Relapsed/Refractory Chronic Lymphocytic Leukemia: Chemoimmunotherapy, Treatment until Progression with Mechanism-Driven Agents or Finite-Duration Therapy?

Antonio Cuneo1 and Robin Foà2.

1 Hematology, Department of Medical Sciences, University of Ferrara, Italy.
2 Hematology, Department of Cellular Biotechnologies and Hematology , Policlinico Umberto 1, 'Sapienza' University , Rome , Italy.

Correspondence to: Antonio Cuneo. Hematology, Department of Medical Sciences, University of Ferrara, Italy. Via Ariosto, 35 – 44121 Ferrara, Italy.Telephone Int+39 0532 236977, Fax: int+39 0532 236654. E-mail address: cut@unife.it

Published: March 1, 2019
Received: 27 January, 2019
Accepted: February 1, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019024 DOI 10.4084/MJHID.2019.024

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) has dramatically improved thanks to the development of mechanism-driven agents including drugs that inhibit kinases in the BCR pathway or BCL2. The treating physician has now the opportunity to decide i) which patient can be still offered chemoimmunotherapy as salvage treatment, ii) which patient at relapse is a candidate to receiving, continuous treatment with ibrutinib, idelalisib and rituximab or venetoclax and iii) which patient may benefit from a fixed-duration treatment using the BCL2 antagonist venetoclax in association with rituximab.
Ibrutinib is the most actively investigated drug in R/R CLL and data at a 7-year follow-up were reported, showing durable efficacy and favorable efficacy profile. The patients with cardiac disease, hypertension, and anticoagulant therapy are not ideal candidates for continuous therapy with this agent. Idelalisib and rituximab were tested in patients with unfavorable characteristics including cytopenias. The short follow-up and treatment-emergent adverse events limit its role to patients unlikely to get a benefit with other agents. Venetoclax and rituximab is the only effective chemo-free approach for the treatment of R/R with a fixed duration (up to 24 months) schedule capable of inducing deep responses in the majority of cases with a reassuring safety profile.
While a deep knowledge of the growing body of scientific evidence is required to inform and guide the appropriate treatment choice and management, physicians cannot disregard the growing problem of sustainability.



Introduction

Treatment of chronic lymphocytic leukemia (CLL) has dramatically improved over the years thanks to the development of effective chemoimmunotherapy (CIT) regimens[1] and of mechanism-driven agents including drugs that inhibit kinases in the BCR pathway or BCL2.[2,3] In treatment-naïve patients, the addition of anti-CD20 monoclonal antibodies to fludarabine-based combinations or to chlorambucil has prolonged survival[4,5,6] and allowed to obtain a minimal residual disease (MRD) negative status in a proportion of cases. In the relapsed/refractory (R/R) setting, the introduction of ibrutinib, idelalisib, and venetoclax have had a major role in prolonging progression-free survival (PFS) and overall survival (OS) in patients with advanced disease and with limited therapeutic options.[7-9] It has also been documented that these novel agents produce better results when used in earlier phases of the disease,[10] though formal proof that they may prolong survival compared with CIT in the first salvage setting is still lacking.[11]
While these new agents were initially developed and received marketing approval as continuous oral treatment given until disease progression or unacceptable toxicity, the design of new trial using venetoclax with the anti-CD20 monoclonal antibody rituximab for a predefined number of cycles, led to the demonstration that a fixed-duration treatment without chemotherapy in R/R CLL may produce complete responses, with many patients becoming MRD-negative in the peripheral blood (PB) and bone marrow (BM).[12-16]
Since these findings appear to hold promise at an extended follow-up[17,18] and since the regulatory agencies granted market authorization to venetoclax and rituximab based on the 24-month schedule of the MURANO study, we are witnessing a rapid paradigm shift in the treatment of R/R CLL. Indeed, the treating physician has now the opportunity to decide i) which patient can be still offered CIT as salvage treatment, ii) which patient is a candidate to receiving continuous treatment at relapse and iii) which patient may benefit from a fixed-duration treatment.

A Role for CIT in the R/R Setting? 

