ASH Clinical News July 2016 | Page 29

CLINICAL NEWS double-UCB unit ) and platelet recovery also were similar ( 58.1 days and 55.9 days ). The 60-day probability of posttransplant recovery was 92.6 percent in the single-unit group and 94.2 percent in the double-unit group .

“ OS two years after transplantation was 74.8 percent in our double-unit arm and 68.8 percent in the singleunit arm , a difference that was not significant ,” the authors wrote . “ The incidence of any degree of chronic GVHD at two years was similar in our two treatment arms , but we found a higher incidence of extensive disease after double-unit transplantation .” ( See TABLE 1 for a detailed comparison of outcomes .)

In the entire study population , 35 patients died after HCT : 19 in the single-unit arm and 16 in the doubleunit arm . Causes of death in the single-unit group included diseaserelated relapse ( n = 15 ), engraftment failure ( n = 2 ), infectious complication ( n = 1 ), and veno-occlusive disease ( n = 1 ), while causes of death in the double-unit cohort included diseaserelated relapse ( n = 8 ), infectious complications ( n = 5 ), adult respiratory distress ( n = 1 ), GVHD ( n = 1 ), and thrombotic microangiopathy ( n = 1 ).

The authors also proposed that double-unit UCB be reserved for patients who lack an UCB unit with adequate cell dose . “ Double-unit transplantation is ineffective at improving outcome when a single-unit UCB containing more than 3 x 10 7 TNC / kg can be used ,” they wrote .

Because this study was conducted in a largely pediatric patient population , the results may not be generalizable to the adult patient population . Differing quality and cell dose of selected cord blood units could have influenced the study results and , in addition , Dr . Michel and authors noted that “ the results in the single-unit arm may be favorably influenced by the degree of UCB recipient HLA compatibility [ given that there was ] a relatively high proportion of 6 / 6 HLA-identical UCB in the single-unit arm ( 19.1 % vs . 7.2 %).”

“ A double-unit strategy proved ineffective at improving the outcome of a UCB transplant when a single cord has an adequate cell dose ,” the authors concluded . “ Approaches to facilitate engraftment and to improve patient survival may include better HLA matching with high-resolution typing of eight instead of six loci , as well as in vivo cord blood priming or expansion .”

REFERENCE

Michel G , Galambrun C , Sirvent A , et al . Single versus double-unit cord blood transplantation for children and young adults with acute leukemia or myelodysplastic syndrome . Blood . 2016 April 20 . [ Epub ahead of print ]

According to a pooled analysis of the GEN501 and SIRIUS studies – the basis for the U . S . Food and Drug Administration ’ s accelerated approval of daratumumab for patients with previously treated multiple myeloma ( MM ) – the anti-CD38 monoclonal antibody showed no new safety signals and led to durable responses .

“ Daratumumab appears to be a safe and reasonably effective option for patients who are beyond a third line of therapy or have double refractory disease ,” Saad Z . Usmani , MD , lead author of the analysis that was published in Blood , told ASH Clinical News .

Dr . Usmani , from the Levine Cancer Institute in Charlotte , North Carolina , and authors analyzed data from both studies , a total of 148 patients with MM who were treated with 16 mg / kg of daratumumab .

The open-label , multi-center , phase I / II , dose-escalation , doseexpansion GEN501 study included MM patients who were relapsed / refractory to two or more previous lines of therapy , including a proteasome inhibitor ( PI ) and an immunomodulatory drug ( IMiD ). After a dose-escalation phase , 16 mg / kg of daratumumab was administered once weekly for the first seven doses after the initial dose – which had a threeweek washout period – followed by twice monthly for the next eight doses , and monthly thereafter . The primary endpoint was safety , and the secondary endpoint was efficacy .

The open-label , multi-center , phase II SIRIUS study included MM patients who had been treated with three or more lines of therapy , including a PI and IMiD , who were also double-refractory . After an interim analysis , patients received 16 mg / kg of daratumumab once weekly for eight weeks , followed by once every two weeks for the next 16 weeks , and once every four weeks thereafter . The primary endpoint was overall response rate ( ORR ), and adverse events ( AEs ) were also monitored .

In the pooled analysis , Dr . Usmani and authors assessed progression-free survival ( PFS ) and overall survival ( OS ) in 42 patients from the GEN501 study and 106 from the SIRIUS study .

Within the entire population , patients received a median of five ( range = 2-14 ) prior lines of therapy , with most ( 76.4 %) receiving more than three prior therapies . Most ( 86.5 %) were double-refractory to a PI and an IMiD , with 39.2 percent refractory to carfilzomib and 55.4 percent refractory to pomalidomide . The median treatment duration was 3.4 months ( range = 0.03-26 months ), and the median number of infusions was 12 ( range = 1-40 infusions ).

The ORR was 31.1 percent , including 13 very good partial responses , four complete responses , and three stringent complete responses .

“ Response achieved by daratumumab-treated patients were rapid ( median time to response = 1 month ), deep ( 14 % with very good partial response or better ), and durable ( median duration of response = 7.6 months ),” the authors wrote .

After a median follow-up of 20.7 months ( range = 0.5-27.1 months ), the median PFS was four months ( 95 % CI 2.8-5.6 ), with 21.6 percent of patients remaining progression-free at 12 months ( 95 % CI 14.4-29.8 ). The median OS was 20.1 months ( 95 % CI 16.6 – not evaluable ); 18- and 24-month OS rates were 56.5 percent ( 95 % CI 47.9-64.2 ) and 45 percent ( 95 % CI 35.5-54.1 ), respectively . At 20.7 months , 36 of the 46 patients who responded to daratumumab were still alive . See TABLE 2 for a full review of treatment responses .

“ The overall response rate of 31 percent suggests that , even though a group of patients clearly benefit from daratumumab as a single agent , perhaps combinations with other drug classes may enhance its activity ,” Dr . Usmani said . Of the 107 patients who were eligible for subsequent therapy , 42 ( 39.2 %) responded to the first subsequent therapy with a partial response or better , while 40 ( 37.4 %) had minimal response / stable disease , and 16 ( 15 %) had progressive disease or were not evaluable . The response was unknown for the remaining nine patients ( 8.4 %).

The most common ( ≥20 %) treatment-related adverse events ( AEs ) included fatigue , nausea , anemia , back pain , cough , upper respiratory tract infection , thrombocytopenia , and neutropenia . Infusion-related reactions occurred in 48 percent of patients , with most occurring during the first infusion ( 95.8 %) and decreasing with subsequent infusions ( 7 %). Most treatment discontinuations were related to progressive disease ( 83.1 %), while 4.1 percent of patients stopped treatment due to AEs . Three deaths occurred that were related to AEs ( viral H1N1 infection , pneumonia , and aspiration pneumonia ), though the authors determined that these were not related to study treatment .

Dr . Usmani noted that daratumumab is being investigated in a number of ongoing trials , including a phase III study of daratumumab in combination with lenalidomide or bortezomib in relapsed / refractory MM and newly diagnosed MM and a phase I study of daratumumab administered subcutaneously in combination with recombinant human hyaluronidase .

The underlying mechanisms of action that explain daratumumab ’ s benefits “ remain to be elucidated ,” the authors wrote , adding that investigators are actively looking at whether daratumumab may enhance a patient ’ s response to subsequent treatments – including those to which they were previously exposed .

REFERENCE

Usmani SZ , Weiss BM , Plesner T , et al . Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma . Blood . 2016 May 23 . [ Epub ahead of print ]

TABLE 2 . Overview of Response to Treatment ( 16 mg / kg of Daratumumab )

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