Post ASH speaker abstracts 2018
Abstracts to support presentations from Debby Yallop, Tobias Menne and Caroline Furness
Acute Lymphoblastic Leukemia/Lymphoma in the Elderly: The Mayo Clinic Experience
Result Type: Paper
Presenter: Kevin Miller
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster I
Kevin C. Miller, BS1, Aref Al-Kali, MD1, William J. Hogan, MBBCh1, Michelle A. Elliott, MD1, Kebede H. Begna, MD1, Naseema Gangat, MBBS1, Mrinal M. Patnaik, MD, MBBS1, Lisa Sproat, MD, MSW2, James M. Foran, MD3, Mark R. Litzow, MD1 and Hassan B. Alkhateeb, MD1*
1Division of Hematology, Mayo Clinic, Rochester, MN
2Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ
3Division of Hematology/Oncology, Mayo Clinic Florida, Jacksonville, FL
Introduction: Elderly patients (≥60 years of age) with acute lymphoblastic leukemia/lymphoma (ALL) have a poor prognosis compared to younger adults. This is thought to be due to comorbidities, treatment-related mortality, adverse disease biology, low rates of complete remission (CR), high risk of relapse, and ineligibility for allogeneic hematopoietic stem cell transplantation (HSCT). Since it is unclear how all these factors play into the poor prognosis of elderly ALL, we sought to describe the presentation, treatment outcomes, and predictors of survival at our multi-site institution.
After IRB approval, we performed a retrospective study of patients (pts) ≥60 years old diagnosed with ALL from 2000-2017 at Mayo Clinic Rochester, Arizona, and Florida. Statistical analysis was performed using JMP 10.0 software.
Results: Baseline characteristics We identified 124 consecutive pts with elderly ALL. The median age at time of diagnosis was 67 (60-86) and 74 (60%) were male. Median time of follow-up was 15.6 months (range 0.2-132). 77 (62%) were deceased at the time of last follow-up: 37 deaths related to disease, 24 due to infection or other causes, and 16 unknown.
At time of diagnosis, 108 (87%) pts had B-cell ALL, of which 40 (37%) were Philadelphia chromosome positive (Ph+). Only 16 (13%) pts had T-cell ALL. Overall, 24 (19%) had an ECOG performance status (PS) ≥2, and 22 (18%) had a Charlson Comorbidity Index (CCI) ≥3. Further baseline characteristics including cytogenetics and FISH studies are detailed in Table 1.
Treatment and Outcomes :102/124 (82%) elected to undergo induction. Of these, 19 (19%) had an up-front dose reduction. The most common induction regimen was Hyper-CVAD, which was used in 62 (61%), concomitantly with rituximab in 21, and tyrosine kinase inhibitors (TKIs) in 17. Asparaginase-based chemotherapy was used in 27 (26%) pts. The remaining 13 (13%) received other regimens. Complete remission (CR/CRi) was achieved in 92 (90%) pts. 11 (11%) had primary refractory disease, of which 7 were refractory to multiple lines of therapy. Median time to CR was 30 days (range 10-352), requiring a median of 1 cycle (range 1-8) of chemotherapy. 5 (5%) died within 60 days of starting treatment, and by Day 100 there were a total of 10 (10%) deaths; these were related to subdural hematoma (3), infection (2), treatment discontinuation (1), and unknown causes (4).
Palliative therapy up-front was chosen in 22/124 (18%), which included chemotherapy (e.g. vincristine and steroids), TKIs or hospice. 7 (32%) of these pts achieved CR within a median time of 54 days (range 23-128). The median overall survival (mOS) in the palliative group was 5.7 months (interquartile range [IQR] 1.7-12.1).
Relapse occurred in 42 (42%) pts within a median time of 9.9 months (range 0-71.5); 10 (24%) of these pts had an extramedullary relapse, including 3 with CNS leukemia. 31 (74%) were treated with salvage chemotherapy, while 10 (21%) chose palliative care. Median survival from the time of relapse was 5.7 months (IQR 2-18).
Overall, 34 (27%) underwent HSCT: allogeneic HSCT in 33, and autologous HSCT in 1. Of these, 29 (85%) were in CR1, and 5 (15%) were in CR2. The median age at time of HSCT was 65 (range 60-73). 3 (9%) died within 100 days of HSCT, due to early relapse (2; both were in CR1) and acute graft-versus-host disease (1). 11 (31%) relapsed after HSCT, within a median time of 9 months (range 1-30). Median survival after HSCT was 27.4 months (IQR 0.7-not reached [NR]).
Predictors of Survival:Elderly ALL across the three Mayo Clinic campuses had a mOS of 20.8 months (IQR 9.4-87.3), which was inferior compared to our adult ALL (age 18-59) cohort in Rochester, who had a mOS of 51.1 months (IQR 15.3-NR) (Figure 1). In univariate analysis, which included the presenting variables shown in Table 1, only age, ECOG PS, CCI, and LDH negatively influenced survival (P<0.05). These factors continued to significantly predict for poor survival in multivariate analysis (Table 2). Conclusions: ALL has worse outcomes in elderly pts compared to younger adults. However, treatment-related mortality was relatively low in our cohort even though the majority of pts underwent induction. Interestingly, we found that survival was influenced by age, ECOG PS, CCI, and LDH at time of diagnosis, rather than by cytogenetics or other biological features. Our data needs to be verified in a larger cohort. Nevertheless, this could be the first step toward a prognostic model in elderly ALL.
A Phase I/II Study of Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) for Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia
Result Type: Paper
Presenter: Nicholas Short
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster II
Nicholas J Short, MD1, Hagop M. Kantarjian, MD1, Farhad Ravandi, MBBS2, Xuelin Huang, PhD3*, Nitin Jain, MD4, Naval Daver, MD1, Deborah A Thomas, MD1, Naveen Pemmaraju, MD1, Rita Khouri5*, Joseph David Khoury, MD6, Jeffrey L. Jorgensen, MD, PhD7*, Yesid Alvarado, MD1, Koji Sasaki, MD1, Marina Konopleva, MD, PhD8, Guillermo Garcia-Manero, MD1, Tapan Kadia, MD9, Jorge E. Cortes, MD1, Christopher B Benton, MD9, Gautam Borthakur, MD1, Jan A. Burger, MD, PhD 10, Maro Ohanian, DO1*, William G Wierda, MD, PhD1, Zeev Estrov, MD1, Steven Kornblau, MD1, Courtney D. DiNardo, MD, MSc1, Alessandra Ferrajoli, MD1, Jovitta Jacob, RN5*, Ameena Manzoor5*, Rebecca Garris, Msc1*, Susan M. O’Brien, MD11 and Elias J. Jabbour, MD 1
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
3The University of Texas, MD Anderson, Houston, TX
4Department of Leukemia, MD Anderson Cancer Center, Houston, TX
5The University of Texas MD Anderson Cancer Center, Houston, TX
6Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
7Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
8Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
9Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
10The University of Texas, MD Anderson Cancer Center, Houston, TX
11Chao Family Comprehensive Cancer Center at UC Irvine Medical Center, Orange, CA
Background: Elderly patients (pts) with acute lymphocytic leukemia (ALL) have a poor outcome, in part due to toxicity with intensive chemotherapy. Inotuzumab ozogamicin (INO), a CD22 monoclonal antibody bound to a toxin, calicheamicin, has single-agent activity in relapsed/refractory ALL. The addition of INO to low-intensity chemotherapy might improve outcomes in older pts with newly diagnosed ALL.
