1. Carlson, Robert H.

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NEW YORK-Complete response (CR) rates for patients with chronic lymphocytic leukemia (CLL) have risen from five percent in the 1960s when the alkylating agents chlorambucil and cyclophosphamide were standard, to 45 percent today with use of chemo-immunotherapy. Meanwhile, new additions to the armamentarium such as immune modulators (IMiDs), tyrosine kinase inhibitors (TKIs), and anti-CD-20 monoclonal antibodies are showing their strengths in clinical trials.


Key questions, therefore, are whether there are now enough data to eliminate chemotherapy from initial treatment for CLL; and if so, whether kinase inhibitors and IMiDs can replace chemotherapy.


Two experts debated those questions here at the Lymphoma & Myeloma International Congress. Jennifer R. Brown, MD, Director of the CLL Center at Dana-Farber Cancer Institute, said that yes, kinase inhibitors and IMiDs can replace chemotherapy. Susan O'Brien, MD, Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, though, said that no, they can't.

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Jennifer Brown: The Problem with Chemotherapy...

The problem with chemotherapy, Brown began, is continuous relapse at progressively shorter intervals and progressive resistance to therapy. She started her argument citing the GCLLSG CLL8 trial of single-agent fludarabine in which about 31 percent of patients had disease progression within two years. Furthermore, she said, "elderly patients-the majority with CLL-tolerate chemotherapy poorly, and patients with 17p and/or complex cytogenetics respond poorly from the start."


Myelosuppression can be persistent with chemotherapy, leading to the risk of therapy-related myelodysplastic syndromes and acute myelogenous leukemia, she explained. Plus there is a risk of immunosuppression, also often persistent, as well as increased infection risks.


In addition, clonal evolution, the selection for pre-existing adverse clones vs. induction of new clones, is a concern with chemotherapy.


So what are the alternatives? Brown pointed to mature data in previously untreated patients with lenalidomide, idelalisib, and ibrutinib, and evolving data on the anti-CD-20 antibody obinutuzumab.


Lenalidomide is active in several hematological malignancies, she continued. In CLL it promotes cell activation and T cell function but is not cytotoxic. It is effective in relapsed/refractory CLL, with an objective response rate of 35 to 50 percent.


"But it can be difficult to tolerate, with tumor flare, tumor lysis, and myelosuppression."


Brown cited one study with impressive results, of upfront therapy for elderly patients. At 24 months of follow-up, the overall survival and progression-free survival rates were 88 and 60 percent, respectively. At four years, overall survival was 82 percent, with no time to failure yet reached (Badoux X et al: Blood 2011;118:3489-3498).


In another study she cited, the best response for lenalidomide did not include any complete responses at 20.7 months of follow-up, but the rate was 53.2 months was 20 percent. Partial response rates were 56 and 52 percent, respectively, and the duration of response was 16.6 and 40.4 months, respectively (Chen C et al: 2012 ASH Annual Meeting, Abstract 718).


"Long-term follow-up of that study demonstrated that when using low doses of single-agent lenalidomide in CLL, prolonged therapy is feasible and may be required for the achievement of durable, high-quality responses," Brown said.


Those researchers also reported that maximal daily doses of 25 mg could be reached and may be needed for optimal response, although recurrent myelosuppression remained a limitation.


"In summary, the mature data on lenalidomide in previously untreated elderly patients look very promising," she said.


However, in July 2013, the industry-sponsored Phase III ORIGIN (CLL008) study of lenalidomide versus chlorambucil was closed early due to excess deaths in the lenalidomide arm in patients over age 80, and many early drop-outs in that age group.


Targeting Kinases

Idelalisib (GS-1101) targets kinases in the BCR pathway and is highly selective for PI3K delta, Brown said. She then cited a study led by her opponent in this debate, the 101-08 Phase II single-arm, open-label study of oral idelalisib plus rituximab in 64 previously untreated patients with a median age of 71 (O'Brien S et al: ASCO 2013 Annual Meeting, Abstract 7005).


The regimen achieved a 19 percent complete response rate but an overall response rate of 97 percent, with estimated progression-free survival (PFS) at 24 months of 93 percent.


The probability of PFS in the intent-to-treat analysis was 93 percent at 24 months for all 64 patients, and 100 percent for the nine patients with TP53 mutation/del(17p).


Adverse events in the idelalisib-rituximab trial were 55 percent for any grade of diarrhea, with 23 percent grade 3 or 4; 42 percent pyrexia, with three percent grade 3-4; nausea 38 percent with two percent grade 3-4; rash 38 percent with eight percent grade 3-4; chills 36 percent of any grade and none grade 3-4; cough three percent, with two percent grade 3 or 4; and fatigue 31 percent but no grade 3-4; pneumonia 27 percent, 17 percent grade 3-4. Transaminase elevations occurred in 23 percent of patients, and neutropenia in 23 percent.


"But all could be managed effectively, and certainly we're used to managing these and worse toxicities with chemotherapy," Brown said.


Of note, she added, was that the response rate with idelalisib-rituximab was preserved in the high-risk TP53 mutation/del(17p) patients.


The other kinase inhibitor Brown discussed was the Bruton tyrosine kinase (Btk) inhibitor ibrutinib, which forms a specific and irreversible bond with cysteine-481 in the Btk to inhibit it. Once-daily dosing results in 24-hour sustained target inhibition.


Brown cited the ibrutinib Phase Ib/2 RESONATE (PCYC-1102-CA) trial, with 31 previously untreated patients age 65 and older with CLL or small lymphocytic leukemia (Byrd J et al, 2013 ASCO Annual Meeting, Abstract TPS8619).


