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MEDICAL FRONTIERS - 16th Congress of the European Hematology Association (EHA)

London, United Kingdom / June 9-12, 2011

London - With the introduction of the first tyrosine kinase inhibitor (TKI) 10 years ago, treatment of chronic myeloid leukemia (CML) was revolutionized. Imatinib became the standard of care and in follow-up analysis of clinical trials it continues to demonstrate durable responses. However, more than one-third of patients become resistant to or intolerant of imatinib. For those patients, more potent second-generation TKIs were introduced and have demonstrated to be superior as initial therapy for CML after 1 year of treatment. At this year’s EHA, 2-year follow-up data from 2 second-generation TKIs were presented showing that responses are sustained over the longer term. Further analyses were presented indicating how response rates may be further improved by identification of prognostic markers for survival in CML patients.

Medical Editor: Dr. Julie Frère, Montréal, Quebec

Despite the unprecedented benefit provided by the tyrosine kinase inhibitor (TKI) imatinib in patients with chronic myeloid leukemia (CML), it was noted in the phase III IRIS trial that 17% of imatinib-treated patients did not achieve a complete cytogenetic response (CCyR), and 10% who did achieve CCyR relapsed. Furthermore, an additional 8% of patients were intolerant of imatinib. Thus, it was inadequate for 35% of the patients (Clin Cancer Res 2011;17:1674-83).

More potent second-generation TKIs have filled a therapeutic gap. Specifically, in randomized clinical trials, first-line treatment with second-generation TKIs showed superior efficacy over imatinib in patients with CML in chronic phase (CML-CP). Significantly higher rates of major molecular response (MMR) and CCyR were reported with nilotinib in the ENESTnd trial (N Engl J Med 2010;362:2251-9) and with dasatinib in the DASISION trial (N Engl J Med 2010;362:2260-70). Longer-term follow-up was planned for both trials to determine whether responses after one year would ultimately translate into improved long-term outcomes, such as event-free survival (EFS) or overall survival (OS), as well as to monitor safety and tolerability.

Two-year Follow-up of First-line Therapy

Two-year follow-up data from the ENESTnd and DASISION trials continue to demonstrate the superiority of the second-generation TKIs over imatinib, reported Prof. Andreas Hochhaus, Director, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Germany.

In the ENESTnd trial, 846 patients were randomly assigned to receive nilotinib 300 or 400 mg b.i.d. or imatinib 400 mg q.d. By 24 months’ follow-up, significantly higher rates of MMR were maintained with both doses of nilotinib (71% and 67%, respectively) compared with imatinib (44%, both P<0.0001) (Figure 1).

MMR rates were superior for nilotinib at both doses regardless of Sokal risk score. “It became clear in development that the response with nilotinib was deeper than with imatinib, so we were interested in looking at complete molecular response (CMR),” Prof. Hochhaus told EHA delegates. Both nilotinib doses were associated with higher rates of CMR4.0 (BCR-ABL transcript levels =0.01%) than imatinib, with the highest rate seen with the 300-mg dose (39% and 33% vs. 18%; P<0.001 for both comparisons). The same pattern was seen for rates of CMR4.5 (BCR-ABL transcript levels =0.0032%), with the highest rate seen with the 300-mg dose (25% and 19% vs. 9%; P<0.0001 and P=0.0006). Rates of CCyR by 24 months were also significantly higher on both 300 and 400 mg b.i.d. at 87% and 85% vs. 77% for imatinib (P=0.0018 and P=0.016, respectively). “A very interesting and unexpected observation was a major improvement in the evolution of the disease to accelerated phase and blast crisis (AP/BC) very early in the course of treatment,” Prof. Hochhaus reported. Twelve patients progressed to AP/BC with imatinib vs. 2 and 3 patients on nilotinib 300- and 400-mg groups (P=0.0059 and P=0.0196).

Figure 1.

Long-lasting, low-grade side effects problematic with imatinib were improved with nilotinib, Prof. Hochhaus reported. “Fluid retention, diarrhea, muscle cramps, nausea and vomiting were all improved.” Headache, pruritus and rash were more common with nilotinib. Neutropenia was improved with nilotinib and thrombocytopenia and anemia remained stable. “An important point is that in the second year of treatment there were only a few new hematological or myelosuppression events,” Prof. Hochhaus observed.

In the phase III DASISION trial, 519 patients were randomized to dasatinib 100 mg or imatinib 400 mg q.d. CCyR rates for dasatinib vs. imatinib were 86% vs. 82% by 24 months, with confirmed CCyR 80% vs. 74% and the median time to CCyR were 3.2 and 6.0 months, respectively. MMR rate was significantly higher with dasatinib than imatinib (64% vs. 46%, P<0.0001) (Figure 2) and median time to MMR was 15 months vs. 36 months. “All these advantages of dasatinib were applicable to patients in different Euro/Hasford risk groups,” Prof. Hochhaus noted. By 24 months, CMR4.5 (BCR-ABLIS =0.0032%) occurred in 17% vs. 8%, respectively (P=0.002).

