CLINICAL NEWS
As of August 2017 ( data cutoff ), seven patients ( 3 adults 31-35 years and 4 pediatric patients 6-13 years ) with different genotypes ( β0 / β0 , β +/ β +, and β0 / β +) have been treated with GLOBE-transduced CD34 + cells at doses ranging from 16 × 10 6 to 19.5 × 10 6 cells / kg .
Patients were followed for a median of 13 months ( range = 8-22 months ). The procedure was well tolerated by all patients , Dr . Marktel noted , with no treatment-related adverse events ( AEs ), no evidence of replication competent lentivirus , and no abnormal clonal proliferation on regular PB and BM analyses . Grade 3 / 4 AEs or serious AEs were mostly infectious in origin , which the researchers called “ expected after a myeloablative autograft .”
The median time to neutrophil engraftment was 19 days ( range = 17-25 days ) and 15 days ( range = 10-21 days ) to platelet engraftment . Multilineage engraftment of gene-modified cells was observed in PB and BM , with a median of 0.58 VCN / cell ( range = 0.37-1.55 VCN / cell ) in BM erythroid cells at six months post-gene therapy . After a median of 16 months follow-up ( range = 8-22 months ), five of the seven patients had a reduced need for transfusions , including three pediatric patients who were transfusion-independent beginning one month after receiving the gene therapy until last followup ( at 13 , 10 , and 8 months , respectively ). Three adult patients had a reduction of transfusion requirement , but were still transfusion-dependent at last follow-up ( at 22 , 18 , and 16 months , respectively ), and one pediatric patient continues to receive regular blood transfusions .
“ Although the number of patients is small , our preliminary results also suggest the benefit could be greater in children than in adults .”
— SARAH MARKTEL , MD
Two Versus Three Cycles of Consolidation Therapy for Patients With AML
Patients with core-binding factor acute myeloid leukemia ( CBF-AML ) who received only two cycles of consolidation chemotherapy experienced similar rates of relapse-free survival ( RFS ) and overall survival ( OS ) as patients who received three cycles . These results raise questions about the value of adding a third cycle of consolidation therapy in this patient population .
“ Patients with CBF-AML exhibit high rates of remission , OS , and RFS even without allogenic hematopoietic cell transplantation ( alloHCT ),” lead author Daniel Sawler , MD , BSc , of the University of Alberta in Edmonton , Canada , said during his presentation at the 2017 ASH Annual Meeting . “ While early studies suggest that three or four cycles of high-dose cytarabine are associated with better outcomes than one cycle , the exact number of consolidation cycles necessary for optimal outcomes is unknown .”
The investigators compared survival and safety outcomes between patients who received two or three cycles of consolidative chemotherapy at two Canadian centers ( in Edmonton and Vancouver ) from 2003 to 2017 . Prior to 2012 , it was standard for patients with CBF-AML treated in Edmonton to receive two cycles of high-dose cytarabine after achieving a complete remission ( CR ) with a single induction cycle . After a change in institutional policy in 2012 , patients received up to three cycles of consolidation treatment . Patients treated in Vancouver underwent similar induction therapy but received up to three consolidative cycles throughout the entire study period .
The pooled data comprised 108 patients ( median age = 48 years ; range = 17-75 years ), including :
• 74 patients ( 68.5 %) in the three-cycle cohort ( median age = 43 years ; range = 19-71 years )
• 34 patients ( 31.5 %) in the two-cycle cohort ( median age = 49 years ; range = 17-75 years )
Six patients in the two-cycle cohort and five patients in the three-cycle cohort received alloHCT during CR1 ( p = 0.09 ). The two groups did not differ in rates of hospitalization , median length of hospital stay , bacteremia events , intensive care requirements , and deaths during consolidation therapy .
Median follow-up from CR was significantly longer in the two-cycle cohort than the three-cycle cohort ( 85 vs . 30 months ; p < 0.0001 ). Among the patients who received two cycles of consolidation , nine died and four relapsed , for a total event rate of 38.2 percent . Among those who received three cycles of consolidation , 18 died and 13 relapsed , for a total event rate of 41.9 percent ( p = 0.83 ).
