia (ALL). However, poor outcomes are still observed in patients who are either refractory to or who have relapsed after conventional chemotherapy. Salvage therapy options are urgently needed for this patient population. Clofarabine is approved as a single agent for treatment of pediatric ALL in second relapse. Previously we reported the safety profile and response rates from the phase 1 study assessing clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory/relapsed acute leukemia (Hijiya, Leukemia, 2009). Here we report the phase 2 results. Methods: Patients (pts) aged 1–21 years with refractory/relapsed ALL were treated at the recommended phase 2 dose of clofarabine 40 mg/m2/day, cyclophosphamide 440 mg/m2/day, and etoposide 100 mg/m2/day. All 3 agents were given IV daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients could receive up to 2 induction cycles, followed by consolidation (max 8 cycles including induction). The primary endpoint was overall remission rate (ORR: complete remission [CR] and CR without platelet recovery [CRp]). Secondary endpoints were safety and tolerability, rate of partial remission (PR), duration of remission (DOR), event-free survival (EFS), 4-month EFS, and overall survival (OS). Minimal residual disease (MRD) by flow cytometry was evaluated as an exploratory endpoint. Results: Phase 2 comprised 25 pts (median follow-up 10.7 weeks [wks]): 16 males and 9 females with a median age of 14.0 years. Twenty-one pts had pre-B cell ALL, 1 pt had T cell ALL and 3 pts had an unknown immunophenotype. Fourteen pts had 2 prior induction regimens, 7 pts had 3 prior induction regimens and 4 pts had 1 prior induction regimen. Fifteen pts (60%) were refractory to their immediately preceding regimen. Four pts had received a prior hematopoietic stem cell transplant (HSCT). The investigator-assessed ORR was 44%; 7 CR (28%) and 4 CRp (16%). Additionally, 3 pts (12%) achieved PR. Eight pts were evaluable for MRD after induction, 5 were MRD negative (defined as <0.01%) and 3 were positive. Overall, 10 pts proceeded to HSCT, including 7 of 11 responders (CR + CRp). The median DOR at the last known follow-up (not censored for alternative therapy) was 15.9 wks (range: 2.9–109.6+) for pts with CR, but was not estimable for pts with CRp (range: 30.1+-67.7+). Median DOR for responders censored at alternative therapy/HSCT was not estimable as most pts received alternate therapy or transplant prior to event occurrence (range: 0.1+-10.9+ wks). Median OS censored at the last known follow-up was 10.7 wks for all patients (range: 1.0–113.1+) and 80.9 wks for responders (range: 8.1–113.1+). The median EFS for responders was 73.9 wks and 44% of all 25 pts were free of events at 4 months. The median cumulative number of clofarabine cycles received was 1 (range: 1–3), with most pts (10 of 11 responders) achieving best response after 1 cycle. The treatment-related non-hematologic adverse events (AEs) occurring in ≥25% of phase 2 pts were vomiting (88%); nausea (72%); febrile neutropenia (60%), pyrexia (52%); decreased appetite (44%); ALT increased, AST increased, hypokalemia, and hypotension (36% each), diarrhea and hyperbilirubinemia (28% each). One pt discontinued study treatment due to treatment-related fungal sinusitis which occurred 17 days after the last dose of study drug. Serious treatment-related AEs, were reported in 84% of pts. Six pts (24%) died within 30 days of receiving last dose of study treatment. Deaths were due to hepatic veno-occlusive disease (2 pts), septic shock (2 pts), pulmonary edema (1 pt) and infection (1 pt). As reported previously, after 4 of the initial 8 pts developed severe hepatotoxicity, the protocol was amended to exclude pts with prior HSCT, viral hepatitis cirrhosis, or elevated conjugated bilirubin levels at study entry (Hijiya, ASH 2008). There were no additional events of severe hepatotoxicity observed in the remaining 17 pts. Conclusions: Combination treatment with clofarabine, etoposide and cyclophosphamide in pediatric pts with refractory or relapsed ALL resulted in an ORR of 44% and negative MRD in heavily treated pts. Ten pts including 7 of 11 responders proceeded to HSCT. The safety profile is acceptable in this relapsed/refractory population. Disclosures: Hijiya: Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine (Clolar) is approved by the US FDA for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This trial examines the use of clofarabine in combination with etoposide and cyclophosphamide. Paul:Genzyme: Employment, Equity Ownership. Borowitz:genzyme: Research Funding; becton-dickinson: Research Funding; Alexion: Consultancy; beckman-coulter: Research Funding. Isakoff:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Silverman:Genzyme: Research Funding; Enzon : Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steinherz:Genzyme: Research Funding. Kadota:Genzyme: Employment, Equity Ownership. Pressey:Genzyme: Research Funding. Shen:Genzyme: Research Funding. Chu:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cooper:Genzyme: Research Funding. Jeha:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Razzouk:Genzyme: Research Funding. Rytting:Genzyme: Research Funding. Barry:Genzyme: Employment, Equity Ownership. Carroll:Genzyme: Research Funding. Gaynon:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Allogeneic Hematopoietic Cell Transplantation May Improve Long-Term Outcomes in Patients with Ph-like Acute Lymphoblastic Leukemia with CRLF2 Overexpression