“What is really important for patients is [the prevention of progression to] AP/BC,” Prof. Hochhaus reported and while not significant at this timepoint, “6 (2.3%) patients have progressed on study in the dasatinib group vs. 13 (5.0%) in the imatinib group.” Three patients on dasatinib and 6 on imatinib who achieved a CCyR transformed to AP/BC, but no patient who achieved MMR had transformed by data cut-off, underlying the importance of the MMR over CCyR, Prof. Hochhaus stressed.

Progression-free survival (PFS), failure-free survival (FFS) and OS showed no major differences between the 2 treatment groups at 24 months. Non-hematologic adverse events (AEs) such as fluid retention, superficial edema, myalgia, nausea and vomiting improved with dasatinib; only pleural effusions were more frequent with dasatinib. Rates of grade 3/4 anemia and neutropenia were similar in the 2 groups, although thrombocytopenia was more frequent with dasatinib. Most cytopenias occu
year.

Figure 2.

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Follow-up from both these studies continues to support the use of nilotinib 300 mg b.i.d. and dasatinib 100 mg/day as recommended treatment for newly diagnosed CML-CP patients, Prof. Hochhaus concluded.

Treatment Failure and Suboptimal Response in First Line

Additional ENESTnd trial analysis revealed lower rates of suboptimal response (SoR) and treatment failure (TF) with nilotinib, despite optimization of imatinib therapy by dose escalation according to European LeukemiaNet (ELN) criteria (J Clin Oncol 2009;27:6041-51). Prof. Giuseppe Saglio, University of Turin, Orbassano, Italy, reported that patients on both nilotinib doses had lower rates of SoR and TF by each ELN milestone (6, 12 and 18 months) and higher rates of optimal response.

SoR and TF rates were lower in nilotinib-treated patients across all Sokal risk categories by 12 months and similar trends were also observed by 18 months (Figure 3). At 18 months, the SoR rates observed were primarily due to lack of MMR. Among patients randomized to imatinib, 82 (29%) received dose escalation to 800 mg/day for suboptimal response or treatment failure. After a median of 9 months later, 21 (26%) patients had achieved MMR, 14 (17%) CCyR without MMR and 47 (57%) had no improvement. Thirty-seven (45%) patients who escalated to imatinib 800 mg/day discontinued treatment on study. Dose escalation was not an effective strategy to overcome SoR and TF on imatinib, as approximately three-quarters of these patients failed to achieve MMR after dose escalation, and nearly half had dose reductions/interruptions and discontinued treatment. In these cases, “It is better to switch directly to second-generation TKI rather than to increase the imatinib dose,” Prof. Saglio commented. Investigators concluded that using ELN 2009 criteria, even with optimization of imatinib by dose
appears to be more effective as front-line therapy.

Figure 3.

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Treatment Response at 36 Months

Three-year follow-up data from a phase II study showed that responses in CML-CP patients treated with nilotinib 400 mg b.i.d. as first line-therapy are stable and failure rate is very low, reported Prof. Gianantonio Rosti, University of Bologna, S. Orsola-Malpighi Hospital, Italy. The GIMEMA CML trial enrolled 73 patients, median age 51 years. At 36 months, OS, PFS, FFS and EFS were 97%, 97%, 97% and 91%, respectively. CCyR rate was 78% at 3 months, 96% at 12 months and remained >90% up to 24 months. At 36 months, it was 62%. However, at the 36-month timepoint, >30% of patients were not evaluated for CyR and hence were counted as non-responders. Only 1 patient had a confirmed loss of CCyR. “All but 2 patients had a MMR,” Prof. Rosti reported. Both had a CCyR and 1 patient (high Sokal risk, T315I mutation) progressed to AP/BC at 6 months and subsequently died. Rates of MMRIS at 3, 12, 24 and 36 months were 52%, 85%, 82% and 71%, respectively (at the 36-month timepoint, ~20% of patients were not evaluated for molecular response and were considered non-responders). Loss of MMR was transient in 9 patients and confirmed in 3. Fifty-five (75%) patients obtained CMR4.0 at least once and 29% of patients are in stable CMR. “We are particularly impressed with the stability of the CMR,” Prof. Rosti stated. “So far, we see that overall 70% of the patients obtain a CMR4.0 at least once, but at different milestones there is still fluctuation, so it is important to follow those patients for a longer time.”

