Six Targeted Agents for CLL Command Spotlight at ASH

OncologyLive, January 2014, Volume 15, Issue 1

A crop of targeted agents have demonstrated promising results in fighting chronic lymphocytic leukemia (CLL), suggesting that a range of emerging therapies and drug combinations may be more effective and better tolerated than standard chemotherapy

Jennifer R. Brown, MD, PhD

A crop of targeted agents have demonstrated promising results in fighting chronic lymphocytic leukemia (CLL), suggesting that a range of emerging therapies and drug combinations may be more effective and better tolerated than standard chemotherapy, according to research presented during the 55th Annual Meeting of the American Society of Hematology (ASH).

Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston, expressed optimism about the impact that new therapeutic strategies might have on patients with CLL.

“These exciting developments in CLL therapy represent a shift toward treatments that hone in on specific regulators of cancer, ultimately providing a safer and more effective treatment regimen,” Brown said during the conference, held December 7-10, 2013, in New Orleans. “These data give us even more reason to believe that the future outlook for CLL patients is bright.”

Among the agents generating excitement during the conference was obinutuzumab (Gazyva), a novel, type 2 anti-CD20 monoclonal antibody that the FDA approved in November 2013 for the treatment of previously untreated CLL in combination with chlorambucil.

Updated data were presented during the ASH meeting showing that the drug, as compared with chlorambucil alone, demonstrated an overall survival (OS) benefit never before seen in an older CLL population with comorbidities, and that the combination generated significantly better progression- free survival (PFS) in comparison with a pairing of rituximab (Rituxan) and chlorambucil, noted Brown.

Also attracting attention were data supporting the efficacy and safety of ibrutinib (Imbruvica), an inhibitor of Bruton tyrosine kinase (BTK), in CLL. In mid-November, the FDA approved ibrutinib for the treatment of patients with mantle cell lymphoma after prior therapy. The FDA is evaluating ibrutinib under its Breakthrough Therapy program, designed to speed up the delivery of new medicines to patients, in CLL and in Waldenström macroglobulinemia.

Brown also expressed excitement about idelalisib, a first-in-class PI3K-delta inhibitor that—in combination with rituximab— sparked a >70% improvement in OS in patients with high-risk relapsed/refractory CLL; IPI-145, an inhibitor of PI3K-delta and -gamma associated with “response rates that are quite high and deep;” and ABT-199, a potent Bcl-2 inhibitor that “clears bone marrow more effectively than kinase inhibitors,” retaining its activity even in patients who have the difficult-to-treat 17p deletion.

Fresh data about ofatumumab (Arzerra), an anti-CD20 monoclonal antibody that the FDA approved for certain CLL populations in 2009, indicate that the agent might have broader applications in the future.

While it seems likely that some of these agents will be useful in combination, that arena, in most cases, has yet to be explored, Brown noted.

“These drugs have mostly been combined with antibodies or chemoimmunotherapy, but we’re interested in combining BTK inhibitors and PI3K inhibitors, and also combining the Bcl-2 inhibitor with BTK or PI3K inhibitors, and then selecting the best antibody, maybe obinutuzumab,” Brown said in an interview with OncologyLive. “For now, chemoimmunotherapy is still the standard of care, especially in young, fit patients, but these drugs will rapidly penetrate the relapsed setting and move upfront fairly soon thereafter.”

Obinutuzumab Bests Rituximab

A study1 presented during the meeting compared obinutuzumab with rituximab, an anti-CD20 agent that is less potent in CLL than it has been in non-Hodgkin lymphoma and other B-cell malignancies, and may not be tolerated well by older patients when paired with chemotherapy, ASH said in a written statement.

In a second-stage analysis of the phase III CLL11 trial, investigators found that patients with CLL and major comorbidities had significantly better outcomes when treated upfront with obinutuzumab and chlorambucil as opposed to rituximab and chlorambucil, or chloramucil alone.

The addition of obinutuzumab to chlorambucil led to a median PFS of 26.7 months as compared with 15.2 months for the rituximab/chlorambucil combination (HR = 0.39; P <.0001). The obinutuzumab/ chlorambucil regimen netted a PFS more than double that of patients who received chlorambucil alone, and a significantly higher objective response rate. A preliminary OS analysis suggested a trend favoring obinutuzumab, Valentin Goede, MD, reported during the ASH meeting.

