Outcome of Infants Younger Than 1 Year with Acute Lymphoblastic Leukemia Treated with the Interfant-06 Protocol; Results from an International Randomised Study

Abstract INTRODUCTION Infant acute lymphoblastic leukemia is a high-risk subtype characterized by a very high incidence of KMT2A (MLL) gene rearrangements. In 1999, a large international consortium (Interfant) commenced; the first Interfant-99 protocol (Pieters et al, Lancet 2007) was used as baseline for the current Interfant-06 study, which run in 18 groups worldwide. AIMS To determine:In a randomised study whether two AML-type courses ADE (araC, daunorubicin, etoposide) and MAE (mitoxantrone, araC, etoposide) after induction improved outcome compared to the consolidation IB course in KMT2A-rearranged cases (MR and HR risk group). With a target of 320 randomised cases, the study had 80% power to detect a DFS difference of 16% at 3 years (41% DFS in the control arm, α=0.05).The prognostic relevance of clinical and biological parameters.The outcome of Interfant-06 versus Interfant-99.The role of SCT in HR patients and in MR patients with MRD ≥ 10e-4 at the start of OCTADAD. As Interfant-99 showed outcome differences between the West-European/North-American groups who started Interfant (original countries) versus other countries that joined later, analyses were also performed separately in these groups. RISK GROUPS AND TREATMENT Three risk groups were defined: low risk (LR) - KMT2A germline; high risk (HR) - KMT2A rearrangement plus age < 6 months plus white blood cell count (WBC) >300 x 10e9/L or a poor prednisone response; medium risk (MR) - comprised all other KMT2A-rearranged cases. Treatment consisted of induction (prednisone prephase, dexamethasone, VCR, asparaginase, DNR), consolidation phase, either IB (araC, 6-MP, cyclofosfamide) or ADE/MAE in the experimental arm, MARMA (HD-araC, HD-MTX, 6-MP, asparaginase), OCTADAD (VCR, dexamethasone, asparaginase, DNR, 6-TG, araC, cyclofosfamide) and maintenance (6-MP, MTX) with intrathecal therapy in all courses. All HR patients were allocated to receive allogeneic stem cell transplantation (SCT). After June 2009, SCT was also undertaken in MR cases with MRD ≥ 10 e-4 at start of OCTADAD as the Interfant-99 update showed a very poor outcome for these patients. RESULTS 651 infants were included (167 LR, 320 MR, 164 HR). In the original countries, 6-yr EFS (SE) and survival rates were 49.4 (2.5) and 62.1 (2.4) respectively, which were each 6% (not significantly) higher than in Interfant-99 study. In the other countries, the 6-yr EFS and survival rates were 39.0 (3.6) and 49.7 (3.7). The outcome of patients treated in the original countries was significantly better than in other countries due to lower rates of toxic death and resistant disease. The 6-year EFS and survival of all 651 cases were 46.1 (2.1) and 58.2 (2.0) respectively. 330/407 eligible cases (81%) were randomised. The 6-yr cumulative incidence (CI) of relapse with ADE/MAE was 47.5 (4.0) which was not significantly (p = 0.11) lower than the 54.9 (4.1) with IB. The 6-yr CI of death in remission was 10.2 (2.4) with ADE/MAE versus 8.3 (2.2) with IB (p = 0.51). This resulted in no significant differences in 6-yr DFS rates of 39.3 (4.0) and 36.8 (3.9) respectively (the 3-yr DFS were 45.3 [3.9] versus 38.6 [3.9]). The 6-yr EFS rate of 164 HR patients was 20.9 (3.4) with the intention to use SCT in all HR patients; 76 of them received SCT as many HR patients had very early events. Out of 23 MR patients with MRD ≥ 10e-4 before OCTADAD, 16 received SCT; 4/23 are in CCR. In total, 14.4% of MR/HR patients receiving SCT died of transplant-related mortality. T(4;11) and t(11;19) translocated cases had a significantly lower EFS than other KMT2A-rearranged cases (p = 0.005). Multivariate analyses identified KMT2A rearrangement, age < 6 months, WBC ≥ 300 x 10e9/L, and poor prednisone response but not CD10, type of MLL translocation and sex as significant predictors of adverse DFS. CONCLUSIONS The Interfant-06 study is by far the largest study performed in infant ALL. The 6-yr survival in West-European/North-American countries is 62%, which is 12% higher than in other participating countries. Two postinduction AML-type chemotherapy courses versus course IB did not lead to a significant better DFS. 6-yr survival rates are 6% higher than on Interfant-99, which is not a statistically significant improvement. Pilot studies by COG and Interfant are currently exploring the feasibility of adding azacytidine and blinatumomab to the Interfant backbone, which may lead to a worldwide randomised trial with these drugs in infant ALL. Disclosures Locatelli: Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vora:Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board; Amgen: Other: Advisory board; Novartis: Other: Advisory board.

