Early morbidity and mortality in childhood acute lymphoblastic leukemia with very high white blood cell count

Patients with white blood cell (WBC) count in peripheral blood 200 × 109/l at diagnosis of acute lymphoblastic leukemia (ALL) constitute 5–8% of all childhood ALL patients and are known to have significantly lower survival rates.1, 2 Hyperleukocytosis at diagnosis of childhood ALL is an oncological emergency associated with early morbidity and mortality related both to microcirculatory leukostasis and hyperviscosity and to severe metabolic and electrolyte derangements due to tumor lysis.3, 4 Since the introduction of urate oxidase, the risk of tumor lysis syndrome (TLS) has been markedly reduced.5, 6, 7, 8 However, clinicians may still reduce the dose of anticancer agents or delay the antileukemic therapy to avoid TLS, but the impact of such modifications on the risk of developing of early complications related to hyperleukocytosis and on survival is uncertain.

We performed a population-based multicenter study of 221 children aged 0–14.9 years with ALL and WBC 200 × 109/l at diagnosis treated in Denmark, Finland, Iceland, Lithuania, Norway or Sweden from January 1992 to October 2011. This constituted 92% of all 241 ALL patients with WBC 200 × 109/l during that period, and 6% of all 3985 newly diagnosed ALL patients.

The diagnosis of ALL was based on histo-/cytomorphology, immunophenotyping, karyotyping and molecular cytogenetics as previously reported.9 For two infants and four non-infants, immunophenotype was lacking or ambiguous. Informed consent to antileukemic treatment was obtained according to the Declaration of Helsinki. The regional or national ethics committees approved the study.

Data were retrieved from the Nordic Society for Paediatric Hematology and Oncology (NOPHO) leukemia registry and from patient files. Morbidity and mortality within a month after admission was registered and analyzed in detail. Of 12 patients registered in the NOPHO leukemia registry with induction deaths, two occured 45 and 59 days after admission, and thus were not included into the present study as early deaths.

Overall, the clinical presentation and the pattern of leukostasis or hyperviscosity associated complications were similar to those previously reported4, 10, 11, 12 (Table 1). In total, 40% (N=92) experienced one or more complications associated with hyperleukocytosis (Table 1 and Supplementary Figure 1). Their initial WBC was moderately higher than for patients without such complications (median (75% range): 396 (245–794) × 109/l vs 317 (219–603) × 109/l, (P=0.001)). Thus, the absolute risk of complications increased 1.5-fold with every WBC increase of 100 × 109/l.

Table 1 Baseline characteristics of the patients and hyperleukocytosis related clinical symptoms and complications

Ten patients (5%) died within the first month of treatment, of whom eight were older than one year at diagnosis and seven of these had T-ALL. Four patients died 13–27 days after admission because of neutropenic septic complications, whereas the remaining six patients died within 14 days from admission because of intracranial hemorrhage (N=5) or massive intracranial infiltrates with secondary brain edema and herniation (N=1). Coagulation disturbances were not demonstrated. Four of these latter six patients had initial WBC of 577, 768, 825 and 925 × 109/l and presented with severe central nervous system symptoms already at admission. Whereas the last two patients developed such symptoms on the third day after the rise in WBC from 305 to 625 × 109/l within 3 days on a prednisolone dose of 11.7 mg/m2/24 h, or after a limited reduction in WBC from 395 to 291 × 109/l. Furthermore, in two of these six patients corticosteroids (CS) were not started (WBC 768 × 109/l) or were delayed (WBC 925 × 109/l) due to efforts to carry out leukapheresis.

In multivariate logistic regression analysis, only WBC (OR (95% CI): 1.004 (1.001–1.006), (P=0.007)) and the presence of neurological symptoms at admission (OR (95% CI): 5.8 (1.3–25.2), (P=0.018)) were independently and significantly associated with risk of early death, whereas neither gender, age, immunophenotype, leukemic karyotype and administration of antileukemic therapy within 24 h after admission versus later, nor hemoglobin at admission or administration of packed red blood cell transfusion when WBC was still 200 × 109/l were found to be of significance.

Initial therapy was heterogeneous and center-dependent as there was no common Nordic/Baltic tumor burden reducing strategy for patients with hyperleukocytosis (Figure 1 and Supplementary Figure 2). The majority (85%) of the patients were initially hydrated with 3000 ml/m2/24 h, and urine was alkalinized and allopurinol given to 89% and 97%, respectively, of those who did not receive urate oxidase. The urate oxidase was administered from 1 to 10 (median: 5) days. It was initiated before or on the same day as the administration of any antileukemic treatment for 96% of the 71 patients who received this treatment with available information on timing of the first dose. Administration of a CS prephase was optional for the seven infants and 159 older patients who were enrolled in NOPHO ALL-92, ALL-2000 or ALL-2008 clinical trials, and was mandatory both for 38 Nordic infants who were enrolled in the Interfant-99 or −06 clinical trials, and for the 17 Lithuanian patients who were treated according to BFM-based chemotherapy. Intrathecal MTX had to be initiated no later than on the first day of any other antileukemic therapy (Supplementary Table 1).