Methods: Pts ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles, given every 4 weeks as permitted by count recovery. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. The first 6 pts received 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles; pt 7 onwards received the phase II dose of 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. After the observation of veno-occlusive disease (VOD), the protocol was amended in 9/2015 to use lower doses of INO. After this amendment (pt 35+), INO was given at 1.3 mg/m2 for cycle 1 followed by 1 mg/m2 for subsequent cycles. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years.
Results: 52 pts have been treated, 4 of whom were in CR at enrollment. Median age was 68 years (range, 60-81 years) and median CD22 expression was 97% (range, 27-100%). 31 pts (60%) were CD20+ and received rituximab. Among 48 pts evaluable for morphologic response, 47 (98%) response (CR, n=39; CRp, n=7; CRi, n=1). Only 1 pt did not respond. MRD negativity by 6-color flow cytometry was achieved in 36/46 pts (78%) after 1 cycle and 49/51 pts (96%) overall. Median times to platelet and ANC recovery in cycle 1 were 23 and 16 days, respectively, and for subsequent cycles were 22 and 17 days, respectively. Prolonged thrombocytopenia (>6 weeks) occurred in 42 pts (81%). The 30-day and 60-day mortality rates were 0% and 4%, respectively. Infections occurred in 27 pts (52%) during induction and in 36 during (69%) during consolidation; 28 pts (54%) had grade 3-4 hyperglycemia, 16 (31%) had grade 3-4 hypokalemia; 10 (19%) had grade 3-4 transaminase elevation, 9 (17%) had grade 3-4 hyperbilirubinemia, and 7 (13%) had grade 3-4 hemorrhage. 4 pts (8%) developed VOD, 1 after subsequent allogeneic SCT. Two of the VOD cases were severe and resulted in death. Among 51 responders, 6 (12%) relapsed, 3 (6%) underwent allogeneic SCT in CR1, 29 (57%) remain on treatment or have completed maintenance, and 12 (24%) died in CR/CRp. Causes of death for pts in CR/CRp included: sepsis (n=5), VOD (n=1), gunshot wound (n=1), dementia and deconditioning (n=1), end stage renal disease (n=1) and unknown causes (n=3). With a median follow-up of 29 months (range, 1-66 months), 35 pts (67%) were alive, 30 of whom (58%) were in CR and MRD negative status. The 3-year continued remission and OS rates were 74% and 56%, respectively (Figure 1). Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab (n=78), mini-hyper-CVD + INO resulted in significantly higher 3-year OS (54% vs 32%; P=0.004).
Conclusions: Mini-hyper-CVD plus INO is safe and effective in elderly pts with newly diagnosed Ph-negative ALL and appears to improve outcomes compared to hyper-CVAD. A prospective study of this regimen is warranted.
First Report of the Gimema LAL1811 Phase II Prospective Study of the Combination of Steroids with Ponatinib As Frontline Therapy of Elderly or Unfit Patients with PhiladelphiaChromosome-Positive Acute Lymphoblastic Leukemia
Number : 99
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Advances in the Treatment of ALL
Giovanni Martinelli1, Alfonso Piciocchi2*, Cristina Papayannidis, MD, PhD3, Stefania Paolini, MD, PhD1*, Valentina Robustelli, PhD4*, Simona Soverini, PhD1,5, Carolina Terragna1*, Roberto M Lemoli, MD6, Fabio Guolo, MD6*, Paolo Di Bartolomeo, M.D7, Monia Lunghi8*, Paolo de Fabritiis9*, Anna Candoni, MD10*, Carmine Selleri, MD11, Federico Simonetti, MD12*, Monica Bocchia, MD13*, Antonella Vitale14*, Luca Frison15*, Alessandra Tedeschi16*, Antonio Cuneo, MD17*, Massimiliano Bonifacio, MD18*, Brunangelo Falini, MD19, Stefano D’Ardia20*, Silvia Trappolini21*, Patrizia Tosi, MD22*, Piero Galieni, MD23*, Francesco Fabbiano, MD24, Maria Chiara Abbenante1*, Giovanni Marconi25, Chiara Sartor26*, Michele Cavo, MD27*, Robin Foà, MD28*, Paola Fazi29*, Marco Vignetti30* and Michele Baccarani, MD1
1Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy
2Italian Group for Adult Hematologic Diseases (GIMEMA), Data Center and Health Outcomes Research Unit, Rome, Italy
3Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Bologna, ITA
4Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
5Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Castel Maggiore, Bologna, Italy
6Department of Internal Medicine (DiMI), Policlinico San Martino, IRCCS per l’Oncologia, Clinic of Hematology, Genova, Italy
7Department of Hematology, Transfusion Medicine and Biotecnology, ” Spirito Santo ” Civic Hospital, Pescara, Italy
8AOU “Maggiore della Carità”, SCDU Ematologia, Novara, ITA
9U.O.C. Ematologia, Ospedale S.Eugenio, Roma, Italy
10Division of Hematology and Bone Marrow Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
11SALERNO UOC di Ematologia e Trapianti di Cellule Staminali Emopoietiche, AOU San Giovanni di Dio e Ruggi D’Aragona, Salerno, ITA
12UOS Ematologia – Ospedale Versilia, Lido Di Camaiore, ITA
13Azienda Ospedaliera Universitaria, University of Siena, Siena, Italy
14Department of Cellular Biotechnologies and Hematology, University La Sapienza, Rome, Italy
15Divisione di Ematologia e Immunologia Clinica Dipartimento di Medicina, Padova, Italy
16Ematologia, Azienda Ospedaliera Ospedale Niguarda Ca’ Granda, Milano, ITA
17Hematology, St. Anna University Hospital, Ferrara, Italy
18Department of Medicine, Section of Haematology, University of Verona, Verona, Italy
19Ospedale S.Maria Della Misercordia, Perugia, ITA
20Ematologia, Ospedaliera S. Giovanni Battista Molinette, Torino, Israel
21SOD Clinica Ematologica, Azienda Ospedaliero – Universitaria Ospedali Riuniti Umberto I, Ancona, Italy
22Hematology Unit, Infermi Hospital Rimini, Rimini, Italy
23U.O.C. Ematologia e Terapia Cellulare, Ospedale Mazzoni, Ascoli Piceno, Italy
24Ospedali Riuniti Villa Sofia-Cervello, Palermo, ITA
25Institute of Hematology “L. e A. Seràgnoli”, Istituto Seragnoli, Bologna, Italy
26Institute of Hematology “L. & A. Seràgnoli”, University of Bologna, Bologna, ITA
27Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
28Hematology Unit, Sapienza University of Rome, Rome, Italy
29Fondazione GIMEMA Onlus, Roma, Italy
30GIMEMA Data Centre, Rome, ITA
Background: The incorporation of tyrosine kinase inhibitors (TKIs) in treatment schemes of Ph+ ALL has remarkably improved survival. In adult patients with Ph+ ALL, ponatinib in combination with chemotherapy showed a 3-year event-free survival rate of 69%, a 3-year overall survival (OS) of 83%, and a higher rate of response when compared with dasatinib plus chemotherapy. However, in unfit or elderly ALL patients, TKIs combined with chemotherapy are associations with higher toxicity. Therefore, we examined the efficacy and safety of steroids plus ponatinib alone for the treatment of elderly or unfit patients with Ph+ ALL in a multi-center Phase II prospective clinical Italian trial, GIMEMA LAL1811 (EudraCT number 2012-002761-35).
