Written in Blood
years ). Most ( 62 %) occurred in patients younger than 18 years .
Forty percent of patients ( n = 101 / 254 ) underwent a cholecystectomy ; among 85 patients who had information on timing of procedures , cholecystectomy was performed with splenectomy in 21 percent ( n = 18 ) and after splenectomy in 66 percent ( n = 56 ). Of the 121 patients who underwent splenectomy without prior or simultaneous cholecystectomy , 58 ( 48 %) required this procedure at a later date . “ Just prior to splenectomy , all patients with PK deficiency should be screened by ultrasound for gallstones ,” the researchers advised . “ If gallstones are present , concurrent cholecystectomy should be considered , as observation of asymptomatic pigmented gallstones may lead to unnecessary complications .”
There was no significant difference in hemoglobin for patients who did or did not require cholecystectomy ( median = 8.8 g / dL vs . 8.9 g / dL ; p = 0.78 ). Those who underwent cholecystectomy :
• had significantly higher total bilirubin levels ( median = 4.2 mg / dL vs . 3.4 mg / dL ; p = 0.0024 )
International Workshop on CLL Updates Guidelines for the Design and Conduct of Clinical Trials
Prompted by advances in the biology and treatment of patients with chronic lymphocytic leukemia ( CLL ), the National Cancer Institute – sponsored International Workshop on CLL has issued an update to its consensus guidelines originally published in 2008 . 1 , 2
“ These guidelines provided definitions intended to standardize the assessment of patients that were adopted by
AIM FOR DEEP
REMISSION
Deep remission refers to MRD-negative remission , defined in the INO-VATE ALL study as leukemic cells comprising < 1 x 10 -4 of bone marrow nucleated cells per flow cytometry . 1
[ regulatory agencies ] for the evaluation of new drugs ,” the guideline panel authors wrote . Michael Hallek , MD , of the University of Cologne in Germany , and co-authors updated the guidelines with the goal of
BESPONSA™ ( inotuzumab ozogamicin ) is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia ( ALL )
integrating new findings into future practice and clinical trials of CLL . Their recommendations were published in Blood . Here , we review the major changes reflected in the guidelines .
• had higher absolute reticulocyte counts ( median = 0.5 × 10 6 cells / uL vs . 0.2 × 10 6 cells / uL ; p = 0.0011 )
• were older at diagnosis ( median = 0.7 years vs . 0.3 years ; p = 0.04 )
“ A genotype-phenotype relationship was identified in this international cohort , in which patients with two missense mutations in the PKLR gene had a lower likelihood of splenectomy [ p < 0.0001 ], fewer lifetime transfusions [ p = 0.0015 ], and a lower rate of iron overload [ p = 0.0013 ],” compared with patients with non-missense mutations , the authors reported .
The study is limited by its retrospective design , limited patient population , and partial reliance on patient records .
Some of the authors are scientific advisors to Agios Pharmaceuticals .
REFERENCE
1 . Grace RF , Bianchi P , van Beers EJ , et al . The clinical spectrum of pyruvate kinase deficiency : data from the pyruvate kinase deficiency natural history study . Blood . 2018 March 16 . [ Epub ahead of print ]
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IMPORTANT SAFETY INFORMATION
WARNING : HEPATOTOXICITY , INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE ( VOD ) ( ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME ) and INCREASED RISK OF POST – HEMATOPOIETIC STEM CELL TRANSPLANT ( HSCT ) NON-RELAPSE MORTALITY ( NRM ):
• Hepatotoxicity , including fatal and life-threatening VOD , occurred in patients who received BESPONSA . The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment . The use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin ≥ upper limit of normal ( ULN ) before HSCT were significantly associated with an increased risk of VOD
• Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease , prior HSCT , increased age , later salvage lines , and a greater number of BESPONSA treatment cycles
• Elevation of liver tests may require dosing interruption , dose reduction , or permanent discontinuation of BESPONSA . Permanently discontinue treatment if VOD occurs . If severe VOD occurs , treat according to standard medical practice
• There was a higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA , resulting in a higher Day 100 post-HSCT mortality rate
Hepatotoxicity , Including Hepatic VOD : Hepatotoxicity , including fatal and life-threatening VOD , occurred in 23 / 164 patients ( 14 %) during or following treatment with BESPONSA or following subsequent HSCT . VOD was reported up to 56 days after the last dose during treatment or follow-up without an intervening HSCT . The median time from HSCT to onset of VOD was 15 days .
Patients with prior VOD or serious ongoing liver disease are at an increased risk of worsening liver disease , including development of VOD , following
The efficacy of BESPONSA was established on the basis of CR ( 35.8 % [ 39 / 109 ; 95 % CI , 26.8-45.5 ] with BESPONSA vs 17.4 % [ 19 / 109 ; 95 % CI , 10.8-25.9 ] with SC ), the duration of CR ( 8.0 months [ 95 % CI , 4.9-10.4 ] with BESPONSA vs 4.9 months [ 95 % CI , 2.9-7.2 ] with SC ), and the proportion of MRD-negative CR ( 89.7 % [ 35 / 39 ; 95 % CI , 75.8-97.1 ] with BESPONSA vs 31.6 % [ 6 / 19 ; 95 % CI , 12.6-56.6 ] with SC ) in the first 218 randomized patients . 1
treatment with BESPONSA . Monitor closely for signs and symptoms of VOD ; these may include elevations in total bilirubin , hepatomegaly ( which may be painful ), rapid weight gain , and ascites . For patients proceeding to HSCT , the recommended duration of treatment with BESPONSA is 2 cycles . A third cycle may be considered for patients who do not achieve a CR or CRi and MRD-negativity after 2 cycles . Monitor liver tests closely during the first month post HSCT , then less frequently thereafter , according to standard medical practice .
Grade 3 / 4 increases in aspartate aminotransferase , alanine aminotransferase , and total bilirubin occurred in 7 / 160 ( 4 %), 7 / 161 ( 4 %), and 8 / 161 ( 5 %) patients , respectively .
Increased Risk of Post-HSCT Non-Relapse Mortality ( NRM ): There was a higher post-HSCT NRM rate in patients receiving BESPONSA , resulting in a higher Day 100 post-HSCT mortality rate . The rate of post-HSCT NRM was 31 / 79 ( 39 %) with BESPONSA and 8 / 35 ( 23 %) with investigator ’ s choice of chemotherapy . In the BESPONSA arm , the most common causes of post- HSCT NRM included VOD and infections . Monitor closely for toxicities post HSCT , including signs and symptoms of infection and VOD .
Myelosuppression : Myelosuppression , and severe , life-threatening , and fatal complications of myelosuppression , including hemorrhagic events and infections , have occurred with BESPONSA . Thrombocytopenia and neutropenia were reported in 83 / 164 patients ( 51 %) and 81 / 164 patients ( 49 %), respectively . Febrile neutropenia was reported in 43 / 164 patients ( 26 %).
Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection , bleeding / hemorrhage , or other effects of myelosuppression during treatment and provide appropriate management . As appropriate , administer prophylactic anti-infectives during and after treatment with BESPONSA . Dose interruption , dose reduction , or permanent discontinuation may be required .
36 ASH Clinical News