Rearrangements of the KMT2A gene are characteristic of infantile acute lymphoblastic leukemia (ALL) and are associated with increased lineage plasticity and resistance to therapy. Here, we describe the case of a 9-month-old infant with infantile ALL who experienced multiple immunophenotypic switches in her leukemia throughout therapy and ultimately achieved remission with the combination of CPX-351 and Inotuzumab. This case highlights the unique clinical challenges infantile ALL poses on monitoring therapeutic response with current methods of measuring minimal residual disease as well as the challenges in treating infantile B-ALL.

A document by Paul Meyers. Click on the document to view its contents.

Standard management of pediatric Non-Hodgkin’s Lymphoma (NHL) patients have included an initial assessment of the disease at presentation to establish it’s extent. This “staging” process has historically assigned patients using traditional classifications which were established decades ago when, like other pediatric malignancies, the more extensive involvement of the cancer for a patient directly correlated with the patient’s long term survival[[1]](#ref-0001). Advances in radiologic technology have evolved in the way the disease extent was evaluated, moving from conventional radiographs, to computerized tomography (CT) to magnetic resonance imaging (MRI) to most recently positron emission tomography (PET)[[2]](#ref-0002). Despite the development and use of PET scans for decades for various cancer diagnoses, the role of PET scans for NHL remains unclear[[3]](#ref-0003). Indeed, its value for many conditions is its ability to assess the response to initial therapy and establish the patient’s risk stratification guiding the remaining treatment plan[[4]](#ref-0004). Such efforts have not occurred in clinical trials of NHL and thus we are left to examine case series and try to discern its value for this disease.

Purpose Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. Methods Oral cabozantinib (25mg/m 2) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75mg/m 2) and cyclophosphamide (250mg/m 2) were administered IV on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. Results Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (7 with Ewing sarcoma; 5 with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis; grade 3 transaminitis; prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. Conclusions The recommended phase 2 doses and schedules for this combination are topotecan 0.75mg/m 2 IV days 1-5, cyclophosphamide 250mg/m 2 IV days 1-5, and cabozantinib 25mg/m 2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity while allowing for potential disease control.

PARANEOPLASTIC JUVENILE IDIOPATHIC ARTHRITIS AS A MANIFESTATION OF A BENIGN TERATOMA IN A FIVE-YEAR-OLD GIRL

LETTER TO THE EDITORTITLE: Sarcoid-like reaction in a child following prolonged therapeutic exposure to dabrafenib and trametinib for BRAF V600E mutated hypothalamic/ chiasmatic gliomaAuthors : Mari Wilhelmsson MD, PhD1,2; Foo Jen Chun MD1; Rae S M Yeung MD, PhD3; Fiona Krtizinger MBChB, MMed4; Tata McKeown, MSc1; Ailish Coblentz, MD5; Birgit Ertl-Wagner, MD5; Uri Tabori MD, PhD1, Ute Bartels MD, PhD 1; Anirban Das MBBS, MD, DM 1AFFILIATIONS: 1. Division of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; 2. Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden. 3. Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada. 4. Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. 5. Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada.WORD COUNT:   853FIGURES:  1RUNNING TITLE: Sarcoid-like reaction with BRAF/MEK-inhibitionKEYWORDS : MEK-inhibitor, BRAF inhibitor, sarcoidosis/sarcoid‑like reaction (S/SLR), Low-grade glioma, pediatric

Background: Anaplastic large cell lymphoma (ALCL) is an uncommon form of Non-Hodgkin Lymphoma (NHL) in younger patients, accounting for less than 15% of cases. The median age at presentation is 12 years and is exceedingly rare in infants. Various prognostic factors, risk stratification and novel treatment strategies have been studied in pediatric ALCL. There is no separate data available on the disease biology, treatment regimens and prognostic factors among infantile ALCL. Outcomes for infants with ALCL have been reported to be inferior to that of older children. The long-term Event Free Survival (EFS) in general among pediatric patients is approximately 70% regardless of the treatment approach. We report a case of an 8month old infant diagnosed with ALK positive ALCL with visceral organ involvement stratified as high risk and treated according to ALCL 99 protocol with excellent clinical response, on regular follow up and is disease free since 2years.

