Acute Lymphoblastic Supportive Care in Pediatric Oncology irantextbook.ir 93df

≥ 200 × 10 9 L Möricke et al. 2008 ; Gaynon et al. 2010 ; Lund et al. 2011 . For the 132 patients with initial WBC ≥200 × 10 9 L in the Scandinavian NOPHO ALL-92 and ALL-2000 protocols, 7 5.3 suffered early death, 6 secondary to neurologic complications, and none secondary to TLS with 5 dying prior to therapy initiation Lund et al. 2011 . Table 6.1 Summary of management strategies and level of evidence for management of pediatric leukemic hyperleukocytosis a Disease Potential side effect Treatment Level of evidence b Acute lymphoblastic leukemia Leukostasis Rapid initiation of chemotherapy 1A Hyperhydration 1C Consider leukapheresis for WBC 400–600 × 10 9 L if no delay in antileukemic chemotherapy initiation 2C Tumor lysis syndrome Hyperhydration 1B One dose of rasburicase prior to antileukemic chemotherapy initiation; see Chap. 3 for more detail 1A Isolated hyperuricemia One dose of prophylactic rasburicase 1B Follow with alkalinization and allopurinol 2C Consider additional rasburicase doses if repeat uric acid 7.5 mgdL 2C DICcoagulopathy FFP to keep PTPTT WNL 1C Fibrinogen concentrate or cryo to keep fi brinogen 150 mgdL 1C Thrombocytopenia Platelet transfusion to keep platelets 50 × 10 9 L if WBC 300–400 × 10 9 L 1C Symptomatic anemia Transfuse small aliquots e.g., 5 mLkg and keep hgb 10 gdL 1C Acute myelogenous leukemia except APL Leukostasis Rapid initiation of chemotherapy 1A Careful hydration 1C Consider leukapheresis 2C Consider HU 2C Tumor lysis syndrome Hyperhydration 1C One dose of rasburicase if uric acid 7.5 mgdL; see Chap. 3 for more detail 2C DICcoagulopathy FFP to keep PTPTT WNL 1C Fibrinogen concentrate or cryo to keep fi brinogen 150 mgdL 1C Thrombocytopenia Platelet transfusion to keep platelets 50 × 10 9 L 1C Isolated hyperuricemia One dose of prophylactic rasburicase 1B Follow with alkalinization and allopurinol 2C Consider additional rasburicase doses if repeat uric acid 7.5 mgdL 2C Symptomatic anemia Transfuse small aliquots e.g., 5 mLkg and keep hgb 10 gdL 1C Acute promyelocytic leukemia DICcoagulopathy Rapid initiation of ATRA or ATO 1A FFP to keep PTPTT WNL 1C Fibrinogen concentrate or cryo to keep fi brinogen 150 mgdL 1C Avoid invasive procedures 1C Unclear benefi t of leukapheresis 2C Thrombocytopenia Platelet transfusion to keep platelets 50 × 10 9 L at the minimum 1C APL differentiation syndromeRAS Dexamethasone 1B Leukocytosis with ATRA or ATO HU 1B Consider holding ATRA or ATO 1C continued 6 Hyperleukocytosis In a follow-up study of 221 NOPHO patients with WBC ≥200 × 10 9 L, Vaitkevičienė et al. 2013 importantly note that all complications sec- ondary to HL, except the need for dialysis, occurred at signifi cantly higher median WBC counts: neurologic WBC 530 × 10 9 L vs. 327 × 10 9 L, respiratory WBC 620 × 10 9 L vs. 336 × 10 9 L, bleeding WBC 420 × 10 9 L vs. 327 × 10 9 L, and dialysis WBC 310 × 10 9 L vs. 357 × 10 9 L. Neurologic and bleeding complica- tions occurred at a signifi cantly higher age, while respiratory distress occurred at a signifi cantly younger age. In multivariate analysis, only WBC count and neurologic symptoms at admission were signifi cantly associated with risk of early death; timing of administration of antileukemic therapy, admission hemoglobin level and administration of packed red blood cells PRBCs were not signifi - cant. Six patients 2.7 died within 2 weeks of presentation, all secondary to neurologic compli- cations, with 4 of the 6 presenting with severe symptoms. Patients receiving mechanical cytore- duction leukapheresis or exchange transfusion prior to chemotherapy initiation had signifi cant delay in antileukemic therapy initiation with no noted survival benefi t. TLS occurred in 12 of patients with statistically higher initial uric acid levels 11.0 vs. 7.7 mgdL. Patients with