Methods: From March 2014 to December 2016, we enrolled 44 patients with untreated Ph+ ALL, ≥ 60 years or unfit (i.e. for intensive chemotherapy and stem cell transplantation). Two out of 44 patients were not elegible for the study.
Patients received oral administration of 45 mg/day of ponatinib for 8 consecutive courses of 6 weeks (w). Steroids were administered from day -14 to day 29 during course 1. Intrathecal therapy with methotrexate, cytarabine and dexametasone was performed every 28 days for central nervous system (CNS) disease prophylaxis. In patients with CNS disease at diagnosis, intrathecal therapy was administered twice a week until complete remission. Dose reduction of ponatinib was allowed for adverse events. Patient samples were obtained at diagnosis and at every course, BCR-ABL mutational analisys and BCR-ABL/ABL ratio by quantitative real time PCR was performed. Complete molecular response (CMR) was defined as BCR-ABL/ABL ratio below 0.01 or undetectable, and with a sensitivity of at least 30,000 molecules of ABL.
Results: Forty-two patients were eligible for the study. Median age was 68 years (range 27-85). Nine out of 42 patients were <60 years and were considered unfit. Twenty-six out of 42 patients had the p190 fusion transcript, 4/42 had p210, 12/42 had p190/p210. Steroid pretreatment was administered to 39; 14/39 patients had a reduction in circulating blasts of 75% or more before starting ponatinib. Primary endpoint (Complete hematological response (CHR) at 24w in 75% of patients) was prematurely reached. CHR was obtained in 40/42 patients (95,2%) after course 1 (6w). Thirty-eight out of 42 patients (90,5%) were in CHR after 8 courses (24w); 2 patients stopped treatment after 6w for disease relapse (1) and for excessive toxicity (1). Two patients dropped out after 12w for medical decision. A CMR was detected in 11/24 patients at 24w (45.8%; 14/38 patients not evaluable). Considering a CMR test sensitivity of at least 10,000 ABL molecules and testing peripheral blood whenever a bone marrow was not obtained, 20/33 patients (60.6% 5/38 patients not evaluable) were in CMR at 24w (figure 1). The median follow-up of the enrolled patients was 11.4 months (range 6-34.5). Overall survival (OS) at 6 months and 1 year was 97.6% (C.I 95%: 93.1%-100.0%) and 87.5% (C.I. 95%: 76.5%-99,9%) respectively (figure2). At week 24, 15/42 patients still received 45 mg of ponatinib daily, only 4/42 patients permanently withdrew study drug. During the study, 75 adverse events (AE) were reported; 36 of the 75 AEs were considered related to ponatinib. Twenty-six of the 75 AEs were considered serious (SAE); 13/26 SAEs were considered related to ponatinib. A death was suspected to be related to ponatinib. We performed BCR-ABL mutational analysis in 22 patients at diagnosis, and 15 patients at 24w. T315L (abundance 100%) was detected in a patient relapsed during ponatinib therapy. We could not identify the emergency of other mutations. Conclusions: Ponatinib and steroid show a high efficacy in newly diagnosed unfit/elderly Ph+ ALL patients. Toxicities were manageable and cardiovascular AEs were limited. In the small cohort of patients relapsed in the study, relapse mechanisms were unclear; only one patient had evidence of mutations that caused resistance to ponatinib. The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway could explain the therapeutic effectiveness.
Acknowledgements. GIMEMA, ELN, AIL, AIRC, Regione-Università 2010-12, FP7 NGS-PTL, HARMONY, Fondazione del Monte BO e RA.
UKALL 2011: Randomised Trial Investigating a Short Induction Dexamethasone Schedule for Children and Young Adults with Acute Lymphoblastic Leukaemia
Result Type: Paper
Presenter: John Moppett
Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Therapy, Excluding CAR-T Cell
Nicholas John Goulden, MD, PhD, MRCPath1*, Amy A Kirkwood2*, John Moppett3*, Sujith Samarasinghe1*, Sarah Lawson, MD4*, Clare Rowntree, MD5*, Rachael Hough, MD, BMBS, FRCP, FRCPath6*, Rajbir Athwal7*, Pamela R. Kearns, PhD, FRCPC8* and Ajay Vora, MD9,10
1Great Ormond Street Hospital, London, United Kingdom
2Cancer Research UK and University College London Cancer Trials Centre, London, United Kingdom
3Bristol Children’s Hospital, Bristol, United Kingdom
4Birmingham Children’s Hospital, Birmingham, United Kingdom
5University Hospital of Wales, Cardiff, United Kingdom
6University College London Hospital, London, United Kingdom
7Cancer Research UK Clinical Trials Unit, Birmingham University, Birmingham, United Kingdom
8Birmingham University, Birmingham, United Kingdom
9University Of Sheffield, Sheffield, United Kingdom
10Department of Pediatric Haematology and Oncology, Great Ormond Street Hospital, The Children’s Hospital, Sheffield, United Kingdom
Dexamethasone is associated with a higher risk of infectious and non-infectious morbidity and mortality than prednisolone in induction therapy of children and young adults with Acute Lymphoblastic Leukaemia (ALL). We tested whether a 2 week induction dexamethasone schedule is less toxic than the standard 4 week schedule. Patients aged 1 -24 years with a new diagnosis of ALL or lymphoblastic lymphoma (excluding mature B lymphoma and ALL) in the UK and Ireland were randomly allocated to receive dexamethasone 5 mg/m2twice daily for 14 days (continuous in age <10 years and discontinuous week on/week off in age > 10 years) (Short) or 3 mg/m2 twice daily for 29 days followed by a 7 day wean (Standard). The primary end-point was a reduction in steroid related toxicity defined as any induction treatment related death, all serious adverse events (SAEs) within 8 weeks of the start of induction, and adverse events (AEs) which were classified as steroid related or contributory.
At diagnosis, patients were stratified by NCI (Standard Risk = age <10 and white cell count <50 x 109/l, High Risk = age > 10 years or white cell count >50x 109/l) and cytogenetic risk to receive one of 3 escalating intensity treatment regimens (A, B, C). NCI standard risk (SR) patients received a 3 drug induction (Regimen A) whilst high risk (HR) patients received 4 drugs including daunorubicin (Regimen B). Patients with poor risk cytogenetics were transferred to Regimen C. Minimal Residual Disease (MRD) was measured at the end of induction (day 29) and end of consolidation (week 14) using a Real Time Quantitative PCR technique with a sensitivity of 0.01%. Patients were classified as MRD low risk (day 29 <0.005%), intermediate risk (day 29 > 0.005% – 5%, week 14 <0.5%) or high risk (day 29 > 5% or week 14 >0.5%).
