CLL/SLL

ASCO® 2016 Education Session – Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When, How Long, How Much, and in Which Combination?

During ASCO 2016, an education session took place on Saturday June 4, 08:00–09:15am, titled ‘Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When, How Long, How Much, and in Which Combination?

This session began by everybody being welcomed and the speakers being introduced by the Chair, Dr John M Pagel, Associate Professor and Associate Member in the Clinical Research Division at the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance in Seattle, Washington. This was then followed by three presentations and a panel question and answer session. All presentations in this session followed the ‘Value’ track.

The first presentation was given by Professor Michael J Hallek who is Professor of Medicine, Director, and Chair of the Department of Internal Medicine at the University of Cologne, Germany. The presentation was called ‘Chronic Lymphocytic Leukemia: Pathogenesis, Prognostic Factors and Role of Chemoimmunotherapy in 2016’.

Professor Hallek succinctly summarized current first-line and second-line treatment options for CLL patients:

Stage

Fitness

Del(17p)/TP53 mut

Therapy

Binet A–B, Rai 0–II, inactive

Irrelevant

Irrelevant

None

Binet C, Rai III–IV, active

Go go

No

FCR (BR in those older than 65 years)

Yes

Ibrutinib, idelalisib plus rituximab, allogeneic SCT (?)

Slow go

No

Ibrutinib or chlorambucil plus obinutuzumab or ofatumumab or rituximab

Yes

Ibrutinib, idelalisib plus rituximab, high dose rituximab or ofatumumab, alemtuzumab

First-line therapy

Response to first-line therapy

Fitness

Therapy (choice may depend on comorbidity)

Refractoriness or progression within 2 years

Go go

Ibrutinib, venetoclax, idelalisib plus rituximab, lenalidomide (plus rituximab), alemtuzumab, FCR, BR –> allogeneic SCT (in second or third line)

Slow go

Ibrutinib, venetoclax, idelalisib plus rituximab, lenalidomide (plus rituximab), alemtuzumab, BR, ofatumumab, high dose rituximab

Progress after 2 years

All

Repeat first-line therapy; if del(17p) or mutated TP53 use novel inhibitors

Second-line therapy




This portion of the session was concluded by stating that we have a much greater understanding of the molecular evolution of CLL. The International Prognostic Index (CLL-IPI) has vastly improved the prognostication of patients and allows the identification of high-risk patients that are potential candidates for novel agents and clinical trials. Professor Hallek emphasized that currently chemoimmunotherapy is the standard care option for physically fit patients, especially those with low risk genetic and cytogenetic characteristics. Chlorambucil and anti-CD20 antibodies (such as rituximab) are being challenged as standard care options by new agents such as ibrutinib for unfit patients. Lastly, there is a critical need for more randomized controlled trials with the aim of comparing chemoimmunotherapy with novel inhibitor combinations.

Targeted Therapy in Chronic Lymphocytic Leukemia: Where Are We Now?’ was the second presentation given during this education session. Jennifer R Brown, MD, PhD, Associate Professor of Medicine at Harvard Medical School and Director of the CLL Center at the Dana-Farber Cancer Institute, was the speaker.

Ibrutinib, a small molecule BTK inhibitor, has achieved superb results but is not a cure for CLL; the majority of results are PRs although they are sustained. In R/R CLL patients, a PFS of 69% at 3 months has been previously reported and this increases to 87% in non-11q/17p patients. PFS in lower-risk elderly patients treated with ibrutinib has been reported as 90% at 18 months. A similar PFS was reported in second-line patients in the RESONATE study. Currently, investigations exploring rituximab alone compared to bendamustine-rituximab combinations show that outcomes are similar. 

There are a number of issues and concerns with the use of ibrutinib for CLL. Firstly, approximately 10–30% of patients discontinue ibrutinib due to the adverse effects they experience such as diarrhea, vomiting, arthralgia, musculoskeletal pain, fatigue, and rash. Secondly, patient who experience progression with ibrutinib generally do not respond to salvage therapy. Moreover, despite the fact that ibrutinib has demonstrated excellent activity in patients harboring del(17p), most studies in these specific patients have found they still have poor outcomes and are at an increased risk of transformation.

Professor Brown moved on from ibrutinib to discuss the PI3K inhibitor idelalisib, which has been found to be highly active in both newly diagnosed and R/R CLL. In previous reports, median PFS has been 19 months in patients with high CIRS and short remission duration. No difference in PFShas been found with idelalisib based on IGHV or del(17p) mutation status. A great concern with idelalisib is its associated toxicity profile, which affects a number of categories:

  • Autoimmune: transaminitis, diarrhea/colitis, and pneumonitis
  • Neutropenia and sepsis: in recent trials which have been stopped, the primary cause of death has been infection; this is not as common when idelalisib is used alone and not combined with bendamustine-rituximab (patients should be closely monitored and growth factors should be used)
  • Opportunistic infections such as Pneumocystis pneumonia (PJP) and Cytomegalovirus (CMV)

In case of PJP or Varicella Zoster Virus (VZV) infection, or neutropenia, prophylaxis is mandatory. Crucially, idelalisib should not be used in the upfront setting unless absolutely necessary. In addition, there is currently very limited data available concerning responses to idelalisib in patients who have failed ibrutinib.