The efficacy of new agents in the presence of TP53 disruption mandates their use in this genetic subset of CLL.[19,20] Furthermore, the progressive lack of efficacy of CIT in patients with multiple relapses[21] and the survival advantage of new oral agents in randomized trials[22] clearly indicate that there is no longer a role for CIT in advanced phases of the disease, independent of the genetic profile. However, the trials comparing CIT with ibrutinib, idelalisib, and rituximab or venetoclax and rituximab were not designed to allow a comparison of the subset or patients receiving the study drugs as first salvage treatment. A recent matched adjusted indirect analysis of ibrutinib compared with bendamustine plus rituximab (BR) in second line showed no difference in OS in a real-world analysis.[11] Traditional prognostic markers, including disease stage and IGHV mutational status allowed to identify patients witnessing a shorter PFS under CIT.[23] In the GIMEMA-ERIC analysis of BR in second line, the PFS was 19 months vs 25 in stage 0-II and stage III-IV, respectively and 21 vs 32 months in patients carrying IGHV gene unmutated and IGHV gene mutated configuration, respectively. The OS with BR as first salvage was 41 months vs 75 months in Rai stage 0-II and III-IV, respectively (unpublished data). Therefore, according to these data and in line with a recent review[24] BR may still represent an option for a limited number of patients preferring second-line treatment of short-duration, provided that they show a favorable genetic profile, have a limited disease and have had a long duration of response to first-line CIT.[25]

Treatment Until Progression

With their unique mechanisms of action disrupting CLL-microenvironment interactions,[26] with consequent redistribution and death of lymphocytes,[27,28] both ibrutinib and idelalisib have been shown to induce a response in over 80% of the R/R patients. Complete responses were achieved in a minority of patients, and these drugs were administered in a continuous schedule until progression or unacceptable toxicity. Initially, venetoclax was given continuously as a single agent in clinical trials enrolling R/R patients,[9] patients with a 17p-[29] and patients relapsing after ibrutinib and/or idelalisib.[30,31] However, thanks to the ability to produce complete and deep responses, protocol-guided drug cessation was allowed in a subsequent phase Ib trial of venetoclax used in combination with rituximab.[32] The durability of responses following drug cessation in deep responders was documented.[33]
Ibrutinib is the most actively investigated drug in R/R CLL and data at a 5-year follow-up of 101 R/R patients were published[10] and recently updated with a 7-year follow-up.[18] Patients had a median age of 64 years, had a good performance status (PS) and had received a median of 4 previous therapies. In this phase 1b-2 study, ibrutinib was able to provide excellent disease control for a prolonged period in the majority of patients, with 52% of patients alive at 7 years and with 5- and 7-year PFS rates of 44% and 32%, respectively. Grade ≥3 cumulative toxicity events after a median exposure to the drug of 39 months included pneumonia in 27% of patients, hypertension in 25% and atrial fibrillation in 9%.[10] At 7 years, 55% of patients developed a serious infection and 9% a major hemorrhage.[18] However, observational studies of ibrutinib clearly showed that elderly patients with comorbidities and/or an ECOG PS >1 were more likely to discontinue treatment due to toxicity[34-38] and that atrial fibrillation occurred more frequently in elderly patients with previous arterial hypertension and pre-existing cardiologic comorbidities.[39] In the real world experience of the Swedish registry[36] an updated analysis at 30-month follow-up of 95 R/R patients (median age of 69 years, del(17p)/TP53 mutation in 63% of the patients, PS grade 2-3 in 27%) showed that 51% of patients had a grade 3-4 infection, 15% developed any grade atrial fibrillation and 20% discontinued due to adverse events. In another analysis, 116 out of 536 R/R patients (21.6%) treated in the U.S. discontinued ibrutinib due to toxicity at a median follow-up of 17 months.[40]
Idelalisib given continuously in association with 8 doses of rituximab showed efficacy in a heavily pre-treated patient population with unfavorable baseline characteristics (median age 71 years, grade ≥3 cytopenia in 1/3 of the cases advanced stage in 2/3 of the cases, high burden of comorbidities in 85% of cases), with an estimated PFS of 66% at 12 months[41] and a discontinuation rate of 8% due to adverse events after a median time of exposure to the dug of 3.8 months.
Venetoclax, given as single-agent until progression, is the only drug of proven efficacy which has been used in phase II trials for CLL progressing after ibrutinib or idelalisib.[30,31] A response was observed in approximately 2/3 of patients, with approximately 3/4 of patients alive without progression at 12 months. The most frequent treatment-emergent adverse events were primarily hematological and included mainly neutropenia in approximately 50% of patients, with grade 3-5 infections occurring in approximately 15% of patients. Laboratory tumor lysis syndrome was recorded in 5% of patients.[29] In a real-world analysis of 141 patients treated in the U.S (median age 67 years, 17p- in 45% of patients, previous exposure to a BCR antagonist in 89%), 72.1% of patients responded, with a projected PFS and OS for the entire cohort at 12 months of 68% and 88%, respectively. Venetoclax was discontinued in 41 patients (29%) due to disease progression (53.8%, n=21), toxicity (20.5%, n=9) or other reasons (25,7%, n=10).[42]

