Talha Munir

Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study

BACKGROUND Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. METHODS In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. FINDINGS Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). INTERPRETATION Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. FUNDING AbbVie and Genentech.

Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL

ARCTIC was a multicenter, randomized-controlled, open, phase IIB non-inferiority trial in previously untreated chronic lymphocytic leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. A total of 200 patients were recruited to assess the primary end point of complete remission (CR) rates according to IWCLL criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The trial closed following a pre-planned interim analysis. At final analysis, CR rates were 76 FCR vs 55% FCM-miniR (adjusted odds ratio: 0.37; 95% confidence interval: 0.19–0.73). MRD-negativity rates were 54 FCR vs 44% FCM-miniR. More participants experienced serious adverse reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective over a lifetime horizon. In summary, FCM-miniR is less well tolerated than FCR with an inferior response and MRD-negativity rate and increased toxicity, and will not be taken forward into a confirmatory trial. The trial demonstrated that oral FCR yields high response rates compared to historical series with intravenous chemotherapy.

Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL.

ADMIRE was a multicenter, randomized-controlled, open, phase IIB superiority trial in previously untreated chronic lymphocytic leukemia. Conventional front-line therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). Initial evidence from non-randomized phase II trials suggested that the addition of mitoxantrone to FCR (FCM-R) improved remission rates. Two hundred and fifteen patients were recruited to assess the primary end point of complete remission (CR) rates according to International Workshop on Chronic Lymphocytic Leukemia criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity and safety. At final analysis, CR rates were 69.8 FCR vs 69.3% FCM-R (adjusted odds ratio (OR): 0.97; 95% confidence interval (CI): (0.53–1.79), P=0.932). MRD-negativity rates were 59.3 FCR vs 50.5% FCM-R (adjusted OR: 0.70; 95% CI: (0.39–1.26), P=0.231). During treatment, 60.0% (n=129) of participants received granulocyte colony-stimulating factor as secondary prophylaxis for neutropenia, a lower proportion on FCR compared with FCM-R (56.1 vs 63.9%). The toxicity of both regimens was acceptable. There are no significant differences between the treatment groups for PFS and OS. The trial demonstrated that the addition of mitoxantrone to FCR did not increase the depth of response. Oral FCR was well tolerated and resulted in impressive responses in terms of CR rates and MRD negativity compared with historical series with intravenous chemotherapy.

An ultra-deep sequencing strategy to detect sub-clonal TP53 mutations in presentation chronic lymphocytic leukaemia cases using multiple polymerases

Chronic lymphocytic leukaemia (CLL) is the most common clonal B-cell disorder characterized by clonal diversity, a relapsing and remitting course, and in its aggressive forms remains largely incurable. Current front-line regimes include agents such as fludarabine, which act primarily via the DNA damage response pathway. Key to this is the transcription factor p53. Mutations in the TP53 gene, altering p53 functionality, are associated with genetic instability, and are present in aggressive CLL. Furthermore, the emergence of clonal TP53 mutations in relapsed CLL, refractory to DNA-damaging therapy, suggests that accurate detection of sub-clonal TP53 mutations prior to and during treatment may be indicative of early relapse. In this study, we describe a novel deep sequencing workflow using multiple polymerases to generate sequencing libraries (MuPol-Seq), facilitating accurate detection of TP53 mutations at a frequency as low as 0.3%, in presentation CLL cases tested. As these mutations were mostly clustered within the regions of TP53 encoding DNA-binding domains, essential for DNA contact and structural architecture, they are likely to be of prognostic relevance in disease progression. The workflow described here has the potential to be implemented routinely to identify rare mutations across a range of diseases.

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10-4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10-4 was achieved in this high-risk population.

Concurrent treatment of aplastic anemia/Paroxysmal Nocturnal Hemoglobinuria syndrome with immunosuppressive therapy and eculizumab: a UK experience

Paroxysmal nocturnal hemoglobinuria (PNH), an ultraorphan disease with a prevalence of 15.9 per million in Europe, is a life threatening disorder characterized by hemolysis, bone marrow failure and thrombosis. Patients with PNH prior to eculizumab had a median survival of between 10 and 22 years. Eculizumab (Soliris®, Alexion), a fully humanized immunoglobulin G (IgG) monoclonal antibody to C5, is currently the only licensed treatment for PNH. Aplastic anemia and PNH are intimately linked, with 40-60% of patients with aplastic anemia having a PNH clone, albeit often small. Patients are at risk of developing clinical PNH on recovery from aplastic anemia, due to PNH clone expansion. Patients with aplastic anemia should be treated according to current guidelines, depending on disease severity and concomitant health problems. Concurrent treatment of PNH and aplastic anemia is uncommon, with aplastic anemia treatment often predating PNH. There are very few publications as to the best course of treatment for these patients. Single case reports and small case series suggest this is safe, and report a positive outcome when patients are treated as per national guidelines whilst remaining on eculizumab, however there is likely a positive reporting bias.

