As ASCO 2014 comes to an end, everyone seems to be buzzing about exciting opportunities for chronic lymphocytic leukemia (CLL) treatment that are new combinations of existing treatments, recently launched novel therapies or new emerging therpaies  in late-stage clinical development.

These treatment opportunities include CD20-targeted monoclonal antibodies (MAbs) (i.e. rituximab, ofatumumab and obinutuzumab); B-cell receptor pathway inhibitors (i.e. ibrutinib, idelalisib); immunomodulators (including lenalidomide and PD-1/PD-L1 monoclonal antibodies), Bcl-2 inhibitors (specifically, ABT-199) and the classic combination of monoclonal antibodies with chemotherapy backbones (e.g. fludarabine/cyclophosphamide/rituximab [FCR] and bendamustine/rituximab [BR]). In addition to these, a new technology which has the potential to be a powerful tool against other types of cancer such as cervical and head and neck cancer is now generating enthusiasm in clinical trials  in CLL namely CAR T-cell therapy.

More monoclonal antibodies, more options

Starting with MAbs, there are now three anti-CD20 MAbs available to CLL patients, either as a first-line treatment or for use in second- and subsequent lines. Rituximab (Roche/Genentech/Chugai's Rituxan/MabThera), the main player in CLL treatment, has been joined by obinutuzumab (Roche's Gazyva/Gazyvar), which is now approved in the first-line setting in combination with chlorambucil, following the positive results from the CLL11 trial. This pivotal Phase III trial showed that obinutuzumab offers a superior median progression-free survival (mPFS) compared with rituximab when used in  treatment-naïve, elderly CLL patients with comorbidities. Whether obinutuzumab's clinical activity could be extrapolated to other CLL patient populations remains to be demonstrated, but the drug has the potential to replace rituximab in the future.

Ofatumumab (GlaxoSmithKline/Genmab's Arzerra), has previously suffered from a rather limited label in relapsed/refractory (R/R) CLL (following fludarabine and alemtuzumab [Sanofi/Genzyme's Campath/MabCampath] failure); however, ofatumumab has now been FDA-approved for first-line CLL treatment, also in combination with chlorambucil. This label expansion is a much needed boost for ofatumumab, considering recently released disappointing results for the drug failure to meet the primary end point in the ORCHARRD trial in DLBCL and ofatumumab's inferior clinical activity in CLL when compared with ibrutinib (discussed later).

Ibrutinib is expected to change medical practice

Perhaps the most exciting drugs currently being developed for CLL are the kinase inhibitors, in particular the Bruton's tyrosing kinase (BTK) inhibitor ibrutinib (Johnson & Johnson/Janssen/Pharmacyclics/Imbruvica) and Gilead Sciences PI3K-delta inhibitor idelalisib. Data on these two drugs presented in Chicago has elicited tremendous excitement. Ibrutinib  gained FDA-approved for R/R CLL treatment in February 2014 based on an open-label multi-center Phase Ib/II trial, and data presented at ASCO this year indicates that the drug is extremely efficacious in this patient population. The eagerly anticipated long-term analysis data presented by Dr. Susan O'Brien on the last day of the conference show that three years post-initiation of ibrutinib monotherapy, the drug demonstrates durable responses in both treatment-naïve and  R/R CLL/SLL patients, including those with  del(17p).  The overall response rate (ORR) achieved by ibrutinib monotherapy was 78 percent for all treated patients and 55.9 percent for those R/R with del(17p). The median duration of response in these high-risk patients was a very impressive 25 months.

The R/R patients included in the analysis had a median of four prior therapies; these are therefore patients who have limited treatment options, so seeing such data is very impressive. The greatly anticipated results from the RESONATE trial, in which R/R CLL patients were treated with either ibrutinib or ofatumumab were presented by Dr. Byrd, and  showed ibrutinib significantly improves PFS. While the mPFS was not reached in the ibrutinib arm, the 6 month PFS rate was 88 percent (compared with the mPFS achieved by patients receiving  ofatumumab, which was 8.1 months). Even more impressively, at 6 months follow-up, 83 percent of patients with high-risk cytogenetic profiles, for example patients with del(17p) and del(11q), in the ibrutinib arm were still alive with no disease progression, compared with 49 percent in the ofatumumab arm. This data adds to the accumulating evidence that ibrutinib is a very efficacious therapy that offers CLL patients, even high-risk patients, significant survival benefits.

