Abstract

We conducted a cross-sectional study using a questionnaire to explore the late effects in survivors of juvenile myelomonocytic leukemia (JMML). The attending pediatric hematologist oncologists completed the questionnaires. All survivors (N=30) had undergone allogeneic hematopoietic stem cell transplantation. Approximately 83% survivors showed more than one late effect. The identified late effects included endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary, neurocognitive, and cardiovascular dysfunction. The prevalence of short stature and cardiovascular and kidney dysfunction was significantly elevated among survivors aged ≥18 years. Therefore, a multidisciplinary follow-up system for survivors of JMML is crucial.

Introduction

Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative/myelodysplastic malignancy, typical in infancy and early childhood, characterized by fever, hepatosplenomegaly, and organ infiltration due to excessive production of monocytic and granulocytic lineage cells.^1,2 Approximately 90% patients with JMML show either somatic or germline mutations in their leukemia cells in the Ras pathway.³ Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for JMML, and a myeloablative preparative regimen based on a combination of busulfan with other cytotoxic agents is recommended.^2,4 The high prevalence of late effects among survivors treated with HSCT is a major issue for hematologists devoted to long-term follow-up because the median age for HSCT is 2–3 years.^5,6 However, limited studies have focused on data regarding the late effects in survivors of JMML who underwent HSCT, particularly in those treated with myeloablative regimens. We aimed to elucidate these effects using a nationwide, retrospective analysis of child and adolescent survivors who underwent HSCT.

Results

In this cross-sectional study, attending pediatric hemato-oncologists completed a questionnaire. Eligible survivors were recruited from a database of the myelodysplastic syndrome central review committee. All survivors—first diagnosed between July 1999 and December 2016—were alive at the time of the survey. The review board of each institution approved this study. The requirement for informed patient consent was waived because of the nature of the study (chart review) and use of an opt-out method to collect study data from the survivors or their guardians.

We evaluated demographic (age, sex, and social background) and medical (treatment for JMML, conditioning regimen, and early morbidity) variables after HSCT (Table 1). The late effects assessed were short stature, underweight, and endocrine, cardiovascular, pulmonary, neurocognitive, gastrointestinal, nephrological, dental, musculoskeletal, ophthalmologic, and secondary neoplasm complications. Hematologist oncologists rated each late effect according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4. We evaluated the prevalence of each late effect before performing univariate analysis between the late effects and demographic and medical variables.

Among the 43 eligible survivors, 30 (70%) were included. More than 80% survivors had more than one late effect, and 10% had more than seven late effects. The median number of late effects (CTCAE grades 1–5) was 3.3. The chi-square test of independence was performed by comparing the number of late effects and age groups. Survivors aged ≥18 years showed a significantly high number of late effects (chi-square: 11.1; df=3; p<0.05).

A busulfan-based conditioning regimen was administered to 24 (80%) survivors. Total body irradiation (TBI)-included conditioning was conducted in four survivors for the first HSCT and in five survivors for the second SCT. Ten survivors underwent a second HSCT. Chronic graft-versus-host disease (GVHD) was observed in 33% survivors, and the most common category of GVHD was skin lesions. Regarding social background, 28 survivors were students, two were graduates, and two were part-time workers.

The prevalence of late effects is illustrated in the descending order in Supplemental Figure S1. The most common late effects were short stature and underweight, which were found in 53% survivors. The third most common late effect was dental problems such as permanent tooth loss. Spinocellular carcinoma of the skin was observed as a secondary neoplasm in one survivor 10 years after receiving TBI-conditioned HSCT. The correlation between the most recently measured height of survivors and time lapsed from diagnosis to survey is plotted in Supplemental Figure S2.

Table 2 showed the odds ratios and 95% confidence interval (CI) of the late effects and risk factors associated with age and conditioning regimen around HSCT. We found significantly greater pulmonary complications in survivors who received HSCT at an age of ≤2 years, with TBI as the conditioning regimen. Thyroid complications were observed in survivors who received multiple HSCTs and those aged ≥18 years at the time of the survey. Significantly high frequencies of heart and kidney complications were observed in survivors ≥18 years. Underweight and heart complications were observed in patients who received TBI as the conditioning regimen.

Discussion

The present study focused on the late effects of survivors of JMML. Strikingly, >80% survivors had at least one late effect, and 10% had more than seven late effects. Our data suggested that older survivors of JMML had more late effects. Allewelt⁷reported that 98% patients who underwent cord blood transplantation with a busulfan-based conditioning regimen experienced at least one late effect. A series of survivors transplanted with both TBI- and busulfan-conditioning regimens showed a high incidence of late effects.⁸ These reports highlight the necessity of clinical care guidelines for long-term follow-up.