The overall response rate was 78% with obinutuzumab and 65% with rituximab (P <.0001), and complete response rates (CRR) were 21% and 7%, respectively. In each group, 58% of patients attained partial responses.

The study found better minimal residual disease (MRD) levels in the obinutuzumab arm.

“Our results suggest that [obinutuzumab] may be a stronger CD20 antibody than rituximab. This could lead to a potential decrease in the total amount of chemotherapy required for an effective combination regimen, translating to less toxicity for the patient,” said Goede, an investigator in the Center for Integrated Oncology at the University Hospital Cologne in Germany. “These findings suggest that [obinutuzumab] has the potential to eventually replace rituximab for the care of CLL patients.”

More grade ≥3 adverse events occurred with obinutuzumab/chlorambucil than with rituximab/ chlorambucil (70% vs 55%). In the obinutuzumab arm, infusion-related reactions and thrombocytopenia were more frequent. Neutropenia, anemia, and infection occurred at similar rates in the two groups.

Ibrutinib Induces High Response Rates

Ibrutinib continues to generate promising results in CLL, according to data from a number of studies presented at ASH.

In a follow-up to a phase I study of ibrutinib monotherapy in patients with CLL and small lymphocytic lymphoma (SLL),2 O’Brien et al reported an overall response rate (ORR) of 86.2% for treatment- naïve patients and 88.3% for relapsed/refractory patients who achieved a partial response (PR) or better. Together, ORR and PR with lymphocytosis showed that 93.1% of treatment-naïve and 93.7% of relapsed/refractory patients achieved an objective response to ibrutinib, the authors wrote.

After a median follow-up of 27.2 months, the median duration of response has not been reached, and at a landmark 30 months, 76.1% of those who responded to the treatment were alive without progression, the investigators stated.

Grade ≥3 adverse events were higher among previously treated patients but decreased after a year of treatment.

“Response rates of 90% with monotherapy are extremely encouraging in a very refractory population,” said Richard R. Furman, MD, head of the CLL and Waldenström’s Macroglobulinemia Program at Weill Cornell Medical College in New York, one of the study’s authors. “There were a great deal of toxicities, primarily related to patients who had been on a lot of prior therapies, including secondary myelodysplasia and AML [acute myeloid leukemia].

“We did a phase II study in previously untreated CLL patients, which gave us the opportunity to observe that toxicities were not really drug-related, so we know that this is extremely well tolerated and safe, and very efficacious,” said Furman. “Now we’re in a phase III pivotal study that will hopefully lead to the drug’s approval.”

In the updated results of a phase II trial,3 another group of investigators found that ibrutinib paired with rituximab was well tolerated and induced a high rate of durable remissions in previously treated patients with high-risk CLL, including the 17p deletion and 53p mutation.

At a median follow-up of 14 months, 87% had achieved partial remission and 8% complete remission, Burger et al wrote. Similarly, a study by Farooqui et al4 found that single-agent ibrutinib achieves equally good and durable results in CLL, regardless of whether patients have the 17p deletion.

Finally, in a phase IB study,5 Brown and her colleagues studied ibrutinib in combination with the established chemoimmunotherapy regimen of bendamustine and rituximab, finding the novel agent active and tolerable in patients with relapsed/ refractory CLL or SLL.

At a median treatment duration of 16 months, the overall response rate was 93% with the novel regimen, and the estimated 12-month PFS was 90%. Responses did not appear to be affected by high-risk features.

“The high ORR and good tolerability compares very favorably with historical controls,” the authors wrote, noting the combination is being evaluated in an international phase III trial (NCT01611090).

Several additional phase III trials evaluating ibrutinib in different therapeutic settings in CLL are under way, with particularly promising early data from the RESONATE trial (NCT01578707) comparing ibrutinib monotherapy with ofatumumab in patients with relapsed or refractory CLL or SLL.

An Independent Data Monitoring Committee recommended the trial be stopped early after a planned interim analysis found that ibrutinib demonstrated a statistically significant improvement in PFS, the drug developer Pharmacyclics said in a January 7 press release.

Idelalisib Beneficial in High-Risk Settings

Idelalisib, a first-in-class oral inhibitor of the delta isoform of the PI3 kinase enzyme, sparked a >70% improvement in OS and a >80% improvement in PFS when combined with rituximab, as compared with rituximab alone, a study showed6.

