ALL treatment-related acute central nervous system symptoms are relatively common and may increase long-term morbidity and decrease quality of life. CNS leukaemia in particular seems to predispose patients to CNS toxicity. Identification of CNS complications and patients at risk of these complications is important for adequate and prompt treatment of these complications. However, awareness is also crucial when designing leukaemia treatment protocols, and should lead to discussion on prophylaxis for some of these symptoms in future, such as thromboprophylaxis of patients at high risk of sinovenous thrombosis.
Among CNS complications, PRES stands out as having more long-term effects, particularly increasing the risk of epilepsy. Relapses occurred more often in PRES patients, an
observation which needs to be evaluated in future studies. However, PRES and any CNS complications may affect leukaemia treatment, and delays or modifications in the treatment increase the risk of relapse. Nordic protocols have involved intensive treatment with MTX and vincristine, which may increase the risk of CNS complications. Vincristine and MTX dosing have already been reduced in the current ALLTogether protocol. The results in this thesis regarding neurotoxicity, especially of PRES, during use of the NOPHO ALL1992 and NOPHO ALL2000 protocols, were the basis for careful monitoring of neurotoxicity in the more recent protocol. Studies of CNS complications and PRES continued in the NOPHO ALL2008 protocol, in which the author of this thesis has participated; these studies have been published recently. Monitoring of neurotoxicity also continues in the current
ALLTogether protocol; however, new biological drugs, some of which have already been put to use in that protocol, can change the spectrum of CNS complications in the future.
In a small study, a low total dose of folinic acid in case of fast clearance of high-dose MTX did not increase neurotoxicity or other severe toxicities. This indicates that MTX
pharmacokinetics may play a more important role in the development of toxicities than previously thought. Using lower LV doses might improve the antileukemic effects of MTX;
this was implemented into the Nordic ALL protocol as early as 2008.
Cranial irradiation as part of CNS prophylaxis is a significant threat to leukaemia survivors.
Meningiomas occurred after long latency periods in a significant portion of leukaemia survivors in the cohort study included in this thesis and the incidence increased after 20 years of cranial irradiation therapy. Other treatment characteristics seemed not be
significant. After exclusion of CRT from leukaemia protocols, the risk of meningiomas is likely to be lower in the future. However, owing to the major developments in leukaemia therapy, there are currently a significant number of cranially irradiated leukaemia survivors in the population, who are at risk of meningioma. This risk is well-recognised today. The literature does not clearly indicate if systematic evaluation of these survivors with brain MRI is
justifiable. The tendency towards recurrence and more aggressive behaviour, as well as smaller size of asymptomatic tumours, supports monitoring.
ACKNOWLEDGEMENTS
The work for this thesis study was carried out at the department of Paediatrics, University of Oulu and at the Children’s Hospital, University of Helsinki and Helsinki University Hospital.
This study was financially supported by Paediatric Research Foundation, Finnish Medical Foundation, Väre Foundation, Alma & K.A Snellman Foundation, Cancer Society of Northern Finland, Childhood Cancer Research Unit Karolinska Institutet, University of Helsinki, University Hospital of Helsinki (HUS) and Oulu University Hospital.
My sincere gratitudes goes to my supervisors: Professor Arja Harila-Saari and Docent Mervi Taskinen. I have had a priviledge to learn from, and work with two experts in paediatric haematology, who have over and over managed to find time to guide me throughout all these years. I thank you Arja not only for introducing me as a young medical student to childhood leukemia research, but particularly for your constant positivity, warm-hearted supervising, unfailing support and trust in me, even when I myself, did not have any. Most of all, I appreciate your enormous clinical and scientific skills, you have been my source of inspiration. Similarly, I thank Mervi, who warmly welcomed me to Helsinki, and whose wise advise and precision I could always rely on and whose vast knowledge both in scientific field and as a clinician I highly appreciate and look up to. I remember working with you on many weekends when you were working as a clinician, and admire your dedication to work with childhood cancer patients.
I thank my reviewers, Professor Marjo Renko and Docent Jukka Vakkila, for your careful review of this thesis, your flexibility and valuable comments, that improved the manuscript further. I am thankful for my follow-up group members, Professor Kim Vettenranta and Docent Jukka Kanerva, for your time and encouragement during this process.
My sincere appreciation goes to all my co-authors in all University Hospitals in Finland and in Karolinska University Hospital in Sweden, and I thank all collaborators for their contribution to the study. Especially, I want to thank Docent Riitta Niinimäki for your friendliness and support, Docent Susanna Ranta for your kind and valuable help in manuscripts, Docent Mats Heyman for your wise advise and effort, Ida Hed-Myberg for her wonderful aid with statistics and Linnéa Holmén for reviewing the language for my thesis. I am grateful to our former research group in Oulu, and look back at our meetings with warm memories. I thank my current and former colleagues and co-workers for your support and understanding, and for many of you, also for your friendship.
I am thankful to all my lovely friends for your support. Mervi, thank you for being there for me. Riikka I cherish our lovely chats that make my day. Ansku, Laura, Milli, Suvi, Jimi and Piia, I value your friendship over the years. I thank my nearly in-law family, Eva (fammo) and Lasse (fafa) for your support and encouragement- I value the Sunday coffees at your house-,
Janna, Martin, Tomas, Ronna and their children for lovely days at summer cottage in Porvoo archipelago.
Finally, my love and appreciation goes to my family for your support you have provided me during these years. I thank my father Erkki, my mother Riitta for always believing in me, and for your invaluable help and babysitting, particularly during the last months, when I finalized my manuscript. Without you, I would not have made it. I am thankful for my dearest sisters Jenni, Mira, and Pia and their husbands /partners Joakim, Cesar and Toni for being there for me always when I needed. Miisa, Tiitus, Isa and Roni, you are suddenly all grown-up, and have given positive energy to me during all these years, and Freja, you are a wonderful new member in the family.
Last, I am grateful for my dear partner Jonas for our lovely children and for reminding me of the important things in life. I am grateful for you being there for me at darker moments during this process, and taking my side, it meant a lot to me. And Nicola, Felix and Wilmer, you bring such energy, love and life in our lives, you are all amazing little sunshines (or superheroes). You mean the world to me.
November 2020, Helsinki Joanna Banerjee
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