Blood ◽

10.1182/blood-2019-130645 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4598-4598

Author(s):

Paul Koller ◽

Rima M. Saliba ◽

Celina Ledesma ◽

Gabriela Rondon ◽

Uday Popat ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Lymphoblastic Leukemia ◽

Hematopoietic Cell ◽

Advisory Committees ◽

Landmark Analysis

Introduction: Philadelphia (Ph) like acute lymphoblastic leukemia (ALL) is a high risk subtype of ALL, with the majority of patients overexpressing CRLF2; CRLF2 overexpression is associated with particularly poor outcomes (Jain, Blood, 2017). To date, the efficacy of hematopoietic cell transplantation (HCT) in these patients is unknown. Methods: In this retrospective study, we evaluated patients with CRLF2 overexpressed ALL who received or did not receive HCT. CRLF2 status was identified via FISH or multi-parameter flow cytometry. We identified 55 patients treated at our institution from 1992-2019 who had CRLF2 overexpression at diagnosis and achieved a first complete remission (CR1). To account for potential survival bias in the HCT group, outcomes between the two groups were compared in a landmark analysis starting at 3 months since CR1. Results: Baseline characteristics and treatment outcomes are described in Table 1. The median age was 32 years and 34 years, respectively, for HCT vs. non-HCT groups. In both groups, patients received high-intensity induction therapy with or without asparaginase. Patients who did not receive HCT were more likely (63%) to have been diagnosed prior to 2013, whereas all those treated with HCT were diagnosed after 2013. This difference reflects a change in practice at our institution after the description of CRLF2 overexpression as a poor prognostic factor. Median peripheral blood platelet count (102 k/uL vs 46 k/uL, p=0.02) and bone marrow blasts (76% vs 91%, p=0.02) at diagnosis were different between the HCT and non-HCT groups, respectively. In the HCT group, the majority of patients underwent myeloablative conditioning (n= 11, 79%) with a matched donor (n=9, 64%). With a median follow up of 26 months from CR1 in both groups, landmark analysis showed a trend for lower 3-year progression rate (25% vs 66%, HR=0.3, p=0.08) and improved progression-free survival (PFS) (51% vs 22%, HR=0.6, p=0.3) and overall survival (OS) (59% vs 35%, HR=0.6, p=0.3) in the HCT versus non-HCT groups. The median PFS was 16 months for the non-HCT group, and has not been reached for the HCT group. In the HCT group, PFS appears to have reached a plateau at 14 months, with 6 of 14 patients remaining alive in remission at a median follow-up of 24 months (range 17-41). Conclusions: CRLF2 overexpression in ALL is associated with a high rate of progression. Allogeneic HCT is beneficial against relapse, showing a trend for improved PFS and OS.A larger sample size and longer follow up is needed to confirm these findings. Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Bioclinical: Consultancy; Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Jain:BMS: Research Funding; Cellectis: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Kantarjian:Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding. Konopleva:Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Agios: Research Funding; Calithera: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding. Kebriaei:Pfizer: Honoraria; Kite: Honoraria; Amgen: Research Funding; Jazz: Consultancy.