Download Full-text

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.

Download Full-text

Clinical Significance of Occult Central Nervous System Disease in Adult ACUTE Lymphoblastic Leukemia. a Multicenter,Report from the Campus ALL/Gimema Network

Blood ◽

10.1182/blood-2018-99-114177 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 658-658 ◽

Cited By ~ 1

Author(s):

Maria Ilaria Del Principe ◽

Elisa Buzzati ◽

Fabio Forghieri ◽

Federica Lessi ◽

Silvia Imbergamo ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Lymphoblastic Leukemia ◽

Advisory Board ◽

Cell Transplant ◽

Advisory Committees ◽

Cns Disease ◽

Wbc Count

Abstract Introduction. In a modern context of improved management of acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement at diagnosis remains an obstacle towards long-term cure. We have previously reported that flow cytometry (FCM) is better than conventional cytology (CC) in demonstrating the presence of leukemic cells in patients' (pts) cerebrospinal fluid (CSF), especially in samples with low cell counts. In the framework of the national Campus ALL program aimed at improving the management of adult ALL patients enrolled in the GIMEMA protocols, we retrospectively evaluated the incidence of occult CNS positivity and its impact on outcome in 221 adult pts with newly diagnosed ALL from 11 centers. Methods. Ninety-four patients (42%) were females and 127 (58%) males, with a median age of 44 years (range 17-80), a median white blood cell (WBC) count of 10.6x109/L (range 0.1-457). One hundred and seventy pts (77%) had B-lineage ALL. Cytogenetic/genetic data were available in 167 (75%) pts: 58 (35%) had a BCR/ABL rearrangement, 14 (8%) a complex karyotype and 11 (6%) a MLL rearrangement. Pts were treated according to the GIMEMA/NILG ALL protocols or with the Hyper-CVAD program. Ninety-eight pts underwent an allogeneic stem cell transplant (ASCT). Median follow up was 26.8 months (range 1-136.6). All CSF samples were evaluated both by CC and FCM. The presence of ≥10 clonally restricted or phenotypically abnormal events was regarded as a FCM positivity. Based on the results of CSF examination, three different categories were recognized: manifest CNS+ (CC+FCM+), occult CNS+ (CC-FCM+) and CNS- (CC-FCM-). Results. Overall, 16 (7%) pts had manifest CNS+, 39 (17%) occult CNS+ and 166 (75%) were CNS-Median age, WBC count, B/T lineage, cytogenetic/genetic features did not differ significantly between the three categories. A complete remission (CR) was achieved in 178 (80%) pts, 9 (4%) died early in induction and 104/178 (58%) experienced a relapse. The frequency of CR rate did not vary significantly across the three identified categories. In univariate analysis, the CNS status correlated significantly with the incidence of relapse (p=.004) and with censor (<.00002). The four-year overall survival (OS) for manifest CNS+, occult CNS+ and CNS- pts was 6%, 17% and 46%, respectively (p=.0007) (Figure). No difference in terms of OS was observed between manifestand occult CNS+ pts (p=.30). In multivariate analysis a baseline status of manifestor occult CNS+ (RR: 1.98, 95%CI 1.47-2.43, p=0.00001) and age>45 years (RR:1.45, 95% CI 1.47-2.43, p=0.04)were independently associated with a lower OS. Conclusions. Our large, multicenter CAMPUS ALL study showed that i) in ALL adult pts, FCM allows to detect occult CNS disease, even in conditions of low spinal fluid leukemic count; ii) the presence of occult CNS disease is associated with an unfavorable outcome. Further prospective studies on larger series are needed to confirm these data. Figure. Figure. Disclosures Del Principe: Gilead: Membership on an entity's Board of Directors or advisory committees. Fracchiolla:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Foà:NOVARTIS: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau.