Study 1166 looked at the regimen in patients with high-risk relapsed/refractory CLL, said Furman, MD, of Weill Cornell, the lead author on the study.

“One of the most important things about idelalisib and these other agents is that they spare the patients all the toxicities of chemotherapy,” said Furman. “Even though the patients in the idelalisib trial were medically unfit and not capable of receiving chemotherapy, I would still recommend idelalisib to all my patients, even if they could tolerate chemotherapy.

“The idea of avoiding the myelosuppression and immunosuppression as well as the long-term risk of bone marrow failure and secondary AML and myelodysplasia that result from chemotherapy should prompt all physicians to think about avoiding chemotherapy in all their CLL patients, even those who are medically fit,” said Furman.

At the trial’s halt due to a positive risk-benefit review, the median PFS in the placebo group was 5.5 months, and not yet reached in the idelalisib arm (HR = 0.15; 95% CI, 0.08-0.28; P <.001). The 24-week PFS was 93% with idelalisib/rituximab and 46% for placebo/rituximab, and consistent across subgroups including age and mutational status.

Analysis of OS yielded a HR of 0.28 (P = .018), and the objective response rate was 6 times higher with idelalisib versus placebo (81% vs 13%; odds ratio = 29.92; P <.0001).

Lymphadenopathy improved in all patients in the idelalisib arm, and 93% of patients—as compared with 4% of those taking placebo—had a ¬50% improvement, the criterion for lymph node response.

More than 90% of patients in each group had at least one adverse event. The most common in the idelalisib group were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common adverse events were infusion-related reaction, fatigue, cough, nausea, and dyspnea.

Early IPI-145 Results Promising

The small-molecule inhibitor IPI-145 is potent without causing one of the typical adverse events of chemotherapy, according to results of a phase I trial7 presented at ASH.

In the study, 47% of participants with relapsed or refractory CLL attained objective responses, including one complete response, when treated with the oral inhibitor of PI3K-delta and -gamma, said Ian W. Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nash - ville, Tennessee.

Additionally, 98% of patients with refractory disease had nodal responses, which did not differ between patients with or without the hard-to-treat 17p deletion or p53 mutation, Flinn said.

The therapy was generally well tolerated, and did not cause the blood cell reduction observed with traditional chemotherapy, he said.

“The efficacy and safety support phase III development of IPI-145 as monotherapy for CLL and in other hematologic malignancies,” Flinn said. “Evolving data suggest IPI-145 is highly active in relapsed and refractory CLL.”

In the study, 52 patients with relapsed/refractory disease were divided into two cohorts taking a lower and a higher dose; a separate cohort of 15 newly diagnosed patients received the lower dose. Refractory patients, half of whom remain on treatment, have been studied for a median 5 to 6 months, and treatment-naïve patients, most of whom are still being treated, for a median 2.7 months.

Flinn said that 42 of 43 evaluable patients with relapsed/refractory disease had a reduction in adenopathy. In the subgroup that received ≤25 mg BID, 24 of 27 patients had nodal responses, defined as ≥50% reduction in adenopathy. In the group that received IPI-145 as first-line therapy, three of six evaluable patients had nodal responses, including two patients with p53 mutations. Similar clinical response rates were seen in patients with or without the 17p(del) or p53 mutation.

In the relapsed/refractory group, patients treated with ≤25 mg BID had an overall response rate of 48%, including six of 12 patients with the 17p deletion or p53 mutation. Among patients who received the maximum tolerated dosage of 75 mg BID, nine of 20 had objective responses, including two of seven patients with the 17p deletion or p53 mutation.

The most common grade ≥3 nonhematologic adverse events were febrile neutropenia and increased international normalized ratio (INR), with rash, diarrhea, fatigue, increased liver enzymes, pneumonitis, and stomatitis also occurring. Some in the treatment-naïve group experienced liver enzyme increases, appendicitis, and fatigue. Hematologic toxicities included grade ≥4 neutropenia in about 40% of patients with relapsed/refractory CLL, and neutropenia in fewer than 10% of newly diagnosed patients. Infections occurred in both the relapsed/refractory group (15%) and in previously untreated patients (<10%).

