Reports

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.

10th Conference of the Canadian Blood and Marrow Transplant Group

Edmonton, Alberta / April 21-24, 2006

According to the National Comprehensive Cancer Network, chronic myelogenous leukemia (CML) accounts for 15% of adult leukemias. Recently, the development of imatinib, a tyrosine kinase inhibitor (TKI), has proven to be a major therapeutic advance. During evaluation, its marked efficacy in late chronic-phase (CP) disease initiated the IRIS (International Randomized Trial of Interferon vs STI571). It randomized 1106 newly diagnosed CP CML patients to imatinib 400 mg/day or to interferon-a (IFN-a) plus cytarabine. The initial results of this randomized trial by O’Brien et al. demonstrated the novel strategy’s greater efficacy in terms of hematological and cytogenetic response, increased rates of progression-free survival and improved tolerability over the INF-a plus cytarabine combination therapy (N Engl J Med 2003;348(11):994-1004). At this meeting, the long-term data of the IRIS trial were presented and appear promising.

IRIS Update

According to updated results from the IRIS study, patients in CP CML who achieve a good cytogenetic response to first-line imatinib early on are extremely likely to continue to do well more than four years later. After 54 months of follow-up, 72% of patients originally assigned to the imatinib arm were still on study agent vs. 3% of patients assigned to the IFN-a treatment arm.

At 54 months, 98% of patients treated with first-line imatinib achieved a complete hematological response (CHR); 92% achieved a major cytogenetic response (MCyR); and 86% achieved a complete cytogenetic response (CCyR). These response rates were actually higher than those achieved at 12 months, at which point 96% of patients had achieved a CHR, 85% had achieved a MCyR and 69% had achieved a CCyR—“which is utterly remarkable,” stated Dr. John Goldman, Professor of Hematology, Imperial College London, UK (Figure 1). Importantly, 90% of patients on imatinib are alive at 54 months with <1% of them progressing to advanced disease.

Figure 1. IRIS: Cumulative best response on first-line TKI treatment at 12 and 54 months

Progression-free Survival

At 54 months, the estimated rates of patients not progressing to advanced phases varied depending on the depth of response patients achieved at 12 months. For patients who had a CCyR and a ³3 log reduction in bcr-abl transcript levels, the estimated rate at 54 months was 100%. This compared with an estimated rate of 95% for those who achieved a CCyR but who had <3 log reduction in transcript levels. For those who did not achieve a CCyR at 12 months, the estimated rate was 89%.

A subset of 124 patients in the original imatinib cohort also had polymerase chain reaction (PCR) evidence of bcr-abl transcript levels at both one and four years after randomization. At one year, 53% of this subgroup had achieved a ³3 log reduction in bcr-abl transcript levels (Figure 2). This percentage increased to 80% at 54 months, Dr. Goldman indicated, “so if you get a good molecular response with imatinib at one year, 3.5 years later, you are still surviving without disease progression, which is really a dramatic result.”

Responders who achieved a 2.5 log reduction in bcr-abl transcript numbers early on in the IRIS study also demonstrated a further 1.7 log reduction by month 24, down to a median of 4.2 log lower than baseline—yet another sign that patients who respond well to first-line imatinib are very unlikely to relapse over the next number of years. “As long as patients continue to respond, you should carry on with the drug,” Dr. Goldman told delegates.

Figure 2.
nse at 1 and 4 years

<img193|center>

It would also appear that the rate of progression to accelerated phase (AP) or blast crisis (BC) diminishes with time on imatinib as well. “This is just a hint that the rate of transformation per annum may actually diminish with time,” Dr. Goldman observed (Table 1).
progression rate decreases over time (minimum 4 years of follow-up)

<img194|center>

CML Management Recommendations

Dr. Jeffrey Lipton, Associate Professor of Medicine, University of Toronto, Ontario, presented recommendations from the Canadian Consensus Group on the Management of Chronic Myelogenous Leukemia (CCGM-CML). Highlights from the 10 main recommendations include the need for physicians to assign a Sokal index category for all patients slated to be treated with imatinib.

In addition to baseline assessment of the Sokal score, the CCGM-CML group recommended that bone marrow aspirate and biopsy be carried out along with bone marrow cytogenetics. Fluorescence in situ hybridization (FISH) is also recommended, as is a baseline quantitative real-time (qRT)-PCR, carried out on either peripheral blood or bone marrow. “The option of allogeneic stem-cell transplant (SCT) should be discussed with all eligible patients,” Dr. Lipton remarked, “and all eligible patients should be referred to a transplantation centre for HLA typing and matching of potential donors.”

For patients who do not elect to undergo SCT as first-line therapy, CCGM-CML members recommend treatment with either imatinib or a protocol approved by the National Cancer Institute’s Central Institutional Review Board for all newly diagnosed patients with CP CML. The same group also recommend that patients on IFN-a ±cytarabine be switched to imatinib if they are experiencing intolerable side effects, as should all patients with less than a CCyR on an IFN-a-based regimen. In contrast, patients who do achieve a CCyR on IFN-a and who can tolerate the therapy should remain on it, although they should be monitored.

Recommended imatinib minimum starting doses in CP CML should be 400 mg/day; for AP CML, doses should start at 600 mg/day, and for those in BC, doses of up to 800 mg/day are recommended. Following failure with IFN-a, a starting dose of 400 mg is also recommended.