Fixed-Duration Treatment

Growing attention is being devoted by the scientific community to fixed-duration chemo-free approaches in CLL which are able to induce complete responses. The efficacy of several studies in R/R CLL have been published or presented in an abstract form (Table 1).
Table 1 Table 1. Efficacy of recently developed fixed-duration approaches based on novel agents for the treatment of R/R CLL.
 Recently, the results of the phase-3 MURANO trial comparing venetoclax for a maximum of 24 months associated with rituximab (VR) for the first six months with the classical bendamustine and rituximab (BR) regimen given for six months in R/R CLL have been reported.
Ninety-two % of patients responded to VR, and 62% attained an undetectable MRD (uMRD) in the PB at six months, compared to 12% in the BR cohort. Sixty-four % of 130 patients who completed the two years of planned treatment with venetoclax had uMRD. Patients with uMRD or detectable MRD at low levels (10-2 to 104 residual cells) had a longer PFS than the remaining patients.[17] At a median of 9.9 months after cessation of venetoclax only 12% of 130 patients who completed the planned treatment progressed and 90% of all patients assigned to the VR arm had not undergone a further treatment for their disease at two years.[12]
In the intention to treat analysis, the VR regimen significantly improved PFS (HR: 0.16; IC 95%: 0.12-0.23; p <0.0001) and OS (HR: 0.50; 95% CI: 0.30-0.85; p = 0.0093; OS rate at 3 years: 87.9% vs 79.5%) compared to BR, which represents one of most widely employed CIT regimen in R/R CLL. Noteworthy, though crossover to venetoclax at progression in the BR arm was not pre-planned, the majority of patients received effective salvage regimen with new drugs.[17]
These findings show for the first time that a fixed-duration treatment may achieve deep and durable response and improve survival in R/R CLL, and are likely to have a significant impact in the treatment of R/R CLL in the clinical practice as the regulatory agencies FDA and EMA granted this regimen marketing authorization.