Download Full-text

Molecular Subtypes with Distinct Clinical Phenotypes and Actionable Targets in Adult B Cell Precursor ALL Treatment According to GMALL Protocols

Blood ◽

10.1182/blood-2020-143032 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-12

Author(s):

Lorenz Bastian ◽

Sonja Hänzelmann ◽

Martin Neumann ◽

Alina Hartmann ◽

Thomas Burmeister ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Medical Writing ◽

Advisory Board ◽

Advisory Committees ◽

Clinical Phenotypes ◽

Male Patients ◽

Molecular Landscape

Targeted interventions and new risk stratification approaches for the improvement of outcomes in B cell precursor acute lymphoblastic leukemia (BCP-ALL) require an understanding of high-risk driver subtypes, their clinical phenotypes and actionable targets. Currently, over 20 BCP-ALL subtypes have been identified based on genomic driver alterations and corresponding gene expression signatures, in particular in pediatric ALL. This complex molecular landscape is so far only partially defined in adult BCP-ALL patients. To characterize driver subtypes and their clinical phenotypes we performed transcriptome sequencing (Illumina) on Ph-negative adult BCP-ALL patients (n=376) treated on subsequent pediatric inspired protocols of the German Acute Lymphoblastic Leukemia Study Group (GMALL). Using random forest analyses of a well-defined patient subset with available WES/gene panel and DNA-methylation data, we established a 300-gene classifier which together with fusion calling and hotspot mutation calling reliably allocated samples to driver subtypes. Subgroup allocation was feasible for n=267 / 308 Ph-negative patients (86.7%) with Ph-like ALL (27.7%) being the most frequently observed subtype followed by DUX4 (14.6%), KMT2A (10.1%), PAX5-plus (9.7%), ZNF384 (9.0%), Near haploid - High hyperdiploid (NH-HeH, 6.0%), Low haploid - Near triploid (LH-NT, 6.0%) and TCF3-PBX1 (5.6%). With frequencies below 5% were observed: PAX5-alt, MEF2D, BCL2/MYC, ETV6-RUNX1, CEBP family member fusions and TCF3-HLF. The age distribution of these driver subtypes varied across our cohort (median age: 37 years, range: 16 - 81; left panel). Adult patients harboring ETV6-RUNX1 fusions (n=4) were 25 years or younger. NH-HeH, PAX5-plus and DUX4 ALL were also observed predominantly in younger patients (median ages: 24, 24, 30 years respectively; p<0.03) Conversely, LH-NT and KMT2A rearranged ALL frequencies increased in older patients (median ages: 47, 46 years respectively; p<0.04). As expected, male patients were slightly more represented in the cohort (55% male). However, significant differences were observed in the sex-distribution of molecular