CLINICAL NEWS
Inotuzumab Ozogamicin Plus Low-Intensity Chemotherapy Is Safe , Effective in Older Patients With ALL
In February 2017 , the U . S . Food and Drug Administration granted inotuzumab ozogamicin priority review for the treatment of adult patients with relapsed / refractory B-cell precursor acute lymphocytic leukemia ( ALL ), based on results of the phase III INO-VATE 1022 trial , which showed that inotuzumab ozogamicin lowered the risk of disease progression and death , compared with standard-of-care chemotherapy .
Because older patients with ALL often do not tolerate standard , intensive chemotherapy well , Nicholas Short , MD , of the MD Anderson Cancer Center in Houston , Texas , and colleagues evaluated whether treating these patients with inotuzumab ozogamicin and lowerintensity chemotherapy ( mini-hyper- CVD ) would similarly benefit them , while limiting toxicity associated with higher-intensity regimens . Dr . Short presented the findings of the phase I / II trial at the 2017 ASCO Annual Meeting .
“ This is a particularly difficult population to treat ,” Dr . Short told ASH Clinical News . “ When treated with full-intensity chemotherapy , they have a relatively unacceptable early mortality from induction and from myelosuppression-related infections , and their long-term survival has been quoted around 20-40 percent , largely because of the toxicity of the regimen .”
The trial enrolled 52 patients ( median age = 68 years ; range = 60-81 years ) who were newly diagnosed with Philadelphia-negative B-cell precursor ALL . Patients received treatment with :
• mini-hyper-CVD : cyclophosphamide and dexamethasone at 50 % dose reduction , no anthracycline , methotrexate at 75 % dose reduction , and cytarabine 0.5 g / m 2
• inotuzumab ozogamicin : 1.3-1.8 mg / m 2 on day 3 of cycle 1 and 0.8- 1.3 mg / m 2 on day 3 of cycles 2-4
All patients received prophylactic intrathecal chemotherapy for the first four cycles ; patients who were CD20- positive received rituximab . Patients who responded to treatment received maintenance therapy with a combination of 6-mercaptopurine , vincristine , methotrexate , and prednisone for up to 3 years .
Patients were followed for a median of 29 months ( range not provided ). Among the 48 patients who were evaluable for response at the time of data presentation , the overall response rate was 98 percent , with 39 patients achieving complete response ( CR ; 81 %), seven achieving CR with incomplete platelet recovery ( CRp ; 15 %), and one achieving CR with incomplete hematologic recovery ( 2 %). One patient did not respond to treatment .
The 3-year overall survival rate was 56 percent , higher than was seen in a historical cohort of older patients treated with hyper-CVAD with or without rituximab ( 54 % vs . 31 %; p = 0.007 ).
The researchers also assessed minimal residual disease ( MRD ), measured by 6-color flow cytometry , and found that the majority of evaluable patients were MRD-negative after one treatment cycle ( n = 36 / 46 ; 78 %). Overall , 49 of 51 responders ( 96 %) achieved MRD-negativity .
“ We found excellent response rates , which were driven in part by a relatively high rate of MRD-negativity , which we know is a good surrogate for long-term outcomes ,” said Dr . Short .
The median times to platelet and absolute neutrophil count recovery in cycle one were 23 days ( range = 11-91 days ) and 16 days ( range = 0-49 days ), respectively , and 22 days ( range = 14- 64 days ) and 17 days ( range = 13-49 days ) for subsequent cycles .
The most common adverse event associated with inotuzumab ozogamicin and mini-hyper-CVD was prolonged thrombocytopenia ( lasting > 6 weeks ), which occurred in 81 percent of patients . Infections during induction and consolidation treatment were also common ( 52 % and 69 %, respectively ).
Four patients ( 8 %) developed venoocclusive disease ( VOD ) – one following allogeneic hematopoietic cell transplantation ( alloHCT ) and three unrelated to alloHCT . The authors noted that “ only one patient developed severe VOD .”
Among the entire cohort of 46 responders , six relapsed ( 13 %) and three underwent alloHCT in first CR ( 7 %). Twenty-seven patients ( 59 %) remained on treatment or completed maintenance and 10 died in CR / CRp .
The study ’ s findings are limited by the small population and its nonrandomized design . Dr . Short noted that the trial is still accruing patients , and future research will focus on altering the dosing of inotuzumab ozogamicin to minimize toxicity .
Dr . Short reports no relevant conflicts of interest .
REFERENCE
Short NJ , Kantarjian HM , O ’ Brien SM , et al . Updated results of a phase I / II study of inotuzumab ozogamicin in combination with low-intensity chemotherapy ( mini-hyper-CVD ) as frontline therapy for older patients with acute lymphoblastic leukemia . Abstract # 7014 . Presented at the 2017 ASCO Annual Meeting , June 5 , 2017 ; Chicago , Illinois .
Minimizing Toxicity , Predicting Efficacy With CD19 CAR T-Cell Therapy in B-Cell ALL
Treatment with CD19-directed chimeric antigen receptor ( CAR ) T cells has induced high rates of complete response in adults with relapsed / refractory B-cell acute lymphocytic leukemia ( ALL ), ranging from 70-80 percent , but the toxicity associated with the treatment – including severe neurotoxicity and cytokine release syndrome ( CRS ) – are serious concerns .
At the 2017 ASCO Annual Meeting , Jae Hong Park , MD , from Memorial Sloan Kettering Cancer Center in New York , and colleagues attempted to answer two critical questions about optimizing the use of CAR T-cell therapy in these patients : how to identify those who would benefit most from the treatment , and how to mitigate the severe neurotoxicity associated with CAR T-cell infusion .
“ The toxicities associated with this therapy are not insignificant . We [ should concentrate on ] identifying patient populations [ who experience ] less toxicity but more clinical benefit .” Dr . Park told ASH Clinical News .
In analyses of a phase I trial of CD19-specific CAR T-cell therapy in patients with relapsed / refractory CD19-positive B-cell ALL , patients with a low disease burden at the time of T-cell infusion had longer remissions and lower risk of severe neurotoxicity , suggesting that CAR T-cell therapy should be incorporated earlier in treatment , before morphologic relapse .
In one report from the trial , the authors evaluated whether certain baseline characteristics at the time of T-cell infusion were associated with durable remission . 1 The trial included 53 patients ( median age = 44 years ; range = 23-74 years ). Patients were excluded if they had active central nervous system disease or active graft-versus-host disease requiring immunosuppressants .
Researchers assessed disease burden ( via bone marrow biopsy ) immediately prior to infusion and classified patients as having minimal residual disease ( MRD ; defined as < 5 % blasts ; n = 21 ) or morphologic disease ( defined as ≥5 % blasts ; n = 27 ).
The remaining five patients had blasts < 5 percent with extramedullary disease .
CAR T cells were infused at doses of 1x10 6 / kg in patients with MRD and 3x10 6 / kg in those with morphologic evidence of disease ; patients also received conditioning with fludarabine and cyclophosphamide .
After a median follow-up of 18 months ( range = 0.2-57.3 months ), the complete remission rate ( CRR ; defined as a neutrophil count of > 1,000x10 6 / L , a platelet count of > 100,000x10 6 / L , and hemoglobin > 10 g / dL ) was 84.6 percent ( n = 44 of 52 evaluable patients ).
CRRs were comparable between the MRD ( 95.2 %) and morphologic disease ( 77 %) cohorts . Response rates also were similar across several patient subgroups , including number of prior therapies , age , and conditioning regimen .
Overall , median event-free survival ( EFS ) and overall survival ( OS ) were 6.1 months
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