Advantages and Disadvantages of Finite Duration vs Continuous Treatment

While the CIT approach to the treatment of R/R CLL has a marginal role in high-income countries nowadays, the development of chemo-free approaches using venetoclax and the antiCD20 monoclonal antibody rituximab poses a challenge to the treating physician who has to discuss with each patient with R/R CLL advantages and disadvantages of continuous oral treatment with new agents or fixed-duration treatment. Since FDA and EMA have approved the use in R/R CLL of ibrutinib, idelalisib with rituximab and venetoclax on a continuous schedule, or venetoclax and rituximab for a fixed duration, the following considerations might be taken into account in the decision process, in the absence of a direct comparison.
- Ibrutinib has been tested in many trials which have now reached a mature follow-up[43,10] and is the only drug with a large body of literature describing the outcome in the real world patient population.[34,36,37,40] Importantly, the excellent efficacy and safety profile was consistent throughout trials which included patients with a good PS. Notably, treatment-limiting adverse events were more frequent during the first year of follow-up; however, the incidence of newly diagnosed hypertension and atrial fibrillation appeared to be constant over a long follow-up period.[10] Outside of clinical trials, elderly patients with comorbidities showed a higher discontinuation rate compared to those on trial.[35] Patients with ECOG PS >1, patients with cardiac disease, hypertension, and on anticoagulant therapy are not ideal candidates for continuous therapy with ibrutinib.[44] Severe infections, including fungal infections[45] represent an emerging issue, even though their incidence is clearly influenced by the longtime of exposure to the drug.
- Idelalisib has been used in a phase 3 trial that mostly included patients >70 years with unfavorable characteristics, many of whom were not enrolled in phase-2 trials of ibrutinib and venetoclax. The short follow-up and treatment-emergent adverse events[41] limit its role to patients unlikely to get a benefit with ibrutinib or venetoclax. The emergence of immune-mediated side effects under treatment may be attenuated in elderly patients with multiple prior therapies.
- Venetoclax and rituximab is the only effective chemo-free approach for the treatment of R/R with a fixed duration (up to 24 months) schedule capable of inducing a response in virtually all cases, with a majority of patients attaining an uMRD in the PB and BM. A complete response was observed in a minority of patients due to a small residual size (<30 mm) adenopathies. Even though the durability of response needs to be established with a longer follow-up, preliminary data on patients attaining an uMRD are unprecedented in this setting of patients. Importantly, preliminary data on few patients indicate that responses can be observed when venetoclax is resumed at disease progression after cessation of treatment.[17,33] The safety profile at a 30-month follow-up is reassuring, and fixed-duration treatment will translate into a lower incidence of treatment-related adverse events compared to continuous treatment.
Treating physicians bear today a great responsibility in offering the best treatment option to each patient with R/R CLL. While a deep knowledge of the growing body of scientific evidence is required to inform and guide the appropriate treatment choice and management, physicians cannot disregard the growing problem of sustainability. In high-income countries, with or without a universal health system coverage, the prices of pharmaceuticals are among the major drivers of the differences in overall health care costs between countries.[46,47] The possibility of using effective regimens for a fixed-duration period may represent a unique opportunity to guarantee a lower cost of treatment and, in the absence of a documented advantage of a given treatment over another potentially equally effective and tolerable, the payer can suggest the practicing hematologist to consider the economic implication of his/her choice. Meanwhile, and most importantly, the regulatory agencies should be able to undertake some recommended actions to negotiate fair prices.[48] Moreover, the definition of validated approaches to stratify the magnitude of clinical benefit[49] along with payment-by-result strategies are urgently required to guarantee the sustainability on national health systems.