T-cell and infant ALL were at increased risk of TLS, ras- buricase signifi cantly reduced the risk of TLS and no patient died from TLS. Initial uric acid level was the only signifi cant factor for the development of TLS on multivariate analysis WBC count, lac- tate dehydrogenase, corticosteroid dose and mechanical cytoreduction were not signifi cant. In their supplemental HL guidelines, Vaitkevičienė et al. 2013 recommend prompt initiation of anti- leukemic therapy after diagnostic evaluations and rasburicase administration with no recommenda- tion for leukapheresis or exchange transfusion. Maurer et al. 1988 similarly reported an 8.4 incidence of WBC 200 × 10 9 L in a pedi- atric ALL cohort. Early death occurred in 7 of 124 5.6 patients, 4 from sepsis, 1 from pneumonia, 1 from GI hemorrhage and 1 from ICH. Four 3.2 patients suffered ICH with 3 occurring at presentation and all with WBC 600 × 10 9 L. Although electrolyte abnormali- ties were decreased in those undergoing leuka- pheresis, risk of renal dysfunction requiring dialysis was low, occurring in only 3 2.4 patients, all of whom had received low-dose prednisone pretreatment. WBC 600 × 10 9 L and massive splenomegaly were the only sig- nifi cant adverse prognostic factors on multivari- ate analysis. In a comprehensive study of HL over a 40-year period at St. Jude Children’s Research Hospital, Lowe et al. 2005 reported 178 of 2,288 7.8 children with ALL presenting with WBC 200 × 10 9 L. Early death occurred in 7 3.9 , 3 from sepsis and 2 each from ICH and Disease Potential side effect Treatment Level of evidence b Chronic myelogenous leukemia Leukostasis Hyperhydration 1C HU 1C Consider leukapheresis 2C Priapism Hyperhydration 1C HU 1C Consider leukapheresis 2C Urologic consultation for therapeutic aspiration and possible intracavernous sympathomimetic therapy 1C Pain management 1C WBC white blood cell, DIC disseminated intravascular coagulation, FFP fresh frozen plasma, PT prothrombin time, PTT partial thromboplastin time, WNL within normal limits, cryo cryoprecipitate, hgb hemoglobin, APL acute promy- elocytic leukemia, HU hydroxyurea, RAS retinoic acid syndrome, ATRA all-trans retinoic acid, ATO arsenic trioxide a See text for full detail b Per Guyatt et al. 2006 ; see Preface Table 6.1 continued A.E. Aguilar et al. respiratory failure. Cytoreduction was performed in those with a median initial leukocyte count of 416 × 10 9 L vs. 295 × 10 9 L in the nonreduced cohort. The time to initiate chemotherapy was signifi cantly longer in the cytoreduced cohort. Neurologic and respiratory complications were statistically more likely with WBC 400 × 10 9 L. Older age was also signifi cant for neurologic complications. Four patients suffered from ICH 2.2 , all with initial WBC 400 × 10 9 L and 3 at initial presentation to the tertiary care institu- tion. Two of the 4 received PRBC transfusion prior to ICH, while the other 2 had initial hemo- globin of 10.1 and 10.2 gdL. The majority of neurologic complications 13 of 16; 81 occurred at presentation; the additional 3 occurred 24 h after presentation, 1 in the cytore- duced group and 2 in the nonreduced cohort. Pulmonary complications occurred more com- monly in the cytoreduced cohort and were equally common before and after cytoreduction. Metabolic complications were common, with hyperkalemia in 10 and hyperphosphatemia in 20 , but only 1 patient died secondary to meta- bolic dysfunction hyperkalemia and overt renal dysfunction was rare. Although it was unclear if cytoreduction was benefi cial in the prevention of TLS or leukostasis symptoms and did not impact early mortality, Lowe et al. 2005 recommend cytoreduction for WBC 400 × 10 9 L. Again, early initiation of chemotherapy in pediatric ALL seems most important although it is unlikely to impact those presenting with severe neurologic dysfunction and may not impact early death.

