CLINICAL NEWS need for vigilance in preventing these and the importance of prophylactic antibiotics .”
Also , because toxicity is a huge concern for patients , Dr . Michaelis encouraged “ more transparent conversations about patients ’ and [ physicians ’] expectations of toxicity and expectations of cure .”
As with midostaurin treatment , the timeliness of mutation results is also a challenge to incorporating CPX-351 into treatment algorithms . “ We don ’ t have results from molecular testing – most importantly FLT3 mutation status – by the time we have to make a decision about induction ,” she explained . “ So , the theoretical question arises , what if you give someone CPX-351 and then midway through , you find out they are FLT3-positive ?”
The cost of CPX-351 also is an obstacle : It is roughly 20 times more expensive than traditionally delivered daunorubicin and cytarabine .
Enasidenib Dr . Ward also discussed the approval of the IDH2 inhibitor enasidenib , which is indicated for the treatment of adult patients with relapsed or refractory AML who harbor an IDH2 mutation . Less than 20 percent of patients with AML have this mutation , and its implications for AML pathogenesis and prognosis are unknown , she explained .
Enasidenib was approved based on results from the single-arm , phase I / II AG221-C-001 study . After a minimum of six months of treatment , 23 percent of patients experienced a complete response for a median of 8.2 months . “ This was not a particularly stable estimate ,” she noted , “ as median follow-up time was only 6.6 months and duration of response appeared to improve with longer follow-up .”
The duration of response is also important to consider in the context of time to best response , which was observed to be as long as 11.2 months , Dr . Ward reported . The product label recommends patients receive enasidenib for a minimum of six months to allow adequate time for response .
FDA reviewers found that enasidenib was generally well tolerated , according to study results . “ While 53 percent of patients had at least one dose interruption for an AE , most were brief interruptions for infections or hyperbilirubinemia ,” she noted . “ Just 10 percent of patients required dose reductions or discontinuations for AEs , and no single event prompted dose reduction or discontinuation in more than two patients .”
“ The most notable toxicity , as predicted by [ enasidenib ’ s ] mechanism of action is differentiation syndrome ,” said Jessica Altman , MD , of the Robert H . Lurie Comprehensive Cancer Center at Northwest University in Chicago , Illinois . Enasidenib works by inducing differentiation of leukemic cells , she explained , and responses are seen frequently without the aplasia that is usually observed when treating patients with cytotoxic chemotherapy . “[ The differentiation syndrome ] should be familiar to us , as it ’ s akin to the differentiation syndrome observed in patients [ with acute promyelocytic leukemia ] treated with all-trans-retinoic acid … but [ its management ] still requires a high degree of vigilance .”
In discussing enasidenib ’ s role in AML treatment , Dr . Altman also noted a consideration unique to the drug ’ s mechanism of action : “ You don ’ t often need to know much about the Krebs cycle when taking care of patients with AML ; however , in this situation , it ’ s important due to the mechanism of action of this agent and an expected toxicity .”
“ It can also take time to attain a response due to this mechanism of action ,” she concluded . “ We are still relatively early in predicting who will respond to enasidenib .”
Gemtuzumab Ozogamicin Gemtuzumab ozogamicin ( GO ), has a complicated history , said Kelly Norsworthy , MD , medical officer of the Division of Hematology Products at the FDA , during her discussion of GO “ then and now .” GO originally received accelerated approval in May 2000 as monotherapy for older patients with relapsed CD33-positive AML . In June 2010 , the drug was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit and demonstrated safety concerns , including early deaths .
“ Researchers hypothesized that repeated lower doses of GO may be able to increase the internalization process of the drug into leukemia cells , enhancing safety ,” Dr . Norsworthy noted . After further testing in phase I and II trials comparing GO monotherapy administered via the original unfractionated dosing regimen and the new fractionated regimen , GO was resubmitted for regulatory approval in 2017 .
The agent was approved based on results from three clinical trials – one investigated GO in combination with chemotherapy , and two investigated GO as a single agent . In the combination study , patients who received GO plus daunorubicin and cytarabine had a longer median event-free survival ( EFS ) than those who received chemotherapy alone ( 17.3 vs . 9.5 months ; p value not provided ).
In the first monotherapy study , which enrolled patients with newly diagnosed AML who could not tolerate or chose not to receive intensive chemotherapy , GO was superior to best supportive care , with ( median OS = 4.9 months vs . 3.6 months ; p value not reported ). In the second monotherapy trial , which was a single-arm study of people with relapsed CD33-positive AML , 26 percent of patients achieved a complete remission that lasted a median of 11.6 months ( range not provided ) after receiving a single course of GO .
The observed mortality rate across studies of the new dose was “ roughly half of that seen with the old dose ,” she reported . Based on these results , “ we can comfortably say the new regimen is at least as effective or better than the old regimen .”
“ An important point to stress is that there is no benefit to the addition of GO seen in those with adverse karyotype ,” added Dr . Altman .
Because the EFS benefit did not extend to this subgroup of patients , the agency recommends that , “ when cytogenetic results become available , clinicians should consider whether the potential benefit of continuing treatment with GO outweighs the risks ,” Dr . Norsworthy noted .
Select grade ≥3 AEs that were more common in the GO arm than the chemotherapy arm included infection ,
Attendees between sessions at the annual meeting .
prolonged thrombocytopenia , hemorrhage , and veno-occlusive liver disease .
Although GO can be used for relapsed disease as a single agent ( based on results of the MyloFrance-1 single-arm study ), Dr . Altman cited the lack of comparative data between regimens as a barrier to routinely using GO in clinical practice . “ We have a plethora of regimens to use in the relapsed setting ,” she said , “ but it ’ s hard to know , without comparative data , which is superior .”
“ Despite the re-approval of GO , there remain several unresolved questions ,” Dr . Altman added , and more clinical trial data are needed to determine how GO should be used with other agents and in adults who are unfit for intensive chemotherapy .
Examining the Risk of Cardiovascular Disease – Related Mortality in Patients With and MDS / CMML
Patients with chronic myelomonocytic leukemia ( CMML ) and myelodysplastic syndromes ( MDS ) have a higher risk of cardiovascular disease ( CVD )– related mortality and cerebrovascular accident ( CVA )– related mortality , according to results presented at the 2017 ASH Annual Meeting .
Lead author Remco J . Molenaar , MD , PhD , from the Taussig Cancer Institute at Cleveland Clinic in Ohio , told ASH Clinical News , “ This is the first study to investigate rates and risks of CVD – related deaths in CMML and MDS , two types of myeloid neoplasms ( MPN ) frequently affected by TET2 mutations , at the population level .” Because mortality risk was particularly high in the first year after diagnosis , he added , these patients likely already had underlying CVD .
Researchers reviewed Surveillance Epidemiology and End Results ( SEER ) registries to gather survival and cause-of-death data on patients with CMML ( n = 4,699 ), MDS ( n = 38,304 ), breast cancer ( n = 1,053,780 ), or prostate cancer ( n = 1,082,390 ). The latter two cancers were selected as controls because they are not associated with mutations typically seen with
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