References   

  1. Hallek M. On the architecture of translational research designed to control chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2018; 2018: 1-8. https://doi.org/10.1182/asheducation-2018.1.1
  2. Foà R, Guarini A. A mechanism-driven treatment for chronic lymphocytic leukemia? N Engl J Med. 2013; 369: 85-7. https://doi.org/10.1056/NEJMe1303054
  3. Rogers KA, Byrd JC. Venetoclax Adds a New Arrow Targeting Relapsed CLL to the Quiver. Cancer Cell. 2016; 29: 3-4. https://doi.org/10.1016/j.ccell.2015.12.010
  4. Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016; 127: 303-9. https://doi.org/10.1182/blood-2015-09-667675
  5. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016; 127: 208-15. https://doi.org/10.1182/blood-2015-06-651125
  6. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370: 1101-10. https://doi.org/10.1056/NEJMoa1313984
  7. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369: 32-42. https://doi.org/10.1056/NEJMoa1215637
  8. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014; 370: 997-1007. https://doi.org/10.1056/NEJMoa1315226
  9. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016; 374: 311-22. https://doi.org/10.1056/NEJMoa1513257
  10. O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018; 131: 1910-1919. https://doi.org/10.1182/blood-2017-10-810044
  11. Cuneo A, Follows G, Rigolin GM, Piciocchi A, Tedeschi A, Trentin L, Perez AM, Coscia M, Laurenti L, Musuraca G, Farina L, Delgado AR, Orlandi EM, Galieni P, Mauro FR, Visco C, Amendola A, Billio A, Marasca R, Chiarenza A, Meneghini V, Ilariucci F, Marchetti M, Molica S, Re F, Gaidano G, Gonzalez M, Forconi F, Ciolli S, Cortelezzi A, Montillo M, Smolej L, Schuh A, Eyre TA, Kennedy B, Bowles KM, Vignetti M, de la Serna J, Moreno C, Foà R, Ghia P; GIMEMA, European Research Initiative on CLL (ERIC) and UK CLL forum. Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study. Haematologica. 2018; 103: 1209-1217. https://doi.org/10.3324/haematol.2018.189837
  12. Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2018; 378: 1107-1120. https://doi.org/10.1056/NEJMoa1713976
  13. Rogers KA, Huang Y, Ruppert AS, Awan FT, Heerema NA, Hoffman C, Lozanski G, Maddocks KJ, Moran ME, Reid MA, Lucas M, Woyach JA, Whitlow WT, Jones JA, Byrd JC. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood. 2018; 132: 1568-1572. https://doi.org/10.1182/blood-2018-05-853564
  14. Cramer P, von Tresckow J, Bahlo J, Robrecht S, Langerbeins P, Al-Sawaf O, Engelke A, Fink AM, Fischer K, Tausch E, Seiler T, Fischer von Weikersthal L, Hebart H, Kreuzer KA, Böttcher S, Ritgen M, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, Hallek M. Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018; 19: 1215-1228. https://doi.org/10.1016/S1470-2045(18)30414-5
  15. von Tresckow J, Cramer P, Bahlo J, Robrecht S, Langerbeins P, Fink AM, Al-Sawaf O, Illmer T, Klaproth H, Estenfelder S, Ritgen M, Fischer K, Wendtner CM, Kreuzer KA, Stilgenbauer S, Böttcher S, Eichhorst BF, Hallek M. CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. Leukemia. 2018 Dec 19. doi: 10.1038/s41375-018-0313-8. Epub ahead of print. https://doi.org/10.1038/s41375-018-0313-8
  16. Hillmen P, Rawstron A, Brock K, Vicente SM, Yates F, Bishop R, Macdonald D, Fegan C, McCaig A, Schuh A, Pettitt A, Gribben JG, Patten PEM, Devereux S, Bloor A, Fox CP, Forconi, F Munir T. Ibrutinib Plus Venetoclax in Relapsed/Refractory CLL: Results of the Bloodwise TAP Clarity Study. Blood 2018; 132: 182.
  17. Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. J Clin Oncol. 2018 Dec 3:JCO1801580. Epub ahead of print. https://doi.org/10.1200/JCO.18.01580
  18. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, SharmanJ, Wierda WG, Zhao W, Heerema NA, Luan Y, Liu EA, Dean JP, O'Brien S. Up to 7 Years of Follow-up of Single-Agent Ibrutinib in the Phase 1b/2 PCYC-1102 Trial of First Line and Relapsed/Refractory Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Blood 2018; 132:3133.
  19. ESMO Guidelines Committee.Appendix 4: Chronic lymphocytic leukaemia: eUpdate published online 27 June 2017 (www.esmo.org/Guidelines/Haematological-Malignancies). Ann Oncol. 2017 Jul 1;28(suppl_4):iv149-iv152. https://doi.org/10.1093/annonc/mdx242