Prognostic Significance of Molecular, Cytogenetic and Hematologic Responses

Researchers from the Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany, reported 2 analyses that evaluated the prognostic significance of hematologic, molecular and cytogenetic markers in patients enrolled in the German CML Study IV. Newly diagnosed CML-CP patients were randomized to standard-dose imatinib 400 mg/day with or without low-dose cytarabine or interferon-a or to high-dose imatinib 800 mg/day. As a result of the first study, Dr. Benjamin Hanfstein reported that after 3 months of imatinib therapy, treatment failure (lack of complete hematologic remission [CHR]) was not predictive for PFS. Suboptimal response (no CyR) showed a trend to significance (P=0.0558), but the lack of a partial CyR at 3 months was identified as a response landmark significantly dividing a poor-risk from a good-risk group (P=0.0367). A group of 160 of 569 patients who did not achieve a response <10% BCR-ABLIS at 3 months was found to be at increased risk of progression on imatinib (P=0.016). After 5 years of imatinib treatment, 87% of these patients remained progression-free compared with 96% of the remaining patients. “We conclude that the 10% BCR-ABL landmark after 3 months of imatinib treatment might be able to identify a high-risk group of about 30% of patients who are likely to benefit from an early switch to a second-generation TKI,” Dr. Hanfstein said.

The second analysis showed that among 848 patients with 12-month molecular data available, 40% achieved <0.1% BCR-ABLIS (MMR), 28% achieved 0.1% to 1% (CCyR) and 31% >1% by 12 months. Independent of treatment approach, patients achieving MMR and CCyR showed significantly higher PFS (97% vs. 95% vs. 87% at 5 years, P=0.0023) and better OS (97% vs. 96% vs. 88% at 5 years, P=0.0011) than the group with >1% BCR-ABL.

A landmark analysis based on the achievement of CCyR at 12 months revealed significantly higher OS in the CCyR group (96% vs. 91% at 5 years, P=0.015). “This is the first study to show that molecular data are predictive for OS,” Dr. Martin Müller declared. “It also supports previous findings from the IRIS (International Randomized Study of Interferon and ST1571) data (Blood 2010;116:3758-65).”

The achievement of CMR4.0 in CML-CP patients represents a stable level of disease with extremely low risk of progression, according to a study presented by Dr. Dongho Kim, The Catholic University of Korea, Seoul, South Korea. In the study, 53 patients who achieved CMR with imatinib 400 mg/day were monitored by RQ-PCR assay at regular intervals. After a median of 72 months, 9 patients had achieved CMR=4.0,<4.5; 13 CMR=4.5,<5.0 and 31 CMR5.0. All patients maintained CHR, CCyR and MMR without disease progression. Survival rate was 98.1%. Seven patients had fluctuating BCR-ABL levels under/over CMR4.0 levels, but the majority maintained CMR4.0 without further progression to advanced disease. However, 67% of patients who achieved CMR=4.0,<4.5 and 31% of those who achieved CMR=4.5,<5.0 had fluctuations under CMR levels, which might have contributed to relapse in >50% patients, Dr. Kim suggested. “Firm conclusions cannot be drawn solely based on the duration of PCR negativity in RQ-PCR assays about which patients can safely discontinue therapy,” he advised. However, with longer follow-up, further significance of achieving different depths of CMR may be determined and the usefulness of more sensitive assays will be examined.

Improving Quality of Life by Switching Treatment

Preliminary analysis of patients with CML-CP who received imatinib 400 mg/day for =3 months shows that switching to nilotinib improved non-hematologic imatinib-related, low-grade AEs in >50% of patients. In addition, overall improvement in symptoms was observed and most patients say they experienced improved quality of life (QOL), noted Dr. Lambert Busque, Université de Montréal, Maisonneuve-Rosemont Hospital, Quebec, who presented data from 15 patients in the ongoing open-label study.

These patients had experienced a total of 75 imatinib-related low-grade (grade 1 or 2) non-hematologic AEs persisting >2 months or recurring >3 times despite best supportive care. Fatigue was the most common event, followed by nausea, arthralgia and muscle spasm. Three months after patients were switched to nilotinib 300 mg b.i.d., 40 of the imatinib-related AEs had resolved completely. Of the remaining AEs, 5 decreased from grade 2 to grade 1, 27 were unchanged and 3 increased in grade. For nilotinib-related, non-hematologic AEs, the dose was reduced in 6 patients. Fourteen grade 3 AEs were reported in 6 patients; 10 were suspected to be nilotinib-related. Most AEs were managed by brief dose interruption. Compared with baseline, 82% of all patients and 83% of patients with grade 3 nilotinib-related AEs reported QOL improvement at the end of 3 months and mean reductions from baseline in the M.D. Anderson Symptom Inventory-CML severity and interference scores. Dr. Busque noted that symptoms persisted in about 20% of patients. “That could be a class effect or they may have been pre-existing symptoms that were not strictly related to the drug,” he suggested. Longer-term evaluation is continuing.