IbrutinIb les résistances

https://healthunlocked.com/cllsupport/posts/131137839/evolution-of-ibrutinib-resistance-in-chronic-lymphocytic-leukemia-cll




The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is a new targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib is given orally on a continuous schedule and induces durable remissions in the majority of CLL patients. However, a small proportion of patients initially responds to the BTKi and then develops resistance. Estimating the frequency, timing, and individ- ual risk of developing resistance to ibrutinib, therefore, would be valuable for long-term management of patients. Computational evolutionary models, based on measured kinetic parameters of patients, allow us to approach these questions and to develop a roadmap for personalized prognosis and treatment management.

Our kinetic models predict that BTKi-resistant mutants exist before initiation of ibrutinib therapy, although they only comprise a mi- nority of the overall tumor burden. Furthermore, we can estimate the time required for resistant cells to grow to detectable levels. We predict that this can be highly variable, depending mostly on growth and death rates of the individual CLL cell clone. For a specific patient, this time can be predicted with a high degree of certainty. Our model can thus be used to predict for how long ibrutinib can suppress the disease in individual patients. Furthermore, the model can suggest whether prior debulking of the tumor with chemo-immunotherapy can prolong progression-free survival under ibrutinib.

Finally, by applying the models to data that document progression during ibrutinib therapy, we estimated that resistant mutants might have a small (<2%) mean fitness advantage in the absence of treatment, compared with sensitive cells.

Is Chronic Lymphocytic Leukemia Still Incurable?

https://ash.confex.com/ash/2012/webprogram/Paper48622.html

 

3929 Is Chronic Lymphocytic Leukemia Still Incurable?

Program: Oral and Poster Abstracts
Session: 642. CLL - Therapy, excluding Transplantation: Poster III

Monday, December 10, 2012, 6:00 PM-8:00 PM

Hall B1-B2, Level 1, Building B (Georgia World Congress Center)

Michael J. Keating, MD¹, Constantine S Tam², William G. Wierda, MD, Ph.D.¹, Susan O'Brien, M.D.³, Deborah A. Thomas, MD⁴, Jorge E. Cortes, MD⁵, Susan Lerner, MS^6* and William Plunkett, PhD⁷

¹Leukemia, MD Anderson Cancer Center, Houston, TX
²Peter McCallum, Melbourne, Australia
³The University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX
⁴Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, TX
⁵Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
⁶MD Anderson Cancer Center, Houston, TX
⁷The University of Texas M.D. Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX

Introduction

Up until now, Chronic Lymphocytic Leukemia (CLL) has been considered incurable except with an allogeneic stem cell transplant.   In the last 10 years, evidence has demonstrated that chemo-immuotherapy with fludarabine, cyclophosphamide, and rituximab, (FCR) has significantly improved CR rates, overall survival (OS), and progression free survival ¹.  Long term follow up data for FCR at MDACC demonstrated that a significant proportion of patients (pts.) were free at 8 years² raising the question of whether pts. are potentially cured.

Definition of cure in a chronic disease such as CLL has not been addressed.  To investigate this possibility we evaluated the outcome characteristics of 222 of the 300 patients (who commenced FCR more than 10 years ago)  in our previously reported study of initial therapy with FCR in CLL². 

Seventy eight (35%) pts were free of relapse and 127 (58%) were alive at 10 years (Fig. 1). Thirty three patients died in CR/PR of infection ( 5), second malignancies (8), Richter’s transformation (8 ). MDS (9), and other causes (3).   One hundred and sixty three pts. (73%) achieved CR, 22 pts. (10%) a nodular PR (nPR), 27 pts. (12%) a PR, and 10 (5%) failed treatment.  The 10 year PFS correlates strongly with response, CR (41%), nPR+PR (15%) (Fig. 2).  None of these patients were transplanted in remission.

FISH analysis was not available at the time of this study.  Conventional karyotyping demonstrated +12 (24 pts), del 11q (15), del 17p (4), other abnormalities (15), diploid (105), and in 59 patients the test was not done or had no metaphases.  The worst outcomes were del 17p and del 11q each significantly inferior to diploid (+12) patients had the best time-to-treatment failure (TTF) with P<.09 compared to diploid.

The 10-year TTF was significantly higher for Rai <3 versus 3 – 4 (P=.02), serum beta-2-microglobulin (β2M) value of ≤ 4 mg/L (p<.001), mutation status of IgVh (P<.001) and number of courses of FCR received. (Table 1)  The causes for receiving <6 courses of FCR were persistent cytopenia (15), infections (6), resistance (5), Richter’s transformation and other malignancies (9), autoimmune hemolysis (5), and other causes and lost to follow-up (16).

Table 1.					10 yr TTF		10 yr OS
Characteristic	Value	Pts.	CR (%)	Χ2	TTF (%)	p-value	OS (%)	p-value
Rai Stage	<3 / 3-4	145/77	78 / 50	.04	38/22	.02	64/50	<.01
Serum b2M	< 4 / >4	129/95	83 / 58	<.001	44/22	<.001	74/40	<.001
IgVh Mutation	Mut/Unmut.	47/82	83 / 77	ns	49/11	<.001	76/46	<.01
# Courses	<6 / 6	57/165	51 / 81	<.001	16/38	.002	70/31	<.001

Of the 77 patients who are still in remission at 10 years, two have relapsed and one developed Richter’s transformation.  Four of 21 patients checked had no residual disease in their blood at 10 years by 4-parameter flow cytometry.  All other 10 yr. TTF patients are being contacted to provide blood for 4-parameter flow residual disease.

Conclusion

The present data suggest that one-third of patients treated with chemoimmunotherapy are potentially cured of CLL.  The characteristics most strongly associated with 10 yr. TTF were Rai stage, serum β2M level, mutation status, and tolerance of chemotherapy.  Second malignancies and transformations are emerging as significantly impairing the likelihood of cure.

¹Hallek M., et al, Lancet. 2010 Oct 2;376(9747):1164-74.² Tam, C., et al, Blood, 2008 Aug 15; 112(4): 975-980.

Figure 1. Survival vs. Time to Fail

Figure 2. Time to Fail By Response