subgroups with a predominance of male patients in Ph-like (65.4%; p=0.045) and NH-HeH (82.4% p=0.024) ALL, while female patients were more frequent in DUX4 (60%, p=0.046) or KMT2A (75.5%; p=0.031) ALL. These data implicate that sex-specific host factors favor the selection of ALL driver alterations in adult ALL patients. We measured MRD by qRT-PCR quantification of patient specific immune gene rearrangement markers in our GMALL central reference lab. Data on MRD status after consolidation I which is the most relevant time-point for identification of high-risk patients in the GMALL protocol, were available in 132 patients (aged 18-55 years; right panel). Ph-like and KMT2A patients showed an unfavorable response to intensive induction with Molecular CR achieved in 60.6% and 61.1% respectively. In ZNF384 ALL patients, only n=5/13 achieved Molecular CR, while n=4 each were MRD-positive or had MRD below the quantitative detection range, suggesting that ZNF384 ALL might be a novel high-risk subgroup in adult BCP-ALL. Gene set enrichment analyses showed comparable patterns of JAK/STAT activation in ZNF384 and Ph-like cases as possible functional underpinning of a shared poor-response phenotype. Actionable genomic alterations were identified in n=13/74 Ph-like patients (17.6%). Out of these, ABL-class fusions as targets of ABL-TKI were identified in n=14 patients (PDGFRB: n=5; ABL1: n=4; CSF1R n=2) and one patient harbored an ETV6-NTRK3 fusion amenable to specific inhibitors. Our data extent the in-depth characterization of BCP-ALL molecular landscape in adult patients. We observe that sex-specific host factors favor the selection of leukemogenic drivers (male predominance: Ph-like, NH-HeH, female predominance: DUX4, KMT2A). ZNF384 ALL seems to be associated with unfavorable therapy response in adults and shares JAK/STAT activation patterns with Ph-like ALL. Figure Disclosures Fiedler: Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; BerGenBio ASA: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; BMS: Honoraria; Gilead: Honoraria; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Other; Morphosys: Membership on an entity's Board of Directors or advisory committees. Viardot:Novartis: Honoraria, Other: advisory board; Kite/Gilead: Honoraria, Other: advisory board; Roche: Honoraria, Other: advisory board; Amgen: Honoraria, Other: advisory board. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Goekbuget:Servier: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Erytech: Consultancy; Kite: Consultancy; Gilead: Consultancy. Brüggemann:Affimed: Research Funding; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy; Regeneron: Research Funding.