The best responses in that trial were 13 percent complete responses and 58 percent partial responses, 13 percent partial responses with lymphocytosis, and 10 percent stable disease. There was no disease progression, and immunoglobulin levels remained stable or increased.


Brown summarized the first part of her presentation, saying that mature follow-up data with lenalidomide, idelalisib, and ibrutinib demonstrate at least comparable and possible improved PFS compared with chemo-immunotherapy.


"Can we improve further on these outcomes?" she asked rhetorically, and move on to the anti-CD-20 antibody.


That drug increases direct cell death and enhances antibody-dependent cell-mediated cytotoxicity (ADCC) and lowers complement-dependent cytotoxicity (CDC).


The ongoing CLL11 study, she noted, planned for 780 patients with previously untreated CLL with comorbidities, will randomly assign patients to chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil.


Kinase inhibitors and IMiDs (with or without anti-CD20 antibody) show durable remissions in previously untreated patients, and additional drugs (IPI-145, ABT199) are poised to add to this landscape, Brown summed up.


She mentioned two upcoming randomized trials comparing novel agents with chemo-immunotherapy:


* An ECOG trial of fludarabine-cyclophosphamide-rituximab (FCR) vs. ibrutinib-rituximab (IR) for patients under age 70; and


* An Alliance trial of bendamustine-rituximab (BR) vs. ibrutinib-rituximab (IR) vs. ibrutinib for CLL patients age 65 and older.



"This is very exciting for upfront treatment of CLL," Brown said.


Susan O'Brien: Chemotherapy Still Best for Most Patients

"The obvious answer to this debate question is 'no,'" O'Brien began in her presentation. To show why novel agents won't replace chemotherapy quite yet, she asked another question: What do we get with chemotherapy? High CR rates for one thing, she said.


Showing slides from Michael Keating, MD, who was originally scheduled for this debate but was not able to attend, she reviewed long-term data from an MD Anderson study of 300 patients (FCR300) treated with FCR. There was a CR rate of 72 percent (217 patients), nodular PR of 10 percent (31 patients), and a PR in 12 percent (37 patients). There were 13 non-responders (4%), and two early deaths (1%).


"That 72 percent CR rate was a bit higher in this single-institution data than in CLL8, but I will remind you that in all [of Brown's] slides we just saw, the CR rate with B cell receptor inhibitors, even in the front-line setting, was only about 10 percent. We're not getting complete remissions with those. Do we need complete remission? I don't know about you, but if I were a patient I would really rather have no disease."


As long as there are circulating lymphocytes, the crosstalk interferes with T cells, and it is very clear that getting into complete remission reduces the infection rate, O'Brien said.


"So yes, CR is still pretty important."


Randomized trial data also supported her point, she added.


For example, in the randomized CLL8 trial's study arm of untreated CLL patients receiving FCR, a 2011 update showed a median progression-free survival time of 57.9 months (Fink et al: 2011 ASH Annual Meeting, Abstract 977).

SUSAN OBRIEN, MD. SU... - Click to enlarge in new windowSUSAN O'BRIEN, MD. SUSAN O'BRIEN, MD: "If you're a CLL patient who needs treatment and don't have an 11q or 17p, would you like to go on a pill you have to take forever, and maybe develop mutations and resistant disease, and don't know what the toxicities might be? Or would you like to be inconvenienced and not have a great time for maybe six months, and then be done and perhaps be on this [PFS] curve for 13 or 14 years? I know which I would vote for."

There are no data for the agents Brown discussed going out that far, O'Brien noted.


"And by the way, these people [on FCR] aren't taking any pills. They're off therapy and in remission."


Also shown in CLL8, FCR is the first regimen ever shown to have a survival benefit in CLL (Fischer et al. 2012 ASH Annual Meeting, Abstract 435).


FCR Not Standard of Care for All CLL

FCR is clearly not for everyone, O'Brien said, starting with the del(17p) population, which account for five to 10 percent in the upfront setting.


It's commonly thought that FCR chemotherapy is not for older patients either, she said, and this would certainly be true for those who do not have normal creatinine clearance, which is often the case in the elderly.


But a creatinine clearance of 70 ml/min or above was an eligibility criterion in CLL8, and in that trial there was no statistically significant difference in toxicities between patients under or over age 70.


This is not a large population, O'Brien noted. She calculated how many of patients with CLL over age 70 years seen in her clinic in one month would have been eligible for that trial: Out of 14 patients, three were over age 80 and ineligible, and seven would not have met the creatinine clearance requirement. So in fact only four patients-29 percent-would have been eligible.


O'Brien added that many of the toxicities seen with FCR are probably due to problems with creatinine clearance. She said she routinely uses FCR in older patients, but she also routinely reduces the dose.


O'Brien concluded with a slide from the FCR300 trial, showing progression-free survival curves plateauing at 50 to 60 percent, out to 168 months.


"If you're a CLL patient who needs treatment and don't have an 11q or 17p, would you like to go on a pill you have to take forever, and maybe develop mutations and resistant disease, and don't know what the toxicities might be? Or would you like to be inconvenienced and not have a great time for maybe six months, and then be done and perhaps be on this [PFS] curve for 13 or 14 years? I know which I would vote for."


Pre-Post Debate Survey

The question put to the audience before and after this debate was: "For the initial treatment of CLL, have recent studies utilizing kinase inhibitors and IMiDs provided enough compelling data to eliminate chemotherapy?"


Voting via the Internet from their tablets or phones, some in the audience of approximately 1,000 who had voted "yes" and most of the "undecided" apparently were persuaded by Susan O'Brien's defense of FCR:

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