Figure 1
figure1

Distribution of white blood cell count in peripheral blood on the day of introduction of induction with vincristine and doxorubicin. Each dot represents one patient. Horizontal bars represent median WBC values. Dashed lines mark median WBC at the day of introduction of induction and median duration of CS prephase. WBC count ( × 109/l); pEFS5y=projected 5-year event-free survival within subsets.

Indications for exchange transfusion or leukapheresis were according to local guidelines, and were performed in 24 and 12 patients, respectively. Such mechanical cytoreduction was given either as the first tumor reducing treatment modality (N=15) or concomitantly with administration of CS and/or intrathecal MTX (N=21). The median (75% range) absolute and relative reduction in WBC per procedure for exchange transfusions was 298 (81–674) × 109/l and 57% (26–82%), respectively, and for leukapheresis it was 165 (67–337) × 109/l and 48% (26–68%), respectively (P=0.11). Antileukemic therapy was delayed more often for the patients with mechanical cytoreduction as first treatment modality (N=15) compared with all the remaining patients (N=191); the median (range) time to administration was: 1.5 (1.0–3.0) vs 1.0 (0–6.0) days, respectively, (P=0.009).

TLS defined according to classification proposed by Cairo and Bishop13 developed in 27 patients (12%): 5 infants, 1 non-infant B-cell precursor (BCP) and 21 T-ALL patients. TLS was present at admission (N=8) or developed within 3 days after initiation of any antileukemic therapy (N=19). Four out of the latter 19 patients developed TLS after only intrathecal MTX had been administered. Patients who developed TLS had significantly higher initial uric acid level than those who did not, both within the cohort of all patients (median: 652 vs 460 μmol/l; P<0.001) and specifically within the T-ALL group (median: 661 vs 420 μmol/l; P<0.001). After initiation of antileukemic therapy, TLS developed in 16 of 118 patients (14%) who received only CS compared with 2 of 60 patients (3%) who recieved both CS and upfront urate oxidase (P=0.03). Eleven patients (5%) were dialyzed (ten patients with T-ALL and one non-infant BCP patient). No patients died owing to TLS or its treatment.

The initial CS dose (calculated as a prednisolone equivalent dose) did not differ significantly for patients who developed TLS vs those who did not (P=0.19). Furthermore, none of the patients who received an initial prednisolone equivalent dose of 60 mg/m2/24 h as prephase (N=11, median WBC 303 × 109/l) or full induction therapy including prednisolone, vincristine and doxorubicin (N=6, median WBC 375 × 109/l) developed TLS. Urate oxidase had been given to 4 out of these 17 patients. Multivariate logistic regression analysis revealed uric acid level at admission to be the only significant risk factor for TLS (OR (95% CI): 1.005 (1.001–1.008), P=0.009), whereas neither gender, age, initial WBC or lactate dehydrogenase, time to start of antileukemic therapy, initial CS dose nor mechanical cytoreduction procedures were significantly associated with the risk of TLS.

There was a borderline significant improval in the 5-year probability of event-free survival being 0.35+/−0.05 for the 84 patients diagnosed before 2002 and 0.51+/−0.05 for the 137 patients diagnosed in the latter period (P=0.07). Cox multivariate regression analysis that explored gender, age, immunophenotype, karyotype, use of mechanical cytoreduction procedures, administration of a CS prephase, and development of TLS, found only BCP phenotype to be associated with an inferior disease-free survival (HR (95% CI) 1.9 (1.2–3.1); P=0.009).

Based on these findings, current Nordic/Baltic guidelines for management of hyperleukocytosis 100 × 109/l and high risk for TLS recommend initiation of full induction with dexamethasone 10 mg/m2/24 h, vincristine and doxorubicin within 24 h and as soon as all required diagnostic samples have been obtained and urate oxidase given (Supplementary Guidelines). For patients with metabolic derangements or clinical symptoms compatible with TLS at admission, to avoid TLS-associated complications, a prephase of prednisolone at a dose of 20 mg/m2/24 h is recommended with rapid dose increments to full induction therapy within 48–72 h. Uric acid level are to be monitored at 8 h intervals and urate oxidase re-administered whenever urate level exceeds 100 μmol/l. The efficacy of this approach will be monitored prospectively.