Download Full-text

Sleeping Beauty Modified CAR+ Lymphocytes Engraft and Exhibit Anti-Tumor Activity in Patient-Derived Xenograft Models of Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v128.22.4022.4022 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4022-4022 ◽

Cited By ~ 1

Author(s):

Chiara F. Magnani ◽

Claudia Mezzanotte ◽

Claudia Cappuzzello ◽

Fabrizio Benedicenti ◽

Michela Bardini ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Large Scale ◽

Lymphoblastic Leukemia ◽

Sleeping Beauty ◽

Advisory Board ◽

Advisory Committees ◽

Cik Cells ◽

Patient Derived Xenograft ◽

Equity Ownership

Abstract Background: Adoptive infusion of T lymphocytes modified with anti-CD19 chimeric antigen receptor (CAR) by viral vectors is a therapeutic option proven effective in the treatment of hematological malignancies. In the context of B-lineage neoplasms, CD19-specific CART cells demonstrated unexpected positive results, achieving complete remission and durable response. To overcome high manufacturing costs, regulatory hurdles and scale-up complexities, we recently established a platform for non-viral gene manipulation of Cytokine-Induced Killer (CIK) cells, an effector T cell population characterized by enrichment in highly cytotoxic CD3+CD56+ cells and reduced risk of GvHD, in compliance with Good manufacturing practices (GMP). Therefore, we investigate whether donor-derived CD19CAR redirected CIK cells can significantly increase anti-leukemic responses in Acute Lymphoblastic Leukemia (ALL) by performing a pre-clinical validation of the non-viral platform. Methods: Large-scale production will be performed by nucleofection in presence of two GMP-grade Sleeping Beauty transposon DNA plasmids, coding for the anti-CD19CD28OX40 CAR transgene and for the SB11 transposase. T cells were differentiated according to a procedure derived from the Eudract n 2008-003185-26 study with the addition of a single stimulation with gamma-irradiated PBMCs to rescue the impaired T-cell expansion induced by electroporation. Results: The feasibility of large scale manufacturing process was verified starting from 30-60X10^6 PBMC, reaching efficient expansion with an average of 69.3±15.2-fold increase (Figure 1A) and stable expression of CD19CAR (average 65%, Figure 1B). Immunophenotypic analysis showed the typical enrichment of the CD3+/CD56+ cell subset, and maintenance of naive and central memory CD8+ and CD4+ T cells. Modified cells displayed a specific and effective cytotoxicity and proliferation towards CD19+ cell lines and primary tumors. In order to determine the biological effect of CARCIK-CD19 cells on disease and the correct dose for optimal activity, we performed a CARCIK-cell dose titration in a xenograft mouse model of common BCP-ALL, bearing the feature of a Ph-like gene rearrangement (PAX5/AUTS2). Mice were treated with 5x106, 10x106, 15x106 CAR+ cells or with 10x106 not transduced (NT) cells. CARCIK-CD19 cells showed a dose-dependent antitumor response and persisted in tumor-bearing animals, in peripheral blood (PB), bone marrow (BM) and spleen (Figure 2). Furthermore, to evaluate whether cryopreservation affects the activity of the cell product, we performed functional experiments with both fresh and frozen/thawed CAR CIK cells in vitro and in an established MLL/ENL patient-derived xenograft model. CARCIK.CD19 cells remained functional after freezing and thawing as evidenced by killing activity and decreased level of leukemic engraftment in the spleen of treated mice. Finally, we evaluated CARCIK-CD19 cell bio-distribution, safety and acute toxicity in NOD-SCID-gamma chain-/- (NSG) mice. The infusion of CARCIK-CD19 cells proved to be safe and well tolerated in all mice tested. The infused cells persisted in time in the hematopoietic and post-injection perfused organs with a follow-up of 3 months. Conclusions: Our findings describe a novel donor-derived non-viral CAR approach characterized by efficient cell transfection, expansion and functionality that could be used as valid and sustainable alternative to patient-derived viral approach with the aim to increase the cure rate of children and adults with leukemia. This study provides the proof-of-concept for designing phase I/II study for relapsing and refractory ALL post Hematopoietic Stem Cell Transplantation. Disclosures Cooper: Ziopharm Oncology: Employment, Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership; City of Hope: Patents & Royalties; Targazyme, Inc.,: Equity Ownership; Immatics: Equity Ownership; Sangamo BioSciences: Patents & Royalties; MD Anderson Cancer Center: Employment; Miltenyi Biotec: Honoraria. Biondi:Cellgene: Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; BMS: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Blinatumomab Is Well Tolerated Maintenance Therapy Following Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-125931 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1298-1298 ◽

Cited By ~ 4

Author(s):

Partow Kebriaei ◽

Pinaki P Banerjee ◽

Christina Ganesh ◽

Mecit Kaplan ◽

Vandana Nandivada ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Checkpoint Inhibitors ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Active Disease