Between April 2012 and April 2017, 1904 eligible patients were randomly allocated to short (951) or standard dexamethasone (953) arms which were balanced for NCI risk, sex, immunophenotype and disease type (ALL or LBL). Analysis was intention to treat. Recruitment was stopped early on the recommendation of the data monitoring committee (IDMC) due to concerns about a non-significant excess of induction treatment related deaths in NCI standard risk patients with the short schedule (Short =9/503 (1.8%), Standard =4/506 (0.8%) (p =16) which led to a futility analysis demonstrating that there was <10% power of showing a significant improvement with short dexamethasone. At a median follow-up of 22.8 months, there is no statistically significant difference in steroid related toxicity, MRD response or relapse free survival between arms (Table).
A shorter induction schedule of dexamethasone 10 mg/m2/day x 2 weeks is no less toxic than 6 mg/m2/day x 4 weeks in children and young adults with ALL.
Maintenance Therapy with Blinatumomab in Adults with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL): Overall Survival in Adults Enrolled in a Phase 3 Open-Label Trial
Result Type: Paper
Presenter: Alessandro Rambaldi
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster II
Alessandro Rambaldi, MD, Prof1,2, Françoise Rigal-Huguet, MD3*, Pavel Zak4*, Paul Cannell, MD5, Kun Nie, PhD6*, Zachary F. Zimmerman, MD, PhD7 and Max S. Topp, MD8
1Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
2Università Statale di Milano, Milano, Italy
3Centre Hospitalier Universitaire (CHU) de Toulouse, Toulouse, France
4Fakultni nemocnice Hradec Králové, Hradec Kralove, CZE
5Royal Perth Hospital, Perth, Australia
6Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA
7Global Development, Amgen Inc., Thousand Oaks, CA
8Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
Introduction: Hematopoietic stem cell transplant (HSCT) after induction/consolidation therapy with standard chemotherapy or targeted therapies, such as blinatumomab or inotuzumab (Kantarjian H, et al. N Engl J Med. 2016;375:740-53), is considered the only treatment option with curative intent for patients with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (r/r Ph- B-precursor ALL). A recent randomized phase 3 study of blinatumomab, a bispecific T-cell engager antibody construct, in patients with r/r Ph- B-precursor ALL, included a maintenance treatment phase to allow patients in hematologic remission to continue blinatumomab (Kantarjian H, et al. N Engl J Med. 2017;376:836-847). In this exploratory analysis, we examined overall survival (OS) for patients who received blinatumomab maintenance therapy and compared outcomes with data pooled from patients who did not receive maintenance therapy in the phase 3 and phase 2 (Topp MS, et al. Lancet Oncol. 2015;16:57‑66) blinatumomab trials.
Methods: Adult patients (≥18 years) in this phase 3 trial were randomized to either blinatumomab or standard of care (SOC) chemotherapy. Patients randomized to blinatumomab received this treatment by continuous intravenous infusion (4 weeks on, 2 weeks off; 9 μg/day on days 1–7 of Cycle 1 and 28 μg/day thereafter) during induction and consolidation cycles. Patients could receive HSCT at any time after cycle 1. Patients who received blinatumomab, and had bone marrow blasts <5% after two induction and three consolidation cycles of blinatumomab, were eligible for blinatumomab maintenance, administered for up to an additional 12 months (4 weeks on therapy, 8 weeks off). Maintenance therapy was discontinued in case of transition to HSCT, investigator discretion, toxicity, relapse, or use of protocol-excluded medications. The cumulative probability of OS over time was estimated using the Simon-Makuch method and the effect of maintenance was analyzed using the Mantel-Byar method. OS was measured from the start of maintenance therapy for patients who were in remission until the start of Cycle 6 (for those who received maintenance) or at Day 211 (landmark date for those who did not receive maintenance). Data from the phase 3 study and an earlier phase 2 study in which maintenance was not offered were pooled to increase the sample size for this OS analysis. Results: As of the primary analysis cutoff, 119 of 271 (43.9%) patients receiving blinatumomab achieved a best response of CR/CRh/CRi within two treatment cycles, and 27 patients continued to the blinatumomab maintenance phase. Three patients completed the maintenance phase, 4 transitioned to HSCT, and one discontinued due to adverse events (AE). Twenty-one (77.8%) patients had a best response of CR during maintenance, 1 (3.7%) patient each had CRh or blast free hypoplastic or aplastic bone marrow, and 2 (7.4%) patients each had hematologic relapse or were not evaluable. The Mantel-Byar analysis demonstrated a relative OR for OS of 0.59 (95% CI, 0.20 – 1.73) P = 0.33 comparing maintenance vs. no maintenance (Figure), representing a 41% reduction in the risk of death associated with maintenance therapy, though not statistically significant. Among patients receiving blinatumomab who entered the maintenance phase, the incidence of adverse events of interest generally was less compared with the incidence during the induction or consolidation phases (Table).
Conclusions: In r/r ALL patients who achieved a hematologic response following blinatumomab induction/consolidation, high response rates with blinatumomab maintenance therapy (beyond cycle 5) were observed, with longer OS compared with patients receiving no maintenance. During maintenance with blinatumomab, no new safety concerns were identified. A lower incidence of adverse events of interest was seen during the maintenance phase, compared with events recorded during the induction/consolidation phases of this, and prior blinatumomab studies.
Research supported by Amgen Inc.
Inotuzumab Ozogamicin (InO) Vs Standard of Care (SC) in Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL): Long-Term Results of the Phase 3 INO-VATE Study
Hagop M. Kantarjian, MD1, Daniel J. DeAngelo, MD, PhD2, Matthias Stelljes, MD3, Michaela Liedtke, MD4*, Wendy Stock, MD5, Nicola Goekbuget, MD6, Susan M. O’Brien, MD7, Elias J. Jabbour, MD 8, Tao Wang, PhD9*, Jane Liang White, ScD10*, Barbara Sleight9*, Erik Vandendries, MD, PhD11* and Anjali S. Advani, MD12
1University of Texas MD Anderson Cancer Center, Houston, TX
2Dana-Farber Cancer Institute, Boston, MA
3Universitätsklinikum Münster, Münster, Germany
4Stanford Cancer Institute, Stanford, CA
5University of Chicago, Chicago, IL
6Dept. of Medicine II, Goethe University Hospital, Frankfurt, Germany
7Irvine Medical Center, University of California, Orange, CA
8Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
9Pfizer, Groton, CT
10Pfizer, Inc, Groton, CT
11Pfizer Inc, New York, NY
12Cleveland Clinic, Cleveland, OH
Introduction: InO, a humanized anti-CD22 antibody conjugated to calicheamicin, produced superior response rates vs SC for R/R ALL in INO-VATE (complete remission rates [CR]/CR with incomplete hematologic recovery [CRi], 80.7% [95% CI, 72.1–87.7] vs 29.4% [21.0–38.8]; 2-sided P<0.001; Kantarjian H. NEJM2016). Here we report the long-term efficacy and safety of InO vs SC (intensive chemotherapy) in patients with R/R ALL.