The value of reporting on end-of-treatment outcome of patients in low-income settingsTrijn Israels MD PhD1,2, Ramandeep Singh Arora DCH, MD3, Lillian Sung MD PhD41 Collaborative African Network for Childhood Cancer Care and Research (CANCaRe Africa), 2 Kamuzu University of Health Sciences, Blantyre, Malawi, 3 Max Super Speciality Hospital, New Delhi, India, 4 Sick Children’s Hospital, Toronto, CanadaCorresponding author:Dr Trijn Israels, CANCaRe Africa, Department of Paediatrics, Kamuzu University of Health Sciences (KuHES), Blantyre, Malawi. Email: cancareafrica@gmail.comWord count: 1256 wordsNumber of Tables: 0Number of Figures: 0Short running title: End-of-treatment outcome reportingKey words: childhood cancer, survival, LIC, indicatorsLIC Low-income countryHIC High-income countryGICC Global Initiative for Childhood CancerEFS Event-free survivalOS Overall survivalTRM Treatment related mortalityDRM Disease related mortalityCANCaRe Africa Collaborative African Network for Childhood Cancer Care and Research

Cure rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer have steadily improved over the past five decades. This is due to intensifying systemic therapy, recognizing and treating the central nervous system as a sanctuary site, and implementing modern risk stratification to deliver varying intensities of therapy based on age, presenting white blood count (WBC), sentinel somatic genetics, and therapy response. Recently, numerous Children’s Oncology Group trials have demonstrated the lack of benefit of intensifying traditional chemotherapy, providing evidence that new approaches are needed to cure the patients for whom cure has been elusive. Distinguishing those who require intensive or novel therapeutic approaches from others who will be cured with minimal therapy is key for future trials. Incorporating new genomic biomarkers and more sensitive measures of minimal/measurable residual disease (MRD) provide opportunities to achieve these goals.

Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children’s Oncology Group cellular therapy-based trials for advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T cell depletion is used and the depth of remission as measured by next-generation sequencing based minimal residual disease assessment pre-transplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.

The Children’s Oncology Group (COG) Rare Tumor committee includes the Infrequent Tumor and Retinoblastoma subcommittees, encompassing a wide range of extracranial solid tumors that don’t fall within another COG disease committee. Current therapeutic trial development focuses on nasopharyngeal carcinoma, adrenocortical carcinoma, pleuropulmonary blastoma, colorectal carcinoma, melanoma, and thyroid carcinoma. Given the rarity of these tumors, novel strategies and international collaborative efforts are necessary to advance research and improve outcomes.

Cost effectiveness of support with out-of-pockets costs to prevent treatment abandonment in Malawi and sub-Saharan Africa; lessons learnt and the way forward – a report from CANCaRe Africa Junious Sichali1, Avi Denburg2, Harriet Khofi3, Cecilia Mdoka1, Deborah Nyirenda4, Yamikani Chimalizeni3, George Chagaluka3, Elizabeth Molyneux3, Marc Y. R. Henrion4,5, Sumit Gupta2, Trijn Israels11 Collaborative African Network for Childhood Cancer Care and Research (CANCaRe Africa), 2Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Canada,3 Kamuzu University of Health Sciences (KUHeS), Blantyre, Malawi, 4 Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi, 5Liverpool School of Tropical Medicine, Liverpool, UKCorresponding author:Dr Trijn Israels, CANCaRe Africa, Department of Paediatrics, Kamuzu University of Health Sciences (KuHES), Blantyre, Malawi. Email: cancareafrica@gmail.comWord count: 1189 wordsNumber of Tables: 0Number of Figures: 0Short running title: Cost-effectiveness of treatment abandonment preventionKey words: childhood cancer, treatment abandonment, cost-effectiveness,LMIC Low- and middle-income countryGICC Global Initiative for Childhood CancerCANCaRe Africa Collaborative African Network for Childhood Cancer Care and ResearchALL Acute lymphoblastic leukaemiaGDP Gross Domestic ProductDALY Disability Adjusted Life Year

Children’s Oncology Group’s 2023 Blueprint For ResearchDouglas S. Hawkins,1 Lia Gore2Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WADepartment of Pediatrics, University of Colorado School of Medicine and Center for Cancer and Blood Disorders, Children’s Hospital Colorado,, Aurora, CO

