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Selecting Second- and Third-Line TKIs in CML: Offering Tolerability in the Context of Indefinite Disease Control

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 56th Annual Meeting of the American Society of Hematology (ASH)

San Francisco, California / December 6-9, 2014

San Francisco - A focus on the relative long-term safety and tolerability of available tyrosine kinase inhibitors (TKIs) for treatment of chronic myeloid leukemia (CML) has been intensified by the evidence that drugs in this class, when maintained, can control this disease indefinitely. Current evidence suggests that the safety and tolerability of TKIs currently approved for second- and third-line treatment of CML are more different than their potency and efficacy. Although new data presented at the 2014 ASH meeting raise the possibility that some proportion of CML patients receiving TKIs may eventually be cured when deep responses are sustained, CML in a large proportion of patients must be controlled with continuous therapy. For this reason, safety and tolerability cannot be divorced from efficacy. For those who can remain on therapy with a sustained cytogenetic response, TKIs are now offering a normal life expectancy.

With the introduction of the first-generation TKI imatinib, CML was transformed from a fatal disease to a potentially chronic condition. Second-generation TKIs initially introduced to reassert control in CML patients who developed resistance to imatinib have generally shown greater potency against the underlying malignant clone, particularly in patients with unfavorable cytogenetic features. However, not all of the second-generation TKIs have been as well tolerated as imatinib. In selecting second- and third-line TKIs to retain control of CML, safety and tolerability are being given new emphasis.

Commenting on this issue in the context of long-term follow-up data presented at the 2014 ASH meeting on the TKI bosutinib, Dr. Jeffrey H. Lipton, Head of CML Group, Princess Margaret Cancer Centre, Toronto, confirmed, “Safety is becoming more of an issue.” Although all of the TKIs currently available for the treatment of CML are capable of achieving and sustaining the deep molecular responses that reduce risk of relapse, Dr. Lipton pointed to substantial differences in the risk of adverse events over long-term treatment and to the relevance of these adverse events to drug selection.

In addition to imatinib, the TKIs currently available for control of CML include nilotinib, dasatinib, bosutinib, and ponatinib. Recently, the U.S. Food and Drug Administration (FDA) narrowed the indication for ponatinib to CML patients with disease positive for the ABL1 T3151 resistance mutation due to concern about an increased rate of vascular events. New safety data presented at the 2014 annual ASH meeting on bosutinib provides an opportunity to emphasize that the safety profile of each TKI is unique.

4-Year Bosutinib Follow-Up

On the basis of the newly released 4-year follow-up data, bosutinib “has an excellent long-term safety profile with no worse vascular concerns than imatinib,” Dr. Lipton commented. “This puts it in a different light than other second-generation drugs such as nilotinib and ponatinib. Dasatinib does not have an increased vascular adverse events incidence but continues to contribute to pleural effusions.”

The long-term multicentre bosutinib study presented at the 2014 ASH meeting, for which Dr. Lipton was a co-author, included 119 patients. It was initiated more than 4 years ago. Relative to data previously published for nilotinib and dasatinib, the most striking result was a low rate of newly emergent adverse events over time. The most common reason for discontinuation due to an adverse event was thrombocytopenia in 6% of patients. Pleural effusions occurred in a small proportion of patients, but were not a common cause of discontinuations. Vascular events were rare and did not increase over time.

“After more than 4 years of treatment, we can say that bosutinib is continuing to demonstrate durable efficacy and manageable toxicity,” reported the principal investigator, Dr. Carlo Gambacorti-Passerini, Director of Clinical Research, San Gerardo Hospital, University of Milan Bicocca, Italy. According to Dr. Gambacorti-Passerini, who was presenting data collected at centres in Europe, the U.S., and Canada, CML remained well controlled on bosutinib therapy. Only 4% of patients over the 4-year follow-up had an on-treatment transformation to accelerated- or blast-phase CML.

