Ibrutinib plus chemoimmunotherapy demonstrates preliminary efficacy in children with relapsed/refractory mature B-NHL

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As a childhood cancer specialist at Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital in Cambridge, UK, and past Chair (2010-2018) of the pediatric NHL subgroup of the National Cancer Research Institute Lymphoma Research Group, I have been involved in pediatric NHL trials for many years.

SPARKLE, sponsored by Janssen, is the first international phase III trial of ibrutinib plus conventional chemoimmunotherapy (rituximab plus ifosfamide, carboplatin, and etoposide [RICE] modified with dexamethasone, or rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone [RVICI]) in children with relapsed/refractory (R/R) mature B-cell non-Hodgkin lymphoma (B-NHL). Part 1 of the study primarily aimed to confirm the pharmacokinetics of the treatment regimen in children compared with those in adults; it was performed at 17 sites internationally. I first presented our findings at the 15th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2019, and we also report the results in our recently published letter to the editor.

But what is the rationale behind this study? Firstly, there is a real need to find more effective treatments for children with R/R mature B-NHL: The reported 2-year overall survival rate for children with R/R disease treated with chemoimmunotherapy is very low, with less than a third surviving [1, 2]. Secondly, the Bruton’s tyrosine kinase inhibitor ibrutinib (approved to treat adults with various B-cell malignancies in several countries [3-5]) inhibited tumor cell growth for Burkitt lymphoma (the predominant mature B-NHL in children) and diffuse large B-cell lymphoma (DLBCL), and prolonged survival in Burkitt lymphoma xenografted mice in preclinical studies [6-9]. Thirdly, in adults, early phase studies indicated the efficacy and safety of ibrutinib alone or in combination with R-CHOP for the treatment of patients with DLBCL [9-11]. For these reasons, we tested ibrutinib with chemoimmunotherapy in children with these difficult-to-treat cancers.

In part 1 of SPARKLE, ibrutinib doses were escalated from 240 to ≤440 mg/m2/day. Of 21 enrolled patients (median age, 8 years [range, 3–17]), 11 received ibrutinib plus modified RICE and 10 received ibrutinib plus RVICI. Eleven patients completed ≥3 planned treatment cycles.

Fig. 1 Ibrutinib exposures with 240–440 mg/m2/day doses. Box/whisker plots of estimated AUC on pharmacokinetic occasions by cycle and day for each dose for a AUCτ (estimated AUC of 24-hour dosing interval) and b AUC (dose*F/CL; predicted AUC at steady state). Solid line represents median, box represents 25%/75%, and whiskers represent 10%/90% confidence interval. Individual symbols represent outliers. c AUCτ versus age and d versus body surface area. Vertical lines represent individual patients, color represents dose, and symbol represents pharmacokinetic occasion. Target AUC range based on adult exposures was 250–1500 ng×h/mL. AUC, area under the plasma concentration–time curve.

Ibrutinib exposure supported the 329 mg/m2/day dose in children aged 12–17 years, but 440 mg/m2/day was needed in younger children (Figure 1). Although all these very ill children experienced treatment-emergent adverse events, including 4 deaths from sepsis, there were some encouraging outcomes. Among 14 patients treated after first relapse, 78.6% were responders, with 5 complete responses. Our findings support further study of these combinations in children with R/R B-NHL. Part 2 of the trial (randomized) is currently ongoing, and we look forward to the results.

References:

  1. Griffin TC, Weitzman S, Weinstein H, Chang M, Cairo M, Hutchison R et al. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 2009; 52(2): 177–181.
  2. Cairo M, Auperin A, Perkins SL, Pinkerton R, Harrison L, Goldman S et al. Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group. Br J Haematol 2018; 182(6): 859–869.
  3. IMBRUVICA (ibrutinib) [prescribing information]. Horsham, PA: Janssen Biotech, Inc.; Sunnyvale, CA: Pharmacyclics LLC. 2018.
  4. IMBRUVICA (ibrutinib) [summary of product characteristics]. Beerse, Belgium: Janssen Pharmaceutical NV. 2018.
  5. Gayko U, Fung M, Clow F, Sun S, Faust E, Price S et al. Development of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies. Ann N Y Acad Sci 2015; 1358: 82–94.
  6. Chu Y, Lee S, Shah T, Yin C, Barth M, Miles RR et al. Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model. Oncoimmunology 2019; 8(1): e1512455.
  7. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463(7277): 88–92.
  8. Schaffer M, Chaturvedi S, Davis C, Aquino R, Stepanchick E, Versele M et al. Identification of potential ibrutinib combinations in hematological malignancies using a combination high-throughput screen. Leuk Lymphoma 2018; 59(4): 931–940.
  9. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31(1): 88–94.
  10. Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 2015; 21(8): 922–926.
  11. Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, Amorim S et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol 2014; 15(9): 1019–1026.

Amos Burke

Consultant Paediatric Oncologist, Cambridge University Hospitals NHS Foundation Trust

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