PERSPECTIVES months ); four patients ( 4.8 %) had Richter ’ s transformation and two ( 2.4 %) had prolymphocytic transformation . Seven of these patients ( 35 %) were alive at data cutoff .
CLINICAL NEWS authors observed . Median MRD in blood was 5.3 × 10 -2 cells / leukocyte at three years and 4.3x10 -2 at four years ; median MRD in BM was 7.3 × 10 -2 cells / leukocyte at three years and 6.2 × 10 -2 cells / leukocyte at four years ( ranges not provided ).
Seven patients who achieved CR were MRD-negative in either blood or BM .
After a median follow-up of 57 months ( range not reported ), the estimated five-year progressionfree survival ( PFS ) was lower in the TP53 cohort than the older cohort ( 58.2 % vs . 81.2 %, respectively ; p = 0.026 ). Median five-year overall survival ( OS ) was 75.7 percent and 83.8 percent , respectively ( p = 0.10 ).
In both cohorts , patients with treatment-naïve disease had better survival outcomes , compared with patients with relapsed / refractory disease :
• TP53 cohort : 74.4 % vs . 19.4 % for PFS ( p = 0.0002 ) and 85.3 % vs . 53.7 % for OS ( p = 0.023 )
• older cohort : no disease progression or deaths were reported in the treatmentnaïve cohort , while the fiveyear PFS and OS were 64.8 % and 71.6 %, respectively
Overall , 20 patients experienced disease progression after a median of 37.6 months ( range = 0.4-54.7
PERSPECTIVES months ); four patients ( 4.8 %) had Richter ’ s transformation and two ( 2.4 %) had prolymphocytic transformation . Seven of these patients ( 35 %) were alive at data cutoff .
“ Most previously untreated patients , even those with a TP53 aberration , achieved durable responses , making intensification of therapy less urgent and avoidance of unnecessary toxicity more important ,” the authors concluded . “ Future research should aim to identify patients at risk of early treatment failure who would benefit most from combination therapy .”
The study is limited by its small patient population and lack of a comparator arm . Also , “ due to the preferential inclusion of patients with TP53 aberration , the genetic risk profile is skewed toward high-risk disease ,” the authors noted .
Pharmacyclics provided support for the study .
The corresponding authors report financial support from Pharmacyclics and Merck . One of the corresponding authors , who developed the study design , is now employed by Merck , but was employed by the National Institutes of Health at the time of the study .
REFERENCE
Ahn IE , Farooqui MZH , Tian X , et al . Depth and durability of response to ibrutinib in CLL : 5-year follow-up of a phase II study . Blood . 2018 February 26 . [ Epub ahead of print ]
“ Ibrutinib has filled a long-standing unmet medical need in several populations of patients with CLL , including the four studied in this trial . The most widely used and proven effective therapy for CLL is the regimen of FCR ( fludarabine , cyclophosphamide , rituximab ), but FCR is not considered appropriate for older patients with CLL or effective for disease with TP53 or del17p mutations . The combination of obinutuzumab and chlorambucil is effective for older patients with CLL , but not for patients with TP53 or del17p disease , and there are no long-term follow-up data to compare with ibrutinib . The only drug with proven efficacy in patients with del17p CLL is the BCL2 inhibitor venetoclax . However , this is a relatively new agent with limited patient numbers and follow-up data .
Although this study reveals that , with prolonged therapy , 27 percent ( older cohort ) and 29 percent ( TP53 cohort ) of patients can achieve CRs , our hope is to take yet another step forward to further increase CR rates and achieve CRs at an earlier phase of therapy . Efforts to achieve this goal are ongoing in several clinical trials in which venetoclax and obinutuzumab are being combined with ibrutinib .
The development of ibrutinib for CLL has been a major step forward in our goal to find a cure for this disease . This study was well-conducted , and the conclusions reached were all appropriate and justified .”
— Kanti Rai , MD , professor at the Donald and Barbara Zucker School of Medicine at Hofstra / Northwell Health
The Effect of Moxetumomab Pasudotox on Minimal Residual Disease in Hairy Cell Leukemia
Nearly two-thirds of patients with relapsed / refractory hairy cell leukemia ( HCL ) who were treated with the anti-CD22 recombinant immunotoxin moxetumomab pasudotox achieved complete remission ( CR ), according to research published in Blood . More than half of these patients also experienced minimal residual disease ( MRD ) -negativity , reported Robert J . Kreitman , MD , of the National Cancer Institute ’ s Center for Cancer Research , and co-authors .
This study expands on a previously reported phase I study of 28 patients with relapsed / refractory HCL , in which moxetumomab pasudotox produced overall response and CR rates during a median 16 weeks of follow-up that were similar to the present study . The updated results include 12 patients from the original study who received the upper dose level of moxetumomab ( 50 μg / kg every other day for 3 doses in 4-week cycles ), plus 21 additional patients enrolled in an expanded 50 μg / kg cohort .
All 33 participants ( age range = 40-77 years ) had a confirmed diagnosis of classic or variant HCL with measurable disease and had received two or more prior systemic therapies , including two courses of a purine analog , unless response to the first course lasted less than two years . Patients were excluded if they had poor hepatic , renal , or pulmonary function ; received therapy within three weeks of enrollment ; or previously received immunotoxin .
The previously reported cohort received 143 treatment cycles without experiencing dose-limiting toxicity ( DLT ), while those in the extension cohort received 88 cycles without DLT , for an average treatment duration of 116 cycles in the entire study group .
Four patients died from disease progression after relapsing and going off study . They died a median of 17 months ( range = 2-29 months ) after the last study dose . One of these patients had a best response of MRD-positive CR and developed grade 2 hemolytic uremic syndrome after five cycles of treatment .
In the combined 33-patient cohort , 29 ( 88 %) responded to moxetumomab treatment and 21 ( 64 %) achieved CR . The median duration of CR was 42.4 months ( range not provided ). No patients relapsed after receiving consolidation therapy , while nine of 14 participants who did not receive consolidation relapsed a median of 13.5 months ( range = 4.9-42.4 months ; p = 0.004 ) after finishing moxetumomab treatment .
CR appeared to be unrelated to the number of prior purine analog courses , prior rituximab , or baseline spleen size . However , none of the four patients who achieved CR had prior splenectomy , compared with 72 percent in the other 29 patients ( p = 0.012 ).
“[ The anti- CD22 drug ] spared T cells and , with its short halflife , avoided prolonged B-cell depletion .”
— ROBERT J . KREITMAN , MD
Median time to CR was 17 weeks ( range = 4-110 weeks ). “ For six patients with longest time to CR ( range = 11-25 months ), positive bone marrow ( BM ) at end of treatment became negative during follow-up , despite no intervening therapy ,” the investigators reported . “ Thus , in the absence of the myelotoxicity expected from chemotherapy , patients responded quickly and achieved CR , usually at the first response assessment … performed after resolution of cytopenias .”
Among the complete responders , nine ( 45 %) had detectable MRD ( via BM aspirate [ BMA ] and / or blood flow cytometry ), and 11 ( 55 %) did not ( one patient was not evaluable for MRD ). Ten of the MRD-negative patients remained in CR at the end of the study , for a median CR duration of 42.2 months ( range = 16.3-72.1 months ). These results
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