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Successful of Chemo-Free Treatment with Dasatinib and Blinatumomab in a Pediatric EBF1-PDGFRβ Positive Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2018-99-113829 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5213-5213

Author(s):

Fara Petruzziello ◽

Giovanna Giagnuolo ◽

Giovanni Cazzaniga ◽

Giuliana Beneduce ◽

Franco Locatelli ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Lymphoblastic Leukemia ◽

Poor Responder ◽

Induction Phase ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Bone Marrow Evaluation

Abstract Recently, a novel subgroup of B Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL), called Philadelphia-like (Ph-like) ALL, has been described. This high-risk group, despite the absence of BCR-ABL1 rearrangement, shows genomic abnormalities that result in aberrant expression of cytokine receptors genes or tyrosine-kinase-activating signaling. These patients are poor responder to conventional chemotherapy but potentially sensitive to Tyrosine-Kinase Inhibitors (TKIs). Herein we report the case of a 10 year-old girl who received diagnosis of precursor B-ALL on February 2018. She started therapy according to observational protocol ALL 2017 of the Italian Association of Pediatric Hemato-Oncology (AIEOP). After pre-phase, the patient resulted prednisone poor responder and continued induction therapy, including daunorubicin, vincristine, PEG-L-Asparaginase, prednisone and intrathecal methotrexate. Bone marrow evaluation showed persistence of disease on day 15 (88% of lymphoblasts) and 33 (60% of blasts) in flow cytometry. At the end of IA induction phase, Minimal Residual Disease (MRD) in RT-PCR showed high positivity (marker 1 = 7.2x10-1, marker 2= 8.11x10-1). At this time, further molecular studies, using RNA targeted next generation sequencing (PanCancer, Illumina), revealed the presence of EBF1-PDGFRβ gene fusion. Since the patient was resistant to conventional therapy and literature's evidences demonstrated potential sensitivity of EBF1-PDGFRβ to TKIs therapy, we decided to add dasatinib, a second generation TKI, to IB induction, with cyclophosphamide, cytarabine and 6-mercapthopurine. After one week of therapy, clinical course was complicated by Klebsiella Pneumoniae sepsis, followed by digestive hemorrhage. Since we retained that the hemorrhagic event could be related to dasatinib, the drug was temporarily discontinued. However, bone marrow evaluation, after only 10 days of dasatinib administration, showed hematologic remission (3% of lymphoblast) and MRD reduction >1 logarithm (markers 1=1-10-2 e markers 2= 9.9 x 10-3). Given the resistance to chemotherapy alone and the excellent response to dasatinib but its related toxicity in combination, we decided to start immunotherapy with blinatumomab, a bi-specific CD3-CD19 monoclonal antibody, alternated to dasatinib, in order to achieve MRD negativity before to proceed with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling. The patient received 2 courses of blinatumomab for 28 days continuous infusion (15 mcg/mq days 1-28), interspersed by 15 days of dasatinib (60 mg/mq/day). After the first cycle the patient achieved complete hematological remission and MRD negativity. MRD negativity was confirmed after first course of dasatinib, second course of blinatumomab and second course of dasatinib. Dasatinib, given alone, was well tolerated and no serious adverse event were reported. Actually, the patient is undergoing HSCT by HLA-identical sister. To our knowledge, only few cases of EBF1-PDGFRβ ALL, treated with TKIs, are described in literature and this is the first in which MRD negativity was obtained with a sequential combination of dasatinib and blinatumumomab, a chemo-free approach, showing efficacy and good tolerability. This case highlights also that screening for targetable lesions at diagnosis or in case of resistance to induction phase is mandatory to identify patients who might benefit from alternative therapies as TKIs, immunotherapy or their combination. A longer follow-up is required to definitively establish the long-term efficacy of this biological approach in our patient. Nevertheless, it is interesting to speculate that alternative treatment with TKIs or immunotherapy could avoid, in the future, an intensive chemotherapy, or probably a transplant approach in selected patients, in order to achieve a durable cure in these Ph-like patients. Disclosures Locatelli: Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Parasole:Baxalta: Membership on an entity's Board of Directors or advisory committees; behring: Consultancy; jazz: Honoraria, Speakers Bureau.

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Blinatumomab in Pediatric Patients with Relapsed/Refractory B-Cell Precursor and Molecularly Resistant Acute Lymphoblastic Leukemia (R/R ALL): Updated Analysis of 110 Patients Treated in an Expanded Access Study (RIALTO)

Blood ◽

10.1182/blood-2019-121615 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1294-1294 ◽

Cited By ~ 2

Author(s):

Franco Locatelli ◽

Gerhard Zugmaier ◽

Peter Bader ◽

Sima Jeha ◽

Paul-Gerhardt Schlegel ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Children And Adolescents ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Expanded Access ◽

