I have decided to focus on Chronic Lymphocytic Leukemia on today’s post, by looking at the latest reports published in December 2018, and looking back at the results of important clinical trials published earlier. I am updating this post today because I have just attended a meeting and realised that I have omitted some important data in my original post, as they had not been published on PubMed yet, but are relevant to this topic.
First up, prognosis. The CLL-IPI working group published a prognostic scoring system in 2016 in which out of 28 variables studied, 5 independent adverse factors were found, namely TP53 mutation or deletion 17p on FISH, beta 2 microglobulin exceeding 3.5 mg/L, unmutated IGHV genes, Rai stage greater than 0 and age greater than 65. These 5 factors were each given a weighted score, and the sum of scores from all 5 factors were categorized into 4 prognostic categories, with 5-year treatment free survival rates of 0, 32, 54 and 78% from the worst prognostic category to the best. Overall survival ranged from 23 to 93%; however given that the patients studied were not treated with novel agents, the usefulness of this index today is in predicting which patients are likely to require treatment sooner. original article here (1) review article here (2)
Next, the watch-and-wait approach. Patients diagnosed with CLL are not treated until they become symptomatic – that is when they have anaemia (hemoglobin less than 10g/L), thrombocytopenia (platelet count less than 100 000 U/L), fatigue, fever, night sweats, weight loss, massive/progressive/symptomatic splenomegaly or lymphadenopathy, symptomatic extranodal disease, autoimmune manifestations of CLL not easily controlled by corticosteroids or have a rapidly increasing peripheral blood lymphocyte count. abstract here (3). Patients not meeting indications for treatment need to be counselled on their increased risk of infections and given appropriate vaccinations. Those who have a higher prognostic score (ie poorer prognosis) may consider enrollment in a clinical trial. review article here(2)
Third, choice of therapy for patients who meet indications for treatment. New data has emerged questioning the role of chemoimmunotherapy in the treatment of CLL. Young, fit patients who do not harbour the TP53 mutation have until very recently been recommended intensive chemoimmunotherapy with fludarabine, cyclophosphamide, rituximab (FCR) for 6 cycles. A randomised, controlled trial in 2010 (CLL8) involving about 400 patients in each arm demonstrating an overall response rate of 90% and a median progression free survival of 57 months in the FCR arm compared with 33 months in the fludarabine + cyclophosphamide arm. 3 year overall survival was 87%, compared with 83% in the comparison arm. abstract here(4)full text here(5). However an abstract presented at a conference in December 2018 presented results of a trial in which 529 patients 70 years old or younger with treatment naive CLL without TP53 deletion were randomised in a 1:2 ratio to receive fludarabine, cyclophosphamide and rituximab or ibrutinib and rituximab. There was significantly longer progression free survival and overall survival in the ibrutinib-rituximab arm. Amongst all the subgroups, only patients with mutated IGHV did not benefit from ibrutinib-rituximab compared to FCR. abstract here (20). In light of these results, patients with CLL who are young and fit, do not harbour TP53 mutations and have mutated IGHV can be recommended six cycles of FCR; others should be considered for ibrutinib-based treatment. In a randomised phase 3 trial including 547 patients with untreated CLL who were older than 65, the patients who received ibrutinib as a single agent had an estimated (the median was not reached) 2 year progression-free survival of 87%, compared to 88% (difference not statistically significant) in patients who received ibrutinib and rituximab and 74% (statistically significantly lower, p<0.001) in patients who received bendamustine and rituximab. full text here(6). In patients with TP53 disruption, traditional chemoimmunotherapy has had limited benefit; in the CLL8 trial, the 3 year PFS for patients with deletion 17p was only 18% compared with 65% in the overall group (4). In a phase 2 study involving 51 untreated CLL patients with TP53 disruption who were given ibrutinib, investigators found a 97% overall response rate, estimated progression free survival of 82% at 24 months and overall survival of 80% at 24 months, which are remarkable in this group of patients with this high-risk mutation. full text here(7).