Methods: In INO-VATE (NCT01564784), adults with CD22-positive ALL due to receive salvage 1 or salvage 2 treatment were randomized 1:1 to InO (n=164; starting dose 1.8 mg/m2/cycle [0.8 mg/m2 on d 1; 0.5 mg/m2on d 8 and 15 of a 21–28 d cycle for ≤6 cycles]) or SC (n=162; either fludarabine/high-dose (HD) cytarabine/granulocyte colony-stimulating factor, HD Ara-C plus mitoxantrone, or HD Ara-C). Outcomes presented herein include overall survival (OS), progression-free survival (PFS), predictors of OS determined by stepwise Cox regression modeling, and safety. Following treatment discontinuation, patients were followed for survival for up to 5 years or 2 years from randomization of the last patient, whichever occurred first.
Results: As of January 5, 2017, median OS follow-up for all randomized patients was 6.6 (range, 0.0‒49.7) mo. OS was longer for InO vs SC with an estimated hazard ratio (HR; InO vs SC) of 0.751 (97.5% CI, 0.568–0.993) and a 1-sided stratified log-rank P=0.0105, indicating a 24.9% reduction in the risk of death in favor of InO (Figure 1). Median OS was 7.7 (95% CI, 6.0–9.2) vs 6.2 (4.7–8.3) mo in InO vs SC pts. At 12 mo, the estimated probability of OS was 33.6% (95% CI, 26.4–40.9) vs 32.0% (24.7–39.6) in InO vs SC patients, respectively, and 22.8% (16.7–29.6) vs 10.0% (5.7–15.5) at 24 mo. InO demonstrated significant improvement in PFS vs SC (HR, 0.450 [97.5% CI, 0.336-0.602]; 1-sided stratified log-rank P˂0.0001; median PFS, 5.0 [95% CI, 3.9–5.8] vs 1.7 [1.4–2.1] mo). At 12 mo, the estimated probability of PFS was 18.2% (95% CI, 12.3–24.9) vs 4.9% (2.0–9.8) in InO vs SC patients, respectively and 13.2% (8.0–19.8) vs not estimable at 24 mo. In multivariate analysis, longer duration of first remission (continuous; P=0.0157), receiving follow-up hematopoietic stem cell transplant (HSCT; P˂0.0001), minimal residual disease negativity (best status; P=0.0085), and attaining CR/CRi (P=0.0214) were associated with lower risk of death in InO patients. In the safety population comprising patients who received ≥1 dose of study drug, 79 (48.2%) InO patients proceeded to HSCT with or without intervening induction or salvage therapy vs 35 (24.5%) SC patients. The most frequent grade ≥3 adverse events were hematologic, primarily cytopenias (InO, 79.9%; SC, 86.7%). Five veno-occlusive disease (VOD) cases (2 in patients with prior HSCT) occurred in InO pts and no VOD occurred in SC patients during treatment or in follow-up without intervening HSCT. Of the 79 InO patients who proceeded to HSCT, 18 (22.8%) experienced VOD (5 in patients with prior HSCT). Of the 35 SC patients who proceeded to HSCT, 3 (8.6%) experienced VOD (1 with prior HSCT).
Conclusions: Long-term follow-up in INO-VATE remained consistent with earlier reports showing that compared with SC, InO produced longer OS, prolonged PFS, and was an effective bridge to HSCT in patients with R/R ALL. Differences in OS were more pronounced at later time points, and differences in PFS were sustained at later time points. The toxicity profile of InO was consistent with previous reports and no new safety concerns were identified.
Preliminary Results of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product, in a First-in-Human Trial (CALM) in Adult Patients with CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia
Result Type: Paper
Presenter: Reuben Benjamin
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Immune-based therapies and rare subgroups
Charlotte Graham, MRCP, BSc, MBBS1,2*, Deborah Yallop, MBBS FRCP FRCPath PhD1*, Agnieszka Jozwik2*, Piers Patten, BSc, MRCP, MRCPath, PhD1,2, Alan Dunlop1*, Rose Ellard1*, Orla Stewart1*, Victoria Potter1*, Victoria Metaxa1*, Shireen Kassam1*, Farzin Farzaneh, PhD3*, Stephen Devereux, FRCP, FRCPath, PhD1, Antonio Pagliuca, MD1, Amina Zinai, MD4*, Florence Binlich, MD4*, Sandra Dupouy, Pharm.D, Ph.D4*, Anne Philippe4*, Svetlana Balandraud, MD4*, Frédéric Dubois4*, Cyril Konto, MD5*, Premal Patel, MD, PhD, BSPharm5*, Ghulam J Mufti, DM, FRCP, FRCPath3,6* and Reuben Benjamin1,2*
1King’s College Hospital NHS Foundation Trust, London, United Kingdom
2King’s College London, London, United Kingdom
3Haematology Department, King’s College London, London, United Kingdom
4Institut de Recherches Internationales Servier, Suresnes, France
5Pfizer, San Francisco
6Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, London, United Kingdom
Background: UCART19 is a genetically modified T-cell product manufactured from non-HLA matched healthy donor cells. Lentiviral-transduced CAR T-cells express (1) an anti-CD19 CAR (anti-CD19 scFv- 41BB- CD3ζ) and (2) an RQR8 “safety switch” that is intended to allow targeted elimination of RQR8+ cells by rituximab. UCART19 has been additionally modified to disrupt the T-cell receptor alpha constant (TRAC) and CD52 genes. The preliminary results of this “off-the-shelf” allogeneic CAR T-cell therapy in a phase I, dose-escalation trial of UCART19 in CD19+ R/R B-ALL adult patients (pts) are described.
Methods: The primary objective of this study is to determine the maximum tolerated dose of UCART19 by investigating up to four dose levels (DL) in separate sequential cohorts. Adult pts (age ≥16 years) with CD19+ R/R B-ALL who have exhausted available treatment options are eligible. Disease burden must be quantifiable morphologically or with a minimal residual disease (MRD) load ≥1x10-3 at the end of the last anti-leukemic treatment. The lymphodepletion regimen combines cyclophosphamide and fludarabine, with or without alemtuzumab (FC or FCA). A single dose of UCART19 is administered on Day 0, and pts are closely monitored for safety and anti-leukemic activity until the end of study, 3 months after UCART19 administration. Pts are then rolled-over into a 15-years long-term follow-up study. The dose escalation follows a modified Toxicity Probability Interval (mTPI) design based on the occurrence of dose-limiting toxicity (DLT) assessed at the end of the 28-day evaluation period post UCART19 (D28).
Results: As of 24 June 2017, the 2 first cohorts (3 pts each) who received the first DL (DL1=6x106 total CAR+ cells) have been completed. Median age was 22.5 years (range 18-42). Pts received 1 to 5 previous lines of treatment with 5 out of 6 pts having undergone an allogeneic stem cell transplant (allo-SCT). Four of them had relapsed within 4-6 months post-transplant. Prior to UCART19 infusion, 4 pts had low disease burden (<5% leukemic blasts in bone marrow (BM)) and 2 pts had high disease burden (69 and 100% blasts respectively). All pts received lymphodepletion with FCA.