As survival rates for childhood cancer have improved, there has been increasing focus on identifying and addressing adverse impacts of cancer and its treatment on children and their families during treatment and into survivorship. The Behavioral Science Committee (BSC) of the Children’s Oncology Group (COG), comprised of psychologists, neuropsychologists, social workers, nurses, physicians, and clinical research associates, aims to improve the lives of children with cancer and their families through research and dissemination of empirically supported knowledge. Key achievements of the BSC include enhanced interprofessional collaboration through integration of liaisons into other key committees within COG, successful measurement of critical neurocognitive outcomes through standardized neurocognitive assessment strategies, contributions to evidence-based guidelines, and optimization of patient-reported outcome measurement. The collection of neurocognitive and behavioral data continues to be an essential function of the BSC, in the context of therapeutic trials that are modifying treatments to maximize event-free survival, minimize adverse outcomes, and optimize quality of life. In addition, through hypothesis-driven research and multi-disciplinary collaborations, the BSC will also begin to prioritize initiatives to expand the systematic collection of predictive factors (e.g., social determinants of health) and psychosocial outcomes, with overarching goals of addressing health inequities in cancer care and outcomes, and promoting evidence-based interventions to improve outcomes for all children, adolescents, and young adults with cancer.

Severe Refractory Hemorrhagic Cystitis after Hematopoietic Cell Transplantation Responds to Recombinant Human Keratinocyte Growth Factor (KGF) - A Case Report and Review of the LiteratureCatherine Hughes1*, Anora Harris1*, Benjamin Watkins1, Muna Qayed1, Suhag Parikh1, Edwin Horwitz1, Elizabeth Stenger1, Kirsten M Williams1, Michelle L Schoettler1

Children with transfusion dependent thalassemia have an impaired ability to synthesize alpha or beta globin which results in anemia. Packed red blood cell (PRBC) transfusions are required to increase hemoglobin which supports appropriate growth and development. PRBC transfusions must be completed with 4 hours however infusion rates vary across institutions. Our institution infuses PRBC’s up to 10mL/kg/hr. A descriptive study of 21 children who received a total of 276 transfusions during 2021 demonstrated that this rate is safe and well tolerated. Shorter transfusion times support patients’ and families’ time, resources, and quality of life and aptly utilize institutional resources.