In summary, this study supports that the main risk factors for TLS are T-cell immunophenotype and an increased level of uric acid at diagnosis, and that with use of contemporary supportive care and urate oxidase, the complications directly associated with hyperleukocytosis pose a significantly greater risk to the patients than do TLS. In addition, reduced initial chemotherapy doses or delaying antileukemic therapy (for example, due to mechanical cytoreduction as first treatment modality) may contribute to worsening of life-threatening leukostasis and risk of early deaths.

References

  1. 1

    Moricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dordelmann M et al. Risk-adjusted therapy of acute lymphobastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008; 111: 4477–4489.

    Article  Google Scholar 

  2. 2

    Vaitkeviciene G, Forestier E, Hellebostad M, Heyman M, Jonsson OG, Lahteenmaki PM et al. High white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia: biological background and prognostic impact. Results from the NOPHO ALL-92 and ALL-2000 studies. Eur J Haematol 2011; 86: 38–46.

    Article  Google Scholar 

  3. 3

    Lund B, Asberg A, Heyman M, Kanerva J, Harila-Saari A, Hasle H et al. Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer 2011; 56: 551–559.

    Article  Google Scholar 

  4. 4

    Lowe EJ, Pui CH, Hancock ML, Geiger TL, Khan RB, Sandlund JT . Early complications in children with acute lymphoblastic leukemia presenting with hyperleukocytosis. Pediatr Blood Cancer 2005; 45: 10–15.

    Article  Google Scholar 

  5. 5

    Renyi I, Bardi E, Udvardi E, Kovacs G, Bartyik K, Kajtar P et al. Prevention and treatment of hyperuricemia with rasburicase in children with leukemia and non-Hodgkin’s lymphoma. Pathol Oncol Res 2007; 13: 57–62.

    Article  Google Scholar 

  6. 6

    Wossmann W, Schrappe M, Meyer U, Zimmermann M, Reiter A . Incidence of tumor lysis syndrome in children with advanced stage Burkitt’s lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase. Ann Hematol 2003; 82: 160–165.

    CAS  Google Scholar 

  7. 7

    Goldman SC, Holcenberg JS, Finklestein JZ, Hutchinson R, Kreissman S, Johnson FL et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001; 97: 2998–3003.

    CAS  Article  Google Scholar 

  8. 8

    Pui CH, Mahmoud HH, Wiley JM, Woods GM, Leverger G, Camitta B et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol 2001; 19: 697–704.

    CAS  Article  Google Scholar 

  9. 9

    Schmiegelow K, Forestier E, Hellebostad M, Heyman M, Kristinsson J, Soderhall S et al. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia 2010; 24: 345–354.

    CAS  Article  Google Scholar 

  10. 10

    Eguiguren JM, Schell MJ, Crist WM, Kunkel K, Rivera GK . Complications and outcome in childhood acute lymphoblastic leukemia with hyperleukocytosis. Blood 1992; 79: 871–875.

    CAS  Google Scholar 

  11. 11

    Harousseau JL, Tobelem G, Schaison G, Chastang C, Auclerc MF, Weil M et al. High risk acute lymphocytic leukemia: a study of 141 cases with initial white blood cell counts over 100,000/cu mm. Cancer 1980; 46: 1996–2003.

    CAS  Article  Google Scholar 

  12. 12

    Bunin NJ, Pui CH . Differing complications of hyperleukocytosis in children with acute lymphoblastic or acute nonlymphoblastic leukemia. J Clin Oncol 1985; 3: 1590–1595.

    CAS  Article  Google Scholar 

  13. 13

    Cairo MS, Bishop M . Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004; 127: 3–11.

    Article  Google Scholar 

  14. 14

    National Cancer InstituteCommon Terminology Criteria for Adverse Events (CTCAE) http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm15-10-2013. 3-1-2013.

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Acknowledgements

This work was supported by Danish Childhood Cancer Foundation; the University Hospital Rigshospitalet, Copenhagen, Denmark; the Research Council of Lithuania, and the Swedish Childhood Cancer Foundation. Kjeld Schmiegelow holds the Danish Childhood Cancer Foundation research professorship in pediatric oncology.

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GV, AHS, AÅ, BL and KS designed the study; GV, MH, OGJ, BL, AHS, MS, MT and AÅ collected data; GV, MH, TZ and KS analyzed data; GV, LR and KS wrote the manuscript. All the authors revised the manuscript and gave their final approval.

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Vaitkeviciene, G., Heyman, M., Jonsson, O. et al. Early morbidity and mortality in childhood acute lymphoblastic leukemia with very high white blood cell count. Leukemia 27, 2259–2262 (2013). https://doi.org/10.1038/leu.2013.137

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