All pts experienced cytokine release syndrome (CRS): 1 G1, 4 G2 and 1 G4. CRS G1 and G2 were manageable by supportive care ± tocilizumab. CRS G4, assessed as a DLT, occurred in the context of neutropenic sepsis, and was considered to be a contributory factor in the patient’s death from multiple organ failure at D15. Time to onset of first CRS symptoms ranged between D5 and D10. CRS correlated with serum cytokine increase (IL-6; IL-10 and INFγ) and UCART19 expansion in the blood. One patient was reported to have probable skin GvHD G1. Only G1 neurotoxic events were observed in 1 patient. Asymptomatic viral reactivations (CMV and/or adenovirus) were seen in 3 pts and resolved with antiviral therapy.
Among the 6 pts, 4 achieved a CRi with MRD negativity at D28 (MRD-ve, defined as a tumor burden <0.01% assessed by flow cytometry and/or qPCR), 1 was refractory to treatment at D28 and 1 died at D15.
All 4 pts achieving MRD-ve remission underwent a subsequent allo-SCT, 3 of them within 3 months of UCART19 infusion and 1 following retreatment with FC lymphodepletion and the same dose of UCART19, this patient having relapsed with CD19+ disease 2 months post initial UCART19 infusion. Post allo-SCT, 1 patient relapsed at 100 days with CD19+ disease, 1 died from infection and 2 remain in complete remission.
Three pts remain alive at 2.4, 5.3 and 10.2 months respectively post UCART19 treatment.
UCART19 (both cells and transgene levels) peaked between D12 and D17 in blood (flow cytometry [figure 1] and qPCR, respectively). UCART19 was detectable in blood from D10 to D28 (up to D42 in 1 patient) and in BM aspirates performed at D14 and D28. In-vivo cell expansion in BM occurred in all but the refractory patient.
Conclusion: Preliminary results of this first-in-human trial of UCART19 treatment in a high risk R/R B-ALL adult population revealed no unexpected toxicities. Asymptomatic lymphodepletion-related viral reactivations and a probable skin GvHD G1 were encountered. CRi with MRD-ve was achieved in 4 out of 5 pts who reached D28. The 2 first cohorts treated at DL1 have been completed and DL2 will now be investigated on which further results may be presented. The study is active in the UK and will be expanded to other EU countries and the US (NCT 02746952).
A Novel Low Affinity CD19CAR Results in Durable Disease Remissions and Prolonged CAR T Cell Persistence without Severe CRS or Neurotoxicity in Patients with Paediatric ALL
Result Type: Paper
Presenter: Sara Ghorashian
Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: CAR-T Cell Immunotherapy
Sara Ghorashian, FRCPath, PhD1, Anne Marijn Kramer, MD2*, Sarah Jayne Albon, BSc, MSc3*, Gary Wright1*, Fernanda Castro4*, Bilyana Popova4*, Joan Casanovas Company5*, Catherine Irving5*, Winston Vetharoy5*, Rachel Richardson5*, Danielle Pinner6,7*, Jan Chu6*, Giovanna Lucchini, MD8*, Juliana Silva, MD9*, Oana Ciocarlie6*, Sarah Inglott6*, Kim Champion4*, Allan Hackshaw10*, Farzin Farzaneh, PhD11*, Robert Chiesa8*, Kanchan Rao8*, Anupama Gopala Rao, MB, MRCP, MRCPath1*, Philip Ancliffe, MD12*, Sujith Samarasinghe13*, Ajay Vora, MD14,15, Paul Veys, MD, PhD8*, Rachael Hough, MD, BMBS, FRCP, FRCPath16*, Robert Wynn, MD17, Martin Pule, PhD18,19* and Persis J Amrolia8,20*
1Department of Haematology, Great Ormond Street Hospital, London, United Kingdom
2UCL Great Ormond Street Institute of Child Health, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
3UCL Great Ormond Street Institute of Child Health, London, GBR
4CRUK UCL Cancer Trials Centre, UCL, London, United Kingdom
5UCL Great Ormond Street Institute of Child Health, UCL, London, United Kingdom
6Bone Marrow Transplantation Department, Great Ormond Street hospital NHS trust, London, United Kingdom
7GREAT ORMOND STREET HOSPITAL, London, United Kingdom
8Bone Marrow Transplantation Department, Great Ormond Street hospital NHS Trust, London, United Kingdom
9Department of Bone Marrow Transplantation, Great Ormond Street Hospital, London, United Kingdom
10CRUK UCL Cancer Trials Centre, UCL, LOndon, United Kingdom
11Haematology Department, King’s College London, London, United Kingdom
12Department of Haematology, Great Ormond Street Hospital, LONDON, GBR
13Haematology Department, Great Ormond Street hospital NHS trust, London, United Kingdom
14Department of Pediatric Haematology and Oncology, Great Ormond Street Hospital, The Children’s Hospital, Sheffield, United Kingdom
15Haematology, Great Ormond Street Hospital, London, United Kingdom
16University College London Hospital, London, United Kingdom
17Dept. of Blood and Marrow Transplantation, Royal Manchester Children’s Hospital, Manchester, United Kingdom
18Autolus, London, GBR
19University College London Cancer Inst. Paul O’Gorman Building, University College London Cancer Inst. Paul O’Gorman Building, London, United Kingdom
20Institute of Child Health, University College London, London, United Kingdom
Introduction: Published studies of CD19 CAR T cells have shown unprecedented response rates in ALL but with a 23-27% incidence of severe Cytokine Release Syndrome (CRS) and 27-50% incidence of severe neurotoxicity which may limit broader application. We developed a novel second generation CD19CAR (CAT-41BBz CAR) with a lower affinity and faster off-rate but equivalent on-rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 10s vs 1260s) utilised in CTL019 currently under consideration by the FDA. Pre-clinical studies indicated T-cells transduced with CAT-41BBz mediate enhanced tumor clearance and show increased expansion in an NSG-NALM6 stress test model (Kramer et al., submitted). We here report interim results from a multi-centre, Phase I clinical study of autologous CAT-41BBz CAR T cells as therapy for high risk/relapsed paediatric ALL, CARPALL (NCT02443831) demonstrating efficacy with an excellent safety profile.
Methods: Autologous T cells were activated with anti-CD3/CD28 beads, transduced with a SIN lentiviral vector encoding CAT-41BBz CAR and expanded for 4 days prior to magnetic bead removal and cryopreservation. Transduction efficiency was assessed using an anti-idiotype antibody. Serum levels of cytokines associated with CRS were measured using cytometric bead array.
All patients received lymphodepletion with fludarabine 150 mg/m2 + cyclophosphamide 1.5g/m2 followed by a single infusion of CAR T cells at a dose of 1x106 CAR+ T cells. Patients were monitored for the presence of CAR T cells in the blood by flow cytometry and by qPCR for the 41BBz junctional region, as well as circulating B cell count monthly for 6 months and then 6 weekly to 1 year. Disease status was assessed in the bone marrow morphologically, by IgH qPCR, as well as by flow cytometric assessment of MRD at the same time-points to establish durability of responses as a stand-alone therapy. The primary end-points were incidence of grade 3-5 toxicity related to CAR T cells within 30 days and the proportion of patients achieving molecular remission.
