Bishwaranjan Jana

A single center experience of a risk stratified approach for children and adolescents with relapsed acute lymphoblastic leukaemia (InPOG ALL R1: InPOG-ALL-19-02) Manash Pratim Gogoi1, Bishwaranjan Jana1, Ritam Siddhanta2, Debparna Saha3, Nandana Das1, Dr Vaskar Saha4, Dr Debjani Ghosh4, Dr Niharendu Ghara4 Clinical Research Unit1, Tata Medical Bio-Repository2, Minimal Residual Disease Laboratory3,Tata Medical Center4 TATA TRANSLATIONAL CANCER RESEARCH CENTRE, TATA MEDICAL CENTER INTRODUCTION High grade toxicity, non-fatal (CTCAE Grade 3-4) Sepsis was the major toxicity, especially with Intensification B • In 20191, we reported early observations (n=55 patients) with a bortezomib-based (a) 55 (74%) of 74 patients in Induction: 7 (13%) were Grade 4 severity modified intensity ALLR3-adapted treatment protocol for curative management of (b) 32 (52%) of 62 patients in consolidation: all Grade 3 relapsed acute lymphoblastic leukaemia (rALL) in children 1-18 years old (c) 22 (73%) of 30 patients in Intensification A (HD AraC, 6 g/m2): all Grade 3 • This protocol (ALLR1) was later registered as an Indian Paediatric Oncology (d) 26 (90%) of 29 patients in Intensification B (HD AraC, 12 g/m2); 6 (21%) Grade 4 Group study protocol for rALL (InPOG-ALL-19-02; Clinical Trials Registry-India CTRI/2019/10/021758). Tata Medical Centre was the first participating centre (30 Non-infection toxicity Oct 2019). a) Steroid associated toxicities in 5 of 74 (7%) patients; Insulin requiring • Here, we report updated observations from ALLR1 at TMC (n=140 patients). hyperglycemia 1 (1%), hypertension 4 (5%) b) Asparaginase associated toxicities in 11 of 74 (15%) patients; 3 (4%) with pancreatitis and 8 (11%) with hypersensitivity METHODS c) Drug-related cholestatic liver grade 5 toxicity in 1 patient Patients: 1-18 years old, untreated first rALL Study Duration: Aug 2016 to Nov 2021; median follow-up, 17 months Risk stratification: based on site & timing of relapse, lineage (B/T), ALL Treatment-related deaths genetics, age, and treatment response (minimal residual disease [MRD]) a) 9 (12%) of 74 patients; one-third (3 of 9) in induction Non-High Risk (NHR): Non-high risk genetics & age < 15 years, with b) 6 (67%) deaths due to sepsis; 3 induction deaths, 3 post-induction deaths (all in  Late (≥ 6 months from end of treatment) isolated extramedullary rALL OR Intensification B)  B-lineage, late bone marrow rALL with end of induction MRD<0·01% OR c) 3 (4%) deaths due to non infection; 1, severe acute GVHD in SCT; 1, drug B-lineage, early (>18 months from diagnosis; < 6 months post-treatment) related cholestatic liver toxicity; 1, unknown causes isolated testicular rALL Second relapse (Median follow up 17 months) High Risk (HR): All other patients with rALL 14 (19%) of 74 patients Non-High Risk: 4 of 74 (5%); High Risk, no SCT: 8 of 74 (11%); High Risk, postInterim maintenance + Radiotherapy + Maintenance SCT: 2 of 74 (3%) 4 Weeks 4 Weeks 4 Weeks Trial withdrawal Induction Consolidation Intensification 5 of 74 (7%) patients Non-High Risk 1 g/m2/dose, 6 doses 1 (1%) Treatment Abandonment and 4 (5%) off protocol Allogeneic Hematopoietic High Risk Stem Cell Transplant + Blinatumomab 1 g/m2/dose, 12 doses Figure 1: Treatment strategy Analysis: Feasibility (proportion with rALL treated on protocol); treatment response (second remission [CR2], MRD response); treatment-related toxicity & deaths; treatment events; treatment outcomes (event-free survival) 2 Year Event Free Survival 2 Year Event Free Survival 87% (95%CI 64-96) 55% (95%CI 41-66) Figure 2: Evolution of ALL R1 treatment 38% (95%CI 23-53) 17% (95%CI 6-31) RESULTS Registered (140) Palliative = 66 (47%) Disease factor: 35 Social factor: 31 ALL R1 (74, 53%) Induction death = 3 (4%) Induction ongoing = 1 (1%) End of induction assessment (70,95%) End of Induction CR2 (62, 89%) High Risk (36) Non-High Risk (26) Figure 4: Kaplan Meier representation of 2 year event free survival in rALL patients treated with curative (74) vs palliative (66) management Post SCT (11) Post Treatment No SCT (4) On treatment (21) On treatment (16) Completed treatment (10) Continuing CR2 8 2 7 10 9 Second relapse 2 1 7 4 1 Treatment related Death 1 1 4 1 0 Trial withdrawal 0 3 1 0 0 One patient in High Risk group received Blinatumomab before transplant and is continuing CR2 Figure 3: ALL R1 treatment flow and events Treatment response Non-remission, end of induction: 8 of 70 (11%) Bone marrow relapsed ALL with MRD ≥ 0·01%, 18 of 37 (49%) [qPCR-based MRD in 25 patients, flow cytometry-based MRD in 12 patients] REFERENCES: Figure 5: Kaplan Meier representation of 2 year event free survival in Non-High Risk (26) vs High Risk (48) rALL patients in ALL R1 CONCLUSION a) Curative treatment of rALL (ALLR1) has a significant survival benefit over palliative management b) Infection is the predominant treatment-related toxicity in ALLR1, majority Grade 3. Severe sepsis and post remission sepsis-related deaths were observed with the Intensification B schedule alone c) Adverse drug reactions were predominantly asparaginase-associated. d) With ALLR1, a third of patients (Non-High Risk rALL) have excellent outcomes with chemo(radio)therapy alone, without SCT e) In High Risk rALL, SCT treatment is necessary for sustained remission f) Social factors precluded curative treatment in nearly half (31/66) with rALL. This included 12 (18%) patients with Non-High Risk rALL. ACKNOWLEDGMENT: • • Parker, C., Krishnan, S., Hamadeh, L., Irving, J.A.E., Kuiper, R.P., Revesz, T., Hoogerbrugge, P., Hancock, J., Sutton, R., Moorman, A.V. & Saha, V.(2019) Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia • with late bone marrow relapses: long-term follow-up of the ALLR3 open-label • randomised trial. Lancet Haematology, 6, e204–e216. • Prakriti Roy, Rubina Islam, Debparna Saha, Manash Gogoi, Deepak Kumar Mishra, Neeraj Arora, Mayur Parihar, Shekhar Krishnan, Vaskar Saha. (2019) Efficacy and safety of a bortezomib and reduced intensity cytarabine based protocol, TMC ALLR1, for relapsed childhood ALL in India. Br J Haematol. Dr Cornelia Eckert (Charite University) for guidance and support in optimizing and establishing PCR-based MRD at our laboratory Tata Medical Bio-repository for banking bone marrow samples for qPCR MRD Patient and families for participating in the study Tata Consultancy Services for the development of integrated data management system