Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia.


Chronic lymphoid leukemia (CLL) is characterized by a variable natural history that is partly predicted by clinical and genomic features.1 Therapy for CLL has evolved from monotherapy with alkylating agents to chemoimmunotherapy.2,3 Each of the combination regimens has shown prolonged rates of progression-free survival, as compared with similar regimens that do not contain antibodies.
Treatment of patients with relapsed CLL often includes regimens such as bendamustine and rituximab,4ofatumumab,5 or investigational agents.6-8 Ofatumumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency on the basis of a single-group study involving patients who had resistance to fludarabine and alemtuzumab therapy; with an overall response rate of 58%,5 ofatumumab has been recommended in international consensus guidelines as a therapeutic option for patients with previously treated CLL.9,10
A short duration of response to initial therapy or adverse cytogenetic abnormalities have been associated with a poor outcome among patients receiving conventional therapy.9,11,12 Identifying new therapies that prolong survival remains an important need for these patients.
Ibrutinib (Imbruvica, Pharmacyclics and Janssen) is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase, an essential enzyme in B-cell receptor signaling, homing, and adhesion.13-15 On the basis of response rates in single-group, phase 2 studies, ibrutinib was recognized by the FDA as a breakthrough therapy and was granted accelerated approval for patients with mantle-cell lymphoma (in November 2013) and CLL (in February 2014) who had received at least one previous therapy. Among patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL), those who received ibrutinib had a response rate of 71%, according to investigator assessment, and a progression-free survival rate of 75% at 2 years.13 In this study, drug toxicity did not result in the discontinuation of ibrutinib in most patients. On the basis of early results of the phase 2 trial, we initiated a multicenter, open-label, randomized, phase 3 trial, the Study of Ibrutinib versus Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE), to compare once-daily oral ibrutinib with an active control single-agent therapy, ofatumumab, in patients with relapsed or refractory CLL or SLL.
DISCUSSION
Among patients with relapsed CLL or SLL, including those who had a short duration of response to prior therapy or who had adverse cytogenetic abnormalities, ibrutinib was superior to ofatumumab with respect to progression-free survival, overall survival, and response rate at a median follow-up of 9.4 months. The positive effect of ibrutinib was observed in subgroups of patients with a high-risk chromosome 17p13.1 deletion and with resistance to previous purine analogue therapy. Similar benefits with respect to progression-free survival were observed regardless of age, clinical stage, and factors such as status with respect to mutations in IGHV. The effect of ibrutinib on overall survival was significant, an effect that was robust despite the crossover of 57 patients to the ibrutinib group after they had disease progression while receiving ofatumumab; this effect was also observed in subgroup and sensitivity analyses.
Except for a few differences, our findings are largely similar to those of other trials of ibrutinib or ofatumumab. In each of the two groups in our study, the response rate as determined by independent assessors was lower than the response rate as determined by investigators. In the phase 2 study of ibrutinib monotherapy,13 in which response was assessed by investigators, the response rate was 71%, which is similar to the 70% response rate assessed by investigators in our study. The independently assessed response rate in the ofatumumab group in our study appears to be lower than that in the pivotal study that was based on 1996 National Cancer Institute guidelines for CLL,23 which did not require CT scanning to confirm response.24 This difference may be due in part to the requirement in our study for serial CT scanning, which was performed every 12 weeks, to confirm response. Another ofatumumab study that compared response assessment between patients who underwent CT scanning and those who did not undergo CT scanning showed substantial differences in the rates of response between the two subgroups, with lower response rates seen in the group that underwent CT scanning.25 Furthermore, the investigator-assessed response rate among patients in the ofatumumab group in our study (21%) was similar to the rate (23%) in a recent study that used 2008 criteria of the International Workshop on Chronic Lymphocytic Leukemia.26 Reassuringly, the results with respect to progression-free survival in the ofatumumab group in our study (median, 8.1 months) are similar to those in historical reports (median, approximately 6 months).5
Previous reports of ofatumumab therapy showed that patients with refractory CLL had a median survival of 12 months26 and 15 months,5 with no plateau in deaths. With a median follow-up of 9.4 months in our study, an early separation in the curves for overall survival favored ibrutinib; however, the median was not reached in either study group. At later time points, the survival curve for ofatumumab began to flatten, which may in part be a reflection of the influence of ibrutinib on patients in the ofatumumab group who crossed over to ibrutinib therapy.
Ibrutinib was associated with toxic effects that were expected on the basis of the results of phase 2 studies. It appears that the drug can be safely administered even in a heavily pretreated and elderly population with baseline coexisting conditions, such as the one in our study. In the ibrutinib group, 32% of the patients had a decreased creatinine clearance, 64% had cytopenias, and 32% had a score on the Cumulative Illness Rating Scale of more than 6 (ranging from 0 to 52, with higher scores indicating worse health status). Toxic effects did not result in frequent dose reductions or treatment discontinuations.
One strength of a randomized, controlled trial is that background disease-related complications may be differentiated from a treatment effect with a new agent. However, it is important to note that patients in the ibrutinib group had a reporting period for adverse events that was more than 3 months longer than that in the ofatumumab group (median duration, 8.6 months vs. 5.3 months), and no exposure-adjusted analysis of adverse events was performed.
The frequencies of renal complications and increased creatinine levels were similar in the two study groups. Although the overall rate of infections was higher in the ibrutinib group, the frequency of infections of grade 3 or higher did not differ significantly between the two groups. Ocular symptoms were collected proactively and were reported more frequently among patients in the ibrutinib group, including a small proportion of patients who reported blurred vision. The development of cataracts in 3% of the patients receiving ibrutinib (as compared with 1% in the control group) bears noting, since longer exposure may be associated with an increased risk.
Atrial fibrillation of any grade was noted in 10 patients in the ibrutinib group, as compared with 1 patient in the ofatumumab group, and led to the discontinuation of ibrutinib in 1 patient. Potential reasons for the higher rate of atrial fibrillation among patients receiving ibrutinib are being explored. In clinical studies in which serial electrocardiographic studies were performed, no evidence of arrhythmias was observed among patients receiving ibrutinib.13,27
An adverse event of interest with ibrutinib from early studies was major hemorrhage, including subdural hematoma. In our study, we excluded patients requiring warfarin but not those requiring other forms of anticoagulation. The rate of major hemorrhage was similar in the two study groups, with one subdural hematoma noted in a patient receiving ibrutinib. Although mild bleeding episodes were more common in the ibrutinib group, adherence to appropriate drug-withholding guidelines perioperatively and precautions regarding the use of antiplatelet agents and anticoagulants resulted in no unexpected major bleeding complications in the ibrutinib group. Further studies of the mechanism of bleeding, including bruising, that was observed among patients receiving ibrutinib have been conducted28 or are planned.
In conclusion, ibrutinib was superior to ofatumumab in difficult-to-treat patients with relapsed or refractory CLL or SLL, as measured by progression-free survival, overall survival, and response. The improvement was observed across all subgroups that were examined, including patients who were resistant to chemoimmunotherapy and those with a chromosome 17p13.1 deletion, which confirms single-agent ibrutinib as an effective therapy for CLL or SLL. Phase 3 studies examining the effect of ibrutinib in previously untreated patients with CLL or SLL are ongoing