Results: We have enrolled 10 patients and treated 8 to date. Six of 8 had relapsed post myeloablative SCT. The median disease burden prior to lymphodepletion was 9% blasts (ranging from molecular CR to 74% blasts, Table 1). It was possible to generate a product meeting release criteria in all but 1 patient (90% feasibility). Median transduction efficiency was 18.1% (range 6.7 to 76.3%). All treated patients received the anticipated dose of 1x106 CAR T cells/kg.
Cytokine release syndrome occurred in all patients (grade 1 n=4, grade 2 n=4), but to date none have developed ≥ grade 3 CRS, required ICU admission or therapy with Tocilizumab. CRS was associated with modest elevations of IL-6, IFN-γ and IL-10 and resolved spontaneously in all. Grade 2 neurotoxicity was observed in 3 patients and resolved spontaneously, but no severe (≥grade 3) neurotoxicity was seen. Five patients had prolonged grade 4 neutropenia lasting > 30 days but this resolved in all by 2 months. Only 1 patient experienced significant infective complications in the context of pre-existing poor marrow reserve following allogeneic SCT.
6/7 (86%) evaluable patients achieved molecular remission at a median of 30 days post infusion (range 30-60 days, Table 1). One patient did not respond and died of CD19+ disease progression. At a median follow-up of 5.9 months (range 28-328 days), 4/7 evaluable patients remain in flow MRD negative remission of whom 3 show no evidence of molecular MRD at 1, 7.5 and 9 months. Two patients relapsed with CD19– disease at 3 and 4 months post infusion: 1 of these remains alive with disease at 11 months and the other died of disease progression.
Reflecting our pre-clinical data with CAT-41BBz CAR, we have seen excellent CAR T cell expansion (median 65459 copies/µg DNA at 1 month, range 609 to 230112) and persistence at up to 11 months post-infusion (Figure 1). All 7 evaluable patients have ongoing CAR T cell persistence detectable by both flow and qPCR as well as ongoing B cell aplasia at last follow-up.
Conclusions: These interim results with a novel low affinity CD19 CAR show similar remission rates to those reported by US studies in paediatric ALL with an improved safety profile. No severe (grade ≥3) CRS or neurotoxicity has occurred to date despite high tumour burden in 4 patients. Excellent CAR T cell expansion has been documented, as well as long duration of CAR T cell persistence and associated B cell aplasia.
Hedgehog Pathway Mutations Drive Oncogenic Transformation in High-Risk T-Cell Acute Lymphoblastic Leukemia
Result Type: Paper
Presenter: Melissa Burns
Program: Oral and Poster Abstracts
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Biology, Signaling Mechanisms, and Response in ALL
Melissa A. Burns, MD1,2, Zi Wei Liao2*, Gayle P. Pouliot, MD, PhD2,3, Kristen E. Stevenson, MS4*, Donna S. Neuberg, ScD4, Aaron R. Thorner, PhD5*, Matthew D. Ducar, MS5*, Emily A. Silverman2*, Stephen P. Hunger, MD6, Mignon L. Loh, MD7, Stuart S. Winter, MD8, Kimberly P. Dunsmore, MD9*, Brent Wood, MD PhD10*, Meenakshi Devidas, PhD11, Marian H. Harris, MD, PhD12*, Lewis B. Silverman, MD2,3,13, Stephen E. Sallan, MD2,3 and Alejandro Gutierrez, MD2,14
1Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA
2Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA
3Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA
5Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA
6Department of Pediatrics and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA
7Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA
8Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM
9Division of Oncology, University of Virginia Children’s Hospital, Charlottesville, VA
10Department of Laboratory Medicine and Division of Hematopathology, University of Washington, Seattle, WA
11Department of Biostatistics, University of Florida, Gainesville, FL
12Department of Pathology, Boston Children’s Hospital, Boston, MA
13Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, MA
14Department of Pediatric Oncology, Children’s Hospital Boston, Boston, MA
Despite recent advances in improving outcome for patients with T-cell acute lymphoblastic leukemia (T-ALL), those who relapse or who have resistant disease are in urgent need of new therapeutic approaches. Recently, mutations in the Hedgehog pathway have been described in T-ALL, but the role of Hedgehog signaling in normal and malignant T-cell development is controversial, and whether these mutations are prognostic or drive oncogenic transformation is unknown, hindering the rationale for therapeutic intervention.
Through targeted next generation sequencing on a cohort of 109 diagnostic lymphoblast specimens from children with newly diagnosed T-ALL enrolled on contemporary clinical trials (DFCI 05-001 and COG AALL0434), we identified mutations in the Hedgehog pathway in 16% of patients (n = 17/109); PTCH1, the major negative regulator of the pathway, was the most frequently mutated Hedgehog pathway gene with 8% of patients harboring heterozygous missense mutations (n = 9/109). Remission bone marrow samples were evaluable by Sanger sequencing for 5 of the 9 PTCH1 mutations, and revealed that 3 of these mutations were absent at remission, indicating a somatic origin, whereas, 2 of these mutations were detected at remission, suggestive of either an underlying cancer predisposition syndrome, or somatic mutations associated with clonal hematopoiesis. Hedgehog pathway mutations predicted resistance to induction chemotherapy, as defined by ≥ 5% residual lymphoblasts in the bone marrow by morphology or flow cytometry (P = 0.009).
To investigate the role of Hedgehog signaling in T-ALL, we focused on PTCH1 because this was the most commonly mutated Hedgehog gene identified. Transduction of wild-type PTCH1 into a PTCH1-mutant T-ALL cell line downregulated Hedgehog pathway activity, impaired viability (P < 0.001), and induced apoptosis (P = 0.005). The effect on both viability and apoptosis was reversed by downstream Hedgehog pathway activation using a small molecule Smoothened agonist (P < 0.001 and P = 0.007, respectively), indicating on-target toxicity. Most of the PTCH1 mutations identified in human T-ALL were significantly less toxic than wild-type PTCH1 when transduced into PTCH1-mutant T-ALL cells, indicating these encode functionally defective alleles.
To test whether PTCH1 mutations accelerate the onset of T-ALL in vivo, we turned to a CRISPR/Cas9 system for tissue-specific gene disruption in transgenic zebrafish. We first identified guide RNAs that effectively mutagenized zebrafish ptch1, or the locus syntenic to the human AAVS1 safe-harbor locus as a negative control. Guide RNAs were cloned into a vector that drives ubiquitous expression of the guide RNA, together with lineage-restricted expression of a Cas9-T2A-GFP self-cleaving protein under the control of the zebrafish rag2 promoter. Using this model, we found that inducing ptch1 mutations in thymocytes accelerated the onset of notch1-induced T-ALL, with a median time to T-ALL onset of 12.3 weeks in the ptch1-mutant group versus median not reached for the aavs1-control group (P = 0.0004). These ptch1-mutant leukemias were transplantable into irradiated wild-type recipients, and subsequent treatment of these animals with the Hedgehog pathway inhibitor cyclopamine had significant therapeutic activity (P = 0.002).
In conclusion, our findings indicate that Hedgehog-activating mutations are associated with resistance to induction chemotherapy and drive oncogenic transformation in high-risk T-ALL. Together, these findings provide a molecular rationale for targeted therapy with Hedgehog pathway inhibitors for patients with PTCH1-mutant high-risk T-ALL.
