ASH Clinical News July 2017 Bonus Issue | Page 34

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( range = 5-11.5 months ) and 12.9 months ( range = 8.7-23.4 months ), respectively . Both EFS and OS were longer in the MRD cohort than in the morphologic disease cohort :

• EFS : not reached ( range = 4.2 to not reached ) vs . 6.3 months ( range = 4.8-9 months ; p = 0.008 )

• OS : not reached ( range = 15.3 to not reached ) vs . 17 months ( range = 8.5-36.2 months ; p = 0.018 )

Patients in the MRD cohort developed substantially less CRS and neurotoxicity , ( p = 0.033 and p < 0.001 , respectively ).

In a second report from the study , authors evaluated whether certain baseline and post-treatment clinical and laboratory factors ( including demographics , treatment regimens , and hematologic parameters ) were associated with the development of CRS or severe ( grade ≥3 ) neurotoxicity . 2

“ Severe neurotoxicity is one of the two most common toxicities associated with CAR T cells , but it remains an enigma ,” Dr . Park explained . “ The mechanism of action is unclear . We wanted to know if there are particular clinical characteristics associated with [ developing this complication ].”

Thirty-one patients experienced neurotoxicity ( grade 1 , n = 8 ; grade 2 , n = 2 ; grade 3 , n = 18 ; grade 4 , n = 3 ).

Disease burden ( defined as ≥50 % blasts ) at the time of T-cell infusion ( p = 0.0045 ) and post-treatment grade ≥3 CRS ( p = 0.0010 ) were significantly associated with serious neurotoxicity , as were the following factors ( p < 0.01 for all ):

• fever

• low platelet count

• high ferritin and mean corpuscular hemoglobin concentration

• elevated granulocyte macrophage colony-stimulating factor , interferon gamma , interleukin ( IL ) -15 , IL-5 , IL-10 , and IL-2 at day 3 of T-cell infusion

• in vivo peak CAR T-cell expansion at day 7

“[ If a patient ] has a higher degree of T-cell expansion , this will generally indicate higher degree of immune activation , translating to severe neurotoxicity ,” Dr . Park explained . The authors found no association between serious neurotoxicity and patient age , weight , T-cell dose , choice of conditioning chemotherapy , or number of prior lines of treatment .

“ Patients with higher disease burden tended to have a higher neurotoxicity , though it is not a clear dichotomy as we see with CRS ,” Dr . Park said . “ Low disease burden patients still get severe neurotoxicity , although less frequently .”

These results should help clinicians identify patients who are at risk for developing severe neurotoxicity and require intervention , and “ patients who might completely recover and revert back to grade 1 or 2 neurotoxicity ,” Dr . Park noted . “ Non-specific immunosuppression with a steroid is the most common [ intervention ], but as we learn more , maybe we could come up with a better , targeted way to manage this neurotoxicity .”

Both reports are limited by small patient populations , lack of a comparator arm , and their retrospective design .

Dr . Park reports research funding from Juno Therapeutics .

REFERENCES

1 . Park JH , Riviere I , Wang X , et al . Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR ( 19-28z ) T-cell therapy . Abstract # 7008 . Presented at the 2017 ASCO Annual Meeting , June 5 , 2017 ; Chicago , Illinois .

2 . Park JH , Santomasso B , Riviere I , et al . Baseline and early post-treatment clinical and laboratory factors associated with severe neurotoxicity following 19-28z CAR T cells in adult patients with relapsed B-ALL . Abstract # 7024 . Presented at the 2017 ASCO Annual Meeting , June 5 , 2017 ; Chicago , Illinois .

For the approximately 12 percent of patients with acute myeloid leukemia ( AML ) with the IDH2 mutation , the oral , selective , small-molecule inhibitor enasidenib could become a new treatment option , according to results of a phase I / II trial presented at the 2017 ASCO Annual Meeting . 1

Among the 239 patients with relapsed / refractory IDH2-mutant AML enrolled in the trial , the overall response rate ( ORR ) was 40 percent , and patients achieved a median overall survival ( OS ) of 9.3 months ( range = 8.2-10.9 months ).