In this study, growth impairment was the most frequent late effect, as described in a series of reports on HSCT for younger children with leukemia; Tomizawa⁹ revealed that 58.9% infantile acute lymphoblastic leukemia survivors, most of whom received HSCT in early infancy, showed short stature. We found a significant negative correlation between the height of survivors and time lapse from diagnosis to when this survey was conducted. Giorgiani¹⁰ reported that survivors treated with busulfan-conditioned regimens grew normally. The third most frequent late effect was dental problems. HSCT in younger children is highly related to dental problems, including microdontia, enamel hypoplasia, and extensive caries. Although the prevalence was relatively low in this study, we confirmed results reported previously.^11,12

In this long-term follow-up study, univariable analysis revealed that the prevalence of kidney, thyroid, and cardiovascular complications was significantly higher in survivors aged ≥18 years than in those aged <18 years. Künkele¹³ reported that 17% acute leukemia survivors treated with HSCT showed renal toxicity.¹³ While they found that TBI with high-dose chemotherapy could be a risk factor, we found no significant correlation between TBI and nephrotoxicity. This discrepancy may be due to the small number of patients who received TBI in this study. Although hypothyroidism is often reported after HSCT for various leukemias, it has rarely been reported in studies of JMML alone.¹⁴Thyroid complications were significantly related to the number of HSCTs, which in turn was related to the cumulative number of cytotoxic drugs or irradiation. We found that heart complications were significantly related to the time lapsed and TBI regimen. Future studies are needed to explore heart function over a longer period after HSCT.

Lastly, pulmonary complications were significantly related to a younger age at the time of HSCT- and TBI-regimen administration. Hoffmeister¹⁵ reported that time lapse after HSCT, single-fraction TBI, diseases such as chronic myeloid leukemia/myelodysplastic syndrome/JMML, and chronic GVHD were significant risk factors for pulmonary complications. Therefore, the results of this study partly confirm those of previous research.

This study has several limitations. First, the number of participants was small. Second, the study design was cross-sectional, preventing us from drawing conclusions regarding causality. Third, in-depth medical surveys were not conducted for all aspects of late effects because of the retrospective hematologist oncologist-oriented survey.

In conclusion, this study revealed that growth, dental, endocrine, and skin complications were common in survivors of JMML. These findings suggest that risk-based late effect follow-up is needed for survivors of JMML to assess and treat potential outcomes.

Acknowledgements

The authors thank all of the attending physicians who provide the information about survivors. This research was supported by AMED under Grant Number 22ck0106611h0003. We would like to thank Editage (www.editage.com) for English language editing.

Conflicts of Interest Statement: The authors declare no financial interests.

References

1. Niemeyer CM, Arico M, Basso G, et al.: Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood.(1997);89:3534-43.

2. Locatelli F, Niemeyer CM: How I treat juvenile myelomonocytic leukemia. Blood.(2015);125:1083-90.

3. Niemeyer CM, Flotho C: Juvenile myelomonocytic leukemia: who’s the driver at the wheel? Blood.(2019);133:1060-70.

4. Locatelli F, Zecca M, Niemeyer C, et al.: Role of allogeneic bone marrow transplantation for the treatment of myelodysplastic syndromes in childhood. The European Working Group on Childhood Myelodysplastic Syndrome (EWOG-MDS) and the Austria-Germany-Italy (AGI) Bone Marrow Transplantation Registry. Bone marrow transplantation.(1996);18 Suppl 2:63-8.

5. Matthes-Martin S, Mann G, Peters C, et al.: Allogeneic bone marrow transplantation for juvenile myelomonocytic leukaemia: a single centre experience and review of the literature. Bone marrow transplantation.(2000);26:377-82.

6. Baker D, Cole C, Price J, et al.: Allogeneic bone marrow transplantation in juvenile myelomonocytic leukemia without total body irradiation. Journal of pediatric hematology/oncology.(2004);26:200-3.

7. Allewelt H, El-Khorazaty J, Mendizabal A, et al.: Late Effects after Umbilical Cord Blood Transplantation in Very Young Children after Busulfan-Based, Myeloablative Conditioning. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.(2016);22:1627-35.

8. Bernard F, Auquier P, Herrmann I, et al.: Health status of childhood leukemia survivors who received hematopoietic cell transplantation after BU or TBI: an LEA study. Bone marrow transplantation.(2014);49:709-16.

9. Tomizawa D, Koh K, Sato T, et al.: Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia.(2007);21:2258-63.

10. Giorgiani G, Bozzola M, Locatelli F, et al.: Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone. Blood.(1995);86:825-31.

11. Holtta P, Alaluusua S, Saarinen-Pihkala UM, et al.: Agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation in young children. Cancer.(2005);103:181-90.

12. Holtta P, Hovi L, Saarinen-Pihkala UM, et al.: Disturbed root development of permanent teeth after pediatric stem cell transplantation. Dental root development after SCT. Cancer.(2005);103:1484-93.

13. Kunkele A, Engelhard M, Hauffa BP, et al.: Long-term follow-up of pediatric patients receiving total body irradiation before hematopoietic stem cell transplantation and post-transplant survival of >2 years. Pediatr Blood Cancer.(2013);60:1792-7.

14. Yusuf U, Frangoul HA, Gooley TA, et al.: Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone marrow transplantation.(2004);33:805-14.

15. Hoffmeister PA, Madtes DK, Storer BE, et al.: Pulmonary function in long-term survivors of pediatric hematopoietic cell transplantation. Pediatr Blood Cancer.(2006);47:594-606.