ABT-199 Effective as Monotherapy

Monotherapy with ABT-199, an oral selective inhibitor of the Bcl-2 protein, induced remissions in patients with relapsed/refractory CLL and SLL, including high-risk patients, according to John F. Seymour, MBBS, PhD, director of the Department of Haematology at the Peter MacCallum Cancer Centre in Melbourne, Australia.

The data presented at ASH were from a phase I, international, dose-escalation study8 of 67 patients with CLL/SLL. By CT scan, 88% of patients had a ≥50% reduction in the sum product of diameters of nodal masses within a median 6 weeks, “indicating that cytoreduction is rapid,” Seymour said.

Eighty-nine percent of patients had at least a 50% reduction in bone marrow infiltrate at week 24, with a median reduction of about 95%, Seymour said. The median time to a 50% reduction in the peripheral blood lymphocyte count (for those with lymphocyte count >5 at baseline) was “quite rapid at 15 days,” Seymour reported. The ORR among all current evaluable patients was 84%, including a 23% CRR. The ORR was 82% among patients with a 17p deletion and 89% among those with fludarabine-refractory disease.

“This is a very heavily pretreated population and, in spite of that, the patients had exceptionally promising response rates that were sustained in those with deletion 17p or fludarabine-refractory disease,” Seymour said. “These are very exciting responses across poor prognostic groups, including complete remissions, and although it was not a prospective objective of the trial, where local labs did flow cytometry, they found that some patients were negative for MRD. In the context of a single agent in relapsed/refractory disease, this drug has demonstrated very encouraging efficacy.”

In the process of escalating the dose from a baseline 50 mg up to 150 mg and then to a final 1200 mg, there was one death attributed to tumor lysis syndrome. The study was temporarily suspended and redesigned using a more conservative three-step dose escalation, along with enhanced prophylactic measures.

Serious adverse events attributed to ABT-199 included three cases of febrile neutropenia and three cases of tumor lysis syndrome, all of which occurred before the modification of the dosing schedule. ABT-199 monotherapy and combination trials in CLL have begun enrolling patients, including a phase II monotherapy study in patients who have relapsed CLL and the 17p deletion.

Ofatumumab Helps Older Patients

Ofatumumab, an anti-CD20 monoclonal antibody approved for the treatment of CLL refractory to chemotherapy, is also beneficial in combination with chlorambucil for older patients who have previously untreated CLL and are unfit for the gold-standard treatment of fludarabinecyclophasphamide- rituximab, a British researcher reported at ASH.

The regimen improves clinical outcomes and can be tolerated by patients regardless of their age or fitness, said Peter Hillmen, MD, PhD, consultant hematologist, Leeds Teaching Hospitals NHS Trust, St. James University Hospital, England.

In vitro, ofatumumab has demonstrated more activity than rituximab, and has been shown to beeffective as monotherapy in CLL patients who are refractory to rituximab.

In the COMPLEMENT 1 study of 447 patients,9 after a median follow-up of 28.9 months, PFS was 22.4 months in the ofatumumab plus chlorambucil arm compared with 13.1 months in the chlorambucil- alone arm (HR = 0.57; P = .001), with a superior ORR (82% vs 69%; P < .001) and CRR (14% vs 1%).

The median duration of response was 22.1 months vs 13.1 months (P < .001) in the ofatumumab/chlorambucil and chlorambucil alone arms, respectively, and the time to next treatment was also significantly longer in the ofatumumab/chlorambucil arm (median: 39.8 months vs 24.7 months [P < .001]).

Withdrawal from treatment due to adverse events was 13% in each arm. Adverse events in the ofatumumab/chlorambucil arm included infusion reactions and neutropenia; 19% of patients in each arm had their chlorambucil dosage reduced as a result of experiencing neutropenia.


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  2. O’Brien S, Furman RR, Fowler N, et al. The Bruton’s tyrosine kinase inhibitor ibrutinib monotherapy demonstrates longterm safety and durability of response in chronic lymphocytic leukemia/small lymphocytic lymphoma patients in an open-label extension study. Blood. 2013;122(21):4163.
  3. Burger JA, Keating MJ, Wierda WG, et al. Ibrutinib in combination with rituximab is well tolerated and induces a high rate of durable remissions in patients with high-risk chronic lymphocytic leukemia: new, updated results of a phase II trial in 40 patients. Blood. 2013;122(21):675.
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