In this study, 119 patients with prior imatinib failure were initiated on 500 mg of bosutinib per day. All had resistance or intolerance to nilotinib, dasatinib, or both. Over the course of treatment, 22 patients (19%) had a dose escalation to 600 mg. The median patient age was 56 years.

MCyR Probability 69% at 4 Years

The probability of maintaining a major cytogenetic response (MCyR) or complete cytogenetic response (CCyR) at 4 years - when 24% of patients were still receiving bosutinib - was 69% and 54%, respectively. Of those who discontinued therapy, 71% did so without transformation. Most of the remaining had progressive disease, which included, in addition to the 4% with transformation, increasing white blood cell count, loss of confirmed CCyR, or death. While an adverse event was the primary reason for discontinuation in 24% of patients, 76% of these discontinuations occurred in the first year. Some were attributed to potentially manageable side effects, such as diarrhea, which occurred in 83% of patients but was of grade 3 or higher severity in only 9%. In analysis of adverse events, diarrhea was self-limiting and uncommon in those remaining on long-term therapy.

By confirming a good cytogenetic and molecular response with bosutinib in long-term treatment of CML, these data are potentially meaningful to TKI selection. Although not a comparative study, the data confirm a low rate of emergent adverse events with bosutinib over time.

“In a drug that has excellent activity in patients who have failed another second-generation drug such as nilotinib or dasatinib, the good adverse event profile is a bonus,” reported Dr. Lipton when asked to provide perspective on this data for CML treatment in Canada.

Stopping TKIs: Long-Term Remissions

Deep and prolonged responses to TKI are critical to prevention of CML relapse, but other data presented at the 2014 ASH meeting suggest that they may also lead to cure in at least some patients. In an update on the ongoing STOP 2G-TKI study, Dr. Delphine Rea, Hôpital Saint-Louis, Paris, France, presented outcomes for 52 patients who discontinued TKI. The study demonstrated a diminishing risk of relapse over time, suggesting that some of those followed the longest might now be cured of CML.

The focus of the data presented was on the 40 patients who continued to demonstrate a major molecular response (MMR) 3 months after discontinuing their TKI. Of patients in this group who have relapsed, most did so within the first 12 months. For those who remained in MMR at 12 months, there was a 59.6% probability of remaining in MMR through the median duration of follow-up, which is now 3.7 years. For those in MMR at 24 months, the probability declined only to 57.4%.

“The diminishing risk of loss of MMR over time has important implications for monitoring these patients,” Dr. Rea reported.

Longer Remissions from Deeper Initial Responses

Notably, the risk for loss of MMR over time correlated with depth of response as measured with PCR. For the 23 patients (58%) who achieved a complete molecular response at least 4.5 logs below the standardized baseline (CMR 4.5) at 3 months, approximately 90% remained in MMR at 24 months. For the remaining 17 patients (42%) who had achieved a CMR 3.5 at 3 months, the rate of MMR at 24 months was 55%. After 48 months of follow-up, the proportion of CMR 4.5 patients who remained in MMR had fallen to less than 70%, but the proportion in the CMR 3.5 group had fallen near 40%.

Relevant to the strategy of discontinuing TKIs in patients with deep molecular responses, Dr. Rea reported that 23 of the 24 patients who have lost MMR in follow-up so far regained MMR when a TKI was restarted. Often the MMR was achieved by restarting the same TKI employed prior to therapy discontinuation. There have been no cases of accelerated- or blast-phase CML in patients participating in the STOP 2G-TKI trial to date.

Conclusion

TKIs provide a highly targeted effect in CML, inhibiting the characteristic cell proliferation that drives disease progression. Although second-generation TKIs have proven effective in defeating the resistance that threatened sustained disease control with imatinib, these agents are not interchangeable. While all have been shown to be capable of suppressing clonal expansion of CML in patients resistant to imatinib, the relative risk of adverse events differs. Despite emerging evidence that some patients may be able to discontinue TKI therapy for sustained periods without relapse, disease control in most patients depends on an acceptably tolerated treatment that can be maintained indefinitely. 

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