Grade 3

Introduction: Although survival rates in children and adolescents with acute lymphoblastic leukemia (ALL) have improved significantly, relapsed or refractory (R/R) ALL remains a leading cause of cancer-related deaths in pediatric patients. Blinatumomab is a bispecific T-cell engager (BiTE®) immuno-oncology therapy that activates endogenous cytotoxic T cells to kill target B cells. We report the primary analysis results of RIALTO, an expanded access study, where pediatric patients with R/R ALL were treated with blinatumomab (NCT02187354). Methods: Enrolled in the study were children and adolescents >28 days and <18 years of age with R/R CD19+ ALL (defined as ≥2 relapses, relapse after allogeneic hematopoietic stem cell transplant [HSCT], or refractory to prior treatments) and ≥5% blasts or <5% blasts but with minimal residual disease (MRD) level ≥10−3. Blinatumomab was given as continuous infusion in a 6-week cycle (4 weeks of treatment and 2 weeks of treatment-free interval) for up to 5 cycles. Patients with <25% blasts were dosed at 15 µg/m2/day, whereas those with ≥25% blasts were dosed at 5 µg/m2/day (days 1-7 of cycle 1) followed by dose increase to 15 µg/m2/day. Any change in therapy (eg, HSCT) was off-protocol and per investigator preference. Primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included incidence of morphological complete response (CR; <5% blasts) and MRD response (<10−4 blasts by PCR or flow cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and HSCT rate after blinatumomab treatment. Data cutoff was September 27, 2018. Results: Of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 60% were 7-17 years of age, 61% had <50% blasts at baseline, and 11% had <5% blasts (n=12; with MRD ≥10−3). Among 12 patients with <5% blasts and MRD-positive disease at baseline, 0 had prior relapse after HSCT and 2 had chromosome translocation mutations. Prior treatments included HSCT (41%) and blinatumomab (5%); 56% of patients had ≥2 relapses and 40% relapsed after HSCT (Table 1). Of 98 patients with ≥5% blasts at baseline, 58 (59%) achieved CR (<5% blasts), 0 achieved partial remission (PR; ≥5 to <25% blasts), and 20 (20%) showed progressive disease (PD; ≥25% blasts) after the first 2 cycles. Of the 58 patients who reached CR, 39 (67%) achieved CR with full recovery of peripheral blood counts, 46 (47%) achieved an MRD response, and 36 (62%) proceeded to HSCT after achieving CR. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response. Among the 12 patients with <5% blasts but with MRD ≥10−3 at baseline, 11 (92%) achieved CR and MRD response and 1 (8%) had disease progression (Table 2). Overall, the response rates were higher among patients with lower tumor burden at baseline. Among 98 patients with ≥5% blasts at baseline, median OS was 13.1 months (95% CI, 9.8-21.3), with median follow-up time of 17.4 months. For patients reaching CR after the first 2 cycles, the median RFS was 8.5 months (95% CI, 3.4-NE), with a median follow-up time of 11.2 months; 38% of patients relapsed and 9% died. Of 110 patients treated with blinatumomab, 99% experienced TEAEs, with 65% being grade ≥3, including neurologic events (6%), cytokine release syndrome (CRS, 2%), cytopenias (38%), elevated liver enzymes (13%), infections (18%), and neutropenia (14%). TRAEs were reported in 74% of patients; 36% were grade ≥3 and 26% were deemed serious. Grade ≥3 TRAEs included neurologic events (5%), CRS (2%), cytopenias (9%), elevated liver enzyme (4%), infections (5%), and neutropenia (6%). Due to TRAEs, 22% of patients interrupted treatment and 5% discontinued treatment. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusion: Overall, the safety profile of blinatumomab in this expanded access study in pediatric patients with R/R ALL was tolerable and consistent with that in other blinatumomab clinical trials. Patients, including those with persistent MRD and genetic disorders at baseline, achieved high rates of CR and MRD responses with low rates of relapse and disease progression. These findings support blinatumomab as a suitable treatment option for pediatric patients with R/R ALL. Disclosures Locatelli: BluebirdBio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Employment, Other: holds stock, Patents & Royalties: & other intellectual property. Bader:Amgen (Brasil), Novartis: Consultancy, Speakers Bureau; Medac: Patents & Royalties, Research Funding; Riemser, Neovii: Research Funding; Celgene: Consultancy. Bourquin:Servier: Other: Travel support. Rossig:BMS, Pfizer, Roche: Other: speaker honoraria; Amgen, Celgene,EUSA Pharma, Genetech, Novartis, Roche: Other: advisory board.

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Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽

10.1182/blood-2020-139661 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Philip C. Amrein ◽

Karen K. Ballen ◽

Kristen E. Stevenson ◽

Traci M. Blonquist ◽

Andrew M. Brunner ◽

...

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Survival Estimate ◽

Grade 3 ◽

Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

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