Results from a Phase III trial presented at the meeting indicate that idelalisib in combination with rituximab is also very efficacious in high-risk, relapsed CLL patients. Idelalisib achieved an ORR of 76.5 percent in the highest risk patient cohort (patients were positive for both del[17p] and TP53mut). These patients are difficult to treat, so a drug offering such clinical activity in this population is a welcome addition to the armamentarium. While the mPFS and MOS have not yet been achieved, results show statistically significant improvements compared with rituximab alone. The combination of idelalisib and rituximab demonstrated an acceptable safety profile, with only 5 percent of patients discontinuing treatment as a result of adverse events (vs. 6 percent in the rituximab + placebo comparator arm). Grade >3 adverse events occurring in more than 10 percent of patients in the idelalisib + rituximab arm included pyrexia (3 percent), fatigue (5 percent), diarrhea (4 percent) and pneumonia (8 percent).

Based on the data presented at the meeting, ibrutinib and idelalisib are expected to compete with one another, especially in the high-risk relapsed patient population.

Is a CLL cure in the pipeline?

Another drug generating significant interest is AbbVie/Roche's ABT-199, a second-generation Bcl-2 inhibitor. A poster presented at ASCO by John Seymour shows ABT-199 can achieve high complete response rates and durable disease control in R/R CLL and SLL. While the drug has had problems with tumor lysis syndrome (TLS) at the start of the trial, following modifications to the dose escalation scheme and following inclusion of TLS aggressive prophylaxis and monitoring, clinical development was restarted and physicians indicate that the rapid response seen with ABT-199 the observed TLS is in fact testament to the drug's efficacy.  ABT-199 may prove to be a great contender to ibrutinib; some physicians talk of ABT-199 potentially achieving a cure for some patients, rather than converting CLL to a chronic disease, which could be possible with ibrutinib treatment. ABT-199 monotherapy activity was observed in R/R CLL patients, including the aforementioned difficult to treat del(17p), and achieved an ORR of 77 percent (high-risk patients achieved a similar ORR). Following ABT-199 treatment, there was no detectable minimal residual disease (MRD) in several patients, including those with high risk disease, and the 24-month PFS achieved at doses of 400 mg or higher was 59 percent for the entire cohort and 54 percent for high-risk patients.

In clinical practice, ABT-199 would likely be combined with an anti CD20 MAb, Dr. Shuo Ma presented interim data from the Phase Ib trial in which ABT-199 was combined with rituximab, and results indicate that the combination demonstrates high antitumor activity in R/R CLL/SLL patients. ABT-199 + rituximab  achieved an impressive ORR of 89 percent , with 36 percent of patients achieving CR/CRi.

ABT-199, either as monotherapy or in combination, is now the subject of Phase II and III clinical trials which are already enrolling patients, and this Bcl-2 inhibitor looks set to become a  significant player in the future treatment of CLL.

Could engineered T-cells be an option for CLL treatment?

A new and exciting therapy currently in development for treating CLL is employing the use of engineered T-cells known as chimeric antigen receptor T-cells, or CAR T-cells.

Phase I data from a trial using autologous CD19-targeted CAR-modified T-cells as a consolidation treatment following purine analog-based first-line therapy in treatment-naïve CLL patients was presented by Jae Hong Park and colleagues. The small Phase I trial included only 7 patients who were induced with pentostatin/cyclophosphamide/rituximab (PCR); all achieved a PR following induction, and were then treated with CART-cells. Only one of these patients, however, achieved a CR, and while 2 patients achieved CR in the bone marrow, they experienced progressive disease in the lymph nodes. This data indicate that while the method looks promising, it appears to be only eradicating CLL in the bone marrow rather than the lymph nodes. The treatment is relatively well tolerated, with a mild and self-limiting cytokine release related to the CAR T-cell persistence.  Undeniably, further work needs to be undertaken to investigate this mechanism of resistance, but physicians remain optimistic that the method could potentially be added to the CLL armamentarium.

These are exciting times to be working in CLL/SLL, and physicians are extremely positive about future treatments.

Dana Gheorghe, Ph.D., is a business insights analyst on the Oncology team at Decision Resources Group.

References:
Seymour JF, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): high complete response rate and durable disease control. Abstract 7015.

Shuo M, et al. ABT-199 (GDC-0199) combined with rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): interim results of a Phase Ib study. Abstract 7013.

O'Brien S, et al. Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. Abstract 7014.

Park JH, et al. Phase I trial of autologous CD19-targeted CAR-modified t cells as consolidation after purine analog-based first-line therapy in patients with previously untreated CLL. Abstract 7020.

Byrd JC, et al. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma. Results from the phase III RESONATE trial. Abstract LBA7008.

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