6.3 Acute Myelogenous Leukemia

Like ALL, HL has been shown to be a negative prognostic factor in long-term outcome in pediat- ric AML patients Inaba et al. 2008 ; Lange et al. 2008 . In analysis of AML-BFM 93 and AML- BFM 98, Creutzig et al. 2004 reported a 19.1 incidence of HL with signifi cantly increased risk of early death with WBC ≥100 × 10 9 L 9.9 vs. 2.1 with WBC 100 × 10 9 L and even more so with WBC ≥200 × 10 9 L 16.9 vs. 2.4 with WBC 200 × 10 9 L. Multivariate analysis found HL, FAB M5 and low-performance status as sig- nifi cant independent prognostic factors. A recent analysis of COG AML studies AAML03P1 and AAML0531 reported an 18.8 incidence of HL with independent risk factors including age ≤ 1 year, FAB M1, M4, and M5, inv16, and FLT3-ITD+ Sung et al. 2012 . These fi ndings have been corroborated by other studies Creutzig et al. 1987 ; Meshinchi et al. 2001 ; Inaba et al. 2008 . TLS was rare although hyperphosphatemia and hyperuricemia were signifi cantly associated with increased initial WBC count. Initial WBC count was signifi cantly associated with hypoxia, pulmonary hemorrhage, CNS ischemia, CNS hemorrhage and death Sung et al. 2012 . Patients with the highest WBC counts ≥400 × 10 9 L were at greatest risk for early death and leukapheresis did not appear to impact early death: 1 of 16 6.3 receiving leukapheresis experienced early death as compared to 3 of 73 4.1 who were not leukapheresed Sung et al. 2012 . Overall, the induction death rate was 3.9 for WBC ≥ 100 × 10 9 L vs. 1.3 for WBC 100 × 10 9 L. In a comprehensive review of retrospective AML studies in both pediatric and adult patients with HL, Oberoi et al. 2014 reported an overall early death rate of 20.1 which was not signifi cantly infl uenced by the use of leukapheresis. Hemorrhage and bleeding 75 was the most common cause of early death followed by leu- kostasis 9.1 ; APL patients constituted only 2–5.5 of all studied patients and pediatric data were not separately analyzed Oberoi et al. 2014 . Inaba et al. 2008 studied newly diagnosed AML patients at St. Jude Children’s Research Hospital and found an 18.3 incidence of HL; in the most recent period, the early death rate was 2.8 as compared to a previous time period with an early death rate of 22.9 . Complications sec- ondary to HL were similar in both time periods and signifi cantly correlated with median WBC count: neurologic WBC 221 × 10 9 L vs. 158 × 10 9 L, pulmonary 240 × 10 9 L vs. 155 × 10 9 L, and renal WBC 275 × 10 9 L vs. 159 × 10 9 L. Leukoreduction was utilized in the later time period at the discre- tion of the treating physician; early death occurred in 1 of 20 patients leukoreduced and 0 of 16 not leukoreduced although those leukoreduced had a signifi cantly higher admission WBC count 206 × 10 9 L vs. 116 × 10 9 L. Metabolic complica- tions were uncommon although more prevalent in those with FAB M4M5 subtypes. Twelve of the 17 deaths occurred due to hemorrhage gastroin- testinal, pulmonary or intracranial. Earlier studies have reported a much higher death rate, likely due in part to less intensive supportive care measures Wald et al. 1982 ; Bunin and Pui 1985 ; Creutzig et al. 2004 ; Inaba et al. 2008 . Although signifi cant data are lack- ing, one study in adult AML M5 patients with HL and pulmonary symptoms has shown poten- tial benefi t with the addition of dexamethasone to improve lung function in the acute period Azoulay et al. 2012 . The utilization of leuka- pheresis in AML is controversial and discussed further in Sect. 6.7 .