Source: NEJM

Advertisements

Vaccine stirs immune activity against advanced, hard-to-treat leukemia.


Novel treatment boosted selective immune attack on leukemia cells in post-transplant patients

Patients with advanced chronic lymphocytic leukemia (CLL) often receive donor transplants that effectively “reboot” their own immune defenses, which then attack and potentially cure the hard-to-treat disease. However, there is a high rate of relapse in these patients, and the transplanted immune cells may also harm normal tissues, causing graft-versus-host disease (GVHD).

Now, scientists at Dana-Farber Cancer Institute report in the
 Journal of Clinical Investigation that they observed a strong and selective immune response in some patients who received, shortly after the transplant, several doses of a “personalized” tumor vaccine composed of their own inactivated leukemia cells combined with an immune stimulant, GM-CSF. Thus the vaccine boosted the power of the transplanted immune system’s ability to attack the cancer – known as the graft-versus-leukemia (GvL) effect.

“Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control” following transplants from donors, saidCatherine Wu, MD, senior author. “Although this was a phase 1 study and not powered to look at questions of clinical efficacy, we did see promising clinical activity.”

There are few treatment options for advanced CLL. Standard transplants, which involve powerful doses of pre-transplant chemotherapy to wipe out as much of the leukemia as possible, have proven too toxic for older patients and those with co-existing diseases. Over the past decade, researchers have developed reduced-intensity conditioning (RIC) regimens, using lower chemotherapy doses that are more tolerable but which rely entirely on the activity of the transplanted immune cells to battle the leukemia. Usually this is insufficient to keep the cancer at bay long-term and the disease progresses.

Furthermore, research has shown that the identifying antigens on the surface of CLL cells in individual patients may differ – that is, they have “personal tumor antigens,” the scientists said. “Based on these principles, vaccination with autologous [the patient’s own stored leukemia cells] irradiated leukemia cells is an attractive approach to expand leukemia-reactive T cells, since this vaccine formulation reliably includes personal tumor antigens.”

To make the vaccine, the researchers mixed the patients’ irradiated leukemia cells with cells that produce GM-CSF (granulocyte-macrophage colony-stimulating factor) and then injected them back into the patient. The combination stirs up a strong response by immune T cells, and the distinctive antigens on the injected leukemia cells direct the T cells to attack similar leukemia cells wherever they are present in the body.

In the phase 1 trial, the vaccine was administered between 30 and 100 days after the transplant, with some patients receiving as many as six vaccine doses. The study enrolled 22 patients with advanced, aggressive CLL. Thirteen of the patients had evidence of the leukemia in their bone marrow at the time of transplant.