Reply to: Clinical trials: A plea to cooperative groups, consortia,

Pediatric erythroblastic transformation of JAK 2-mutated prefibrotic primary myelofibrosis with concurrent PHF6 mutationsTokiko Oshiro1, Satoru Hamada1, Sinobu Kiyuna1, Hideki Sakiyama1, Nobuyuki Hyakuna2, Tomoko Tamaki3, Hideki Muramatsu4, Koichi Nakanishi5Department of Pediatrics, University of Ryukyus HospitalOkinawa prefectural Red Cross Blood CenterDepartment of Pathology and Oncology, Graduate school of Medicine, University of RyukyusDepartment of Pediatrics, Graduate School of Medicine, University of NagoyaDepartment of Pediatrics, Graduate School of Medicine, University of The RyukyusCorrespondence: Satoru Hamada,Department of Pediatrics, Faculty of Medicine, University of Ryukyus, 207 Uehara, Nishihara-cho, Okinawa 903-0125, Japanshamada@med.u-ryukyu.ac.jpTo the Editor: Primary myelofibrosis (PMF) is a rare condition in children. According to the 2016 World Health Organization (WHO), classification of myeloproliferative neoplasms (MPN), PMF is divided into prefibrotic PMF (pre-PMF) and overt fibrotic PMF1. Pre-PMF is the proliferation of predominantly abnormal megakaryocytes and minimal or no reticulin fibrosis. Therefore, the lack of fibrosis in the early phase of thrombocytosis can be misdiagnosed as essential thrombocythemia2. One significant complication of MPN is leukemic transformation (LT); however, only a few cases of PMF in children have been reported3. The clinical utility of the three driver mutations in JAK2 , CALR, and MPL has been shown, especially when JAK2 is central to the pathogenesis of the MPN phenotype4. Additional mutations in ASXL1, SRSF2, IDH1/2, or EZH2 have been shown5. PHF6is an X-linked tumor suppressor gene with a somatic mutation that causes an aggressive type of myeloid neoplasm6. Here, we report a case of pediatricJAK2 -mutated pre-PMF with concurrent PHF6 mutations that transformed into AML within a year of diagnosis.A 14-year-old boy with no medical history was admitted to our hospital with lumbago. Physical examination revealed splenomegaly (5 cm below the costal margins). A complete blood count showed a white blood cell (WBC) count of 5.8×109/L, neutrophil count of 31%, lymphocyte count of 36%, red blood cell count of 7.34×109/L, hemoglobin concentration of 140 g/L, and platelet count of 1010×109/L. The patient was diagnosed with essential thrombocythemia based on bone marrow findings, which showed hypercellularity (80-100%), increasing with separated circled-multinucleated megakaryocytes, hyper-segmented-megakaryocytes, atypical megakaryocytes, and micromegakaryocytes (Figure 1A), and was treated with anagrelide. At this time, there were no blasts or reticulin fibers. The patient had no karyotypic abnormalities. After written informed consent was obtained, target capture-based next generation sequencing (NGS) was performed on bone marrow DNA for the following genes: MPL, ASXL1, CBL, JAK3, EZH2, IDH1, IDH2, JAK1, PHF6, SF 3B1, TET2, TP53, U2AF1, JAK2, NRAS/KRAS and IKZF1 by previous described methods7. Among these mutations, JAK2 V617F with mutant allele percentage 4% and PHF6 p.Q121Xmutation with 64% were identified. In addition, we generated an MPN gene panel (JAK2 V617F, JAK2 exon12, MPL W515L, MPL W515K, CALR type1-5 ) using DNA microarray methods (SRL International Inc. Japan) and only the JAK2V617F mutation was identified. As the platelet count decreased, his symptoms became well-controlled. However, teardrop-shaped red blood cells and myeloblasts were observed in the peripheral blood six months later, and we performed a bone marrow biopsy. Results indicated hypercellularity (80-100%) with moderate fibrosis (MF grade 1; Figure 1B). Therefore, ruxolitinib was administered for myelofibrosis. Five months later, he showed elevated lactate dehydrogenase (LDH) levels and thrombocytopenia. Bone marrow aspiration revealed increased cellularity with predominant erythropoiesis and 40% erythroblasts (Figure 1C). Flow cytometric analyses revealed 14% glycophorin A and 90% CD34 positive blast cells. No reticulin fibrosis progression was observed. The cytogenetic analysis revealed a normal karyotype. The patient was diagnosed with acute erythroleukemia secondary to PMF. He underwent HLA haploidentical peripheral blood stem cell transplantation(haplo-HCT) from his mother, using post-transplantation cyclophosphamide (PT-Cy) for graft-versus-host disease (GVHD) prophylaxis. The conditioning regimen consisted of total body irradiation (12 Gy delivered in six fractions from days -8 to -6), fludarabine (30mg/m2 from days -5 to -2), and cytarabine (3,000 mg/m2×2 from days -5 to -4). GVHD prophylaxis consisted of high-dose PT-Cy (50 mg/kg intravenously on days 3 and 4) in combination with tacrolimus and mycophenolate mofetil from day 5 onward. Infused donor cells were 5.4×106/kg CD34 cells and 4.0×108/kg CD3 positive T cells. Engraftment occurred on day 21, and complete chimerism was achieved on day 33. He had several transplantation-related complications, including grade II acute GVHD (gut), which was treated with prednisolone; BK virus-associated hemorrhagic cystitis; and bronchiolitis obliterans syndrome (Supplementary Figure). He has been in complete remission for 7 years after