6.4 Acute Promyelocytic Leukemia

HL is an uncommon presenting feature in APL although pediatric patients have an increased incidence of microgranular APL M3v with concomitant HL Rovelli et al. 1992 ; Guglielmi et al. 1998 ; de Botton et al. 2004 . HL can more commonly be seen as part of APL differentia- tion syndrome previously called retinoic acid syndrome after commencement of either all- trans retinoic acid ATRA or arsenic trioxide ATO therapy Vahdat et al. 1994 ; Camacho et al. 2000 ; Levy et al. 2008 ; Zhang et al. 2008 ; Sanz et al. 2009 ; Zhou et al. 2010 . In some studies, increasing leukocytosis WBC 10 × 10 9 L was a risk factor for the develop- ment of the clinical fi ndings of APL differentia- tion syndrome such as unexplained fever, weight gain, respiratory distress, pulmonary infi ltrates, pleural effusions or pericarditis Frankel et al. 1992 ; Vahdat et al. 1994 ; Camacho et al. 2000 . HL either at diagnosis or after initiation of dif- ferentiating therapy is a risk factor for early death, especially from ICH secondary to dis- seminated intravascular coagulation DIC Rovelli et al. 1992 ; Roberts et al. 2000 ; Zhang et al. 2008 ; Zhou et al. 2010 . Due to the risk of early death from DIC and hemorrhage, especially in those with the highest WBC counts, it is vital to initiate supportive care and induction therapy with ATRA andor ATO emergently Sanz et al. 2005 , 2009 ; Tallman and Altman 2009 . In lieu of random- ized data, expert guidelines recommend treat- ment of coagulopathy with fresh frozen plasma, fi brinogen fi brinogen concentrate or cryopre- cipitate, and platelet transfusion to maintain fi brinogen 150 mgdL and platelets 50 × 10 9 L at the minimum in those with HL, with frequent i.e., every 6–8 h monitoring and correction Sanz et al. 2005 , 2009 ; Tallman and Altman 2009 . Studies on the complementary use of antifi brinolytics such as tranexamic acid have not shown benefi t Sanz et al. 2009 . Diagnostic lumbar puncture and placement of a central venous catheter should be avoided until the coagulopathy has resolved Sanz et al. 2005 , 2009 ; Tallman and Altman 2009 . Initiation of treatment with a differentiating agent should start prior to genetic confi rmation of diagnosis in those cases with suffi cient clinical suspicion Sanz et al. 2005 , 2009 ; Tallman and Altman 2009 . The clinician should be cognizant of the risk for HL development and concomitant DIC after initiation of either ATRA or ATO. In the pediatric North American INT0129 APL trial, hydroxyurea was initiated at a dose of 1 gm 2 and ATRA held if the WBC rose to 30 × 10 9 L during ATRA therapy until the WBC count was 10 × 10 9 L Gregory et al. 2009 . In a Chinese study of 19 children with APL who received single-agent ATO, all developed an increase in WBC count with induction ATO with 5 having WBC 100 × 10 9 L Zhou et al. 2010 . The two children with the highest WBC counts, 178 × 10 9 L and 252 × 10 9 L after ATO initiation, both died from ICH. Zhou et al. 2010 initiated hydroxyurea for all WBC 20 × 10 9 L while also decreasing the ATO dose or even holding it in patients with severe leukocytosis. The benefi t of holding ATO therapy with HL is unclear Levy et al. 2008 ; Sanz et al. 2009 . Oral corticoste- roids, which are utilized as treatment for APL differentiation syndrome, have also been sug- gested as a prophylactic agent with WBC 5–50 × 10 9 L or with the initiation of induction therapy in all patients to prevent the development