The combination of ibrutinib with obinutuzumab showed favourable outcomes in comparison with chlorambucil plus obinutuzumab, with estimated 30 month progression-free survival of 79% in the ibrutinib-obinutuzumab arm abstract here(8), but without a direct comparison, the advantage of the combination over ibrutinib monotherapy is unknown. Sequential bendamustine, obinutuzumab and ibrutinib was tested in 61 patients by the German CLL group, with patients with high tumour burden receiving 2 cycles of bendamustine as pre-induction, all patients (61 in all) receiving 6 cycles of ibrutinib plus obinutuzumab, followed by a minimal-residual-disease (MRD) -triggered maintenance phase, and this showed promising results, with an overall response rate of 100%, and no MRD detected in 47.5% abstract here(9), but this study is limited by its small patient number and the lack of a comparator. A cross-trial comparison of ibrutinib monotherapy versus chemoimmunotherapy regimens including fludarabine+cyclophosphamide+ rituximab, bendamustine+rituximab, chlorambucil+obinutuzumab, chlorambucil+rituximab, and chlorambucil+ofatumumab suggested that, within limits of a cross-trial comparison, progression free survival was favourable in patients receiving ibrutinib monotherapy compared to those receiving chemoimmunotherapy, with comparable overall survival. abstract here (10)
In the relapsed-refractory setting, the following approaches can be considered. Ibrutinib-naive patients should proceed on to ibrutinib monotherapy. The RESONATE study comparing ibrutinib versus ofatumumab in patients with relapsed CLL involving 391 patients in total showed progression free survival (PFS) of 74% at 24 months. Median PFS was not reached in the ibrutinib arm and was 8.1 months in the ofatumumab arm. full text here(11).
Ibrutinib therapy is a long-term treatment – unlike FCR which is given for six cycles, it is given indefinitely until disease progression. Problems associated with such an approach are adverse effects, compliance and cost. A real-world analysis of patients with relapsed CLL given ibrutinib in a compassionate-use program reported a high (49%) rate of discontinuation of ibrutinib, mainly due to toxicity (40%) or CLL progression/Richter transformation (36%), with second malignancy, need for dual antiplatelets, sudden death, and allogeneic stem cell transplant as other causes. The main toxicities were moderate to severe infections (51%), neutropenia (41%), thrombocytopenia (20%) and atrial fibrillation (15%). Richter transformation occurred in 13% of patients, possibly due to the advanced nature of disease in this patient population. Overall response rate, progression free survival and overall survival were 84%, 52% and 63% at 30 months respectively. full text here(12). Other known toxicities of ibrutinib include diarrhea (53.8%), fatigue (34%), nausea (31%), hypertension (5%) and bleeding (20%) from the RESONATE trial(11). Richter transformation, in which CLL transforms into diffuse large B cell lymphoma, is particularly problematic in the setting of ibrutinib patients – such patients have a markedly short life expectancy (3.5 months in one report. full text here (21) ).
Subsequent options include venetoclax in combination with an anti-CD20 antibody. In the MURANO study in which 389 patients with relapsed CLL were randomised to venetoclax plus rituximab for 6 cycles followed by venetoclax maintenance until the end of the two year study period or bendamustine plus rituximab for 6 cycles, 2 year progression free survival in the venetoclax plus rituximab arm was 85% vs 36% in the bendamustine plus rituximab arm full text here(13). In a recent update, the investigators reported estimated 3 year progression free survival rate of 71.4% and overall survival of 87.9% in the venetoclax-rituximab arm, as well as an undetectable MRD rate at the end of therapy of 62% in the venetoclax-rituximab arm vs 15.2%, 79.5% and 13.3% respectively in the bendamustine-rituximab arm. Patients with undetectable MRD had a longer progression free survival (PFS) than patients with detectable MRD, and of patients with detectable MRD, those with low levels had better PFS than those with high levels. Given the risk of tumour lysis with venetoclax, a ramp-up dosing schedule is recommended by the manufacturers. (https://www.rxabbvie.com/pdf/venclexta.pdf) Venetoclax given in combination with obinutuzumab is the subject of study by the Dutch-Belgian HOVON group, with an early report indicating downgrading of tumour lysis risk with obinutuzumab pre-treatment as well as high rates of undetectable MRD in patients treated with this combination regimen (2 cycles of obinutuzumab followed by 6 cycles of obinutuzumab plus venetoclax followed by 12 cycles of venetoclax followed by randomization into either 12 cycles of venetoclax maintenance or MRD guided venetoclax maintenance with a maximum of 12 cycles) full text here (14)