Background: Patients with high-risk or multiply relapsed B-lineage acute lymphoblastic leukemia (ALL) have a very high rate of relapse, even after allogeneic hematopoietic cell transplantation (HCT). In an effort to reduce the risk for relapse, we investigated the role of blinatumomab (Blin), a bi-specific T cell immunotherapy targeting CD19, as maintenance therapy following allogeneic HCT for adult patients with advanced B ALL. We rationalized that this is an ideal agent with little cytotoxicity, and the potential to provide immune protection against disease relapse during the first year post HCT when graft versus leukemia (GVL) is still maturing. Methods: Adult patients with B-ALL deemed high risk for relapse defined as disease stage beyond CR1, any active disease including MRD, or presence of high risk molecular mutations or karyotype at time of HCT, or patients with evidence of MRD immediately following HCT, were eligible for study enrollment; prior Blin treatment was allowed. Patients with active disease defined as >5% malignant blasts or active GVHD requiring steroid therapy post HCT were excluded. Patients were scheduled to receive 4 cycles of Blin as a continuous intravenous infusion at the dose of 28 microgram/24 hours over 4 weeks, with the first cycle to be administered within the first 3 months post HCT after count recovery; the subsequent cycles were administered at 6, 9, and 12 months following HCT (day of hematopoietic progenitor cell infusion). Dose escalation for cycle 1 and hospitalization for observation during cycles 1 and 2 followed standard FDA issued guidelines. Results: 14 patients enrolled to date with 12 patients treated with median age 30 years (range, 21-65 years); two patients did not proceed with treatment due to graft versus host disease (GVHD). Patient characteristics and outcomes are listed in Table 1. The median days to start of therapy post HCT was 84 (range, 38-105 days). The treatment was well tolerated with no reported cytokine release syndrome, GVHD, graft failure, or grade 5 adverse events (AE). A cumulative 26 cycles of Blin were administered with 7 Blin-related grade 3 or 4 AEs reported (leukopenia n=4, transaminitis n=2, rash n=1). Grade 2 neurotoxicity manifesting as confusion and dysphagia requiring temporary suspension of therapy and short course steroids noted in 1 patient. Median follow up was 8.5 months post HCT (range 2-35 months). All 4 patients who were MRD positive prior to start of Blin have progressed and 2 have died. None of the 8 patients who were MRD negative post transplant has relapsed. We performed multiparametric flow cytometry studies on serial peripheral blood patient samples collected prospectively at multiple time points to measure T cell subsets, T-cell function and cell surface expression of various checkpoint inhibitors including PD1, TIGIT, Tim3, 2B4 and CD160. Samples were studied on an X-20 Fortessa, and the data analyzed using Kaluza software. Interestingly, the 4 patients who progressed on Blin maintenance had lower CD8 to CD4 ratio compared to non-progressors (17:60 vs. 46:42) (Figure 1). Furthermore, compared to healthy controls, we observed higher levels of checkpoint molecules as multiple checkpoints per cell. PD1 and TIGIT upregulation and co-expression were more common in progressing patients compared to non-progressors (Figure 2). Conclusion: We observed that Blin maintenance following allogeneic HCT for B ALL is well tolerated. More patients need to be treated to confirm the efficacy of this approach. This approach is encouraging for high risk ALL patients who are MRD negative post transplant. Strategies to increase CD8 levels and blockade against checkpoint inhibitors may overcome resistance to therapy. Disclosures Kebriaei: Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Jabbour:Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Johnson and Johnson: Consultancy; Actinium: Consultancy.

Download Full-text

Comorbidities Reduce Response to Induction Treatment and Survival in Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-130160 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2587-2587 ◽

Cited By ~ 1

Author(s):

Ilaria Tanasi ◽

Veronica Tagliaferri ◽

Cristina Tecchio ◽

Fiorenza Aprili ◽

Giovanna De Matteis ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Board Of Directors ◽

