CLL: Treatment in the Novel Era Treatment after failure of kinase inhibitors

Michael Gregor Zentrum für Hämatologie Luzerner Kantonsspital [email protected] Disclosure of conflicts of interest

1. Employment or Leadership Position: none

2. Advisory Role or Expert Testimony: AbbVie, Gilead, Janssen, Roche

3. Stock Ownership: none

4. Patent, Copyright, Licensing: none

5. Honoraria: AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche

6. Financing of Scientific Research: none

7. Other Financial Relationships: none

8. Immaterial Conflicts of Interest: none

2 Treatment algorithm for 1st-line therapy of CLL / SLL

Symptomatic or advanced stage CLL

IGHV IGHV Mutated TP53 Unmutated No del(17p) or dysfunction No del(17p) or TP53 TP53

Unfit: Unfit: Ibrutinib or Fit: Venetoclax+Obi Fit: CIT or Venetoclax (+Obi) Ibrutinib or CIT or Ibrutinib CIT or Ibrutinib Venetoclax+Obi or Idelalisib + R or CIT or Ibrutinib

3 adapted from Eichhorst B et al. ESMO guideline 2019 (submitted). Treatment algorithm for 1st-line therapy of CLL / SLL

Symptomatic or advanced stage CLL

IGHV IGHV Mutated TP53 Unmutated No del(17p) or dysfunction No del(17p) or TP53 TP53

Unfit: Unfit: Ibrutinib or Fit: Venetoclax+Obi Fit: CIT or Venetoclax (+Obi) Ibrutinib or CIT or Ibrutinib CIT or Ibrutinib Venetoclax+Obi or Idelalisib + R or CIT or Ibrutinib

4 adapted from Eichhorst B et al. ESMO guideline 2019 (submitted). Treatment algorithm for treatment of rel/ref CLL / SLL

relapsed CLL with symptoms

Short remission TP53 Long remission duration (< 36 dysfunction duration (> 36 months) months)

Repeat Ibrutinib or Ibrutinib or # Venetoclax +R * frontline or Venetoclax +R * or Venetoclax change to or Idelalisib + R * or Venetoclax Ibrutinib or Consider allo SCT alone* * Venetoclax +R * in fit or Idelalisib + R or Idelalisib + R or other CIT

5 adapted from Eichhorst B et al. ESMO guideline 2019 (submitted). Treatment algorithm for treatment of rel/ref CLL / SLL

relapsed CLL with symptoms

Short remission TP53 Long remission duration (< 36 dysfunction duration (> 36 months) months)

Repeat Ibrutinib or Ibrutinib or # Venetoclax +R * frontline or Venetoclax +R * or Venetoclax change to or idelalisib + R * or Venetoclax Ibrutinib or Consider allo SCT alone* * Venetoclax +R * in fit or Idelalisib + R or Idelalisib + R or other CIT

6 adapted from Eichhorst B et al. ESMO guideline 2019 (submitted). Changing use of novel agents for CLL

Past Yesterday Today / Tomorrow Future BCR-I in very advanced CLL with del17p/TP53mut CLL patients with no Venetoclax combinations disease (refractory and/or → Ibrutinib 1st line longterm benefit of CIT duration either fixed or very high-risk) → Venetoclax after failure → Ibrutinib 1st line adapted to response of BCR-I CLL refractory to CIT or CLL patients unfit for Venetoclax + Ab early relapse (<3y) intensive CIT Venetoclax + BCR-I → Ibrutinib or Idelalisib+R → Venetoclax + Obi Venetoclax + BCR-I + AB Novel novel agents

Hazard ratio 0.37 (95%-CI 0.25-0.56)

PFS @2y 98%

Byrd JC et al. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia N Engl J Med. 2014; 371: 213–223 Woyach JA et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untrea-ted CLL. N Engl J Med. 2018; 379:2517-2528 7 Jain N et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med. 2019; 380:2095-2103 Definition of failure of BCR-inhibitors in CLL

CLL

IWCLL 2018: “Responses that should be considered clinically beneficial include CR and PR; all others (eg, stable disease, nonresponse, PD, death from any cause) should be rated as a treatment failure.” also PD @ 6m

Accepted for chemoimmunotherapy, less clear for continuous therapies with BCR-I due to initial lymphocytosis (PR-L, not PD!) and sometimes clinical improvement with persistent (therapy related) cytopenia or minor findings (e.g. splenomegaly).

