Recently the Oncology Times asked Dr. Richard Furman his opinion on whether a complete response (CR) and minimal residual disease (MRD) negativity are still requisites for the successful treatment of CLL patients. MRD refers to the small number of leukemic cells that remain in a patient after treatment and can only be detectable using sensitive techniques. In patients who achieve complete responses, MRD can remain and cause relapse. Dr. Furman believes that while MRD negativity is always preferred, it is not the most important measure of outcomes. He stated,
“The most important part of the debate surrounds survival. From a patient’s perspective, overall survival is the single most important goal,” Furman said. “If achieving MRD negativity comes at a cost of toxicities, short term or long term, it may not translate into improved survival.”
The combination of fludarabine, cyclophosphamide, and rituximab (FCR) generates deeper remissions and more MRD negativity than fludarabine and rituximab (FR), but can have an impact upon long term marrow health, leading to 8 percent of patients developing secondary myeloid neoplasias (MDS and AML). We may have 60 percent long-term survival with FCR in mutated CLL patients, but if we are losing 8 percent of patients to bone marrow failure, that has to be considered. Still the long-term effects of FCR chemotherapy are unknown.
Fortunately, CLL patients have another option with BCR and Bcl2 antagonists that may markedly improve survival. The ideal circumstance for a CLL patient would be to obtain MRD negativity without having any additional toxicities. This is where the novel treatments, including BCR antagonists, BCL2 antagonists, and CAR T cells will hopefully take us. With BCR antagonists, the depth or remission continues to improve with continued therapy. While almost all of the initial responses were partial responses with very few complete responses, over time the number of complete responses has increased. This will hopefully translate into MRD negative responses one day. This is the importance of progression free survival, as these patients who have not progressed, and remain on therapy, have the potential to continue to improve their response.
Improved survival of CLL patients over the past few decades shows an apparent change in the natural history of the disease. But Furman claims the advance in overall survival is related to lead-time bias. “We are diagnosing patients earlier in Binet stage A. There has been an increase in overall survival for patients as a group. By stage, there is no benefit for Binet stage A and B. A benefit is seen for Binet stage C. This may be due to better supportive therapies and novel agents, or to a shift to earlier stage disease at diagnosis,” he said, noting there is a great need for prognostic markers.
The full debate and rest of Dr. Furman’s response can be read on the Oncology Times website.
CLL patients who relapse after or are refractory to ibrutinib or idelalisib often have few treatment options and poor outcomes. In an ongoing phase II study, presented at the 2016 annual ASCO meeting, researchers investigated the activity of venetoclax in patients with CLL who have relapsed or become refractory to ibrutinib or idelalisib. Venetoclax (Venclexta, ABT-199), is the first FDA-approves treatment that inhibits the BCL-2 (B-cell lymphoma 2) protein. The BCL-2 protein plays an important role in enabling CLL cells to survive. CLL cells and other lymphomas over express and are more dependent upon BCL-2 protein than normal cells. Therefore, when venetoclax inhibits the protein, the CLL cells die, while the normal cells continue unharmed.
54 patients were enrolled into the two arms of the trial based upon whether they were relapsed or refractory to ibrutinib (Arm A, 38 patients) or idelalisib (Arm B, 10 patients). 48 patients were evaluable for responses. The overall response rate for ibrutinib treated patients was 61% (CR=8%; PR=53%) and for idelalisib was 50% (CR=0%; PR=50%). Side effects were found in less than 20% of patients with the most common including neutropenia, diarrhea, nausea, anemia, fatigue, and hypophosphatemia. These results show that venetoclax displays promising activity for CLL patients who have relapsed or are refractory to both ibrutinib and idelalisib and can be safely administered.
Further research is required to demonstrate the depth and duration of response, but these initial results are positive.
Acalabrutinib is a second generation Bruton’s tyrosine kinase (BTK) inhibitor that targets the B-cell receptor signaling and is considered a prime target for the treatment of CLL. Acalabrutinib inhibits BTK activity preventing the activation of the B-cell antigen receptor pathway, and leads to CLL cell death. Recently at the 2016 ASCO annual meeting researchers presented preliminary results from an ongoing phase 1-2 study using acalabrutinib to treat patients with previously untreated CLL. Of the 74 patients enrolled in the trial 72 were evaluable for response. Acalabrutinib was well tolerated, with 72 of 74 patients remaining on treatment at time of analysis and evaluable for response. Neither of the two patients discontinued treatment for drug related adverse events.
The most common side effects were headaches, diarrhea, arthralgia, contusion, nausea, and weight increase, all characterized as mild. Treatment related lymphocytosis occurred in 53% of patients and was resolved in 97% of the affected patients at a median of 7 weeks. Patients who took acalabrutinib experienced a 96% overall response rate (PR=86%, PR-L=10%) with the median time to response being 2-8 months. For patients with untreated CLL the initial safety profile and high response rates are promising. Based on these results a phase 3 trial of acalabrutinib versus ibrutinib has commenced to further study the use of acalabrutinib in the treatment of patients with CLL.