transplantation. Considering that the bone marrow features are characterized by increasing cellularity with atypical megakaryocytes at clinical onset, the patient should first be diagnosed with pre-PMF.Our patient developed AML (FAB M6) 11 months after the diagnosis of pre-PMF. In terms of time to progression, median time (range) to progression was 11.8 years (7.9-15.7 years) in pre-PMF8. According to the Dynamic International Prognostic Scoring System (DIPSS) Plus score, our case was classified as low-risk. Candidate genes contributing to LT from MPN to AML have been identified, including TP53, TET2, ASXL1, EZH2, IDH1/2, RUNX1, U2AF1, NRAS/KRAS , and SRSF2 5. The adverse impact of molecular characteristics on survival in pre-PMF and overt PMF has been reported as a high mutation risk in EZH2, ASXL1, IDH1, IDH2 , and SRSF2 8. In our case, no additional somatic alterations were detected; however, a PHF6 mutation was identified. Somatic PHF6 mutations have been found in 2–3% of AML6, 9. The percentage of blasts in the bone marrow tends to be higher in patients with myeloid malignancies harboringPHF6 mutations6. AML with high PHF6expression levels than controls correlated with shorter overall survival10. Furthermore, increased PHF6 levels may be associated with CD34 positivity10. In a case series of MPN with increased fibrosis and blast crisis, 22 patients withPHF6 mutations in MPN were enriched11. Thus,PHF 6 mutations can contribute to myeloid leukemic transformation in JAK2 -mutated pre-PMF.AcknowledgementsWe are grateful to our patients and his family. And we would like to thank our colleagues for helpful discussion regarding this case.Conflict-of-interestThe authors declare that there is no conflict of interest.【References】(1) Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(12):1262-1271.(2) Edahiro Y, Araki M, Inano T, Ito M, Morishita S, Misawa K, Fukuda Y, Imai M, Ohsaka A, Komatsu N. Clinical and molecular features of patients with prefibrotic primary myelofibrosis previously diagnosed as having essential thrombocythemia in Japan. Eur J Haematol. 2019;102(6):516-520.(3) DeLario MR, Sheehan AM, Ataya R, Bertuch AA, Vega C, Webb CR, Lopez-Terrada D, Venkateswaran L. Clinical, histopathologic, and genetic features of pediatric primary myelofibrosis–an entity different from adults. Am J Hematol. 2012;87(5):461-464.(4) Nangalia J, Green TR. The evolving genomic landscape of myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2014;2014(1):287-296.(5) Andrew J. Dunbar, Raajit K. Rampal, Ross Levine; Leukemia secondary to myeloproliferative neoplasms. Blood 2020;136(1):61–70.(6) Mori T, Nagata Y, Makishima H, Sanada M, Shiozawa Y, Kon A, Yoshizato T, Sato-Otsubo A, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Ishiyama K, Miyawaki S, Mori H, Nakamaki T, Kihara R, Kiyoi H, Koeffler HP, Shih LY, Miyano S, Naoe T, Haferlach C, Kern W, Haferlach T, Ogawa S, Yoshida K. Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms. Leukemia. 2016;30(11):2270-2273.(7) Muramatsu H, Okuno Y, Yoshida K, Shiraishi Y, Doisaki S, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Takahashi Y, Kanno H, Yamaguchi H, Ohga S, Manabe A, Harigae H, Kunishima S, Ishii E, Kobayashi M, Koike K, Watanabe K, Ito E, Takata M, Yabe M, Ogawa S, Miyano S, Kojima S. Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. Genet Med. 2017;19(7):796-802.(8) Guglielmelli P, Pacilli A, Rotunno G, Rumi E, Rosti V, Delaini F, Maffioli M, Fanelli T, Pancrazzi A, Pietra D, Salmoiraghi S, Mannarelli C, Franci A, Paoli C, Rambaldi A, Passamonti F, Barosi G, Barbui T, Cazzola M, Vannucchi AM; AGIMM Group. Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. Blood. 2017;129(24):3227-3236.(9) de Rooij JD, van den Heuvel-Eibrink MM, van de Rijdt NK, Verboon LJ, de Haas V, Trka J, Baruchel A, Reinhardt D, Pieters R, Fornerod M, Zwaan CM. PHF6 mutations in paediatric acute myeloid leukaemia. Br J Haematol. 2016;175(5):967-971.(10) Mousa NO, Gado M, Assem MM, Dawood KM, Osman A. Expression profiling of some Acute Myeloid Leukemia - associated markers to assess their diagnostic/prognostic potential. Genet Mol Biol. 2021;44(1):e20190268.(11) Kurzer JH, Weinberg OK. PHF6 Mutations in Hematologic Malignancies. Front Oncol. 2021;11:704471.Figure legendsFigure 1A. Bone marrow aspiration at first visit(day-370).Square (A) shows a separated circular multinucleated megakaryocyte, (B) a hypersegmented megakaryocyte, (C) an atypical megakaryocyte, and (D) a micromegakaryocyte.Figure 1B. Bone marrow biopsy on day-170.Silver impregnation shows moderate myelofibrosis. Arrows indicate reticulin fibers.Figure 1C. Bone marrow smear (1000×, May-Grunwald-Giemsa stain). The smear shows abnormal megakaryoblasts with round or oval nuclei, loose chromatin, agranular cytoplasm with blebs.Supplemental Figure 1. Clinical course of patients.A bone marrow biopsy on day-170 shows myelofibrosis, and bone marrow aspiration on day-30 shows erythroleukemia. aGVHD, acute graft-versus host disease; PSL, prednisolone; TBI, total body irradiation; FLU, fludarabine; Ara-C, cytarabine; CY, cyclophosphamide; MMF, mycophenolate mofetil; Haplo-SCT, haploidentical stem cell transplantation; BMA, bone marrow aspiration; BMB, bone marrow biopsy; BM, bone marrow.