Four patients did not receive the vaccine because they developed GVHD following the transplant. The remaining 18 received at least one vaccine dose; seven patients stopped receiving the vaccine after they developed GVHD.

When examined six months post-transplant, the majority of patients showed evidence of clinical response: 10 had complete remissions and six had partial remissions. After a median follow-up of 2.9 years, 13 patients (72 percent) had remained in continuous complete remission; one patient had stable disease, three patients developed progressive disease and two of those patients died.

The results support the safety and biological activity of whole tumor-cell vaccination in hematological malignancies, said the authors, and that giving the vaccine shortly after transplant may have been critical in its effectiveness. In addition, they said a key to the vaccine’s potency was the development by Dana-Farber scientists of GM-CSF-secreting “bystander” cells that can be used against lymphoid malignancies – which was not possible previously.

However, the authors noted that further randomized studies in larger patient groups will be necessary to determine if this strategy “will translate into a true clinical benefit for patients with advanced CLL.”

Source:DFCI

Ibrutinib Highly Active in Patients with Chronic Lymphocytic Leukemia with 17p Deletion.


The targeted agent ibrutinib produced rapid and durable control of disease in both treatment-naïve and relapsed/refractory patients with 17p deletion chronic lymphocytic leukemia, according to the results of a study presented at the 12th International Conference on Malignant Lymphoma held June 19-22, 2013 in Lugano, Switzerland.

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia. The American Cancer Society estimates that approximately 15,000 people will be diagnosed with CLL this year. Currently, there are approximately 95,000 people in the United States living with CLL.

CLL is characterized by the production of atypical lymphocytes. Lymphocytes are specialized immune cells that exist in two forms: B- and T-cells. These cells are produced in the bone marrow and each serves a specific function in aiding the body to fight infection. The large majority of CLL cases involve mature B-lymphocytes that tend to live much longer than normal. B-lymphocytes accumulate in the blood, bone marrow, lymph nodes, and spleen. This results in overcrowding of these areas and suppression of the formation and function of blood and immune cells. Additionally, the cancerous lymphocytes themselves do not function normally, leading to a further reduction in the body’s ability to fight infection.

Although there are effective treatments for CLL, some populations are harder to treat and tend to have worse outcomes. Many elderly patients are unable to tolerate current aggressive standard treatments. Also, individuals with a deletion in the short arm of chromosome 17 (referred to as del 17p) have poor outcomes with chemotherapy.

Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL. In other words, the targeted therapy attacks the pathway that mediates disease progression.

Researchers conducted a phase II, single-agent study that included 29 patients with del 17p CLL—15 who were treatment-naïve and 14 with relapsed/refractory disease. Patients were treated with 420?mg of ibrutinib daily until disease progression and response was evaluated at 6?months and every 6?months thereafter. After a median follow-up of 9 months, the results showed a promising response.

At 6 months, 88 percent of 25 evaluable patients had a nodal response (defined as 70% median reduction in lymph node size), 48 percent had a partial response by International Workshop on CLL (IWCLL) criteria, and 40 percent had a partial response with lymphocytosis. One patient had progressive disease (presumed transformation). Nodal response was observed in 93 percent of the patients with relapsed/refractory disease and in 82 percent of treatment-naive patients.

The estimated event-free survival at 12 months was 90 percent. All patients showed a reduction in splenomegaly, with a median reduction in spleen volume of 446 mL (46%) from baseline. At 6 months, the researchers repeated bone marrow biopsy and fluorescence in situ hybridization (FISH) measurement in 23 patients. The bone marrow biopsy revealted that tumor burden decreased by a median 76 percent (from baseline) as assessed by immunohistochemistry for CD79a. FISH was used to quantify the percentage of tumor cells with the 17p deletion—at 6 months, there was a median reduction of 55 percent in 15 out of 18 patients, no change in 1 patient, and an increase in 3 patients.

Treatment was tolerated—non-hematologic toxicities of grade 3 or higher were observed in 14 percent of patients. Two deaths occurred during the study, but were not considered treatment-related.

The researchers concluded that single-agent ibrutinib is effective in treatment-naïve and relapsed/refractory patients with del 17p CLL and produces rapid and durable control of disease. Research will be ongoing to evaluate single-agent inbrutinib as a strategy for this group of high-risk patients.

 

Reference:

Wiestner A, Farooqui M, Valdez J, et al. Single agent ibrutinib (PCI-32765) is highly effective in chronic lymphocytic leukemia patients with 17p deletion. Hematological Oncology: Special Issue: 12th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, June 19–22, 2013. 31 (SI): 96-150. Abstract 008.

 

Source: cancerconnect.com

 

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia.


BACKGROUND

The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton’s tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.

METHODS

We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.

RESULTS

Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.

CONCLUSIONS

Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.

Source: NEJM