The group also stressed the importance of monitoring patient response. As outlined by Dr. Lipton, the CCGM-CML group recommend bone marrow cytogenetics be carried out both at diagnosis and annually thereafter if a MCyR to imatinib is maintained. The group also recommend that qRT-PCR be done every three months after baseline diagnosis (although FISH may be substituted every three months until patients achieve a CCyR). If there is a ³0.5 log increase in bcr-abl transcripts, qRT-PCR should be repeated within four weeks and mutational analysis is recommended.

A small percentage of patients either fail first-line imatinib or lose their initial response to it over time. When this occurs, physicians need to reconsider their strategy if the following milestones are not met: CHR at 3 months; MCyR at 6 months; CCyR at 12 months; and major molecular response at 18 months. Disease progression while patients are on therapy is defined as either transformation from CP to AP or BC; clonal evolution in Philadelphia chromosome-positive (Ph+) cells; loss of a CCyR; an increase of ³0.5 log in bcr-abl transcripts in patients who had previously achieved a CCyR or better; or the detection of abl mutations with loss of response.

If patients are eligible for allogeneic SCT, then it should be considered for patients who progress on imatinib, consensus group members stated. For those who are not eligible for transplantation, the dose should first be escalated up to 800 mg/day, provided there is no evidence of an abl mutation such as T315I that confers complete resistance to imatinib.

Finally, when patients fail to respond to the higher dose, an experimental agent such as AMN-107 (nilotinib) or dasatinib may then be considered, again provided there is no evidence of the T315I mutation to which both dasatinib and nilotinib are also resistant.

New Experimental Agents

Presented at the American Society of Hematology late last year by Dr. Hagop Kantarjian, The University of Texas M.D. Anderson Cancer Center, Houston, preliminary results evaluating nilotinib in imatinib-resistant patients appear promising. They are, however, limited to slightly over 100 patients.

In a phase I study, multicentre investigators treated 119 patients with imatinib-resistant CML in CP, AP or BC. A small number of the group had Ph+ acute lymphoid leukemia (ALL) and not CML. As of June 2005, patients had been treated for a median of 120 days. Response to nilotinib depended on disease phase but for those in CP CML, 50% achieved a cytogenetic response, as did 100% of those in clonal evolution CML.

Among CML patients who had no evidence of a bcr-abl mutation prior to treatment with nilotinib, 59% achieved a cytogenetic response compared to 41% for patients who did show evidence of a bcr-abl mutation prior to treatment. A nilotinib dose of 400 mg b.i.d. is currently being tested in ongoing phase II clinical trials.

Another second-generation TKI, dasatinib, is similarly undergoing clinical trials in imatinib-resistant or intolerant patients in all phases of CML. Available data for 84 patients showed that of 40 dasatinib-treated CP patients with a mean duration of CML of eight years, some 88% achieved a CHR, while MCyR was observed in 40% of patients, with a CCyR being observed in 33%.

In advanced disease, 44 patients have received dasatinib for a median of three to seven months. In this cohort, major hematological response has been observed in 80% of the group overall, while the CHR rate was 50% in AP, 18% in myeloid BC and 50% in lymphoid BC/Ph+ ALL. Overall rates of MCyR and CCyR in advanced disease were 36% and 21%, respectively. Reversible grade 3 to 4 myelosuppression was observed in all cohorts, but was especially prevalent in advanced disease. Eight per cent of patients developed pleural effusions which were managed without needing to discontinue the study agent. Otherwise, treatment was well tolerated.

Questions and Answers

This question-and-answer section is based on interviews with Dr. Jeffrey Lipton, Associate Professor of Medicine, University of Toronto, Ontario; and Dr. John Goldman, Professor of Hematology, Imperial College London, UK.

Q: The practice of SCT has fallen since the arrival of imatinib but your group is still recommending physicians discuss this option with eligible patients. Why?

Dr. Lipton: Survival of patients under the age of 55 who have undergone transplantation in CP CML is around 85% some 70 months’ post-transplant, so this is a good long-term option for eligible patients. Moreover, if patients relapse following transplantation, it doesn’t mean you can’t salvage them with imatinib because patients who relapse after allogeneic SCT do respond to imatinib and it works well. As well, many patients don’t want to spend years on imatinib and if they want a transplant and are good candidates for one, they should have that choice.

Q: Is there any evidence that imatinib can be discontinued in patients who achieve a solid molecular response to first-line therapy?

Dr. Lipton: No, there is currently no evidence that patients can stop treatment and sustain their response. Treatment has to be maintained indefinitely as long as patients continue to respond. Our guidelines state this, in fact. Q: Yet can patients take a drug holiday and go back on imatinib when they start to lose their response?

Dr. Lipton: There is a lot out there on patient Web sites suggesting that drug holidays are possible—and they’re not—so you need to find out if patients are in fact doing this. You also have to make sure compliance is optimal and if you don’t ask, patients probably won’t tell you. So you need to talk to patients about missing doses, or taking a smaller dose than you’ve prescribed, or taking unreported drug holidays for any reason, including cost and side effects, especially if response to imatinib appears to be less than optimal.

Q: What role do you see for dasatinib and nilotinib in the treatment of CML patients?

Dr. Goldman: They are both considered second-generation TKIs but I don’t think that we are in a position to distinguish between the two at the present time; they are equivalent in terms of efficacy, although their side-effect profiles are somewhat different. As to when we should use them: first of all, you have to define imatinib failure, which we have problems with, but once a patient has satisfied your definition of imatinib failure, your two main alternatives are transplantation or second-generation TKIs. Most patients are not eligible for transplantation, so the second-generation TKIs will be valuable for patients who do not do well on single-agent imatinib.