Management of thrombosis in paroxysmal nocturnal hemoglobinuria: a clinician’s guide:

Paroxysmal nocturnal haemoglobinuria (PNH), an ultra-orphan disease with a prevalence of 15.9 per million in Europe, is a life-threatening disorder, characterized by haemolysis, bone marrow failure and thrombosis. Patients with PNH prior to the availability of eculizumab had a median survival of between 10 and 22 years, with thrombosis accounting for 22–67% of deaths. 29–44% of patients had at least one thrombosis. This paper provides a clinician’s guide to the diagnosis, management and complications of PNH, with an emphasis on thrombosis.

Significant hemolysis is not required for thrombosis in paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH), a rare hematological condition, presents with hemolytic or thrombotic symptoms. PNH stem cells arise due to somatic mutations in the phosphatidylinositol glycan A gene in bone marrow stem cells, resulting in loss of the glycosylphosphatidylinositol anchor

Highly selective SYK inhibitor, GSK143, abrogates survival signals in chronic lymphocytic leukaemia

resistance in chronic myeloid leukemia. Leukemia Supplements, 3 (Suppl. 1), S5–S6. Illangakoon, U.E., Mahalingam, S., Colombo, P. & Edirisinghe, M. (2016) Tailoring the surface of polymeric nanofibres generated by pressurised gyration. Surface Innovations, 4, 167–178. Imamura, Y., Mukohara, T., Shimono, Y., Funakoshi, Y., Chayahara, N., Toyoda, M., Kiyota, N., Takao, S., Kono, S., Nakatsura, T. & Minami, H. (2015) Comparison of 2Dand 3D-culture models as drug-testing platforms in breast cancer. Oncology Reports, 33, 1837– 1843. Kunz-Schughart, L.A., Freyer, J.P., Hofstaedter, F. & Ebner, R. (2004) The use of 3-D cultures for high-throughput screening: the multicellular spheroid model. Journal of Biomolecular Screening., 9, 273–285. Parmar, A., Marz, S., Rushton, S., Holzwarth, C., Lind, K., Kayser, S., Dohner, K., Peschel, C., Oostendorp, R.A. & Gotze, K.S. (2011) Stromal niche cells protect early leukemic FLT3-ITD+ progenitor cells against first-generation FLT3 tyrosine kinase inhibitors. Cancer Research, 71, 4696–4706. Traer, E., MacKenzie, R., Snead, J., Agarwal, A., Eiring, A.M., O’Hare, T., Druker, B.J. & Deininger, M.W. (2012) Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia, 26, 1140–1143. Wu, X., Mahalingam, S., VanOosten, S.K., Wisdom, C., Tamerler, C. & Edirisinghe, M. (2017) New generation of tunable bioactive shape memory mats integrated with genetically engineered proteins. Macromolecular Bioscience., 17, 1600270.

GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) trial: study protocol for a phase II/III randomised controlled trial

BackgroundChronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Achieving minimal residual disease (MRD) negativity in CLL is an independent predictor of survival even with a variety of different treatment approaches and regardless of the line of therapy.Methods/designGA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) is a seamless phase II/III, multi-centre, randomised, controlled, open, parallel-group trial for patients with CLL who have recently responded to chemotherapy. Participants will be randomised to receive either obinutuzumab (GA-101) consolidation or no treatment (as is standard). The phase II trial will assess safety and short-term efficacy in order to advise on continuation to a phase III trial. The primary objective for phase III is to assess the effect of consolidation therapy on progression-free survival (PFS). One hundred eighty-eight participants are planned to be recruited from forty research centres in the United Kingdom.DiscussionThere is evidence that achieving MRD eradication with alemtuzumab consolidation is associated with improvements in survival and time to progression. This trial will assess whether obinutuzumab is safe in a consolidation setting and effective at eradicating MRD and improving PFS.Trial registrationISRCTN, 64035629. Registered on 12 January 2015.EudraCT, 2014-000880-42. Registered on 12 November 2014.