Jennifer Brown emphasized that it is crucial to be vigilant in regard to the onset of the what is now thought of as a classic pattern of toxicity with idelalisib; the risk is higher in less heavily pretreated and younger patients. It is advised to interrupt/delay treatment early upon the appearance of significant transaminities, diarrhea, or intestinal pneumonitis. Moreover, thorough evaluation for infections is critical and if infections are deemed to be drug-related and not resolving then steroids should be administered.

Following this, it was asked if chemotherapy should be replaced by novel biologic agents. Biologics are oral, which is far more convenient for patients. They have shown high efficacy even in high risk disease; the difference from chemotherapy is most apparent in relapsed patients and randomized studies comparing biologics with chemoimmunotherapy are ongoing to determine their efficacy in the first-line setting. The downsides to therapy with biologic agents is that they have to be administered continuously and indefinitely compared to 6 months of chemotherapy. In addition, HCPs are reluctant to abandon FCR in patients with mutated IGHV which can result in cure. Biologics, on the most part, are well tolerated; however, they do result in numerous low-grade adverse events which can inpact on a patient's quality of life and the long-term effects are currently unknown. Also, as patients become older their ability to tolerate biologics does decrease. Lastly, negatives to biologic agents include cost and the fact it is unknown whether salvage therapy will work in cases which relapse.

There are some strategies available to us to tackle the negatives of biologics. For example, to overcome toxicity, we should aim to find novel, effective combinations that are able to achieve deep remissions. Moreover, therapy can be delayed for relatively short (6–24 months) time periods, allowing for "treatment holidays".

The last presentation was given by the session’s Chair, Dr John M Pagel, and was titled ‘CLL 2016: Select Unanswered Questions’. This presentation is associated with an ASCO 2016 Educational Book of the same title, authored by Brown, Hallek and Pagel.

This talk included data from a retrospective, multicentric analysis of 178 patients with CLL who discontinued ibrutinib (n=143) or idelalisib (n=35) based regimens for any reason (Mato A. et al. ASH 2015; abstract 719).




 

Baseline characteristics

Result

Total No.

Median age (range) years,

60 (33–89)

178

Median no. of prior therapies (range),

3.0 (0–11)

8% untreated (n=14)

178

Del(17p) present (FISH), %

34

155

Del(11q) present (FISH), %

27

152

TP53 mutation present, %

27

95

Complex karyotype (≥3), %

29

128

ZAP-70 positive CLL, %

67

60

IGHV mutated, %

69

49

  • 10% of ibrutinib (5% 140mg, 5% 280mg daily) and 32% of idelalisib (32% 100mg BID) were initiated at doses less than FDA labeled dose
  • Prior to discontinuation, dose modification in 23% ibrutinib and 30% idelalisib patients; dose held in 42% of ibrutinib and 65% idelalisib pts
  • Overall median time on Kinase Inhibitor (KI) therapy = 5 months (4.8 month ibrutinib; 5.5 months idelalisib)
  • ORR to KI = 63% (CR 15%, PR 39%, PR-L 9%)
  • The most frequent reasons for discontinuation of KI therapy was toxicity (58% ibrutinib; 60% idelalisib), CLL progression (24% ibrutinib; 30% idelalisib), and RT DLBCL (8% ibrutinib; 7% idelalisib)

Following this, data from the Fred Hutchinson Cancer Research Center regarding Chimeric Antigen Receptor (CAR)-T cell therapy for CLL was presented.

In total 9 pts (CLL n=8; CLL/PLL n=1) aged between 36 and 70 years old were administered lymphodepleting chemotherapy and CAR-T cells. The median number of prior therapies of these patients were 7; 2 patients had failed previous allo-SCT and all patients had previously received ibrutinib. Lymphodepleting chemotherapy in the majority of patients (n=7) was cyclophosphamide 30–60mg/kg and fludarabine 25mg/mfor 3–5 cycles. One patient received just cyclophosphamide at 2g/mand one further patient only received fludarabine at 25mg/m2 for 3 cycles.

In terms of CAR-T cells, CD8 central memoral cells were selected in 3 of the 9 patients; CD8 bulk selection due to circulating tumor in 6 of 9 patients. Three patients received 2x105/kg cells, 5 patients received 2x106, and one patient received 2x107 cells. 

An ORR was observed in 8 of 9 patients (89%) with CRs in 4 patients (44%), these were ongoing 2–14 months post-infusion of CAR-T cells. MRD-negativity was determined in the bone marrow by flow cytometry in 8 of 9 patients (89%). Severe Cytokine Release Syndrome occurred in one patient (11%) who died 3 months post-infusion (pulmonary aspergillosis). Grade 3–4 neurotoxicity was reported in 3 of 9 patients (33%).

Dr Pagel then focused on what we can currently say about CLL and what is required in the future. Currently, novel inhibitors have been found to be highly effective and potentially could result in long-lasting remission. In addition, if relapse occurs to these inhibitors, subsequent treatments are still effective including chemoimmunotherapy. Specifically in patients harboring del(17p) or with complex karyotype, relapses are severe and sudden and hard to treat. It is hypothesized that venetoclax may result in responses in patients refractory to kinase inhibitors. For now, chemoimmunotherapy for fit patients remains the first-line standard of care.

In the future, trials need to be conducted to define novel combinations. There is a need for more randomized trials in both newly diagnosed and R/R patients, rather than single center observational studies. Novel treatment regimens and strategies are required for Richter transformation and further exploration into the use of immunotherapy and CAR-T cell therapy should be undertaken.