  20. Wierda WG, Byrd JC, Abramson JS, Bilgrami SF, Bociek G, Brander D, Brown J, Chanan-Khan AA, Chavez JC, Coutre SE, Davis RS, Fletcher CD, Hill B, Kahl BS, Kamdar M, Kaplan LD, Khan N, Kipps TJ, Ma S, Malek S, Mato A, Mosse C, Neppalli VT, Shadman M, Siddiqi T, Stephens D, Wagner N, Dwyer MA, Sundar H.. NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019 J Natl Compr Canc Netw. 2019;17:12-20. https://doi.org/10.6004/jnccn.2019.0002
  21. Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011; 117: 3016-24. https://doi.org/10.1182/blood-2010-08-304683
  22. Hallek M, Shanafelt TD, Eichhorst B. Chronic lymphocytic leukaemia. Lancet. 2018; 391: 1524-1537. https://doi.org/10.1016/S0140-6736(18)30422-7
  23. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016; 17: 779-790. https://doi.org/10.1016/S1470-2045(16)30029-8
  24. Brown JR. Relapsed CLL: sequencing, combinations, and novel agents. Hematology Am Soc Hematol Educ Program. 2018; 2018: 248-255. https://doi.org/10.1182/asheducation-2018.1.248
  25. Tam CS, O'Brien S, Plunkett W, Wierda W, Ferrajoli A, Wang X, Do KA, Cortes J, Khouri I, Kantarjian H, Lerner S, Keating MJ. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood. 2014; 124: 3059-64. https://doi.org/10.1182/blood-2014-06-583765
  26. Ten Hacken E, Burger JA. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment. Biochim Biophis Acta. 2016; 1863: 401-413. https://doi.org/10.1016/j.bbamcr.2015.07.009
  27. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, Burger JA. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012; 119: 1182-9. https://doi.org/10.1182/blood-2011-10-386417
  28. Burger JA, Li KW, Keating MJ, Sivina M, Amer AM, Garg N, Ferrajoli A, Huang X, Kantarjian H, Wierda WG, O'Brien S, Hellerstein MK, Turner SM, Emson CL, Chen SS, Yan XJ, Wodarz D, Chiorazzi N. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib. JCI Insight. 2017; 2: e8990. https://doi.org/10.1172/jci.insight.89904
  29. Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Böttcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Enschede SH, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016; 17: 768-778. https://doi.org/10.1016/S1470-2045(16)30019-5
  30. Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, Furman RR, Lamanna N, Barr PM, Zhou L, Chyla B, Salem AH, Verdugo M, Humerickhouse RA, Potluri J, Coutre S, Woyach J, Byrd JC. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018; 19: 65-75. https://doi.org/10.1016/S1470-2045(17)30909-9
  31. Coutre S, Choi M, Furman RR, Eradat H, Heffner L, Jones JA, Chyla B, Zhou L, Agarwal S, Waskiewicz T, Verdugo M, Humerickhouse RA, Potluri J, Wierda WG, Davids MS. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018; 131: 1704-1711. https://doi.org/10.1182/blood-2017-06-788133
  32. Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, Davids MS, Anderson MA, Beaven AW, Rosen ST, Tam CS, Prine B, Agarwal SK, Munasinghe W, Zhu M, Lash LL, Desai M, Cerri E, Verdugo M, Kim SY, Humerickhouse RA, Gordon GB, Kipps TJ, Roberts AW. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017; 18: 230-240. https://doi.org/10.1016/S1470-2045(17)30012-8
  33. Brander DM, Seymour JF, Ma S, Anderson MA, Choi MY, Kipps TJ, Humphrey K, Masud A, Nandam R, Kim SY, Verdugo ME, Roberts AW. Durability of Responses on Continuous Therapy and Following Drug Cessation in Deep Responders with Venetoclax and Rituximab. Blood. 2018; 132: 183.
  34. UK CLL Forum. Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica. 2016; 101: 1563-1572. https://doi.org/10.3324/haematol.2016.147900
  35. Ghia P, Cuneo A. Ibrutinib in the real world patient: many lights and some shades. Haematologica. 2016; 101: 1448-1450. https://doi.org/10.3324/haematol.2016.155986
  36. Winqvist M, Andersson PO, Asklid A, Karlsson K, Karlsson C, Lauri B, Lundin J, Mattsson M, Norin S, Sandstedt A, Rosenquist R, Späth F, Hansson L, Österborg A. Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow-up of the Swedish compassionate use cohort. Haematologica. 2018 Dec 4. pii: haematol.2018.198820. Epub ahead of print. https://doi.org/10.3324/haematol.2018.198820