“ I ’ m extraordinarily optimistic about [ these response rates ] in this heavily pretreated patient population ,” lead author Eytan M . Stein , MD , from Memorial Sloan Kettering Cancer Center in New York , told ASH Clinical News . “ I ’ m encouraged that this drug will make a real difference to patients .” Dr . Stein presented results from the dose-escalation and dose-expansion phases of the multicenter , open-label trial , which were also published recently in Blood . 2

Patients with AML have increased levels of 2-hydroxyglutarate ( 2HG ), Dr . Stein explained , “ which freezes myeloid cells in an undifferentiated state and the IDH2-mutant protein keeps those cells from growing .” By blocking IDH2 and lowering levels of 2HG , enasidenib “ allows those immature cells to start maturing . It ’ s a differentiation therapy , rather than a cytotoxic therapy .”

All patients ( median age = 70 years ; range = 19-100 years ) received enasidenib . In the doseescalation phase , which included 113 patients , the maximum tolerated dose was not reached at doses of up to 650 mg daily . Median 2HG reductions from baseline were 92 percent , 90 percent , and 93 percent in patients receiving enasidenib < 100 mg , 100 mg , or > 100 mg daily ; respectively . Based on the drug ’ s pharmacodynamic profile and efficacy , the researchers selected enasidenib 100 mg oncedaily , administered in 28-day treatment cycles , for the dose-expansion phase ( n = 126 ).

This phase included four subgroups of patients : patients ≥60 years or < 60 years with relapsed / refractory AML following a hematopoietic cell transplantation ; patients ≥60 years with previously untreated AML who declined standard-of-care chemotherapy ; and those ineligible for other arms .

In the 176 patients with relapsed / refractory AML , the ORR was 40.3 percent , including 34 complete remissions ( CRs ; for a CR rate of 20.2 %). For the 109 patients who received enasidenib 100 mg / day , the ORR was 38.5 percent ( TABLE 1 ).

The median duration of response was 5.8 months ( range = 3.9-7.4 months ) in the overall population and 5.6 months ( range = 3.8-9.7 months ) in the 100 mg / day group .

Overall , 36.3 percent of relapsed / refractory patients achieved RBC transfusion-independence and 36.4 percent achieved platelet transfusion-independence . For patients in CR , these rates were 95.5 percent and 94.1 percent , respectively .

“ The median overall survival of longer than 9 months was impressive for a group of patients with relapsed / refractory AML ,” Dr . Stein noted . Patients in CR with enasidenib also had longer median OS ( 19.7 months ; range = 11.6 months to not estimable ), compared with non-responders ( 7.0 months ; range = 5.0-8.3 months ; p value not reported ).

Patients received a median of five treatment cycles ( range = 1-25 ). The most common any-grade adverse events ( AEs ) were : nausea ( 46 %), hyperbilirubinemia ( 45 %), diarrhea ( 40 %), and fatigue ( 40 %). Treatment-related grade 3 / 4 AEs included : indirect hyperbilirubinemia ( 12 %), thrombocytopenia ( 6 %), and anemia ( 5 %). Serious treatmentrelated IDH-inhibitor-associated differentiation syndrome was reported in 8 percent of patients , and two of these patients died during study follow-up .

Response also was associated with myeloid differentiation , though baseline 2HG levels and mIDH2 variant allele frequency were similar between responders and non-responders . “ Unlike cytotoxic chemotherapy , responses to enasidenib may require several treatment cycles and responses can improve over time with continued treatment ,” the authors concluded .

The study ’ s findings are limited by the lack of a comparator arm .

Dr . Stein noted that enasidenib is being compared with standard-of-care therapies ( either induction chemotherapy or azacitidine ) in an ongoing , randomized , phase III trial of patients with relapsed / refractory , IDH2-mutant AML . “ We ’ re hoping that [ enasidenib ] combined with standard-of-care therapies will be more effective than standard-of-care therapies alone ,” he said .

Dr . Stein reports research funding from Celgene .

REFERENCES

1 . Stein EM , DiNardo CD , Pollyea DA , et al . Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia ( R / R AML ): Results of a phase I dose-escalation and expansion study . Abstract # 7004 . Presented at the 2017 ASCO Annual Meeting ; June 6 , 2017 ; Chicago , Illinois .

2 . Stein EM , DiNardo CD , Pollyea DA , et al . Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia . Blood . 2017 June 6 . [ Epub ahead of print ]

TABLE 1 . Response Rates for Patients With IDH2-Mutant Relapsed / Refractory AML

All ( n = 176 )

100 mg / day ( n = 109 )

32 ASH Clinical News July 2017 Bonus Mid-Year Edition