Haematology + Oncology News (Vol.9_No.2)

NEWS 5

Vol. 9 • No. 2 • 2016 • H aematology & O ncology N ews

Minimal residual disease a powerful prognostic factor in AML BY PATRICE WENDLING Frontline Medical News From the New England Journal of Medicine T he presence of minimal re- sidual disease predicts relapse in patients with NMP1-mutated Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr Ivey reported. “We could find no specific mo- lecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the pres- ence of minimal residual disease was 24%,” he observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persis- tent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.” The presence of MRD is also known to be an important inde- pendent prognostic factor in acute lymphoblastic leukaemia, but since AML has a greater molecular heter- ogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr Burke noted. The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups. The study was supported by grants from Bloodwise and the National In- stitute for Health Research. Mr Ivey and Dr Burke reported having no disclosures.

acute myeloid leukaemia and is su- perior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplanta- tion, a new study has found. At 3 years, patients with mini- mal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs 30%; univariate hazard ratio, 4.80; P < 0.001) and a lower rate of survival (24% vs 75%; univariate HR, 4.38; P < 0.001), Adam Ivey of King’s College London reported. In an editorial that accompanied the study Dr Michael J. Burke from the Children’s Hospital of Wiscon- sin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML”. In adult AML, assessment of MRD has taken a back seat to analy- ses of cytogenetic and molecular le- sions in determining a patient’s risk and treatment strategy. Typically,

In multivariate analysis, the presence of MRD was the only sig- nificant prognostic factor for relapse (HR, 5.09; P < 0.001) or death (HR, 4.84; P < 0.001). The results were validated in an in- dependent cohort of 91AML17 study patients. It confirmed that MRD in peripheral blood predicts worse out- come at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs 31% (P = 0.001) and overall survival rates of 40% vs 87% (P = 0.001), reported the investiga- tors, including senior author Professor David Grimwade, also from King’s College London. The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and be- cause of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr Burke observed.

cycles of induction chemotherapy in the UK National Cancer Research Institute AML17 trial. MRD, defined as persistence of NPM1-mutated transcripts in pe- ripheral blood, was present in 15% of patients after the second chemo- therapy cycle. Patients with MRD were sig- nificantly more likely than those without MRD to have a high UK Medical Research Council clinical risk score and to carry the FLT3-ITD mutation. On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3- ITD mutations.

allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3- internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease. The role of transplantation is unclear, however, for cytogeneti- cally standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1). To address this issue, the investi- gators used a reverse-transcriptase quantitative polymerase chain re- action assay to evaluate 2569 bone marrow and peripheral-blood sam- ples from 346 patients with NPM1 mutations who had completed two

RETHINK WHAT'S POSSIBLE...

CLL ZYDELIG + rituximab delivers significant efficacy for a broad range of relapsed CLL patients vs. rituximab + placebo 1-3

FL ZYDELIG monotherapy delivers rapid and durable efficacy in refractory FL patients after ≥ 2 lines of therapy 4

ZYDELIG has a manageable safety profile across a broad range of relapsed CLL and FL patients with most AEs grade 1-2 1,4-6

PBS Information: This product is not listed on the PBS.

SEE APPROVED PRODUCT INFORMATION BEFORE PRESCRIBING. APPROVED PRODUCT INFORMATION AVAILABLE FROM HTTPS://WWW.EBS.TGA.GOV.AU/EBS/PICMI/PICMIREPOSITORY.NSF/PDF? OPENAGENT&ID=CP-2015-PI-01225-1 Minimum Product Information ZYDELIG ® (idelalisib) 100 mg and 150 mg Tablets. INDICATIONS: with rituximab for CLL/SLL where chemo-immunotherapy is unsuitable, either: upon relapse after at least one prior therapy, or first-line with 17p deletion or TP53 mutation. Monotherapy of refractory follicular lymphoma after at least two prior systemic therapies. DOSAGE AND ADMINISTRATION: 150 mg twice daily. Dose modification may be required. CONTRAINDICATIONS: hypersensitivity. PRECAUTIONS: Hepatotoxicity: monitoring required. Hepatitis Infection and Reactivation: prior screen for HBV and HCV. Diarrhoea/Colitis: assessment of hydration and dose interruption shouldbeconsidered inseverecases. Pneumonitis: Dose interruptionshouldbeconsideredwithanyseverityofsymptomaticpneumonitis. Immunisation: Vaccinationprior to treatmentofpatientsatsubstantialriskofan infection. Neutropenia, Anaemia, Lymphopenia and Thrombocytopenia. Severe Cutaneous Reactions: life-threatening (Grade ≥ 3) cutaneous reactions. Fatal cases of SJS-TEN have occurred when patients were treated with Zydelig when administered concomitantly with other medications associated with SJS-TEN. Treatment should be interrupted immediately if SJS or TEN is suspected and permanently discontinued where there is a case of severe cutaneous reaction. Intestinal Perforation: discontinue permanently. Progressive Multifocal Leukoencephalopathy (PML): diagnosis should be considered with new onset of, or changes in pre-existing neurologic signs and symptoms. Transient Lymphocytosis. Infections: patients with signs of infection should be promptly treated. Effects on Fertility: highly-effective contraception during and 1 month after. Pregnancy (Cat. D). Lactation. Children (<18 years). INTERACTIONS WITH OTHER MEDICINES: Effects of other drugs on Zydelig: CYP3A Inducers (rifampin, phenytoin, St. John’s Wort, or carbamazepine). CYP3A Inhibitors (ketoconazole). Effects of Zydelig on other drugs: CYP3A Substrates (alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, quinidine, ergotamine, dihydroergotamine, midazolam, certain antiarrhythmics, calcium channel blockers, benzodiazepines, HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) inhibitors,

and warfarin), refer to full PI. ADVERSE EFFECTS: Neutropenia, Pneumonitis, Diarrhoea/Colitis, Transaminases increased, Rash, Pyrexia. This is not the full Product Information. Please review the full Product Information before prescribing. Product Information is available on request from Gilead Sciences Pty Ltd. Date of preparation 16 December 2015. References: 1. Furman RR et al. N Engl J Med 2014;370:997–1007. 2. Sharman JP SE et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG ) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. The American Society of Hematology (ASH) 56th Annual Meeting, 6–9 December 2014, San Francisco, CA, USA: Abstract 330. 3. Coutre SE et al. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin Oncol 2014;32(Suppl): Abstract 7012. 4. Gopal AK et al. N Engl J Med 2014;370:1008–18 4. Salles G et al. Idelalisib efficacy and safety in follicular lymphoma patients from a phase 2 study. J Clin Oncol 2015;33(Suppl): Abstract 8529. 6. Zydelig Product Information, 16 December 2015.

ZYDELIG is a registered trademark of Gilead Sciences Inc. Gilead Sciences Pty Ltd. ABN 71 072 611 708 Level 6, 417 St Kilda Rd, Melbourne, VIC 3004 Australia. Phone: 61 3 9272 4400 Call Toll Free: 1800 806 112 Fax: 61 3 9272 4411 ZDG/AU/16-01/MI/1031 Prepared January 2016 GIL0053/HONC2

GIL0053_HON_Half_A3_Horz_190x260_R2.indd 1

15/01/2016 12:00 pm