  37. Mauro FR, Soddu S, Frustaci AM, Orsucci L, Motta M, Scarfo L, Zinzani PL, Falzetti F, Farina L, Marasca R, Cortelezzi A, Carlo-Stella C, Molica S, Coscia M, Zaja F, Laurenti L, de Fabritiis P, Gaidano G, Gobbi M, Tani M, Di Renzo N, Fazi P, Vignetti M, Cuneo A, Foà R. Outcome of Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Treated with Ibrutinib within a Named Patient Program (NPP) in Italy. a Real-Life Retrospective Study. Blood. 2018; 132: 3147.
  38. Gordon MJ, Churnetski M, Alqahtani H, Rivera X, Kittai A, Amrock SM, James S, Hoff S, Manda S, Spurgeon SE, Choi M, Cohen JB, Persky D, Danilov AV. Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib. Cancer. 2018; 124: 3192-3200. https://doi.org/10.1002/cncr.31554
  39. Reda G, Fattizzo B, Cassin R, Mattiello V, Tonella T, Giannarelli D, Massari F, Cortelezzi A. Predictors of atrial fibrillation in ibrutinib-treated CLL patients: a prospective study. J Hematol Oncol. 2018; 11: 79. https://doi.org/10.1186/s13045-018-0626-0
  40. Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, Howlett C, Skarbnik A, Cheson BD, Zent C, Pu J, Kiselev P, Goy A, Claxton D, Isaac K, Kennard KH, Timlin C, Landsburg D, Winter A, Nasta SD, Bachow SH, Schuster SJ, Dorsey C, Svoboda J, Barr P, Ujjani CS. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018; 103: 874-879. https://doi.org/10.3324/haematol.2017.182907
  41. Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Hallek M, Coiffier B, O'BrienS, Tausch E, Kreuzer KA, Jiang W, Lazarov M, Li D, Jahn TM, Stilgenbauer S. 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. Blood. 2014; 124: 330.
  42. Mato AR, Thompson M, Allan JN, Brander DM, Pagel JM, Ujjani CS, Hill BT, Lamanna N, Lansigan F, Jacobs R, Shadman M, Skarbnik AP, Pu JJ, Barr PM, Sehgal AR, Cheson BD, Zent CS, Tuncer HH, Schuster SJ, Pickens PV, Shah NN, Goy A, Winter AM, Garcia C, Kennard K, Isaac K, Dorsey C, Gashonia LM, Singavi AK, Roeker LE, Zelenetz A, Williams A, Howlett C, Weissbrot H, Ali N, Khajavian S, Sitlinger A, Tranchito E, Rhodes J, Felsenfeld J, Bailey N, Patel B, Burns TF, Yacur M, Malhotra M, Svoboda J, Furman RR, Nabhan C. Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica. 2018; 103: 1511-1517. https://doi.org/10.3324/haematol.2018.193615
  43. Ahn IE, Farooqui MZH, Tian X, Valdez J, Sun C, Soto S, Lotter J, Housel S, Stetler-Stevenson M, Yuan CM, Maric I, Calvo KR, Nierman P, Hughes TE, Saba NS, Marti GE, Pittaluga S, Herman SEM, Niemann CU, Pedersen LB, Geisler CH, Childs R, Aue G, Wiestner A. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018; 131: 2357-2366. https://doi.org/10.1182/blood-2017-12-820910
  44. Brown JR. How I treat CLL patients with ibrutinib. Blood. 2018; 131: 379-386. https://doi.org/10.1182/blood-2017-08-764712
  45. Ghez D, Calleja A, Protin C, Baron M, Ledoux MP, Damaj G, Dupont M, Dreyfus B, Ferrant E, Herbaux C, Laribi K, Le Calloch R, Malphettes M, Paul F, Souchet L, Truchan-Graczyk M, Delavigne K, Dartigeas C, Ysebaert L; French Innovative Leukemia Organization (FILO) CLL group. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018; 131: 1955-1959. https://doi.org/10.1182/blood-2017-11-818286
  46. Papanicolas I, Woskie LR, Jha AK. Health Care Spending in the United States and Other High-Income Countries. JAMA. 2018; 319: 1024-1039. https://doi.org/10.1001/jama.2018.1150
  47. Vogler S, Vitry A, Babar ZU. Cancer drugs in 16 European countries, Australia, and New Zealand: a cross-country price comparison study. Lancet Oncol. 2016; 17: 39-47. https://doi.org/10.1016/S1470-2045(15)00449-0
  48. Luzzatto L, Hyry HI, Schieppati A, Costa E, Simoens S, Schaefer F, Roos JCP, Merlini G, Kääriäinen H, Garattini S, Hollak CE, Remuzzi G; Second Workshop on Orphan Drugs participants. Outrageous prices of orphan drugs: a call for collaboration. Lancet. 2018; 392: 791-794. https://doi.org/10.1016/S0140-6736(18)31069-9
  49. Cherny NI, Sullivan R, Dafni U, Kerst JM, Sobrero A, Zielinski C, de Vries EGE, Piccart MJ. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol. 2017; 28: 2901-2905. https://doi.org/10.1093/annonc/mdw258

[TOP]