Subsequent treatment options for patients failing ibrutinib and venetoclax include idelalisib. In a randomised phase 3 trial comparing treatment of relapsed CLL patients with idelalisib + rituximab versus rituximab alone, progression-free survival was 66% at 12 months in the idelalisib + rituximab arm compared to 13% in the rituximab arm. abstract here (15). A more recent randomised placebo controlled trial comparing idelalisib + bendamustine + rituximab and bendamustine + rituximab involving 416 patients with relapsed / refractory CLL showed a median progression-free survival of 21 months in the idelalisib arm, compared to 11 months in the comparator arm. full text here(16). Idelalisib is associated with colitis, hepatotoxicity and pneumonitis and as these toxicities are related to disturbance of immune regulation, can be treated by withholding the drug and corticosteroids. review article here(17). A second generation drug of the same class, duvelisib, has recently been approved by the FDA. In a randomised, phase 3 study, 319 patients with relapsed/refractory CLL were given duvelisib or ofatumumab. The median progression free survival in the duvelisib arm was 13.3 months compared to 9.9 months in the ofatumumab arm (statistically significant). Important toxicities included neutropenia, diarrhea and pneumonia. full text here(18)
Finally, further options for relapsed/refractory patients are enrollment in clinical trials, such as those employing newer novel agents (for example umbralisib, acalabrutinib), new combinations of novel agents with chemoimmunotherapy and CAR-T cell therapy. A report of anti-CD19 CAR-T cell therapy following lymphodepletion with cyclophosphamide and/or fludarabine in 24 patients with CLL who had previously received ibrutinib showed an overall response rate of 71%. Median progression free survival was 8.5 months. Median overall survival was not reached at the end of 24 months. Of 21 patients evaluated, 81% had no MRD detectable by flow cytometry. 7 out of 12 patients who had a malignant IGH sequence detected before lymphodepletion and had no detectable disease by flow cytometry 4 weeks after CAR T cell infusion had no detectable malignant IGH sequence at this time-point. These 7 patients had a better progression free survival than those who had detectable malignant IGH sequences. One patient died of neurotoxicity from cytokine release syndrome. full text here(19)
I hope this has been useful to you, and good luck on your journey.
Footnotes
Drug classes – examples
- Chemotherapy – Fludarabine, cyclophosphamide, bendamustine
- Immunotherapy (antibodies) – Rituximab, ofatumumab, obinutuzumab
- Bruton-kinase inhibitor – Ibrutinib, acalabrutinib
- BCL2-inhibitor – Venetoclax
- PI3K-inhibitor – Idelalisib, duvelisib, umbralisib
References
(1) CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncology 2016; 17:779-790).
(2) Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer Journal 2018; 8:93 https://www.nature.com/articles/s41408-018-0131-2
(3) Hallek, M. et al. Guidelines for the diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood 2018; 131(25):2745-2760
(4) Hallek, M. et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label phase 3 trial. Lancet 2010; 376:1164-1174
(5) Fischer et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215
(6) Woyach JA et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. New England Journal of Medicine 2018; 379:2517-2528
(7) Farooqui, M. Z. et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16:169 –176
(8) Moreno C et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukemia (iLLUMINATE): a multicentre, randomised, open-label phase 3 trial. Lancet Oncol 2018 https://doi.org/10.1016/S1470-2045(18)30788-5
(9) von Tresckow et al. CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. Leukemia 2018; doi: 10.1038/s41375-018-0313-8
(10) Robak T et al. Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naive patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies. American Journal of Hematology 2018;93(11):1402-1410.
(11) Brown, J. R. et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia 2017;32:83
(12)Winqvist M et al. 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. Hematologica 2018;103:xxx doi:10.3324/haematol.2018.198820
(13) Seymour, J.F. et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. New England Journal of Medicine 2018; 378:1107-1120
(14) Kater AP et al. Obinutuzumab pretreatment abrogates tumour lysis risk while maintaining undetectable MRD for venetoclax + obinutuzumab in CLL. Blood Advances 2018;2(24):3566-3571
(15) Sharman JP, Coutre SE, Furman RR, 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.Blood. 2014;124 (abstr 33)
(16) Zelenetz AD et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed/refractory CLL – interim results of a phase 3 randomized, double-blind placebo controlled trial. Lancet Oncol. 2017;18(3):297–311
(17) Brown JR, Hallek MJ and Pagel JM. Chemoimmunotherapy versus targeted treatment in chronic lymphocytic leukemia: When, how long, how much, and in which combination? Am Soc Clin Oncol Educ Book 2016;35:e387-98
(18) Flinn IW et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 2018; 132(23):2446-2455
(19) Turtle C.J. et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. Journal of Clinical Oncology 2017;35:3010-3020.
(20) Shanafelt T.D. et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN cancer research group (E1912). ASH 2018;Abst LBA-4.
(21) Maddocks K.J. et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncology 2015;1(1):80-87.
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