An International Collaborative Phase 2 Trial of Dasatinib and Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Advances in the Treatment of ALL
Stephen P. Hunger, MD1, Vaskar Saha, MD, PhD2*, Meenakshi Devidas3*, Maria Grazia Valsecchi4*, Julie Gastier Foster5*, Gianni Cazzaniga, PhD6, Shalini C. Reshmi, PhD7, Michael Borowitz, MD, PhD8, Anthony Moorman9*, Nyla A. Heerema, PhD10, Andrew J. Carroll III, PhD11*, Phillip Barnette12*, M. Monica Monica Gramatges, MD13, Kelly Maloney, MD14*, Weili Sun, MD, PhD15, Rene Swanink16*, Amanda Termuhlen17*, Mignon L. Loh, MD18, Elizabeth A. Raetz, MD19, Lewis B. Silverman, MD20,21, Martin Schrappe, MD, PhD22, Kirk R. Schultz23*, William Slayton, MD24*, Diane Healey16* and Andrea Biondi, MD25
1Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA
2University of Manchester, Manchester, United Kingdom
3Department of Biostatistics, College of Medicine, University of Florida, Gainesville, FL
4University of Milano Bicocca, Monza, Italy
5The Ohio State University College of Medicine, Columbus, OH
6Fondazione Tettamanti ONLUS, Monza, Italy
7Institute for Genomic Medicine, /The Ohio State University, Columbus, OH
8Johns Hopkins Medical Institutions, Baltimore, MD
9Newcastle University, Newcastle upon Tyne, United Kingdom
10Department of Pathology, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH
11University of Alabama at Birmingham, Birmingham, AL
12Primary Children’s Hospital, Salt Lake City, UT
13Texas Children’s Cancer and Hematology Services, Baylor College of Medicine, Houston, TX
14Center for Cancer and Blood Disorders, Department of Pediatrics, Children’s Hospital Colorado and the University of Colorado School of Medicine, Aurora, CO
15City of Hope National Medical Center, Duarte, CA
16Bristol-Myers Squibb, Princeton, NJ
17Children’s Hospital Los Angeles, Los Angeles, CA
18Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA
19Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT
20Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
21Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, MA
22Christian-Albrechts University; University Medical Center, Kiel, Germany
23Department of Pediatrics, British Columbia Children’s Hospital, Vancouver, BC, Canada
24University of Florida, Gainesville, FL
25University of North Carolina, Chapel Hill, NC
Introduction: Ph+ ALL comprises ~5% of childhood and adolescent ALL. Prior to development of tyrosine kinase inhibitor (TKI) therapy, survival rates were poor. Less than half of patients (pts) survived despite treatment with intensive chemotherapy and frequent use of allogeneic hematopoietic stem cell transplant (HSCT) in first remission (CR1). The Children’s Oncology Group (COG) AALL0031 trial (Schultz, JCO 2009) and the EsPhALL trial (Biondi, Lancet Oncology 2012) showed adding imatinib to different intensive chemotherapy backbones improved event-free (EFS) and overall survival (OS) in pediatric Ph+ ALL. Dasatinib is attractive to study in Ph+ ALL because it is a dual ABL/SRC TKI that is 300 times more potent than imatinib in vitro, is active against most ABL1 TKI domain mutations that cause imatinib resistance, and accumulates in the central nervous system (CNS), a sanctuary site for ALL where imatinib penetration is poor.
Methods: We conducted a phase 2 trial of dasatinib added to the EsPhALL chemotherapy backbone in pediatric (>1-17.99 years (yrs) of age) Ph+ ALL pts at COG sites in North America and Australia and EsPhALL sites in Italy and the United Kingdom. Protocol therapy added continuous daily dasatinib (60 mg/m2) at day 15 of induction chemotherapy. The study measured minimal residual disease (MRD) by Ig/TCR PCR, flow cytometry, and BCR-ABL1 RT-PCR, with clinical actions based upon a single method, in this hierarchical order. Pts with MRD ≥ 0.05% at the end of block Ib (day 78) and those with MRD 0.005-0.05% at end of Ib who remained MRD positive at any detectable level after three additional high-risk (HR) chemotherapy blocks underwent HSCT in CR1. Dasatinib treatment post HSCT was optional. The remaining pts received chemotherapy plus daily dasatinib for 2 yrs, with cranial irradiation limited to CNS3 pts. The primary study endpoint was 3-year EFS assessed when all patients completed 3 years of follow-up.
Results: From April 2012 to May 2014, 109 pts enrolled; 3 did not meet inclusion criteria and received no trial therapy. The median age was 9.0 yrs (range 1-17), 54% were males, and 80% were Caucasian. 71% had CNS1 status at baseline, 24% CNS2, and 5% CNS3. Safety analysis included all treated pts (N=106) and efficacy analysis included all treated Ph+ ALL pts (N=104; 2 pts were retrospectively diagnosed with blast crisis CML). The database lock date was 8/17/16; at this time all pts had completed therapy and 75% had ≥3 yrs of follow-up. Two pts discontinued dasatinib for toxicity (1 allergy and 1 prolonged myelosuppression post HSCT). Nineteen pts met study criteria for HSCT, and 15 received HSCT in CR1 (14.2% of pts). The remaining 91 pts (85.8%) received EsPhALL chemotherapy plus dasatinib without HSCT. Patients tolerated dasatinib combined with chemotherapy well. The primary toxicity was febrile neutropenia and infection: Grade 3+ febrile neutropenia occurred in 75.5% of pts, Grade 3+ sepsis in 18.9%; and Grade 3+ bacteremia in 13.2%. Elevated ALT (21.7%) and AST (10.4%) were the only non-hematologic, non-infectious Grade 3+ adverse events attributed to dasatinib reported in >10% of pts. Relevant Grade 3+ non-hematologic, non-infectious toxicities attributed to dasatinib included pleural effusion (3.8%), edema (3.8%), hemorrhage (2.8%), and cardiac failure (0.8%). No cases of pulmonary hypertension or pulmonary arterial hypertension were reported. All 104 treated Ph+ ALL pts achieved CR. As of the database lock date, 33 events had occurred including 5 deaths (3 in HR3 and 2 in reinduction) due to proven or suspected infection in the 91 patients receiving chemotherapy plus dasatinib, 2 deaths from infection post-HSCT in the 15 HSCT pts, and 26 relapses (chemotherapy 22/86; HSCT 4/12). Sites of relapse included isolated bone marrow (BM; 14), CNS (4), BM+CNS (3), BM+other (2), and other (3). At the time of the interim analysis the 3-yr EFS is 66.0% (95% CI, 54.8-75.0) and the 3-yr OS is 92.3% (95% CI, 85.2-96.1); updated results with all patients having at least 3 years of follow-up will be presented.
Conclusions: Addition of dasatinib to the EsPhALL chemotherapy regimen is safe and effective in pediatric Ph+ ALL pts. With only 14% of pts undergoing SCT in CR1, as compared to 80% in the EsPhALL imatinib trial, this trial demonstrates similar outcomes with 3-yr EFS/OS 66.0%/92.3% in this trial vs. published 4-yr EFS/OS 61.9%/72.1% in the EsPhALL imatinib trial.