Prognostic Value ◽

Lymphoblastic Leukemia ◽

Age Group ◽

Cell Precursor ◽

Advisory Committees ◽

Risk Class ◽

Pre Treatment

Background. Comorbidities have a well-established prognostic value in the majority of hematologic neoplasms. However, the impact of comorbidities on adult patients with acute lymphoblastic leukemia (ALL) has been poorly investigated to date. Aims. In this retrospective study of a monocentric cohort of 112 adults with Philadelphia-negative (Ph-neg) ALL consecutively diagnosed between 1990 and 2018 we aimed to assess the association between comorbidities at diagnosis and remission rate, the frequency and severity of adverse events (AE) during frontline treatment, and long-term outcome. Patients and methods. Patients were included, regardless of age, if treated within or according to clinical protocols aimed at curing. Patients initially treated with low-intensity/palliative care were not considered. Ph-positive patients were excluded, as their treatment modalities markedly changed over years due to the availability of tyrosine kinase inhibitors. Patients were defined as high risk if one or more of the following features were present: WBC >30x109/L for B-cell precursor (BCP) or >100x109/L for T-cell precursor (TCP), pro-B, early or mature T ALL phenotype, high risk cytogenetics (according to the ESMO 2016 guidelines), or central nervous system involvement. Comorbidities recorded at diagnosis were classified according to the Charlson Comorbidity Index (CCI). Classification and grading of AE was performed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Responses were defined according to the ESMO 2016 guidelines. Minimal residual disease (MRD) was assessed by 6- or 8-colour flow cytometry with a 10-4 sensitivity. Variables tested for association with complete remission (CR) and MRD-negative status were: age group (stratified into quartiles), gender, phenotype (BCP or TCP), WBC, karyotype, risk class, and CCI score. Event-free survival (EFS) was calculated from the first CR to relapse or death. Overall survival (OS) was calculated from diagnosis until death. EFS and OS were estimated using the Kaplan-Meier method. Results. Median age at diagnosis was 43 years (range 14-75). BCP and TCP were 78% and 22%, respectively. Overall, 51 patients (46%) were considered as standard risk, 46 (41%) as high risk, and 15 (13%) were unclassifiable due to the lack of cytogenetics. CCI score distribution was as follows: 0 (n=66; 59%), 1 (n=18; 16%), 2 (n=9; 8%), and ≥3 (n=19; 17%). CR after induction therapy was obtained by 95/112 patients (85%). CCI was the only variable significantly associated to CR achievement (0-1 vs ≥2: 91% vs 68%; p=0.012). MRD status at the end of induction was evaluable in 64 out of 95 patients in CR and was negative in 28 (44%). No pretreatment variable predicted for the achievement of MRD complete response. Eight patients (7%) died before the first response evaluation; early death rate was significantly higher in patients with CCI ≥2 than in patients with CCI 0-1 (21% vs 2%; p=0.003). Conversely no differences in AE frequency and severity were observed according to CCI (p=0.847) or age group (p=0.881). After a median follow-up of 35 months, 46 patients (41%) were alive. OS was significantly longer in patients with CCI 0-1 as compared to CCI ≥2 (median 87 months, 95%CI: 31 to not reached vs 13 months, 95%CI: 5-36; p<0.001). Notably, pre-treatment risk stratification lost prognostic value in predicting OS and EFS in CCI 0-1 patients, while in CCI ≥2 patients retained its significance (Figure). Overall, 58 patients (52%) were primary refractory or relapsed. Relapse rate was similar according to age groups, phenotype, risk class, and CCI score. CR rate after salvage treatment (CR2) was higher in younger patients (≤43 vs >43 years: 81% vs 44%; p=0.014) and tended to be higher in patients treated with blinatumomab or inotuzumab rather than with standard chemotherapy (82% vs 55%, p=0.17). While there were no differences in CR2 according to CCI group, median survival after first relapse was 12.1 months (95%CI: 7.83-15.24) for CCI 0-1 vs 6.92 months (95%CI: 2.49-12.59) for CCI≥2(p=0.021). Conclusions. Comorbidities have a significant prognostic impact in intensively-treated adults with Ph-neg ALL. Patients with low comorbidities (CCI 0-1) had superior CR rates and less incidence of toxic death after induction, and pre-treatment high risk features did not have a detrimental impact in this group. Figure Disclosures Krampera: Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Bonifacio:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria.

Download Full-text

High Frequency and Poor Outcome of Ph-like Acute Lymphoblastic Leukemia in Adults

Blood ◽

10.1182/blood.v126.23.2618.2618 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2618-2618 ◽

Cited By ~ 4

Author(s):

Kathryn G. Roberts ◽

Debbie Payne-Turner ◽

Kelly McCastlain ◽

Zhaohui Gu ◽

Ilaria Iacobucci ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitors ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Rna Seq ◽

