In the JournalsPerspective

Midostaurin regimen safe, effective in older patients with acute myeloid leukemia

Treatment with midostaurin plus intensive chemotherapy appeared safe among older adults with acute myeloid leukemia and a FLT3 internal tandem duplication mutation, according to results of a prospective, phase 2 trial published in Blood.

Midostaurin (Rydapt, Novartis), a multitargeted kinase inhibitor, also significantly improved EFS among older as well as younger patients with FLT3-IDT AML compared with historical controls.

“After the approval by FDA and [European Medicines Agency] of midostaurin for patients with FLT3-mutated AML, our hypothesis-generating trial is the first to show efficacy and safety data of midostaurin in older patients with FLT3-[internal tandem duplication (ITD)] given in combination with intensive chemotherapy, and as single-agent maintenance after [allogeneic hematopoietic stem cell transplantation],” Richard F. Schlenk, MD, professor of internal medicine at the University Hospital of Ulm, Germany, and colleagues wrote.

In the prospective, multi-institutional study, Schlenk and colleagues evaluated 284 patients (aged 18-60 years, n = 198; aged 61-70 years, n = 86) with AML and centrally verified FLT3-ITD. All patients received induction therapy with idarubicin, cytarabine and etoposide and midostaurin. Patients who achieved complete remission or complete remission with incomplete hematological recovery underwent consolidation therapy, with allogeneic HSCT performed during first complete remission at the researchers’ discretion. Patients who could not undergo transplantation received up to four cycles of high-dose cytarabine.

Results showed that by the end of induction therapy, 217 patients (74.6%) attained complete remission or complete remission with incomplete hematological recovery, 51 patients (18%) had refractory disease and 16 patients (5.6%) had died.

Most patients (72.4%) in complete remission or complete remission with incomplete hematological recovery subsequently received allogeneic HSCT. Ninety-seven patients (34%) underwent maintenance therapy, including 75 after allogeneic HSCT (median time on maintenance, 9 months) and 22 after consolidation with cytarabine (median maintenance, 10.5 months).

Researchers observed 2-year EFS rates of 34% (95% CI, 24-47) among older patients vs. 39% (95% CI, 33-47) for younger patients, and 2-year OS rates of 46% (95% CI, 35-59) vs. 53% (95% CI, 46-61).

Researchers also conducted a propensity score-weighted analysis comparing EFS rates with those of 415 historical controls from five prospective trials. Results showed significant risk reduction for an event with midostaurin (HR = 0.58; 95% CI, 0.48-0.7). Subgroup analysis based on age group revealed significant differences in both younger (HR = 0.61; 95% CI, 0.49-0.76) and older patients (HR = 0.42; 95% CI, 0.29-0.61).

“In summary, we show that midostaurin plus intensive chemotherapy can be safely administered also in older patients,” the researchers wrote. “Compared to historical controls, midostaurin significantly improved EFS. Allogeneic [HSCT] in first remission after midostaurin and chemotherapy is feasible and highly effective irrespective of age.” – Jennifer Byrne

Disclosures: Schlenk reports advisory board roles, honoraria and research funding from Novartis. Please see the full study for all other authors’ relevant financial disclosures.

Treatment with midostaurin plus intensive chemotherapy appeared safe among older adults with acute myeloid leukemia and a FLT3 internal tandem duplication mutation, according to results of a prospective, phase 2 trial published in Blood.

Midostaurin (Rydapt, Novartis), a multitargeted kinase inhibitor, also significantly improved EFS among older as well as younger patients with FLT3-IDT AML compared with historical controls.

“After the approval by FDA and [European Medicines Agency] of midostaurin for patients with FLT3-mutated AML, our hypothesis-generating trial is the first to show efficacy and safety data of midostaurin in older patients with FLT3-[internal tandem duplication (ITD)] given in combination with intensive chemotherapy, and as single-agent maintenance after [allogeneic hematopoietic stem cell transplantation],” Richard F. Schlenk, MD, professor of internal medicine at the University Hospital of Ulm, Germany, and colleagues wrote.

In the prospective, multi-institutional study, Schlenk and colleagues evaluated 284 patients (aged 18-60 years, n = 198; aged 61-70 years, n = 86) with AML and centrally verified FLT3-ITD. All patients received induction therapy with idarubicin, cytarabine and etoposide and midostaurin. Patients who achieved complete remission or complete remission with incomplete hematological recovery underwent consolidation therapy, with allogeneic HSCT performed during first complete remission at the researchers’ discretion. Patients who could not undergo transplantation received up to four cycles of high-dose cytarabine.