At five years , survival outcomes did not significantly differ between the two- and three-cycle cohorts :
• 5-year OS : 73 % vs . 71 %, respectively ( p = 0.96 )
• 5-year RFS : 63 % vs . 57 % ( p = 0.61 )
• 5-year event-free survival : 54 % vs . 52 % ( p = 0.88 )
“ There was no appreciable difference in overall rate of consolidation complications ,” the authors reported , with similar numbers of patients in both cohorts receiving chemotherapy intensification due to residual disease . Multivariate analyses also showed that age , cytogenetics , and proceeding to transplantation in CR1 did not influence rates of OS or RFS between the two groups .
“ These data suggest that the use of two chemotherapy consolidation cycles , compared with three , does not diminish [ survival ] in patients with CBF-AML ,” the authors concluded . “ Reduction in chemotherapy may provide both economic and quality-of-life benefits for patients .”
The findings are limited by its retrospective design , differential follow-up , and that it does not comment on the value of receiving four cycles of consolidation . A larger , randomized , prospective study comparing two cycles of consolidation chemotherapy with three or more is needed .
The authors report financial relationships with Novartis , Roche , and Sanofi .
REFERENCE
Sawler D , Sanford D , Brandwein JM , et al . Two cycles of consolidation chemotherapy are associated with similar clinical outcomes to three cycles in AML patients with favorable risk cytogenetics . Abstract # 464 . Presented at the 2017 American Society of Hematology Annual Meeting , December 10 , 2017 ; Atlanta , GA .
Compared with previous trials in which the genetically modified HSCs were infused intravenously , the “ intra-bone ” administration demonstrated earlier evidence of successful engraftment , suggesting that this is a promising route of administration for gene therapy , Dr . Marktel said .
“ Although the number of patients is small , our preliminary results also suggest the benefit could be greater in children than in adults ,” Dr . Marktel concluded . “ Our hypothesis is that younger stem cells in pediatric patients may be more favorably corrected by gene therapy and in general may lead to better engraftment and performance .”
The authors report financial relationships with Glaxo- SmithKline , which licensed the beta-thalassemia gene therapy and funded this clinical trial .
REFERENCE
Marktel S , Cicalese MP , Giglio F , et al . Gene therapy for beta thalassemia : preliminary results from the PHASE I / II Tiget-Bthal trial of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector . Abstract # 355 . Presented at the 2017 American Society of Hematology Annual Meeting , December 10 , 2017 ; Atlanta , GA .
Palliative Care Use Infrequent in Patients with Hematologic Malignancies
Use of palliative care services among patients with hematologic malignancies is “ sporadic at best ” and there is no clear subgroup receiving uniform care , according to a review of use patterns among nearly 300,000 patients . This study represents the largest-ever analysis of palliative care practice patterns and trends , noted lead author Sikander Ailawadhi , MD , of the Division of Hematology-Oncology at the Mayo Clinic in Jacksonville , Florida . Dr . Ailawadhi presented the findings at the 2017 ASH Annual Meeting .
“ We noted significant heterogeneity in practice patterns by all characteristics studied , underscoring the need for standardized implementation with public , health-care provider , institutional , and political will ,” the authors noted . To define potential patterns in palliative care use among this patient population , the researchers used the
2016 National Cancer Database ( NCDB ) to identify 293,518 patients with non-Hodgkin lymphoma ( n = 147,614 ), multiple myeloma ( MM ; n = 59,572 ), chronic lymphocytic leukemia ( CLL ; n = 20,634 ), acute myeloid leukemia ( AML ; n = 55,827 ), or Hodgkin lymphoma ( n = 9,871 ) who were diagnosed between 2004 and 2013 .
Patients who died during the study period but who had received palliative care as part of initial therapy ( n = 15,352 ; 5.2 %) for these diagnoses were stratified by survival duration : less than six months , six to 24 months , 24 to 60 months , and > 60 months .
Palliative care services used by enrolled patients included surgery , radiation , or chemotherapy in 68 percent of patients ; pain management only in 14.5 percent ; and pain management and surgery , radiation , or chemotherapy in 5 percent . The remaining 12.5 percent of patients
ASHClinicalNews . org ASH Clinical News
33