With survival rates of childhood acute lymphoblastic leukaemia (ALL) reaching 90%, the inevitable question is, can we do less? Risk-stratified ALL therapy has led to a low (10%) cumulative risk of relapse (CIR), leading some to question the value of routine, scheduled follow-up and blood counts. In a population-based ALL study from the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, Jensen et al1 reported that scheduled follow-up diagnosed only 49% of relapses. Surprisingly, relapses diagnosed during scheduled visits did not fare better (5-year overall survival 63% compared to 72% for relapses detected by extra visits; hazard ratio 0·95). The authors concluded that after completing ALL therapy, scheduled visits yielded no extra benefit. However, this conclusion should be interpreted with caution. Jensen et al. excluded those who underwent haematopoietic stem cell transplantation (HSCT). Also excluded were 262 of 600 (44%) cases of relapses that had occurred during therapy. Patients who were post-HSCT or with relapsed leukaemia had a significantly higher risk of relapse and complications. While Jensen et al. studied only the most feared complications, that is relapse and secondary malignancies, scheduled visits enabled screening for potential severe chronic health conditions (CHCs) and school coping issues. Why did patients, who were diagnosed with relapse during scheduled visits, counter-intuitively, have poorer outcomes? We suggest that they had poorer outcomes because they had significantly higher risk factors.1 Specifically, their median time to relapse was signficantly shorter at 39 months (vs 45 months; P = 0·009). In addition, they had an increased incidence of isolated bone marrow relapse (P = 0·02). Thus, scheduled visits picked up higher risk relapses, which was, in fact, advantageous. To diagnose one subclinical relapse, Jensen et al. calculated that as many as 1269 blood tests had to be done.1 This calculation remained theoretical and biased; all scheduled patients diagnosed with symptoms and signs of relapse were excluded. Such exclusion unnecessarily disadvantaged against scheduled visits. In fact, all patients had scheduled visits; extra visits were additional. Equally important, 58 of 130 (45%) patients who were diagnosed with relapse during extra visits suffered symptoms for >2 weeks. Such delays in diagnosis were of equal concern. After more than 2 years of treatment, the value of a scheduled visit goes beyond just diagnosing relapse alone. The Children’s Cancer Survivor Study2 reported that severe CHCs occurred in 21% of survivors of ALL. However, in risk-stratified standard risk (SR) patients, these severe CHCs were reduced to 11%. Yet, despite this reduction, compared to their siblings, ALL SR survivors experienced increased severe CHC [relative risk (RR) 1·9]. Compared to the general population, this increase in CHC was not associated with increased mortality. In four groups of ALL survivors: (1) relapsed ALL; (2) SCT; (3) cranial or total body irradiation; and (4) high-risk patients, an increased risk of severe CHC and neurocognitive impairment remained.2 We have reported that ALL survivors, especially those treated with cranial radiotherapy, had increased chronic inflammation and accelerated ageing.3 Arguably, to better manage severe CHC, these patients need more, not fewer, scheduled visits and care. For decades, the key concern of both doctors and patients is relapse. Relapse can be catastrophic; it means a resistant disease requiring more intensive therapies with increased morbidity and mortality. Recently, cell-based therapy such as chimeric antigen receptor T-cell therapy against CD19 (CAR-T CD19) cured 50% of B-lymphoblastic leukaemia in second relapse.4 With more effective therapy, relapse may be salvageable. To, carefully, do less and not lose hard-fought gains, we need to choose who can be safely followed up less frequently. From the minimal residual disease-stratified Malaysia-Singapore ALL 2003 experience,5 after completing therapy, the lowest risk patients (Malaysia-Singapore 2003 SR) had only 1·7% CIR (Table I). Similarly, after completing NOPHO ALL 2008 therapy,1 the CIR was only 3·4%. The choice is clear: low-risk ALL patients, treated using reduced intensity protocols without cranial radiotherapy, can be followed less. The authors thank Dr Edwynn Chiew and Mr Chen ZW for providing the updated data on MS2003. All the authors contributed to the writing of the paper. Yeoh AE received speaker fee from Amgen (2020). The other authors have no conflicts of interest.
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Jan 4, 2024
Riitta Niinimäki + 3