Results showed that by the end of induction therapy, 217 patients (74.6%) attained complete remission or complete remission with incomplete hematological recovery, 51 patients (18%) had refractory disease and 16 patients (5.6%) had died.

Most patients (72.4%) in complete remission or complete remission with incomplete hematological recovery subsequently received allogeneic HSCT. Ninety-seven patients (34%) underwent maintenance therapy, including 75 after allogeneic HSCT (median time on maintenance, 9 months) and 22 after consolidation with cytarabine (median maintenance, 10.5 months).

Researchers observed 2-year EFS rates of 34% (95% CI, 24-47) among older patients vs. 39% (95% CI, 33-47) for younger patients, and 2-year OS rates of 46% (95% CI, 35-59) vs. 53% (95% CI, 46-61).

Researchers also conducted a propensity score-weighted analysis comparing EFS rates with those of 415 historical controls from five prospective trials. Results showed significant risk reduction for an event with midostaurin (HR = 0.58; 95% CI, 0.48-0.7). Subgroup analysis based on age group revealed significant differences in both younger (HR = 0.61; 95% CI, 0.49-0.76) and older patients (HR = 0.42; 95% CI, 0.29-0.61).

“In summary, we show that midostaurin plus intensive chemotherapy can be safely administered also in older patients,” the researchers wrote. “Compared to historical controls, midostaurin significantly improved EFS. Allogeneic [HSCT] in first remission after midostaurin and chemotherapy is feasible and highly effective irrespective of age.” – Jennifer Byrne

Disclosures: Schlenk reports advisory board roles, honoraria and research funding from Novartis. Please see the full study for all other authors’ relevant financial disclosures.

    Perspective
    Amir T. Fathi

    Amir T. Fathi

    The last few years has witnessed a dizzying number of regulatory approvals for novel therapeutic approaches targeting AML. Among the agents approved in AML was the FLT3 inhibitor midostaurin, in combination with standard induction therapy, as upfront therapy for FLT3-mutated patients. This approval was based on data from the global placebo-controlled phase 3 RATIFY study, which compared standard “7 + 3” induction chemotherapy vs. “7 + 3” combined with midostaurin. Results demonstrated a survival benefit in younger FLT3-mutated patients receiving the latter.

    The adjoining study provided data from a large European cohort of FLT3-mutated patients, all of whom were treated with midostaurin plus induction chemotherapy, and a substantial subset of whom proceeded to HSCT. Researchers also provided data on a number of patients who went on to receive maintenance therapy with midostaurin following HSCT.

    The results and their interpretation are intriguing. Schlenk and colleagues demonstrated that the combination of induction with midostaurin is feasible and efficacious in patients who are older (aged 61-70 years), adding to the data we now have for younger patients treated on the RATIFY study.

    Midostaurin plus induction also was associated with a high rate of remission in this study, and an EFS that was markedly improved when compared with historical controls. Additionally, these data suggest again that transplant following this combination therapy is feasible and effective for younger and some older patients with FLT3-mutated AML.

    Despite this, the authors also rightly provide some words of caution. Midostaurin as maintenance was only administered in a minority of patients and, when used, did not appear to be well-tolerated in all patients. Grade 3 or higher gastrointestinal adverse events, infections and cytopenias were reported in a large proportion of patients treated with maintenance therapy, often leading to pauses or discontinuation in therapy.

    Nevertheless, in total, these data add value. The combination of midostaurin with induction can be suitable for a subset of patients, especially those whose consolidative destination may be HSCT. However, post-HSCT maintenance — now increasingly studied as a promising strategy for FLT3-mutated patients — may be more challenging with less specific FLT3 tyrosine kinase inhibitors such as midostaurin, which can be associated with impactful adverse events in a vulnerable patient population. Maintenance strategies with more specific and well-tolerated therapies require further study and may provide the right balance between tolerability and improved outcomes.

    Reference:

    Stone RM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1614359.

    • Amir T. Fathi, MD
    • Massachusetts General Hospital

    Disclosures: Fathi reports advisory/consultant roles with Amphivena, Astellas, Boston Biomedical, Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, PTC Therapeutics, Novartis and Takeda, and clinical trial support from Agios, Celgene, Seattle Genetics and Takeda.