General understanding failure of BCR-I includes: • Insufficient response at a defined timepoint - Progression under continuous treatment • Relapse after response - Side effects requiring permanent stopping of BCR-I • Mutations (predicting loss of response)

8 Hallek M et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018; 131: 2745-2760. Discontinuation of Ibrutinib

MDACC, 33/127 patients teated in 4 clinical trial discontinued ibrutinib. Reasons: Transformation (7), Progression (7), SCT (3), side effects (14), other (2)

Historic data: 2010 – 2014. Poor-risk patients without any further options!

Jain P et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062-2067. 9 Discontinuation of Ibrutinib real world data

Reason for Median time to Survival According to Cause of Discontinuation Median OS discontinuation discontinuation 100 (Months) (n=90) (Months) Toxicity Progression Intolerance 80 16 33 (n=29; 32%) Transformation Other reasons 60 Progression 22.3 16 (n=19; 21%) 40 Transformation 13.2 2.3 (n=9; 10%) 20 Percent Survival Percent Miscellaneous p<0.0001 10.4 11 (n=28; 31%) 0 0 4820 9640 14460 Time (months)

Survival was associated with the reason for discontinuation; patients who had toxicity had better survival compared with those who had progressive CLL or disease transformation.

Jain P et al. Long‐term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib. Cancer. 2017;123(12):2268-2273. 10 Discontinuation of Ibrutinib real world data

. Connect® Chronic Lymphocytic Leukemia Registry in US (2014-2016). . 621 ibrutinib-treated patients. ∅ FU 17 months. . 42% of patients discontinued ibrutinib (∅ 7 months).

Mato AR et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103: 874-879. 11 Discontinuation of Ibrutinib real world data

. Reasons for stopping ibrutinib due to toxicity:

. Front-line treatment: . arthralgia (42%), . atrial fibrillation (25%), . rash (17%). How was . R/R patients: the management of toxicities? . atrial fibrillation (12%), . infection (11%), . pneumonitis (10%), . bleeding (9%), . diarrhea (7%).

Mato AR et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103: 874-879. 12 Management of toxicities of ibrutinib

. Most patients will have some toxicities!

. Check co-medications (drug-interactions → CYP3A4)

. Identify patients with high-risk for specific toxicities Individual e.g. cardiac disease → risk for atrial fibrillation, anticoagulation or antiaggregation, immunodeficiency and risk for infections. . Inform about potential toxicities (e.g. early onset diarrhea, arthralgia, cytopenias).

. Symptomatic treatment of mild toxicities.

. Dose reductions are frequently required. (without impact on outcome!)

Gribben JG, et al. Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice. Brit J Hematol. 2018; 180:666-679 13 Intolerance of BCR-I: Idelalisib

. Phase-III Idela+R vs, placebo+R . Longterm results

Immunologic side effects mostly during first 2 years (diarrhea/colitis, hepatitis, pneumonitis) Increased rate of infections during follow-up After 1 year 58% of patients on idelalisib, after 2 years 29% of patients on idelalisib.

Sharman JP et al. Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia). J Clin Oncol 2019; 37:1391-1402. Coutré SE et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leukemia & Lymphoma 56:10, 2779-2786 14 Treatment Options in Intolerance of BCR-I

Watch and wait: . Patients with response to BCR-I may not need any treatment after stopping!

. Consider: previous therapies, length of therapy with BCR-I, quality of response, type and severity of toxicity, patient’s wish.

. Some patients will have a symptomatic relapse within weeks, therefore plan further treatment. . Some patients will be without any treatment for several months ((1-2 years))

15 Treatment Options in Intolerance of BCR-I

Chemoimmunotherapy?

. Can be considered in patients with favourable risk factors for response to CIT (no del17p, no TP53 mutation, mutated IgHV) after first-line ibrutinib or minimal previous exposition to CIT.

Only 5 patients with previous ibrutinib

Fischer K et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med 2019;380:2225-36 Seymour JF et al. Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 2018;378:1107-20. 16 Treatment Options in Intolerance of BCR-I

BCR-I after intolerance of previous BCR-I: . Some patients with lower grade toxicity or reversible risk factors (e.g. stop of anticoagulation) may accept same agent for a second time, often at a lower dose.

. Same class of BCR-I (e.g. BTK-I: acalabrutinib, PI3K-I: Duvelisib, both not available in Europe)

Phase-II, 33 patients, median 4 prior therapies

. Change of BCR-I (ibrutinib ↔ idelalisib) ?