Advisory Committees ◽

Leukemia Group

Abstract Introduction: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. The prevalence of Ph-like ALL increases with age and accounts for over 25% of patients with B-progenitor ALL between the ages of 21-39 years. However, the frequency, outcome and genetic basis of Ph-like ALL in adults over the age of 39 is unknown. The goals of this study were to define the prevalence of Ph-like ALL across the adult age spectrum, assess response to conventional chemotherapy, and define the genetic landscape of Ph-like ALL in adults. Methods: We studied 692 adults with B-ALL obtained from multiple groups including the Alliance (Cancer and Leukemia Group B), ECOG-ACRIN, MD Anderson Cancer Center, Northern Italy Leukemia Group, Princess Margaret Cancer Centre, SWOG and UK NCRI. The cohort was divided into three age groups: 21-39 years (median age 28±6 years, n=333), 40-59 years (median age 47±6 years, n=246) and 60-79 years (median age 67±7 years, n=101). RNA samples were screened using a Taqman low density array (LDA) card that identifies patients with the Ph-like ALL gene signature, in addition to BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, MLL-rearranged and ERG altered ALL. Cytogenetic data was also available for the majority of cases. High expression of CRLF2 was determined by the LDA card, and CRLF2 rearrangement (IGH-CRLF2 or P2RY8-CFRLF2) was confirmed using fluorescence in situ hybridization. Total stranded transcriptome sequencing (RNA-seq) using the Illumina platform was performed on 99 cases and sequencing data was analyzed using FusionCatcher and CICERO. Results: The overall prevalence of ETV6-RUNX1, TCF3-PBX1 and ERG ALL in adults was low (1.3%, 3.6% and 3.1%, respectively), whilst the prevalence of patients with BCR-ABL1, Ph-like and MLL-rearranged ALL was 20%, 24% and 14%, respectively. Ph-like ALL comprised 26% of patients between 21-39 years of age and 20% of patients aged 40-79. Patients with BCR-ABL1 and Ph-like ALL presented with higher white blood counts at diagnosis compared to non Ph-like ALL patients (57.7 and 65.0 vs 28.5 x 109/L). Patients with Ph-like ALL were also more likely to be male compared to patients with BCR-ABL1 and non Ph-like ALL, with 66% vs 50% and 50%, respectively(p<0.0001; Fisher's exact test). The outcome of patients with Ph-like ALL was markedly inferior to other ALL subtypes (excluding patients with BCR-ABL1 and MLL rearrangement), with 5-year event free survival rates of 23.2±5.4 vs 51.2±4.7 (p<0.0001) and overall survival rates of 26.5±5.5 vs 56.3±4.6 (p<0.0001). We then characterized the kinase-activating alterations in adult Ph-like ALL. Similar to previous reports, 99 of 186 (53%) of patients with Ph-like ALL had high expression of CRLF2. Of 75 cases tested, 56 harbored IGH-CRLF2 and 19 P2RY8-CRLF2. Of the 87 Ph-like ALL patients with low CRLF2 expression, we identified rearrangements involving tyrosine kinase or cytokine receptor genes in 45 patients: ABL1 (n=5 patients), ABL2 (n=7), CSF1R (n=1), EPOR (n=8), JAK2 (n=18), PDGFRA (n=1), PDGFRB (n=2), PTK2B (n=1) and TYK2 (n=2). Nine of these 45 fusions have not previously been identified in Ph-like ALL including MEF2D-CSF1R, HMBOX1-JAK2, SMU1-JAK2, SNX29-JAK2 (n=2 patients), ZNF340-JAK2, FIP1L1-PDGFRA, TMEM2-PTK2B and ZNF340-TYK2. Exome sequencing is being performed on cases that do not harbor a kinase fusion by RNA-seq analysis. Conclusion: Ph-like ALL is common across the age spectrum of adult ALL, comprising over 20% of patients from ages 21-79 years, with a notably high prevalence of fusions involving JAK2. These findings warrant the development of clinical trials that assess the efficacy of tyrosine kinase inhibitors to improve the treatment outcome, similar to those that are being established for pediatric ALL. Disclosures Fielding: Amgen: Consultancy, Honoraria. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Mullighan:Amgen: Honoraria; Incyte: Consultancy.

Download Full-text

Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽

10.1182/blood-2021-147639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 797-797

Author(s):

Talha Badar ◽

Mark R. Litzow ◽

Rory M. Shallis ◽

Jan Philipp Bewersdorf ◽

Antoine Saliba ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Advisory Board ◽

Novel Therapies ◽

Advisory Committees ◽

Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Download Full-text

Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

Download Full-text