Awan FT et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Advances. 2019; 3: 1553-62. 17 Treatment Options in Intolerance of BCR-I

Venetoclax vs. BCR-I: . Retrospective “real world” data (683 patients, 258 stopped ibrutinib, 58 stopped idelalisib):

. Ibrutinib → idelalisib with lower response . Idelalisib → ibrutinib with lower CR rate . Both with shorter PFS . CIT poor in r/r CLL failing BCR-I

Mato AR et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Annals of Oncology 2017; 28: 1050–1056. 18 Failure of BCR-I due to progressive disease

“Because most patients will not attain a complete response, and many will have circulating leukemia cells for long periods of time, determining which patients are indeed relapsing can be a challenge.”

Woyach JA. How I manage ibrutinib-refractory chronic lymphocytic leukemia Blood 2017; 129: 1270-1274). Maddocks KJ et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015; 1: 80-87. 19 Evaluation of suspected transformation in CLL:

When to suspect transformation of CLL • Asymmetric growth of lymph nodes or fast growth of bulky disease (e.g. abdominal) • Early progression, onset of B symptoms • Sudden and excessive rise of LDH (without e.g. hemolysis)

Sensitivity 91% Specifity 80% PPV 53% NPV 97%

Hodgkin Second cancer

Adapted from Rossi D et al. Biology and treatment of Richter syndrome. Blood. 2018; 131: 2761-2772. 20 Treatment of Transformation of CLL

. Hodgkin: treat acording to stage and fitness of the patient (“ABVD”)

. Clonally related DLBCL:

Recommendation: Followed by allo SCT. Due to poor response and fitness rarely done. Option autologous SCT.

. Use of new strategies warranted: . Novel agents, combination of novel agents . Combination of chemoimmunotherapy and novel agents . CAR-T cells . Inclusion in clinical trials whenever possible.

Allan JN, Furman RR. Current trends in the management ofRichter’s syndrome. Int. J. Hematol. Oncol. 2019; 7(4). Langerbeins P et al. Poor efficacy and tolerability of R-CHOP in relapsed/refractory chronic lymphocytic leukemia and Richtertransformation. Am. J. Hematol. 2014; 89:E239–E243. 21 Molecular mechanisms of resistance to ibrutinib

50% - 80% 10% 5 -10%

15-40 %

. BTK C481S mutation cannot be inhibited by BTK inhibitors with colvalent binding (ibrutinib, acalabrutinib) novel non covalent inhibitors (other binding site) may be active. . Downstream mutations of PLCγ2 induce resistance to othe BCR-I. . Laboratory testing for mutations is not standardized.

22 Treatment of CLL resistant to BCR-I (Ibrutinib)

. Venetoclax monotherapy after Ibrutinib failure (PD not intolerance) . Phase-II, multicenter, US, 2014 – 2016, 91 patients median 4 previous therapies.

. Today less pretreated patients. . Results probably better with addition of monoclonal ab. . Not satisfactory for younger patients.

Jones JA et al. 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 23 Treatment of CLL resistant to BCR-I (Idelalisib)

. Venetoclax monotherapy after Idelalisib + R / Idelalisib failure (PD not intolerance) . Phase-II, multicenter, US, 2014 – 2016, 36 patients, median 3 previous therapies (10 ibrutinib).

OS @ 1 y 94%. . Today less pretreated patients. . Results probably better with addition of monoclonal ab. . Not satisfactory for younger patients.

Coutre AR et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018; 131: 1704-1711. 24 Allogeneic Stem Cell Transplantation in CLL

Allo SCT in Heidelberg

Allogeneic SCT is still a valid option for fit CLL patients with very-high-risk disease or refractory to BCR-I, who are unlikly to have longterm benefit from a bcl2-inhibitor.

Dreger P et al. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies . Blood 2018; 132.:892-902 Hoffmann A et al. Allogeneic transplantation in high-risk chronic lymphocytic leukemia: a single-center, intent-to-treat analysis . Haematologica 2019; 104: e305. 25 My treatment algorithm for CLL after failure of BCR-I

Failure of BCR-I

Toxicity, Intolerance, Resistance Patient’s choice*

Treatment Transformation CLL needed ? - (clonally realated DLBCL)

+ Watch and wait Venetoclax + R Clinical trial Venetoclax + R Change of BCR-I + R-CHOP Venetoclax CIT (selected pts) Followed by allo SCT Consider allo SCT Same BCR-I*

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